       GMHC Treatment Issues, Volume 10, Number 6/7 - June/July 1996

       published by Gay Men's Health Crisis, Treatment Education
       Department, 129 West 29th Street, New York, NY 10011


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       Flying by the Seat of Our Pants
       by Dave Gilden

       Last March, the United States Food and Drug Administration
authorized the sale of two additional protease inhibitors, indinavir
and ritonavir. This makes for eight anti-HIV drugs currently on the
U.S. market, compared to only four as recently as last fall.
Continuing this historic expansion, nevirapine will shortly join the
ranks (see page 25). On the heels of nevirapine are two more protease
inhibitors and five reverse transcriptase inhibitors in advanced human
testing. AIDS-related opportunistic conditions also have seen
significant developments. In particular, new agents have been
proffered over the past year for preventing CMV and MAC as well as for
combating AIDS-related weight loss.

       Tests for viral load -- the Roche PCR version is newly approved
in the U.S. (see page 21) -- may help make some sense of this
therapeutic kaleidoscope. Unfortunately, research on the relation of
HIV levels to disease has been inadequate. Viral load tests' potential
for settling questions of overall therapeutic strategy and for guiding
individuals' treatment decisions requires further delineation. Opinion
differs in the meantime about the optimal starting point for
pharmacological intervention, when to change therapy and which
regimens have the best therapeutic indices and duration of effect.

       When patients and doctors lack sufficient carefully collected
study data, they can only rely on their own and others' clinical
experience to guide them. In an effort to further disseminate that
experience, we at Treatment Issues surveyed a group of prominent HIV
specialists in North America, Europe and Australia. We recapitulate
their answers in the pages that follow.

       Our respondents have large AIDS practices conducted in diverse
care settings -- public clinics, private practice, health maintenance
organizations and university hospitals. Many work within the
constraints of managed care, payer formularies, Medicaid and ADAP
programs. The questions they answered were open-ended and intended to
stimulate discussion of diverse treatment strategies.

       Our goal was to uncover the range of approaches followed today
by experts in the field rather than to systematically reflect the
opinions of all physicians who treat HIV and AIDS. We therefore have
included answers illustrating both dominant trends and contrarian
views. Statements attributed to individuals may be paraphrased and are
not necessarily the complete response to any given question. The
tables do provide a quick overview of all the responses, but because
of the survey's eclectic nature, we urge that readers carefully look
at the individual responses rather than just peruse the summaries.

       Associating Viral Load and Physical Health

       The most striking observation to come from these respondents is
the remark by several that they are seeing clinical improvement in
patients (i.e., patients noticeably feel better) at the same time as
these patients' HIV levels are dramatically reduced by the new
treatments. Such observations complement a published report by a group
of Australians -- among them was David Cooper, one of our survey
participants -- on the partial restoration of 21 volunteers' immune
function during an early ritonavir monotherapy trial (see Journal of
Infectious Disease, February 1996; 173(2):321-9). Reducing the
inflammatory response and cell killing that HIV infection provokes may
have a number of immediate benefits in terms of a person's overall
functioning.

       The great hope that currently available combination regimens
are potent enough to lead to at least limited recovery remains
entirely speculative. It is notable that the latest word from the
Australians describe the qualitative immune improvements they observed
as "small and transient and occurr[ing] in a minority of subjects"
(see page 27 of this issue).

       Our respondents had divergent opinions as to how far viral load
has to drop before their patients reach a safe zone. One result is a
wide variety of practices concerning initial and subsequent anti-HIV
therapy. Several of the less mainstream doctors remain so unconvinced
by the present data that they continue to concentrate on aggressively
preventing OIs rather than HIV. (This in itself could be a potent
antiviral strategy because keeping the immune system relatively quiet
reduces the number of activated cells vulnerable to HIV. Lending
credibility to this approach is, among others, a recent article on the
HIV-simulating effect of tetanus toxoid vaccination. See the New
England Journal of Medicine, May 9, 1996, pages 1222-30.)

       Responsibility for the confusion over viral load lies at least
in part with the developers of viral load tests. The companies have
not taken the lead in establishing the worth (as opposed to the
accuracy) of their products. University and government researchers
instead have been active in establishing guidelines for interpreting
viral load tests results. This has turned out to be a slow process,
with most of the available data arising from retrospective reviews of
trials testing specific drugs. Even though Roche's PCR-based Amplicor
test kit has been licensed in the U.S., trials that directly observe
the usefulness of viral loads in treatment decisions are only now
getting under way. The difficulties of creating ethical designs for
such trials and recruiting volunteers for them will surely mount as
viral load testing becomes more widely available. (See pages 21-24 of
this issue for an examination of the currently available viral tests
and what is known of their uses.)

       Holding Off on the Protease Inhibitors

       With little to guide them, our respondents tend to be
conservative about bringing out the heavy guns against HIV. They
generally choose two nucleoside analogs as first-line therapy in
patients with relatively low viral load and high CD4 counts. Protease
inhibitors are added only when patients start to worsen or have
exceptionally high viral loads to begin with. Still, the present
strategies are a marked change from the recent past, when AZT
monotherapy would no doubt have been most frequently mentioned as the
preferred first line therapy for HIV, to be applied mainly when CD4
counts were clearly deficient and physical symptoms evident.

       Several recent combination drug trials have affected this
evolution in treatment strategies. Especially important were ACTG 175
(which tested AZT vs. ddI vs. AZT/ddI and AZT/ddC) and the AZT/3TC
trials. AZT/3TC was by far the most commonly mentioned initial
regimen. Not only does it have documented substantial and sustained
antiviral activity in treatment- naive people, but also its side
effect record seems less than that of other possible nucleoside analog
pairings.

       By comparison, only one doctor mentioned using the non-
nucleoside reverse transcriptase inhibitor nevirapine, for which there
has been little available data. This drug, currently available in the
U.S. through an expanded access program, could be administered with
protease inhibitors as an alternative to nucleoside analog regimens or
combined with both types of agents to create extra powerful four-drug
combinations. (But beware of nevirapine's potential to accelerate
liver metabolism of protease inhibitors -- see page 25.)

       The reluctance to employ the protease inhibitors stems from
fears of increased toxicity, drug interactions and the evolution of
drug resistant virus. Patient fatigue could be a big factor, too, in
creating difficulties for managing and adjusting multiple drug
combinations that must be taken without let-up over long periods of
time. It was generally considered best to leave well enough alone when
viral loads could be brought and kept down to low levels without the
protease inhibitors.

       Trials that further explore protease inhibitor use obviously
are needed to optimize their use. Such trials would help decide when
protease inhibitor therapy can be omitted, when it should be initiated
and when it is perhaps no longer needed. And what about using two
protease inhibitors concurrently? Another major effort should go to
simplifying drug combinations as much as possible. Some two-drug
combinations may be as good as combinations of three weaker or more
toxic drugs, for example.

       The thorniest questions concern the evolution of drug resistant
HIV: how do you detect it and what drugs can you switch to when it
occurs? The amount of cross-resistance to the various protease
inhibitors that HIV mutations can confer requires further exploration,
as does the clinical significance of that resistance. Finally, some
therapeutic strategies may delay the emergence of drug resistance
better than others.

       The question of how clinical research should proceed -- who
should carry out what studies at this point -- is now the subject of a
national working group sponsored by the Keystone Center. This broadly
based committee, composed of representatives of the scientific and
activist communities, the pharmaceutical industry, health insurers,
and the government, will report its conclusions this August to Vice
President Al Gore.

       Eradicating HIV

       Until the threat of resistance and cross-resistance is more
fully mapped out, fears will persist of wasting drugs by using them
unnecessarily: during the early asymptomatic period of HIV infection,
the relatively intact immune system usually keeps viral loads low by
itself. From now on all treatment studies will be faced with the
fundamental question we need to know -- how much viral suppression is
sufficient to keep HIV permanently in check?

       There are glimmers of hope that the best combinations of
presently available agents are indeed strong enough to suppress HIV
over the long-term. Ironically, the best prospects for accomplishing
this feat occur during the low HIV levels typical of early disease.
The June conference "Can HIV Be Eradicated from an Infected
Individual?" (summarized on pages 26-27) was conducted by scientists
who foresee using a protease inhibitor plus several other drugs to
keep viral loads below currently detectable limits for indefinite
lengths of time. The emergence of drug-resistant HIV might be blocked
by the virus' inability to develop the large number of needed genetic
alterations in the face of such forceful constraints on its
replication. After some years, the HIV infection might even peter out
as chronically infected cells die off without replacement by newly
infected ones.

       Our present ability to conquer HIV may turn out to be greatly
limited still, but this goal cannot be altogether out of reach. After
all, a few people already control their HIV infection without any
treatment (and a tiny number seem to eliminate the virus entirely).
AZT monotherapy increased the number of success stories somewhat. With
the aid of effective therapies, the number of such durable resistors
can only increase further. But this is all logical deduction. Reducing
viral load below viral load assays' level of detection does not mean
that HIV is absent from the body, just that the amount of virus has
been reduced beyond a purely artificial threshold set by technology.
There is no evidence that people whose viral load is undetectable
cannot transmit HIV, for example. The data is also insufficient to say
how long it takes for HIV to re-emerge despite continued treatment
with potent drug combinations or how often this occurs. Certainly, no
one on record has stopped treatment without witnessing a rebound in
HIV.

       Economic Constraints

       These high hopes come at a time when health care delivery faces
unprecedented financial pressures, and the new economic constraints
can limit physicians' ability to try out the most advanced therapies
without waiting for their acceptance by the medical authorities. In
our survey, this obstacle arose most commonly in regard to use of
viral load testing by U.S. doctors, whose patients could not obtain
reimbursement from private and public health plans for what has been
an unapproved and costly technique. The failure of state AIDS Drug
Assistance Programs (ADAPs) in the U.S. to add newly approved drugs to
their formularies in a timely fashion was another frequently mentioned
impediment to accessing necessary therapy. More generally, the rise of
managed care has restricted treatment options even for those covered
by inclusive health plans (see pages 17-20).

       Comprehensive care centers for HIV/AIDS were mentioned by
several of our respondents as a way to bring together the expertise
necessary to keep up with the rapidly evolving, increasingly complex
standards of care. Since new standards can be vaguely determined and
poorly backed up by experimental data, therapy is best practiced in a
collegial setting. As always, open communication needs to exist within
teams of specialists advising patients on the different conditions
stemming from HIV infection. More urgent than ever is consultation
between people in the same field.

       But commitment to excellence weakens as economic pressures
intensify. The following survey is one small attempt to bridge the gap
between health care providers in this uncertain era.

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       Treating HIV and AIDS: A Survey of Current Practices

       A. Antiretroviral Therapy and Viral Load Testing

       1. What antiretroviral regimen do you now recommend for your
HIV-positive patients? How do you decide when to start antiretroviral
therapy in an individual patient? When you consider developing a new
treatment strategy for a patient, to what extent do you consider the
patient's individual needs, lifestyle and ability to comply?

       Preferred Regimens

       Most use two drugs (25 percent) or choose between two or three
drugs (25 percent) based on the patient's condition. The three drug
combination includes a protease inhibitor. The most popular two drug
combination is AZT plus 3TC mentioned as a choice for first-line
therapy by 67 percent of participants. Reasons cited for this
combination included tolerability (3TC), CNS penetration (AZT) and the
potential for prolonged sensitivity or resensitization of the virus to
AZT with the use of 3TC. AZT plus ddI is the second most popular
combination (33 percent), followed by d4T plus 3TC (25 percent).

       Hardy: I recommend combination therapy for all patients --
initially with ZDV/3TC, d4T/3TC or d4T/ddI. A protease inhibitor is
added if a patient's initial HIV RNA is greater than 100,000 and the
patient is agreeable to triple-drug therapy. (See accompanying article
on HIV RNA viral load on pages 21-24.)

       Mayer: My clinical practice has changed over the past year to
never start antiretroviral therapy without a combination of drugs. The
most common combinations that I would start with in an
antiretroviral-naive patient would be AZT plus 3TC, or AZT plus ddI.

       Katz: I start with AZT/3TC (AZT has best CNS penetration, and
is a reasonably effective drug if tolerated). The AZT/3TC combination
data looked better than that for AZT/ddC and while AZT/ddI may be
comparable, ddI is difficult to administer. The upcoming
Glaxo-Wellcome combined dosing of 300 mg AZT plus 150 mg 3TC should
make compliance even better. 3TC is preferred from the onset also
because of the reversal of AZT resistance and the fact that this drug
is clearly the best tolerated of the reverse transcriptase inhibitors.
In patients for whom compliance seems to be a huge issue, I might
start with d4T/3TC; also for patients who simply won't take AZT.

       Volberding: I recommend two nucleosides as the "standard"
platform, either AZT/ddI, AZT/ddC or AZT/3TC. If the patient is
intolerant of or refuses AZT then I use d4T/ddI or d4T/3TC. I add a
protease inhibitor to this platform if HIV RNA is very high (greater
than 100,000), the CD4 is very low (less than 100 or falling by more
than 200 cells per year), the patient is symptomatic or if the two
nucleoside analogs do not drop HIV RNA by more than half a log.

       Some institute three-drug combinations including a protease
       inhibitor at the very initiation of antiretroviral therapy.

       Johnson: I start AZT plus 3TC in my HIV-positive patients
independent of CD4 cell count. I start the AZT one month prior to the
3TC to make sure that it is tolerated. I have been adding indinavir to
AZT plus 3TC for just about everyone, independent of CD4 cell count or
viral load level.

       Rhame: 3TC plus AZT plus ritonavir if early and the patient is
willing to accept the chance of side effects. Otherwise, especially if
the patient is on many other medications, 3TC plus AZT plus indinavir.

       Giordano: For everyone with a viral burden greater than 10,000,
AZT plus 3TC plus Crixivan or ritonavir. Ong: AZT plus 3TC plus
ritonavir in those with CD4 less than 500, a recent decline in CD4
count or recent changes in clinical status.

       When they begin, some continue to consider monotherapy an
       option which is almost invariably ddI, cited as a first-line
       option by 19 percent of participants.

       Vella: Monotherapy with ddI, for instance, is a reasonable
alternative for patients who refuse a heavier regimen or show
intolerance to AZT.

       Yancey: Some patients are probably still appropriate for
single-drug reverse transcriptase inhibitor therapy (not AZT) or a
combo within this class.

       And those who stand out as particularly conservative,
       aggressive or alternative on when to use antiretrovirals.

       Sonnabend: There is little data to support a rational decision
on antiretroviral therapy. Since ACTG 175 and Delta are about the only
source of evidence, although unpublished, I can recommend ddI even
alone for people with under 400 CD4 cells whose status is declining
(on the basis of 175). For those who are stable above 300, I don't
know what to recommend and discuss this. Individuals who are stable
can do very well without antiretroviral therapy. Most of my patients
who are stable are content to do without antiretroviral therapy.

       Bihari: The only antiretroviral regimen I use on a significant
scale is AZT plus 3TC. I recommend it in general to patients with less
than 200 CD4 cells. [This combination is particularly effective in]
AZT-naive patients. Ninety percent of my patients are AZT-naive
because of my past reluctance to use AZT monotherapy.

       When to Begin

       Most commonly, respondents use a combination of symptoms and
       surrogate markers (CD4 and viral load) when deciding to begin
       antiretroviral therapy (42 percent). However, the precise
       CD4/viral load values leading to initiating treatment varied
       greatly. Some clinicians described algorithms (a few are
       reprinted on page 7).

       Mayer: The types of criteria that I utilize in recommending
initiation of antiretroviral therapy include a pattern of consistent
drop in CD4 count, a CD4 count less than 500 cells/mm3, an HIV load
detected by plasma bDNA or a QC-PCR greater than 10,000 RNA
equivalents per ml and/or constitutional symptoms or thrush.

       Jger: The criteria considered before starting an
antiretroviral therapy are numerous and varied: CD4 count less than
ca. 300 cells/ml for greater than one month and/or bDNA greater than
50,000 copies/ml greater than one month and/or the clinical impression
of disease progression, e.g., recurrent minor infections, weight loss,
lymphadenopathy and/or the occurrence of an OI.

       Montaner: Therapy is begun if symptoms, a CD4 less than 500 or
a viral load greater than 10,000 copies/ml is/are present.

       Vella: Antiretroviral therapy is initiated when CD4 cell count
is at or below 500/mm3 or HIV RNA titer exceeds 5,000 copies/ml or
symptoms are present, irrespective of CD4 and HIV RNA values.

       Hirsch: Decisions are made by the patient after discussion.
Factors considered are HIV RNA, CD4 cell count, clinical status,
lifestyle, ability to comply and cost, among others.

       Volberding: All symptomatic HIV-positive; all patients with CD4
less than 500; all patients with CD4 greater than 500 and HIV RNA
greater than 50,000; all patients who, after discussion, wish to be
treated.

       Para: Start when the patient is ready and the CD4 is less than
500 if the viral load is greater than 10,000 or when the CD4 is
greater than 500 if the viral load is greater than 100,000.

       However, many begin their patients on therapy based
       predominately on CD4 counts (25 percent), but this may
       partially be due to the limited availability of the viral load
       tests in certain areas.

       Birnbaum: I usually recommend starting therapy below 500 CD4
count but have given it to some patients felt to be in the very early
stages of infection (less than one year) with more than 500 CD4 cells.
Much of this depends upon the patients' interest and willingness to
take drugs.

       Rhame: If their CD4 is below 200, I press them hard to start.
With CD4's between 200 and 500, I press them gently to start. If their
CD4 is above 500, I'll start if they press me.

       Fewer use viral load alone (17 percent) as a reason to begin
       therapy.

       Hardy: HIV RNA levels greater than 5,000 copies/ml are
associated with decreased survival and increased risk of developing
AIDS. I use viral load measurements greater than 5,000 /ml as my
starting point to initiate antiretroviral therapy regardless of CD4
cell counts or percent.

       Katz: Starting therapy: I get a viral load (bDNA) on every new
patient -- anyone with over 100,000 gets two reverse transcriptase
inhibitors immediately, anyone with 10,000- 100,000 gets told by me
that if I were them, I would start, but they might want to
repeat/observe for a while. For under 10,000 I repeat in three to four
months, but for the patient who absolutely wants to be maximally
aggressive at whatever T-cell/viral load, I would give two drugs
without hesitation at this time.

       Patient Considerations

       Essentially everyone considered the patient's lifestyle, wishes
       or compliance when prescribing therapy.

       Mayer: The most important thing for any patient to feel is that
he or she has a great number of choices and that no choice is to be
considered permanent and that all choices should be re-evaluated in
light of new information. It is essential for the patient to feel that
he or she is in control and that the medical providers are allies in
their care. Our clinical encounters should be times when they ask as
many questions as possible and patients only elect to begin or add
treatments once they feel that they have enough information to make an
intelligent and informed choice.

       Jger: The patient's lifestyle and needs, but, above all,
ability to comply, play a major role in developing a treatment
strategy; without the patient's cooperation, even the best possible
treatment is doomed to end in frustration and failure.

       Abrams: I usually prescribe antiretroviral therapy to patients
who ask me for it. They usually know what they want and ask for it
specifically.

       2. What factors would enter into a decision to switch or stop
          antiretroviral therapy in an individual patient?

       Toxicity and adverse events were mentioned most frequently as
       reasons to stop or switch therapy (78 percent), followed by a
       combination of symptoms and surrogate markers (64 percent).
       Patient's request was cited by 22 percent of participants.

       Mayer: Any subjective experiences that might be considered
toxicities have to be at the top of the list, including nausea,
fatigue, weakness, headaches, etc. Since we know that with some drugs
the experiences may be highly transient (e.g., such as when
individuals start AZT), I may counsel the patient to see if they can
tolerate the symptoms over several days. Other symptoms may resolve
after a drug holiday and reinstitution of the treatment at a lower
dose level (e.g., sensory neuropathy with d4T), but often these
symptomatic toxicities necessitate changing treatment independent of
clinical responses. Other factors that might lead to changes in
treatment would include a rapid drop in CD4 count, a rapid increase in
HIV load, the onset of new minor (thrush) or major opportunistic
infections and/or constitutional symptomatology.

       Johnson: I stop therapy based on an individual's compliance and
tolerance of a particular regimen. Most of my patients tolerate
therapy across all HIV-1 disease stages. I have been switching therapy
mainly based on symptoms suggestive of viremia, although I will
probably obtain a viral load test more often in the future to decide
if a person is failing from a serologic standpoint.

       Jger: Factors which would lead to a change or stop in
antiretroviral therapy include: side effects not tolerable and/or
treatable (e.g., nausea, vomiting, headaches, (poly- )neuropathy), WHO
grade three or higher changes in laboratory parameters (GOT/GPT, AP,
anemia, CD4, viral load greater than at baseline, etc.) and/or during
an acute opportunistic infection. The antiviral therapy is then
re-started as soon as possible when the OI is stable.

       Katz: Intolerance is an easy one -- if they can't take the
drug, I switch. If neuropathy occurs on a 'D-drug' [ddI, ddC, d4T], I
stop completely (assume they're on 3TC already, as most of my patients
would be), push AZT to the extent it can be. I have seen only a few
patients (less than 2 percent) who are intolerant of all reverse
transcriptase inhibitors. For a patient who can take only 3TC (e.g.,
AZT-induced headaches/nausea and 'D-induced' neuropathy) I start a
protease inhibitor as the second drug regardless of viral
load/T-cells.

       Viral load -- anytime it goes over 100,000, therapy must be
switched. If it was undetectable, however, and now is above 10,000, I
will propose a switch.

       Clinically -- let's not forget the patient with sustained low
viral load and tolerating meds well but who is developing new symptoms
or T-calls falling steadily (unlikely if viral load is low). I would
propose adding a drug here, probably a PI if already on two reverse
transcriptase inhibitors.

       Hardy: Poor compliance, especially on protease inhibitors. It
is probably better to be on no antiretroviral therapy rather than
suboptimal dosing.

       Youle: Toxicities which occur on rechallenge or are not
amenable to reasonable supportive therapies.

       A number of doctors discontinue therapy in very late stage
       patients.

       Carpenter: We make the decision to stop whenever side effects
of antiretroviral therapy exceed potential benefits of therapy. This
is fairly common in very advanced illness, when the need to treat CMV,
MAI and to prevent PCP is more important than the continuation of
antiretroviral therapy.

       Cooper: I stop therapy when no further benefit is demonstrated,
there's too much toxicity or there's more benefit from prophylaxis
[alone].

       Jger: Although it is difficult to decide, patients who are at
the "point of no return," i.e., show no positive response to
medications, have several OIs simultaneously and/or are, in general,
very ill are no longer treated with antiretroviral agents.

       Some doctors consider discontinuation of therapy, when
       treatment reduces viral load to a very low level, and stays
       there when treatment is stopped.

       Cooper: I stop therapy if a patient becomes asymptomatic with
viral load below 10,000 off therapy.

       Cohen: Some buzz is starting on using powerful regimens to get
virus load to undetectable for about one month and it [viral load]
staying low even when drugs are stopped.

       3. Are you making use of HIV RNA viral load assays? If so, what
          absolute levels or changes do you consider significant? How
          often do you recommend these tests? How does the
          availability of viral load assays alter your treatment
          strategy?

       Eighty-three percent have access to viral load testing. With
the exception of one physician who believes there is little evidence
which supports "early intervention," all those who have access use
viral load in making treatment decisions. Those who have had access
the longest appeared to have more confidence in its use as a reliable
indicator of when treatment was necessary and/or of treatment
response. This greater confidence in turn yields more aggressive use
of these assays. Many who cannot offer the test cited payer
constraints and managed care obstacles and would like broader access
to help in patient assessment and response to therapy.

       Viral load is most commonly checked before initiating therapy,
four to eight weeks after initiating therapy and then every three or
four months. Of those who use viral load, approximately two-thirds
offered their view on what absolute levels or changes were considered
significant and these were quite varied. Six believed levels greater
than 5,000 were significant; four believed 10,000; one believed
50,000; three believed 100,000; one said no absolute level was
significant; one said that any detectable virus was significant. In
terms of changes, one believed that a change of 0.3 log was
significant; eight believed 0.5-0.6 log; two believed 1.0 log; one
said no absolute level of change was significant. Two respondents
stated that the goal of therapy was to keep viral load below
detection; two said the goal was to keep it below 5,000; four liked to
keep it below 10,000.

       Here are examples of viral load's impact on some
       specific strategies.

       Mayer: I am starting to use HIV RNA viral load assays more
frequently and am tending to obtain a baseline value on each new
patient that I see. I consider an HIV RNA viral load level of greater
than 10,000 copies/ml to be significant and have tried to use
antiretroviral therapy to keep the level below that threshold. I do
not use the viral load to the exclusion of other important clinical
markers. However, I would consider an increase in the HIV load of a
log to be of significance and to warrant re-evaluation of the current
antiretroviral regimen that the patient is taking.

       Collier: I like to see HIV RNA that becomes undetectable. I am
more aggressive with treatment at higher CD4 counts if HIV RNA is
high.

       Bihari: I recommend this test every three months in all of my
patients. I consider a change of 0.5 log or more significant enough to
influence treatment decisions.

       Rhame: I use the level for starting considerations to "adjust"
the CD4; e.g., CD4 of 250 with load of 100,000 would adjust to CD4
200. For change, greater than 0.5 log seems significant.

       Standish: I consider a 0.3 log unit drop
significant. I recommend them every three months and I am using this
test more frequently in patients with whom I am doing informal
patient-oriented single-subject studies of herbs.

       Some physicians stressed the extreme importance of monitoring
       and treating viral load. Many believe it has changed their
       approach to the treatment of HIV.

       Hardy: I've been making use of viral load assays for 20 months
now and recommend antiretroviral therapy for HIV seropositive persons
with HIV RNA greater than 5,000/ml. Persons with HIV do clinically
better with lowering their viral load, especially with dramatic
decreases from greater than 50,000/ml to less than 500/ml. It's
amazing and wonderful to see. A ray of optimism is emerging.

       Braun: Any amount of detectable virus is significant. The
availability of viral load along with the susceptibility assay [viral
genotyping] heighten the certainty of effectiveness of treatment.

       Giordano: Check it six weeks after altering antivirals and
every three months when a satisfactory viral load is achieved. Treat
the viral load!

       Dieterich: I use viral load to make all treatment decisions,
and [the goal is to] keep it below 5,000 copies/ml.

       Vella: We believe that viral load is the most reliable marker
for disease progression and recommend therapy when HIV RNA exceeds
5,000 (possibly 10,000) copies/ml of plasma. Patients with more than
30,000 copies are at high risk of progression. To be considered as
successful, antiretroviral treatment should cause at least a 1 log
decrease in viral load. However, not only the magnitude is important,
but also the durability of the response.

       Katz: Over
100,000 necessitates beginning or changing therapy. Under 10,000
necessitates no change, but between 10,000 and 100,000 I feel the
patient out for how aggressive he/she wishes to be. I'm prescribing
more drug with higher T- cells than I would have in past.

       Barriers to access continue to be a problem. This may change
       with the recent U.S. FDA approval of the Roche Amplicor test.

       Birnbaum: Viral load assays
are not available to my patient population [Kings County Hospital,
Brooklyn] so I have not made a single treatment decision based upon
them. I look forward to the opportunity to use these tests.

       Brosgart: A major problem is that managed care doesn't want to
pay.

       Johnson: I think it is expensive to get two baseline viral load
tests, and I sometimes can only justify getting a viral load test four
weeks after initiation of triple therapy.

       Ong: We see Medicaid patients almost exclusively in an inner
city environment. HIV RNA viral load assays are not presently Medicaid
reimbursed.

       Para: Without FDA approval and with lack of payment, I am not
using RNA to the fullest extent.

       Jger: In patients on treatment, we tend to test every six to
eight weeks. Financially it is difficult to justify testing more
often, although being able to document monthly changes would surely be
beneficial.

       But some practitioners raised a number of issues about the use
       of the test.

       Stein: A change of 0.5 log [three-fold] is needed to be
significant given the test's and biologic variability. This assumes
that the specimen was actually handled correctly, that the plasma or
serum is used consistently and that the same assay is being compared.
In follow-up, it is not as clear. It is most useful when one is
unclear whether therapy is working or not. [But viral load monitoring]
probably doesn't add a lot to the follow-up of asymptomatic and CD4
stable patients.

       Para: I don't feel comfortable about non-research handling and
reliability of the result. Research specimens are carefully processed
and quality controlled. Others are sent out. RNA is useful for
prognosis and assessing response to therapy but I am unsure what
absolute values to use. You need a three- to five-fold change in a
single patient to believe it's a real change.

       Cotton: I'm using viral load assays but so far my practice is
far more 'art' than science. I'm using the test to decide to switch or
add therapies but, once again, only in a qualitative way.

       Sonnabend: I have no evidence that this [viral load] means
anything in patients above 100 CD4 cells. I don't know how to use this
test for treatment decisions but do so anyway in order to learn
something. It is obviously important as a prognostic indicator. I'm
worried that now that viral load tests are available, that the results
will influence treatment decisions. There is no evidence that's
convincing that early intervention makes much difference. So why
should this [test] change that?

       4. When do you recommend the use of protease inhibitors? What
          sort of experience have you had with these drugs? (Please
          relate your overall impression of their effectiveness and
          also patient tolerance and compliance with dosing schedule,
          mentioning distinct characteristics of each particular
          drug.)

       The majority (66 percent) of physicians cited a combination of
critical CD4/viral load levels or changes as the reason to initiate
protease inhibitor treatment. Symptoms or patient request was cited by
8 percent, while only 8 percent always use protease inhibitors as
first-line therapy. One participant stated that he never uses protease
inhibitors and another questioned the clinical relevance of the
increased CD4 count.

       Approximately 50 percent of survey participants commented on
specific protease inhibitors. While indinavir and ritonavir were
uniformly considered effective, saquinavir was considered too weak or
too poorly bioavailable to be effective in its current form (85
percent). Indinavir and saquinavir were almost universally considered
well tolerated while 89 percent of comments on ritonavir noted its
poor tolerability (mostly gastrointestinal) or difficult drug
interaction issues. Some expressed hope that a slower dose escalation
strategy over two weeks would reduce these side effects but others
noted that these GI adverse effects are worse than what was seen in
the clinical trials despite the slow dose escalation. Four physicians
noted the difficulty with indinavir access through Stadtlanders or
problems with the Merck Patient Assistance Program.

       Overall, one might characterize the response to protease
inhibitors as tempered optimism. The increased CD4 counts and decline
in viral loads were viewed as encouraging but duration of response was
questioned. Drug interactions (particularly, ritonavir), side effects
(particularly, gastrointestinal problems with ritonavir) and
compliance requirements (particularly, coordinating meals with thrice
daily indinavir) were frequently noted as problems.

       An example of aggressive protease inhibitor use.

       Giordano: [I use] protease inhibitors almost always and have
extensive experience. Tolerance: ritonavir is excellent after four
weeks if prescribed correctly (dose escalate over two weeks);
indinavir and saquinavir are excellent. Efficacy: saquinavir is not
effective; ritonavir and indinavir are effective. Advanced disease is
reversible if protease inhibitors are used.

       Most add protease inhibitors when they believe nucleosides
       alone are not enough.

       Cooper: [I use protease inhibitors in those] failing double
nucleosides and have extensive experience. These drugs are very
effective and generally well tolerated. Compliance is good if careful
explanation is given to the patient. Saquinavir is less potent and
well tolerated; indinavir is potent and well tolerated; ritonavir is
potent and slightly less tolerated.

       Jger: We recommend their use as a monotherapy when other
regimens are not tolerable and/or effective or we combine them with
other antiretrovirals when those begin losing their effect as seen in
rising bDNA levels and/or falling CD4 counts.

       Cotton: I am generally reserving protease inhibitors for
patients with less than 300 CD4 cells who have viral loads greater
than 10,000 despite nucleoside therapy (usually AZT/3TC).

       Montaner: Given the issues of cost, toxicity and drug
interactions, I reserve them as second-line therapy.

       Dieterich: I have vast experience with protease inhibitors and
use them when the patient's T-cells fall below 500 with a viral load
greater than 20,000. Saquinavir is not toxic but not effective. Norvir
is effective but toxic. Crixivan is the most effective and least
toxic.

       Some concerns.

       Bihari: I have chosen to recommend the avoidance
of protease inhibitors until the Roche/Abbott study of the
saquinavir/ritonavir combination has shown what doses of each are safe
in combination.

       Matula: [Use when] patients fail other combinations.
There are good increases in CD4 counts but I'm not sure how effective.
One female patient went from CD4 of 21 to 380 and still broke through
her PCP prophylaxis.

       Vella: Protease inhibitors appear to be highly effective.
However, their use has some drawbacks, especially when they are given
to advanced patients, who are likely to assume many other medications.
[Drawbacks include] the high number of capsules that must be swallowed
and the side effects (especially the gastrointestinal disturbances
with ritonavir).

       Mayer: I have to review the patient's medication list and
discuss with him or her their eating patterns, given the need to
administer indinavir on an empty stomach or with a very light meal.
Because of the issue of drug compliance in relation to meals, several
patients have been started on ritonavir. I have had complaints about
"metal mouth" and gastrointestinal discomfort with both ritonavir and
indinavir so I really cannot say one drug is better tolerated than the
other.

       Sonnabend: I only prescribe protease
inhibitors for people with less than 100 CD4 cells who are
symptomatic, as I have good evidence for benefit in this population.
Why waste them (with resistance developing) in healthy people who may
need them later? They are more toxic, particularly GI toxicity, than
generally presented, particularly ritonavir which also has the worst
problem with interactions with other drugs.

       And some comments on specific agents.

       Saquinavir: Most felt the drug to be safe, but not very
       effective. Respondents were hopeful about the new formulation

       Braun: Thirty percent to 60 percent of patients respond to
saquinavir. Collier: I rarely use saquinavir unless other protease
inhibitors are contraindicated.

       Montaner: Saquinavir is the less desirable of them due to poor
bioavailability. Katzenstein: Awaiting for formulation with increased
bioavailability.

       Volberding: Saquinavir is easy to use, but there are few
indications for the current formulation due to poor levels. I'm
watching the new formulation closely. If higher levels, will we see
more toxicity, drug interactions?

       Indinavir: Almost everyone is pleased with its efficacy and
       patient tolerance, but there's some frustration with the
       Stadtlanders' distribution program.

       Carpenter: I have had 20 months of experience with indinavir.
Patient compliance has been excellent! Hardy: Efficacy is excellent,
RNA declines 99 percent to 100 percent and it is generally well
tolerated. There is a rare increase in total bilirubin. I have seen
two patients with kidney stones, but patient acceptance is good.

       Katz: Indinavir clearly has the best profile of ease of dosing
and patient acceptance presently. It's the cheapest by far of the
three (30 percent price advantage versus ritonavir).

       Volberding: Indinavir is the current 'winner' in terms of
toxicity/benefit balances. Eight-hour dosing a real problem with
compliance (especially the need to avoid meals). Stadtlanders is a
very cumbersome bureaucracy.

       Johnson: My impression is that indinavir is well tolerated,
although it has been difficult to obtain this drug through the Merck
Patient Assistance Program.

       Ong: Because of the difficulty in indinavir access, I have used
ritonavir.

       Rhame: It's a big hassle getting indinavir.

       Yancey: Coordination with meals is difficult. Less indinavir is
prescribed secondary to the monopoly by Stadtlanders.

       Ritonavir: Almost everyone is impressed by the efficacy but
most are disturbed by the toxicity and drug interactions.

       Saag: Ritonavir is OK if patients can tolerate it. There are
more patients with intolerance than we observed in the studies. I
don't know why.

       Collier: Tolerance to ritonavir has been a problem even with
the initial gradual dose escalation.

       Ong: Ritonavir: nausea, vomiting and diarrhea can be problems.
Hopefully, the new starting dose regimen will be better tolerated.

       Braun: Only 30 percent to 40 percent of patients tolerate
ritonavir even with an empowered patient tapering up over two weeks.

       Katzenstein: Ritonavir is a great concept
but a difficult drug over long term in advanced patients because of
interactions with other meds.

       Starrett: Wasted patients need to eat so the indinavir schedule
may not be optimal. Patients who don't have regular schedules of
medications would be best with twice daily dosing of ritonavir.

       5. Do you prescribe or do many of your patients take on their
          own additional, unapproved anti-HIV therapies (for example,
          acyclovir, hydroxyurea, N-acetylcysteine, or vitamin
          supplementation)? How are they used and what is your
          evaluation of their effectiveness?

       With the exception of two physicians, participants do not,
       themselves, actively prescribe alternative therapies. However,
       72 percent have patients who use alternative therapies. The
       consensus was that if alternatives did not seem to have
       negative effects, physicians did not have a problem with
       patients using them. Of those who mentioned alternative
       therapies, 42 percent mentioned acyclovir while 38 percent
       mentioned vitamins. But of those who mentioned acyclovir only
       nine participants actively recommended its use.

       Abrams: Most of my patients take acyclovir with or without
other antiviral drugs. I believe HSV probably upregulates HIV and have
thought it wise to suppress it.

       Katz: I still recommend it, especially in persons who have a
history of herpes and patients who can't tolerate many therapies and
have low T-cells.

       Mayer: If patients have problems with herpes simplex
recurrences and the costs of acyclovir isn't a disincentive that leads
to underutilization of other medications, I am comfortable based on
the data from several studies that suggest a survival benefit, with
maintaining patients with CD4 counts less than 100 on acyclovir 800
mg, five times at day. On the other hand, because several other
studies did not corroborate this survival benefit, and given the
drug's cost and concerns about compliance with polypharmacy, there are
many patients for whom I do not recommend acyclovir when their CD4
counts drop below 100 cells/mm3.

       Sonnabend: I have always believed that acyclovir was
potentially beneficial since I have believed that herpes viruses are
important factors.

       Braun: We are switching all patients from higher
doses to acyclovir 400 mg twice daily.

       Several physicians offered opinions on some alternative
       therapies.

       Birnbaum: I have found that Chinese herbs when properly
prescribed by a Chinese herbalist have been very effective treatments,
mostly for fatigue and wasting. One patient used kambucha mushrooms to
treat PML and had a remission of signs and symptoms.

       Giordano: NAC and acyclovir are not effective; hydroxyurea is
effective but use it only on study; vitamin supplementation is of
unknown efficacy.

       Cooper: Hydroxyurea: I'm not impressed with the results. NAC
doesn't work.

       Katz: Hydroxyurea: I wish more patients would glom onto this. I
think it's clearly worth a shot, but I have no one on it. I'm eager to
see the studies. I recommend vitamin/mineral supplementation for all
patients at any T-cell level (see Baum et al, Micronutrients and HIV
Progression, J. AIDS, 1995). I have nothing more than anecdotal
experience that patients on vitamin/mineral supplementation do better,
but they are generally doing 42 other things simultaneously.

       Sonnabend: NAC and antioxidants can't hurt.

       Braun: S-7 flavor tea was used once and
worsened the patient's renal status. QoXing was used once and was
poorly tolerated. Patients have abandoned NAC. We encourage
multivitamins but are neutral on Vitamin B12 and antioxidants. With
DHEA, we see no objective improvement but it's hard to monitor.
Thalidomide is excellent for ulcers and great for diarrhea with some
limited improvement in wasting.

       Two physicians stood out as using alternative therapies as the
       foundation for their anti-HIV therapy.

       Bihari: I prescribe acyclovir 3,200 mg/day to all HIV- positive
patients. I also prescribe naltrexone 3 mg at bedtime to all patients
regardless of CD4 level. Naltrexone stops the CD4 decline in 80
percent of patients and in 90 percent of those with more than 200 CD4
cells. I also recommend NAC 600 mg three times daily and several
antioxidants to all patients.

       Standish: Now that viral load testing is readily available for
many patients, I am trying botanicals, homeopathics and hyperthermia.
Thus far, nothing I've tried has substantially reduced viral load,
with the exception of high dilutional growth factors and cytokines.
All of my patients are using alternative methods. Acupuncture is the
most common and perhaps the most useful. I have yet to see anything
that produces dramatic improvements of immune markers such as CD4. We
are using a lot of DHEA too, if a patient's serum levels are low or
low normal. It seems to help overall energy. We hope to be doing a
small trial of DHEA soon. We are working hard at Bastyr's clinic to
keep the intestines healthy using acidophilus, glutamine, NAC,
UltraClear Sustain, beta carotene, Vitamin C, Vitamin E, quercitin.
Also we're using CoQ10 more and more.

       6. Do payer constraints influence your treatment decisions (for
          example, Medicaid, ADAP or formularies)? Is so, please
          explain. Of total participants, 69 percent cited payer
          constraints influencing treatment decisions.

       Of the seven physicians from outside the U.S., three had no
       problem with payment: one from each of Italy, Germany and
       Australia. One physician from Canada, one from France and two
       from the U.K. cited payer constraints. Within the U.S., 72
       percent cited payer constraints. Many cited that Medicaid is
       far better than ADAP, where choices are much more limited;
       however, Medicaid was often cited as the reason for not being
       able to use viral load assays.

       Examples of problems.

       Brosgart: Yes, yes. Many payers refuse off-label drug use.
Managed care has prior authorization and restricted formularies. ADAP
has a long lag between licensure and inclusion on its formulary.
Managed care has fixed pharmacy dollars but lots of new experimental
drugs. The HIV specialist is being squeezed by managed care. We need
to effectively advocate to treat patients. Often we're not considered
primary care, as a way of keeping patients out of health plans.
Delivering comprehensive, coordinated high quality care costs more up
front but saves on big ticket items (hospitals, ER).

       Volberding: We need to find a way to get HMOs to provide HIV
centers of excellence without fear of adverse selection.

       Saag: Absolutely, I live in Alabama. Medicaid is inaccessible
for most (need less than $479 a month income; net worth less than
$3,000). Ryan White: no Title I; limited Title II/III. We spend hours
per week applying for assistance.

       Abrams: Medicaid usually pays. ADAP has just put 3TC on the
formulary. No protease inhibitors are yet on in California, but most
of my patients utilize the federal insurance program, not ADAP.

       Birnbaum: Most of my patients are Medicaid covered. If they
have Medicaid, there's no problem prescribing these meds. If they are
covered by ADAP only, my treatment choices are limited to what ADAP
covers. If they are uninsured, I am limited to my hospital formulary
of AZT plus ddI only plus a supply of a few months worth of 3TC which
was donated to my clinic.

       Kessler: Yes, viral load is not paid for by public aid or
Medicare.

       Ong: We cannot use HIV RNA plasma levels

       Para: Yes, we don't get RNA on these [Medicaid, ADAP] patients
unless they are in trials. We cannot get protease inhibitors on ADAP.

       Stein: Medicaid has, at present, better coverage than [New
York] ADAP or the VA for antivirals. HMOs can be a problem.

       Katlama: We are very concerned about the long-term cost of
treatments. I do not use very expensive drugs which don't have optimal
efficacy. Even more difficult for alternative medicine.

       Standish: Yes, payer constraints severely and
adversely influence what treatments are possible for many of my
patients. It is rare that third party payers will reimburse for
natural and alternative medicines. Some insurance companies don't
cover viral loads, or not as often as I think medically necessary. In
Washington State, alternative medicine is now being covered by
insurers, reluctantly and incompletely. Being part of the insurance
game presents even more constraints. We have a horrible system in the
United States. Some good news.

       Katz: We have a very liberal formulary at Kaiser, and every
HIV-approved drug is on it, so this is not a consideration.

       Cohen: [Massachusetts] ADAP covers all antivirals except
indinavir (which we get instead from Merck). The only other rare
problem is that ADAP doesn't cover unlimited fluconazole and
acyclovir.

       Jger: Fortunately, the social medical system in Germany
allows (nearly) complete coverage of all necessary medication and/or
therapy regimens. Thus, all of the approved antiretroviral substances
including protease inhibitors can be prescribed, also in combination.

       And in a word . . .

       Rhame: Only when they won't pay.

       B. Opportunistic Infections

       7. Do you recommend prophylaxis for CMV, MAC or fungal
          infections? If so, with what agent and in what patient
          population?

       For opportunistic infection prophylaxis, the trends were very
       clear. Only 11 percent prescribe primary prophylaxis for fungal
       infections. Concerns about azole resistance were cited.
       Approximately 17 percent prescribe prophylaxis for CMV, most
       commonly at CD4 counts below 25. The negative CPCRA oral
       ganciclovir CMV prophylaxis study (see Treatment Issues,
       October 1995, page 10), the large number of pills, toxicity and
       cost were the most common reasons cited for not prescribing
       prophylactic oral ganciclovir.

       Primary prophylaxis for MAC, conversely, was quite popular (83
       percent). Of the 22 participants who cited their choice of
       therapy, 82 percent prescribe macrolides (clarithromycin or
       azithromycin). Recent data on macrolide prophylaxis was cited
       by many. A few physicians described a recent switch from
       rifabutin to macrolides and some cited difficulty in using
       rifabutin with the protease inhibitors as the reason for a
       macrolide preference. Of the 21 physicians who described when
       they start MAC prophylaxis, eleven initiated therapy at a CD4
       count below 50, seven started below 100, and two started below
       25.

       Those who are most aggressive with prophylaxis are also the
       most conservative with antiretroviral therapy. One physician
       cited occupational risks for fungal infections.

       Although MAC prophylaxis was common, there were some concerns.

       Katz: Until recently, I have used rifabutin (since its 1992
approval). Then with the protease interactions, I started using
clarithromycin. Now, it's all a big wash. More and more at Kaiser our
infectious disease specialists are suggesting not using any and either
getting blood cultures every three months or treating at the first MAC
symptoms. It has become a reasonably treatable condition nowadays and
patients generally prefer to have one less drug to take; so does the
health care economy. The effect this [prophylaxis] will have on
ultimate development of MAC and possibly cross-resistant
clarithromycin-azithromycin strains remains to be seen. If we lose the
ability to fight this infection with either of these two drugs, we're
back in the mid-80s--with four to five drugs, IVs and still not great
results.

       Johnson: I have not been routinely recommending prophylaxis for
CMV, MAC or fungal infections. I am concerned that many of these
agents may interrupt or alter levels of antiviral therapies. I have
mainly focused on maximal antiretroviral suppression, rather than
starting prophylaxis for these opportunistic infections. However, my
thinking has changed based on the data from Dr. Diane Havlir and the
California Collaborative Treatment Group. I will likely start
azithromycin weekly to prevent MAC. I am also very aggressive about
early initiation of clarithromycin and ethambutol for empiric
treatment of MAC.

       Brosgart: Yes, in those with CD4 less than 75. First
choice is a macrolide (azithromycin is number 1; clarithromycin is
number 2); second choice is rifabutin.

       Saag: For CD4 less than 25, take two drugs: clarithromycin and
ethambutol.

       Bihari: If the CD4 cells are below 100, Biaxin 500 mg/day with
ethambutol, 800 mg/day to prevent MAC.

       CMV prophylaxis.

       Abrams: No, I agree with the CPCRA study.

       Brosgart: All patients with CD4 less than 100 are seen by an
ophthalmologist every three months. No oral ganciclovir prophylaxis:
it's of limited benefit, too toxic and expensive.*

       Mayer: Based on the CPCRA study of primary CMV prophylaxis, we
do not routinely start empiric therapy with ganciclovir based on the
CD4 count criterion. We hope that in the near future that quantitative
CMV measurements in the plasma will enable us to predict which
patients are most likely to progress with CMV retinitis.

       Bihari: In those with CD4 cells below 150, start acyclovir,
4,800 mg/day to prevent CMV infections.

       Fungal prophylaxis.

       Brosgart: Fungal prophylaxis only if severe, chronic, recurrent
disease.

       Bihari: In patients with CD4 cells below 200, Diflucan 100
mg/day to prevent cryptococcal meningitis.

       Rhame: Fluconazole for CD4 less than 100 . . . more anti
candida effort required [for female patients]. Prevention of
histoplasmosis as a rationale for azole prophylaxis is not adequately
appreciated.

       Hardy: Only for those with CD4 less than 100 and chronic
exposure to fungi, coccidiodomycosis (gardeners, construction).

       8. Do you recommend TB prophylaxis for patients who are HIV-
          positive and anergic?

       Only three participants answered this question, affirmatively.
       Some of those who answered, no, explained that they reserved
       prophylaxis for those with high risk histories or a positive
       PPD (skin test for TB exposure).

       Mayer: We definitely recommend TB prophylaxis of INH with
Vitamin B-6 for one year for patients who are HIV-positive and anergic
in our community, given our experience with several recent outbreaks.

       Ong: Yes, for patients who receive directly observed preventive
therapy in our drug treatment centers.

       9. What treatments do you utilize to reverse weight loss and
          wasting (nutritional, human growth hormone, anabolic
          steroids, thalidomide or other anti-TNF compounds, etc.)?

       The most common interventions for weight loss are anabolic
       steroids (72 percent) and nutritional counseling/supple-
       mentation (67 percent). Often mentioned were Megace (42
       percent), Marinol (33 percent) and human growth hormone (19
       percent).

       Although these agents were used by many, views on their utility
       were anything but uniform.

       Brosgart: Nutritional counseling; rule out hypogonodal and
hypoadrenal. Deal with nausea and oral ulcers. Try to give most meds
with meals. I love thalidomide. I like to put my patients in trials so
we can learn more about treatment or preventing weight loss and
wasting. Sometimes patients are just losing weight because they don't
have food.

       Cohen: New antivirals are clearly effective as an antiwasting
treatment. I have seen big weight gains with ritonavir. A few patients
have done thalidomide but had more side effects than benefits.

       Mayer: Our first line of defense is enteral supplementation
tailored to a regimen that patients can maximally tolerate. We also
recommend that the patient engage in weight bearing exercise in order
to maximally benefit with a positive anabolic reaction.

       Bihari: In general, identifying a slowly developing OI that is
causing weight loss and treating it is the most common approach. AZT
plus 3TC reversed weight loss and wasting in patients more effectively
than growth hormone, thalidomide, Trental or anabolic steroids.

       Anabolic steroids, particularly testosterone, are the most
       common pharmaceutical interventions for wasting but physicians
       did not describe their effects in any great detail. Some
       mentioned oxandrolone, one mentioned decadurobolin.

       Volberding: Anabolics are the easiest way to get some benefit.

       Cohen: Intramuscular testosterone with or without decadurobolin
in many (male) patients. I'm considering oxandrolone. Human growth
hormone's price was cited as a problem. Volberding: HGH works, but
it's way too expensive.

       Brosgart: I rarely use rHGH; it's expensive and of limited
benefit. It's a last resort.

       Cohen: I don't use HGH. It's not clearly worth the price.

       Mayer: In patients who have lost more than 5 percent of lean
body weight, we begin discussions about the possibility of utilizing
human growth hormone, which to date has impressed us as the most
effective agent in reversing catabolism. Megace and marinol.

       Volberding: Megace: poor side effects and all fat. Marinol: not
too effective but some like it (many more prefer marijuana which is
available in SF through a local buyers' club).

       Brosgart: We use Megace and Marinol. Cohen: I will use
Marinol/Megace to improve appetite (as well as suggest marijuana if
helpful). An alternative approach.

       Standish: We are beginning to try high dilutional insulin
growth factor and Sea Cure protein supplements. I think early total
parenteral nutrition [TPN] helps a lot. It's hard to get other doctors
to see the wisdom of early TPN.

       C. General

       10. If you see significant numbers of women or children with
           HIV, can you comment on age or gender-related differences
           in treatment of the virus or opportunistic infections?

       Unfortunately we received little or no responses about treating
       children. The vast majority of those with experience in
       treating women believed there was little significant
       difference. The need for diligent screening for vaginal
       infection (particularly candidiasis) and cervical cancer were
       emphasized. An increased incidence of oral/esophageal
       candidiasis and a decreased incidence of KS were noted. Two
       physicians believe that women present with more advanced
       disease.

       Women.

       Bihari: I see a lot of women who represent 30 percent to 35
percent of my practice. Apart from the obvious differences (i.e., need
for frequent PAP smears, alertness to and aggressive treatment for
vaginal infections and pregnancy issues), I find no differences in the
treatment of the virus or OIs.

       Brosgart: Women are 25 percent of my population. There are few
differences when adjusted for CD4. We often must weight-adjust meds.

       Carpenter: I have not noticed gender-related differences in
treatment of the virus. OI treatment is also similar, the only
difference being the gender specificity of vulvovaginal candidiasis.

       Johnson: Unfortunately, due to the demographics of HIV-1
infection in Alabama, I see a significant number of women
(approximately 50 percent of my clinic). I think that these women tend
to get diagnosed at a later disease stage, but that their
complications are not terribly different from those of adult men. The
women in my clinic do seem to have more difficulty with vaginal
candidiasis during antibiotic therapy for other infections. They also
tend to have unrecognized concomitant STDs such as human
papillomavirus.

       Mayer: With regard to the major opportunistic infections that
men can develop, the women seem to develop them at a similar rate and
do not have substantively different clinical patterns with these
opportunistic infections, except for a slightly increased propensity
toward mucosal candidial infection, resulting in a slightly higher
annual rate of candidial esophagitis. The major clinical differences
in HIV- infected women compared to men is that there is substantial
gynecological morbidity that the women experience in the course of
their HIV infection. With meticulous gynecological care, invasive
cervical carcinoma is rare; however, atypical PAP smears are common
and require careful follow-up with quarterly PAP smears and colposcopy
when abnormalities persist. Prompt, but specific surgical procedures
can help avert wider spread of localized cervical neoplasia. Several
of my colleagues have seen women with recurrent pelvic inflammatory
disease. Traditional sexually transmitted diseases have been uncommon
among the HIV-infected women that we followed, but recurrent candidial
vaginitis, bacterial vaginosis and trichomoniasis may be common causes
of clinical discomfort and require prompt diagnosis and treatment.
Several of the women that we follow have recurrent sinusitis and
pneumonia but the prevalence and incidence rates for these conditions
have not been radically different from that of demographically similar
men.

       Saag: We have no data about menopause.

       Cotton: I do think there are emerging issues in antiviral
treatment of women in terms of how to treat women with plans for
conception, etc.

       Standish: Women are simply much sicker when I begin working
with them. They also seem to tolerate less well anti- retrovirals,
ganciclovir and MAI regimens.

       Volberding: Women present a different array of social and
financial issues.

       A note about adolescents.

       Birnbaum: In general, it has been historically difficult to get
adolescents to take antiretroviral medications. More recently, since
the advent of widespread use of combination therapy many actually have
started requesting to start on combination therapy and to use protease
inhibitors. Many are reluctant to use OI prophylaxis but usually do
so, at least for PCP, after they have been given the information to
make an educated decision. As a general rule I try to prescribe
medications that have once or twice a day dosing, as this tends to
improve compliance.

       11. Do you have any further observations from your practice
           that you would like to report (particularly findings that
           are not commonly discussed)?

       Carpenter: A comprehensive care program in a single site is of
critical importance, I think, with maintaining adequate long-term
compliance with any regimen.

       Johnson:
Indeed, the majority of my patients have more problems related to
wasting syndrome and ultimate demise than from opportunistic
infections. I also think that IV amikacin is the drug of choice for
MAC relapsed episodes and give a four-to-six week course on top of
oral therapy for relapses. By giving this drug intravenously by home
health nursing five days of the week for four to six weeks, I have
been impressed that several patients have resumed excellent quality of
life. Finally, it is my impression that patients with CD4 less than 10
cells/mm3 can tolerate double and triple antiretroviral therapy well,
despite prior observations about enhanced toxicity. I think that it is
a myth that patients with advanced HIV-1 disease cannot benefit from
antiviral therapy, which can reduce the frequency and severity of
their opportunistic infections. Many of these patients have survived
for years with excellent quality of life despite their advanced
disease stage.

       Bihari: My long-term patients very rarely develop OIs
and 85 percent to 90 percent have long term stability of CD4s. The
three major factors are: 1) low dose naltrexone; 2) aggressive OI
prophylaxis as described in question seven; 3) the effectiveness of
AZT plus 3TC in AZT-naive patients and the fact that 90 percent of my
patients are AZT-naive because of my past reluctance to use AZT
monotherapy.

       Saag: Patients are living longer with new problems:
fluconazole-resistant cryptococcus after two to three years of
secondary prophylaxis and resistant CMV. There may be less HIV
dementia. There is a significant change in demographics: more poor,
more African Americans, more women, more heterosexuals (despite the
Wall Street Journal!).

       Para: I stress the importance of regular exercise in reducing
symptoms.

       Standish: We have done a little experimental work with high
dilutional growth factors and cytokines. This seems like a promising
area. GM-CSF 200C seems to elevate platelets in thrombocytopenic
patients, for example. We need NIAID funding for this to go forward. *
Carol Brosgart was a principal investigator of the negative CPCRA 023
oral ganciclovir prophylaxis study.

       ----------------------------------------------------------
       We sent surveys to 79 leading AIDS physicians in the U.S.,
       Canada and Europe; 36 (46 percent) responded. We are very
       grateful to all those who participated in this rather
       cumbersome open-ended survey:

       Donald Abrams, Community Consortium, San Francisco, CA
       Bernard Bihari, New York, NY
       Jeff Birnbaum, Kings County Hospital, Brooklyn, NY
       James Braun, New York, NY
       Carol Brosgart, East Bay AIDS Center, Berkeley, CA
       Charles Carpenter, Brown University/Miriam Hospital,
       Providence, RI
       Cal Cohen, CRI/New England, Brookline, MA
       Ann Collier, University of Washington, Seattle, Washington
       David Cooper, National Centre in HIV, Sydney, Australia
       Deborah Cotton, Massachusetts General Hospital, Boston, MA
       Douglas Dieterich, New York University Medical Center, New
         York, NY
       Brian Gazzard, Chelsea & Westminster Hospital, London,
         England
       Michael Giordano, New York Hospital-Cornell Medical Center,
         NY, NY
       W. David Hardy, UCLA School of Medicine, Los Angeles, CA
       Martin Hirsch, Massachusetts General Hospital, Boston, MA
       Hans Jger, Munich, Germany
       Victoria Johnson, University of Alabama, Birmingham, AL
       Christine Katlama, Hpital Piti Salptrire, Paris, France
       Mark Katz, Kaiser Permanente, Los Angeles, CA
       David Katzenstein, Stanford University Medical Center,
         Stanford, CA
       Harold Kessler, Rush-Presbyterian-St. Luke's Medical Center,
         Chicago, IL
       George Matula, Kaiser Permanente, San Francisco, CA
       Kenneth Mayer, Memorial Hospital of Rhode Island, Pawtucket,
         RI
       Julio Montaner, St. Pauls Hospital, Vancouver, Canada
       Kenneth Ong, Catholic Medical Center, Jamaica, NY
       Michael Para, Ohio State ACTU, Columbus, OH
       Frank Rhame, University of Minnesota, Minneapolis, MN
       Michael Saag, University of Alabama, Birmingham, AL
       Joseph Sonnabend, New York, NY
       Leanna Standish, Bastyr University, Seattle, WA
       Barbara Starrett, New York, NY
       Daniel Stein, Albany Medical College, Albany, NY
       Stephano Vella, Instituto Superiore Di Sanita
       Paul Volberding, University of California, San Francisco, CA
       Todd Yancey, New York, NY
       Mike Youle, St. Stephen's Clinic (Kobler Center), London,
         England

       -------------------------------------------------------------
       As brand names and abbreviations for pharmaceuticals may vary
       worldwide, the following table lists those used in survey
       responses.


       Generic Name         Brand Name	       Abbreviations
       ------------         ----------           -------------
       acyclovir            Zovirax              ACV
       azithromycin         Zithromax
       clarithromycin       Biaxin, Klaricid
       delavirdine          Rescriptor
       didanosine           Videx                ddI
       fluconazole          Diflucan
       ganciclovir          Cytovene             DHPG
       indinavir            Crixivan
       ketoconazole         Nizoral
       lamivudine           Epivir               3TC
       nevirapine           Viramune
       rifabutin            Mycobutin
       ritonavir            Norvir
       saquinavir           Invirase
       stavudine            Zerit                d4T
       trimethoprim/        Bactrim, Septra      TMP/SMX
         sulfamethoxazole
       zalcitabine          Hivid                ddC
       zidovudine           Retrovir             AZT, ZDV


       ----------------------------------------
       Regimens Mentioned as First-line Therapy
	                                   Respondents
	                                    #	  %
       AZT/3TC                            24     67%
       AZT/ddI                            12     33%
       d4T/3TC                             9     25%
       ddI monotherapy                     7     19%
       AZT/ddC                             5     14%
       ddI/d4T                             3      8%
       d4T monotherapy                     1      3%
       d4T/ddC                             1      3%
       AZT/d4T                             1      3%
       Reverse trascriptase inhibitors
         plus "protease inhibitor"         4	11%
       RTIs plus Crixivan                  4	11%
       RTIs plus Crixivan or Norvir        1	 3%

       ------------------------------------------
       Starting Treatment: Examples of Algorithms

       Charles Carpenter, Brown University/Miriam Hospital,
       Providence, RI

       I. Initial Therapy

       1. Asymptomatic, CD4 350-500

          AZT plus ddI or
          AZT plus 3TC

       2. Asymptomatic, CD4 less than 350 or symptomatic at any CD4
          count

          AZT plus 3TC plus indinavir

       II. New Regimen

       Begin when patient becomes symptomatic or CD4 drops below
       pretreatment baseline or when viral load exceeds 10,000
       copies/ml.

       Michael Para, Ohio State ACTU, Columbus, OH

       1. Naive, CD4 greater than 300

          AZT plus 3TC or
          AZT plus ddI (new formulation) or
          d4T plus 3TC

       2. Drug-experienced CD4 greater than 200-300

          Depends on what experienced with: change both.

       3. CD4 less than 200-300

          Drug-naive: AZT plus 3TC plus indinavir (or ritonavir)

          Drug-experienced: depends on what experienced with:
          nucleoside (new or old)+nucleoside (new)+indinavir (or
          ritonavir)

       Mike Youle, St. Stephen's Clinic (Kobler Center), London, U.K.
       Naive Subjects:

       1. At seroconversion: Combo ddI/AZT/protease

       2  CD4 greater than 350 Nothing or short-term trial If not a
          trial, then ddI or ddI plus AZT

       3. CD4 200-350 Longer term study If not a trial, start ddI or
          ddI plus AZT then add 3TC +/- nevirapine or open 3TC then
          add protease inhibitor

       4. CD4
          less than 200 Short-term ddI plus AZT then add 3TC plus d4T if
       no response, add one or more protease inhibitors James Braun,
       Stacy Kreiswirth, Paul Hergenroeder, New York, NY

       I. Initial Therapy at Any Stage with Detectable Viral Load:

       1. Nucleoside therapy with two drugs AZT/3TC, AZT/ddI, AZT/ddC,
          d4T/ddI, d4T/3TC

       2. Check viral load if less than 300 or undetectable,
          keep two-drug nucleoside combination if viral load still
       detectable, add protease inhibitor

          a) saquinavir
          b) indinavir
          c) ritonavir (The preference for saquinavir is because of
             the potential cross resistance to saquinavir for patients
             treated with indinavir. Ritonavir is third choice due to
             poor patient tolerance. Use ketoconazole 200 mg/day in
             all saquinavir treated patients.)

       II. Experienced patients with an upsurge in viral load with or
           without a fall in CD4 count with or without occurrence of
           clinical symptoms/deterioration:

       1. Check patient's HIV for genetic resistance to drugs

       2. Select two nucleoside analogs based on genotype and
          tolerance

       3. Check viral load in three to five weeks if detectable, add
          protease inhibitor

          a) saquinavir
          b) indinavir
          c) ritonavir (If there are not two nucleosides to which the
             patient is not resistant and can tolerate, than use a
             single nucleoside, but not AZT, with a protease
             inhibitor.)

       ---------------------------------
       When to Start Protease Inhibitors

	                                               Respondents
                                                        #      %

       Critical CD4 Level/Change                       12     33%
       Critical Viral Load Level/Change                12     33%
       Always as First-Line Therapy                     3      8%
       When Symptoms Appear                             3      8%
       Patient Request                                  3      8%
       Never                                            1      3%


       Primary Prophylaxis for OIs
	                                               Respondents
                                                        #      %

       MAC
              Yes                                      30     83%
              No                                        5     14%
              Individualized                            1      3%
              Rifabutin First-line                      4     18%
              Macrolide First-line                     18     82%

       CMV
              Yes                                       6     17%
              No                                       29     81%
              Individualized                            1      3%

       Fungal
              Yes                                       4     11%
              No                                       31     86%
              Individualized                            1      3%

       ---------------------------
       Preventing PCP Breakthrough

       Assuming that PCP prophylaxis was universal, we did not
specifically ask about it. However, Dr. Victoria Johnson, University
of Alabama, offered an interesting perspective on preventing PCP
breakthrough:

       I have found that I can reduce episodes of breakthrough PCP
with a combination of dapsone 100 mg po daily plus monthly
pentamidine, which has reduced hospital admissions for several
patients that had recurrent hospitalizations. I find this approach is
well tolerated. I am also employing monthly aerosolized pentamidine
for patients with memory loss who don't remember to take daily
Bactrim.

       -------------------------
       Therapies for Weight Loss
                                                 Respondents
                                                  #       %
       Anabolic Steroids                         26	72%
       Nutritional Support                       24     67%
       Megace                                    15     42%
       Marinol                                   12     33%
       Human Growth Hormone                       7     19%
       Thalidomide                                6     17%
       Total Parenteral Nutrition                 4     11%
       Marijuana                                  3      8%
       Other                                      2      6%

       ---------------------------------
       We need HIV-positive men and women to participate in the Bastyr
University Study of alternative medicine in HIV/AIDS to find out if
any of these alternative approaches are helping people. Please call
800-475-0135 to enroll or find out more.

       - Leanna Standish, Bastyr University, Seattle


       *************************************
       Weekly Fluconazole to Prevent Candida

       Few of our survey respondents administered prophylaxis for
fungal infections of any sort, although several noted that vaginal
yeast infections ("candidiasis" caused by the yeast species Candida
albicans) were a special problem for women with HIV. These specialists
also noted that such women seemed to have more oral and esophageal
candidiasis than HIV- positive men.

       A recently concluded trial conducted in women by the
government-sponsored Community Programs for Clinical Research on AIDS
(CPCRA) has found that 200 mg of fluconazole taken weekly can cut the
risk of developing oral/throat or vaginal yeast infections by half.
The effect on yeast in the esophagus could not be determined because
of its low rate of occurrence during the study.

       This placebo-controlled trial, known as CPCRA 010, enrolled 323
women with CD4 counts less than 350 (average CD4 count: 199). The
median time on study medication was sixteen months for those receiving
fluconazole and ten months for those on placebo.

       Use of fluconazole to prevent fungal or yeast infections has
been widely shunned because of the risk of developing drug- resistant
microbes. Such resistance would render fluconazole useless for the
valuable treatment role it now performs. In CPCRA 010, however, the
incidence of fluconazole-resistant candidiasis was low and equal in
both the fluconazole and placebo arms. But although weekly fluconazole
reduced the frequency with which Candida albicans was isolated in
vaginal secretions, there was increased isolation of closely related,
though less pathogenic species of yeast.

       The researchers concluded that weekly fluconazole could have a
useful role in preventing recurrent mucosal candida infection in
women. In the study, women with a recent history of repeated vaginal
candidiasis had a significantly higher risk of new episodes. The women
who had previously had candida in the mouth, pharynx or esophagus were
at higher risk for another infection in those areas, as were women who
had AIDS or used one of the standard preventive drugs for Pneumocystis
carinii pneumonia.

       - Dave Gilden

       *******************************************
       Health Care Quality versus Economics in HIV
       by Gabriel Torres, M.D.

       The cost of HIV care can be astronomical, particularly during
the late stages of AIDS. At the same time, the high cost of health
insurance has forced many individuals and employee groups into
"managed care" programs such as HMOs (health maintenance
organizations) devoted to providing the cheapest health care possible.
Government financial support for indigent programs like Medicaid is
decreasing, too. Third- party payers are attempting to increase
cost-efficiency by such measures as emphasizing preventive care,
reducing duplication of services and avoiding expensive
pharmaceuticals and medical procedures. Capitation initiatives focus
on cost containment by limiting the annual amount of reimbursement for
a given individual's health care. Competition for the large patient
pools often driven into the managed care plans is a further factor in
minimizing cost. (See box on page 18.)

       Occasionally, the highest quality of care may be the most
cost-efficient. For example, prophylaxis with Bactrim
(trimethoprim/sulfamethoxazole, or TMP/SMX), oral dapsone or
aerosolized pentamidine can dramatically reduce the incidence of
Pneumocystis carinii pneumonia (PCP) and is significantly less
expensive than care of acute PCP. Several studies have shown that
TMP/SMX is significantly more cost-effective than aerosolized
pentamidine in patients at risk for PCP.1,2 In addition, if the signs
and symptoms of PCP are identified early in the course of the
infection, less costly and better tolerated oral regimens can be used
for treatment.

       Some managed care companies have developed working "models of
care" that reduce costs through lessened utilization of acute care
hospitals, emergency rooms, lung specialists, diagnostic procedures
and intravenous therapies for PCP. One such model has been implemented
by the Community Medical Alliance (CMA). This organization was prepaid
by the Massachusetts Medicaid Program on a fully capitated basis to
provide comprehensive services to a subset of the greater Boston AIDS
population receiving Supplemental Security Income (SSI, a federal
disability program). The CMA's model used physician/nurse practitioner
teams to direct a contracted network of medical specialty, home
health, personal care, private duty nursing, home infusion, day care,
foster care, mental health, substance abuse, hospital, hospice care
and skilled nursing facility providers.

       A study was performed to evaluate the cost-effectiveness and
quality of care that this model provided.3 The endpoints in the study
were the incidence of PCP, general health outcome and location of
care. (Due to episodes of illness or disability, over one-third of all
medical visits were made in the home by one of the team members or
providers in the network.)

       An analysis looked at 113 enrollees with median CD4 counts of
61 who received over 81 patient-years of care. During this period,
fourteen PCP cases occurred -- a rate of 17.2 per 100 patient-years.
This rate is significantly less than that observed in the same
population before enrollment in the program (58.7 per 100
patient-years) or the rate in a comparable New York City population
(39.6 per 100 patient- years).4 Over half (57 percent) of the episodes
were managed at home, three partially in the hospital and three
totally in the hospital. There was just one death, for a total PCP
mortality of 7.1 percent, which compares favorably with rates of 12 to
33 percent reported in the literature.

       Review of patient medical records demonstrated that 73 percent
of the patients had evidence of adequate PCP prophylaxis. The study's
author, Robert J. Master, M.D., of the Boston University School of
Public Health, inferred that compliance with PCP prophylaxis through
the coordinated team approach had reduced the incidence of PCP. In
addition, the author implied that the shift to home care was possible
due to the early identification of the signs and symptoms of PCP.
Timely diagnosis allowed for treatment at a stage when the infection
was comparatively mild and treatable with oral antibiotics under the
supervision of a nurse practitioner.

       Although this model may be possible for such easily manageable
infections as PCP, it is unclear whether it could work for other
conditions such as disseminated MAC or CMV infections, wasting and
diarrheal disorders and systemic lymphoma. These have rapidly become
the leading causes of hospitalization of AIDS patients over the last
several years.

       MAC and CMV can be prevented to some degree through the use of
drugs such as clarithromycin and oral ganciclovir, but those drugs are
more costly and toxic than TMP/SMX or dapsone. They also have more
drug-drug interactions that require intensive monitoring. The rates of
infection that occur despite prophylaxis are higher, too. When
infections do break through, they may require multi-drug regimens,
intravenous infusions and more intense monitoring or nursing care
during their acute treatment phase. Lymphomas usually require
expensive diagnostic work-ups followed by radiation and combination
chemotherapy. These regimens are costly in themselves and toxic. Their
use necessitates extremely close monitoring, which usually is possible
only in an acute care hospital.

       Nevertheless, many of these treatments may be administered at
home these days, as intravenous infusions administered through either
peripherally inserted or central venous catheters. Establishing
whether costs are reduced and quality of life improved in this new era
will require further studies of nonhospital care models, including the
use of allied health professionals such as nurse practitioners to
coordinate care.

       Physician and Hospital Experience

       Additional studies suggest that other trends at some health
care management organizations -- such as not reimbursing for certain
procedures and limiting the choice of primary health care providers to
doctors who have agreed with HMOs to charge less but who have little
or no experience treating AIDS patients -- may decrease quality of
care.

       A recently published study has demonstrated that experience of
primary care physicians in management of AIDS is significantly
associated with survival of their patients. The study conducted at a
health care maintenance organization in Seattle by Kitahata et al5
evaluated outcomes of 403 adult male patients diagnosed between 1984
and 1994 and cared for by 125 primary care physicians. The researchers
rated physicians based on their experience caring for AIDS patients
during their residency and the cumulative number of patients with AIDS
that they had cared for in their practices.

       The median survival of patients who had physicians with the
least experience in managing AIDS was fourteen months, as compared to
26 months for the patients of physicians with the most experience. The
authors controlled for CD4 count, severity of illness and year of
diagnosis. They were still able to show a 43 percent reduction in the
risk of death for patients in the hands of the most AIDS-experienced
physicians as compared to those cared for by the least experienced
physicians. CD4 monitoring was more frequent, and PCP prophylaxis and
antiretroviral therapies more extensively utilized by those doctors
with the longest AIDS track record.

       Several studies have demonstrated that hospitals that have
treated more AIDS-related PCP had a lower in-patient AIDS mortality
rate.6,7 This may be due to earlier recognition of the disease, more
aggressive diagnostic evaluations and appropriate treatment regimens
in facilities with the most AIDS-experienced staff

       Reimbursement and Outcome

       Whatever practitioners' skill, problems obtaining reimbursement
for medical procedures or treatments can undermine their ability to
provide quality care. A recently published survey of 387 HIV/AIDS
specialists8 found that 40 percent of all the drugs they prescribed
were for indications that were not officially approved (mostly for
treatment and prevention of opportunistic infections). Although such
usage frequently reflected the accepted standard of care, half of the
doctors responding reported that they had seen third- party payers
deny reimbursement for "off-label" prescriptions. The authors
concluded that when faced with such obstacles many patients will
receive less effective, albeit covered, therapies or be hospitalized
to gain access to the preferred therapy.

       In another study, the survival for patients insured under
Medicaid was lower than those who were privately insured.9 This seemed
to be related to fewer diagnostic procedures such as bronchoscopies
(used to diagnose PCP), which are reimbursed at a very low rate by
Medicaid and thus less frequently used in people covered by this
program. Medicaid patients with PCP in the study were 1.7 times more
likely to die in the hospital, and only nine percent had bronchoscopy
within two days of hospitalization compared to 32 percent of privately
insured patients.

       It remains to be seen how the health care experience of people
with HIV will be affected by the advent of intensive viral monitoring
early in disease and of high-priced but potent antiretroviral agents
such as protease inhibitors. This added cost may be offset by
prevention or delay of opportunistic infections and malignancies that
require expensive clinical management. For many people, access to
these new measures may depend on how the cost equation balances out.

              1  Freedberg KA et al. Journal of Acquired Deficiency
       Syndromes. May 1991; 4(5):521-31.

              2  Castellano AR, Nettleman MD. Journal of the American
       Medical Association. August 14, 1991; 266(6):820-4.

              3  Master RJ. Journal of Ambulatory Care Management. Jan
       1996; 19(1):38-45.

              4  Bennett C et al. Journal of Acquired Deficiency
       Syndromes. Jan 1992; 5(1):1-6.

              5  Kitahata MM et al. New England Journal of Medicine.
       Mar 14, 1996; 334(11):701-6.

              6  Bennett C et al. Journal of the American Medical
       Association. May 26, 1989; 261(20):2975-9.

              7  Stone VE et al. Journal of the American Medical
       Association. Nov 18, 1992; 268(19):2655-61.

              8  Brosgart C et al., Journal of Acquired Immune
       Deficiency Syndromes and Human Retrovirology. May 1, 1996;
       12(1):56-62.

              9  Horner RD et al. American Journal of Respiratory
       Critical Care Medicine. Nov 1995; 152(5 Pt 1):1435-42.

       *************************************
       Managed Care and the Patient with HIV
       by Gabriel Torres, M.D.

       Managed care plans reimburse providers using a method called
capitation. Capitation pays providers on a fixed "fee-per- head" (per
capita) basis regardless of the types and amounts of services provided
to any given individual. This directly contrasts with the traditional
"fee for service" system in which providers are paid for each service
delivered. Capitation means doctors get the same amount of money for a
person they never see as for a very sick person for whom they provide
many services.

       The goal of managed care is to contain costs by coordinating
care through a "gatekeeper," a general practitioner who decides on all
referrals for diagnostic services, specialists, emergency care and
hospitalizations. Gatekeepers often receive incentives from the plans
for minimally serving patients; thus they minimize the number and
types of referrals they make. Many plans have gatekeepers without
appropriate HIV expertise but nonetheless refrain from referring
patients to HIV or infectious disease specialists offering
state-of-the art HIV care.

       Capitation also provides incentives for early detection and
preventive care to avoid higher costs for serious illness, but managed
care plans often lack adequate outreach and culturally appropriate
health education and HIV prevention services. In addition, many plans
limit their drug formularies, nutritional services or range of
therapies offered to include only the least costly option. Such
restrictions may pose problems for HIV-positive patients, who may not
receive the best treatment for their particular condition or stage of
illness.

       There are various sorts of managed care organizations,
including two types of health maintenance organizations (HMOs): the
traditional staff or group model and the independent practice
association (IPA). The staff or group model HMO employs salaried
doctors serving only plan members. IPAs are HMOs that contract with
independent doctors and hospitals to provide care for their enrollees
according to treatment protocols, per-case fees and review and
approval rules set by the plan. In both cases, care is prepaid and
members are covered only when using HMO-designated providers and
hospitals.

       Preferred provider organizations (PPOs) offer enrollees a
network of "preferred" providers who deliver care according to set fee
schedules. The managed care company may review individual providers'
treatment decisions, but PPOs do not control decision making as
closely as HMOs. They reimburse providers according to negotiated
rates by the service rather than through captitated payments. PPO
members may choose out- of-plan physicians but will be forced to pay
higher out-of- pocket costs for doing so.

       Employers more and more are choosing managed care plans to cut
costs even though such plans have been reluctant to cover "high risk"
groups such as people with HIV. HIV-positive beneficiaries should
educate themselves on the services provided by each plan. Some
features that are left out may be important in managing HIV infection,
including mental health and substance abuse coverage. It is also
advisable to ascertain which medications, nutritional supports and
alternative treatments are in the plan's formulary, as some therapies
may have been "carved out" from the program, and to determine the HIV
expertise of the network or HMO physicians. A plan's complaint and
grievance procedures also are important should needed services be
denied.

       Patients insured under the Medicaid or Medicare programs also
are experiencing a growing shift toward mandatory managed care plans,
although many state Medicaid programs have little experience providing
HIV care under this new type of system. Small pilot programs have been
initiated in California at the AIDS Health Care Foundation and in
Baltimore at the Johns Hopkins University. These trial programs have
assumed full responsibility for managing of HIV-positive patients
insured under Medicaid.

       In New York State, a planning process has begun to develop
Special Needs Plans (SNPs), under the auspices of the New York State
AIDS Institute. The SNPs would coordinate HIV care through regional
networks of providers who work in unison and share the risk. These
networks will ensure that all needed services, including
hospitalization, outpatient care, substance abuse treatment, home
care, emergency care, hospice care, case management, clinical trials
and nutritional services, come under the umbrella of a lead or group
of lead agencies who shoulder the financial risk. Pilot SNPs
implemented next year are expected to have safeguards to avoid the
pitfalls found in traditional HMOs.

       -----------------------------
       Physician Training Threatened

       The results of the Kitahata study imply that the continuing
training of physicians devoted to HIV care is crucial to their optimal
management of patients. Recent Congressional threats to the funding of
the Education and Training Centers (ETCs), the federal program to
train medical professionals in HIV care, may affect the ability of
many providers to receive state-of-the-art medical information. ETC
training can improve practice patterns and result in better health
care outcomes for AIDS patients. On-going advocacy in Congress is
needed to continue to support funding for the ETCs as a vehicle for
keeping physicians current on HIV treatment.

       *************************************************
       Post-Exposure Prophylaxis for Health Care Workers
       by Dave Gilden

       The U.S. Public Health Service has issued some very tentative
recommendations on using antiviral agents as "post-exposure
prophylaxis" (PEP) to prevent HIV infection in health care workers
exposed to the virus on the job. (See the Morbidity and Mortality
Weekly Report (MMWR), June 7, 1996, pages 468- 72). The agency first
classified HIV exposures by levels of risk and then examined the value
of using the various available medications at the different risk
levels. In deciding which drugs are appropriate, the PHS follow a
logic remarkably similar to that invoked by the doctors in our survey
when deciding on therapy for established HIV infection.

       Level of risk was determined by two factors: the type of
exposure and type of HIV-infected source material. The highest risk
exposure concerned occasions when the worker's skin was punctured
("percutaneous" exposure, by a contaminated needle, say). The second
highest risk was from mucous membrane exposure (for example, the mouth
or eyes), and the lowest risk was when HIV containing material
splashed on the skin.

       The most risky source material was blood from an HIV-positive
person, particularly if larger volumes of blood were involved or if
the source person was experiencing either late-stage AIDS or initial
HIV infection (blood from such people presumably has high HIV levels).
Lower risk sources include other potentially infectious body fluids
(such as semen, vaginal secretions and internal fluids, including
amniotic fluid) while the source least likely to spread HIV was such
fluids as urine and saliva. The highest risk scenario -- percutaneous
exposure to HIV-tainted blood -- has an average 0.3 percent risk of
HIV transmission.

       The choice of preventive agent was first of all AZT, because
this is the only drug for which there is any relevant data at all. One
retrospective study indicated that it reduced the risk of occupational
HIV transmission by 79 percent (see the MMWR, Dec. 22, 1995, pages
929-33). Then 3TC was added to the mix because trials in people with
established HIV found that the AZT/3TC combination suppressed HIV more
than AZT alone. Finally, the protease inhibitor indinavir (Crixivan)
was considered. Indinavir was favored over both saquinavir and
ritonavir because of the former's weak anti-HIV activity and the
latter's greater side effects and interactions with other drugs.

       But even indinavir was thought to have too many toxicities to
be administered except in the highest risk situations or in cases in
which AZT-resistant strains are likely. (Non- nucleoside reverse
transcriptase inhibitors like nevirapine -- see page 25 -- were not
considered at all. Nevirapine's propensity for causing skin rashes
does pose problems for its use in this setting, though.) For moderate
risk incidents, AZT/3TC should be "offered" -- rather than
"recommended" -- to the individual. Indinavir is regarded as probably
unjustified in these situations. For accidents carrying the least risk
of transmission, nothing should be done.

       PEP should commence within hours of HIV exposure. It will not
reduce the chances of HIV transmission if initiated more than a day
after exposure. Even if started late, though, PEP's capacity to reduce
viral loads during primary HIV infection might improve an individual's
long-term prognosis. In all cases, the PEP doses recommended are the
same as for treating established HIV. The length of time treatment
should be administered is unknown, but the PHS considers four weeks a
safe bet for preventing HIV.

       ***********************
       Viral Load Comes of Age
       by Theo Smart

       On June 3, the Food and Drug Administration (FDA) granted Roche
Molecular Systems license to market the Amplicor HIV-1 Monitor Test
(this company's HIV viral load or viral burden assay). Virtually
simultaneously, guidelines on how to use the viral load tests in
clinical practice, developed by a panel sponsored by the International
AIDS Society (IAS), were published in the journal Nature Medicine.1
The two events indicated that viral load -- the quantity of free virus
in plasma (fluid portion of blood) as measured by the concentration of
HIV RNA (genetic material) -- is now widely accepted by the medical
establishment as a marker of disease status. The IAS consensus
statement and the FDA approval together should increase the odds that
insurance companies, Medicaid and other third party reimbursers now
will pay for the test. When and how frequently people will be able to
receive reimbursement for viral load testing is unclear -- there was
little resemblance between the FDA and IAS views of how the test
should be used, and it remains to be seen which perspective will have
greater influence.

       According to its FDA-approved labeling, the Roche viral load
test can be used to predict the risk of disease progression in people
with HIV. The FDA also allowed mention on the label that the test has
been used as an aid in assessing the activity of antiretroviral
therapy, and in fact, that changes in viral load as measured by the
test contributed to the approval of 3TC and the protease inhibitors.
But the agency shied clear of endorsing the use of the test for
patient monitoring by insisting on the following caveat: "the clinical
significance of changes in HIV RNA measurements has not been fully
established although several large studies that will more fully
determine the role of comparative HIV RNA measurements in patient
management are now in progress."

       In contrast to the FDA, the IAS panel of experts believes that
there are enough available data to use the test not only to determine
the risk of disease progression, but to decide when to initiate
therapy, whether a new treatment is having an effect and when to
switch treatments because the current treatment is failing. Both the
FDA and the IAS recommend that the viral load tests should be used in
conjunction with other surrogate markers, in particular CD4 cell
counts, which, the IAS panel said, remain, "the best predictor for the
risk of developing an AIDS-related complication." High viral loads may
predict rapid progression (see below) but it is the loss of CD4 cells
that puts one in imminent danger of contracting PCP or another
opportunistic infection.

       One Virus, Three Ways to Count It

       One of the FDA Blood Products Advisory Committee's chief
stumbling blocks when reviewing Roche's application last March (see
page twelve of the March Treatment Issues), was that many of the data
supporting the use of viral load were generated using different assays
(and blood samples processed several different ways).

       The three available tests do indeed work differently:

       * In Roche's PCR assay, plasma containing HIV RNA is exposed to
         an enzyme that converts the RNA into DNA. Repeated polymerase
         chain reactions (PCR) clone millions of copies of the DNA
         particles, which bind to primers (molecules designed to form
         a strong bond with the targeted genetic material) on a plate.
         The plates are then washed with a solution containing colored
         "tags" that stick to the DNA and are subsequently counted by
         a machine. The test measures from 400 copies to 800,000
         copies of HIV RNA per milliliter of blood plasma.

       * Chiron's "bDNA" test, in contrast, first captures the target
         HIV RNA with primers on a plate. The plate is washed with a
         solution containing "branched" DNA molecules (the bDNA),
         which bind to the HIV RNA. There is no cloning stage, rather
         the signal from the bound bDNA is amplified. Each bDNA
         molecule has multiple sites (the branches) for an alkaline
         phosphatase label capable of generating light in the presence
         of another reagent. The light emitted by the bDNA molecules
         is counted by a machine. The second generation bDNA assay can
         detect HIV RNA or DNA or other genetic targets within a range
         of 500 to 1,600,000 copies/ml.

       * Lastly, Organon Tecknika's NASBA test (Nucleic Acid
         Sequence-Based Amplification) is similar to the Roche PCR
         assay and can detect between 400 and 5,000,000 copies of HIV
         RNA. In contrast to the other assays, heparin, an
         anticoagulant commonly added to blood specimens when
         extracting plasma, can be used in the initial processing of
         the blood sample before freezing. (Heparin added to samples
         tested with Roche's or Chiron's assay yield RNA counts around
         a third lower than they would if another anticoagulant had
         been used.)

       The FDA was considering only the Roche viral load assay this
spring, with Chiron's version now undergoing separate review. The IAS
panel recommendations apply to all three viral load tests regardless
of FDA status. While the tests are not standardized with each other, a
number of studies have shown that they tally up very similar viral
loads from the same plasma sample. Though the FDA's Blood Products
Advisory Committee hesitated to extrapolate data generated by the bDNA
or NASBA test to use of the Roche test, the IAS panel treated them as
equivalent. "The IAS guidelines are guesswork by a bunch of people
working with incomplete data, while the FDA was being more cautious,"
stated Robert Combs, M.D., a member of the IAS panel.

       By necessity, the IAS group considered together data produced
by all three tests. Yet there are slight variations between these
tests, and, for reasons of consistency, the panel advised that people
continue with the assay used to establish their initial value.

       Vaccinations (against the flu, hepatitis, tetanus and
pneumococcus) have been shown to cause a significant rise in viral
load that can persist for weeks after the immunization. Intercurrent
herpes outbreaks and opportunistic infections can boost viral loads
even more. The IAS panel recommends that viral load should not be
measured until one month after immunizations or acute illnesses, but
some studies suggest that vaccination induced increases in viral load
can persist for a longer period.

       Each company's tests are subject to a certain amount of
technical variability which, according to one study, may increase
substantially for measurements at the lower limit of detection (see
Treatment Issues, September 1995, pages 12- 14). There also may be a
degree of biologic variability unrelated to major infections or
vaccinations. Together, these variations seldom exceed 0.5 log (a
three-fold difference). To be on the safe side, Dr. Coombs, who is one
of the leading experts on viral load, has said, "You always need two
baselines [at least one confirmatory test] for making clinical
decisions."

       Prognosis

       The FDA and the IAS panel agreed that data from several cohorts
show viral load to be a good prognostic indicator. Treatment Issues
has covered this application of viral load extensively in the past
(see November, 1994, pages 4-6, 10- 11; December 1995, pages 1, 3-4;
February 1996, pages 1, 12- 16) In summary, the NIH, the Aaron Diamond
Institute, researchers studying disease course in the MACS cohort and
others have found that viral load several months after seroconversion,
and at any timepoint thereafter, can be used to determine whether the
individual will have a rapid, moderate or slow rate of disease
progression.

       There is a range of opinion on what precise figures to use for
predicting disease outcome. The FDA cited data from trials ACTG 116A
and 116B/117 (AZT vs. ddI studies), where the frequency of disease
progression within five years exceeded 60 percent in patients with
viral loads over 250,000 copies/ml. Progression was rare in those with
fewer than 11,000 copies/ml unless they also had very low CD4 cells
counts. This observation underscores the need to consider viral load
in conjunction with CD4 count. The disadvantage of the two ACTG trials
is they say little about the use of viral load for prognosis beyond
five years.

       The IAS guidelines also refer to recently published data
(using the bDNA assay) from 180 patients from the MACS cohort
with a follow-up period of up to 11.2 years. In his analysis,
John Mellors, M.D., determined that time to progression
within ten years in patients with more than 500 CD4 cells was
greater than 70 percent if their viral load was above 10,200
copies/ml.2 But Dr. Mellors retrospectively tested frozen
samples of heparinized blood. As noted above, heparinization
reduces measurable viral load by more than one third, and the
effect of long-term storage on further diminishing observed
viral load is unclear.

       Monitoring the Effect of Treatment

       Pivotal studies testing AZT/3TC, ritonavir, and indinavir and
NIH-sponsored studies ACTG 229 (testing saquinavir/ddC,
saquinavir/AZT, and all three together), ACTG 175 (AZT, ddI, AZT/ddI
and AZT/ddC), ACTG 116A, 116B/117 and VA 298 (early versus deferred
AZT) all found that viral load tests indicate when a drug is having an
antiviral effect. Even when the relatively impotent AZT is used, there
is a very rapid drop in viral load within the first several days. This
has been seen with every approved antiviral tested. Furthermore,
rebounds in viral load back to baseline levels are correlated with
loss of CD4 cells and clinical deterioration in a number of studies.
Although mentioned in the Roche test's labeling, it is hard to
understand why the FDA could not explicitly approve the use of the
test to demonstrate whether a new drug is working. The proposition
that antiretroviral therapies could have their effect by any mechanism
other than anti-HIV activity seems straight out of Lewis Carroll.

       If an antiretroviral drug does not reduce the level of HIV, why
take it? The FDA has implied that it does not really intend to
constrain frequent monitoring of viral load while on therapy. In the
FDA's internal briefing paper ("Talk Paper") on the Roche test, the
agency employs a broad definition of prognosis, noting that in ACTG
116B/117, a five-fold increase in viral load eight weeks after
beginning therapy was "prognostic of progression." If this ACTG
finding comes under the "prognosis" rubric, one might then be
justified in checking viral load every other month while on therapy to
make certain that it has not gone up.

       To the FDA's credit, treatment should improve one's physical
condition, not merely ameliorate a laboratory marker like viral load.
Although therapeutically induced reductions in viral load are
generally associated with increases in CD4 cell counts and, in some
studies, with a reduction in opportunistic conditions and death, the
data do not show that the greatest reductions in viral load
consistently produce the greatest physical or CD4 cell improvements.
For example, in ACTG 229, AZT/ddC effected the largest reduction of
viral load, but AZT/saquinavir produced a better rise in CD4 cell
counts. One factor could be the toxicity of the nucleoside analog ddC
compared to the protease inhibitor saquinavir -- one-third of the
volunteers on AZT/ddC had reduced CD4 counts even as their viral load
went down, compared to one-tenth of those in the AZT/saquinavir arm.
Dr. Coombs commented, "There might be other ways a protease inhibitor
improves CD4 count. Viral load didn't explain all the treatment effect
of the therapy."

       The rate of CD4 decline after a rebound in viral load also
appears related to the particular drugs being administered and not
merely to the increase in viral load itself. Preservation of CD4 cell
count gains have been reported in protease inhibitor studies even as
viral load has returned to baseline.

       In ACTG 175, the AZT/ddI and AZT/ddC arms reduced viral burden
more than the ddI arm, but the volunteers on ddI alone did at least as
well physically as those on the more potent combinations. At the
advisory committee meeting in March, representatives of the FDA noted
that such discrepancies made it difficult to establish algorithms to
aid physicians employing viral load to manage individual patients.
Such algorithms should be established by a number of ongoing or
planned studies that are designed to show, regardless of the therapy
used, that it is the reduction in viral load that slows disease
progression. But it is unlikely that equally potent regimens will
always have the same clinical effect since their differing toxicity
can impair responses.

       The guidelines from IAS panel (which do not mention many of the
conflicting data) recommend a general algorithm based nearly as much
upon theory as clinical data. The IAS panel believes that the goal of
therapy should be to reduce viral load levels to below the limit of
detection, or at least below 5,000 copies/ml. This desirable goal may
not be achievable in all patients. There is a danger that while
attempting to reach the 5,000 copy level, physicians will rapidly
shift through their entire therapeutic arsenal and create HIV
resistant to all available agents. Less dramatic reductions in viral
burden may stabilize a patient and stretch out the available therapies
so that they can be relied on when symptoms reflecting serious immune
deficiency appear. But there are no data at present to support either
the "hard and early" or the "soft and early" approach.

       The odds are that there is less of a chance for HIV to become
resistant to a drug when there is less of it replicating. Even
reducing viral load to undetectable levels may not be enough to
prevent eventual treatment failure, though. At the lower limit of
detection for the present viral load tests (around 500 HIV RNA
copies/ml), the virus may still be replicating in the blood, not to
mention viral reservoirs in the lymph nodes, where HIV concentrations
are much higher than in the blood, or in other organs including the
brain that drugs may not reach well. As long as the virus can
reproduce, there is a chance of drug resistance emerging.

       Initiating Therapy

       The most controversial aspect of the IAS viral load
recommendations is the use of the test to decide when to initiate
therapy. The panel concluded that practitioners should consider
treatment of individuals with viral loads greater than 5,000 to 10,000
copies/ml and definitely should treat those with viral loads in excess
of 30,000 to 50,000 because such individuals are supposed to be in
immediate danger of progression.

       The viral load ranges given indicate that the panel members
could not settle on a single absolute value that predicted
progression. But long-term prognosis is not the only factor to
consider when initiating treatment -- especially when there is a
potential to exhaust the available therapies and no clear evidence
that treating low levels of viral load early in the course of disease
has any effect on progression.

       There is a wide range of opinion among clinicians in our survey
regarding when to treat on the basis of viral load. Most respondents
still rely on a combination of symptoms and lab tests to initiate
treatment. They usually believe therapy should drive viral load down
below at least 10,000 copies/ml to achieve disease stability.

       Early intervention: David Ho, M.D., has written that the
establishment of a viral load set-point after the initial acute phase
of HIV infection provides a rationale for early intervention -- that
if you can lower the viral load during this critical period, you may
be able to effect a long-term delay in disease progression.3 One
six-month study of AZT in early patients with primary HIV infection
found that those who received treatment were less likely to develop
"soft" clinical endpoints, such as thrush, than those who received no
treatment.4 This is not resounding proof that treatment at this stage
of disease will have any lasting impact, but Dr. Ho is conducting
several studies with more potent antiviral regimens that should
provide clearer evidence of benefit.

       Other Factors in Treatment Decisions

       The FDA approval of the Roche viral load test is a watershed
event that will increase access to the tests in the U.S. But again,
viral load is not the only factor to take into consideration when
making treatment decisions. Some strains of the virus may be more
dangerous than others, and there are suggestions that this may be the
case for AZT-resistant strains. Conversely, if drug resistance one day
breeds a less pathogenic virus, it might be missed if people are
quickly shuffled to a different therapy just because their viral load
is once again on the rise.

       Dr. Coombs noted, "I think there is a host range in which
patients contain the virus. There is no evidence of clinical benefit
to driving the virus population very much lower." Everyone's immune
system is different, though. Some people may be able to sustain higher
viral loads without progressing or, alternatively, progress at much
lower viral loads.

       In ACTG 116A and 116B/117, disease progression continued in a
number of advanced patients with low viral loads and in patients whose
viral load was reduced to low levels in response to therapy. If viral
load and CD4 cell counts both decline on therapy, is that treatment
adequate? Clearly no. Finally, starting therapy in asymptomatic
patients with low viral loads who are not prepared to comply with
arduous therapy may be irresponsible or downright dangerous since
there is always the potential of exhausting therapeutic options by
breeding drug-resistant HIV. Given the dangers involved, initiating
and switching therapy are matters that must be carefully weighed using
all available pertinent information. Viral load is but one of a
constellation of tools to help people make those choices, but no
single surrogate marker can dictate all treatment decisions.

              1  Saag MS. et al. Nature Medicine. June 1996; 2(6):625-
       629.

              2  Mellors JW et al. Science. May 24, 1996; 272(5265):1167-
       1170.

              3  Ho D. The New England Journal of Medicine. August 17,
       1995; 333(7):450-1.

              4  Kinloch De Los S et al. The New England Journal of
       Medicine. August 17, 1995; 333(7):408-13.


       ******************************************
       Summary of the IAS Interim Recommendations

       Parameter                     Recommendations

       Plasma HIV RNA level          More than 5,000-10,000 copies/ml and
       that suggests initiation      a CD4 cell count/clinical status
       of treatment.                 suggestive of progression; >30,000-
                                     50,000 regardless of laboratory/
                                     clinical status.

       Target HIV RNA level after    Undetectable; <5,000 copies/ml
       initiation of treatment       is acceptable.

       Minimal decrease in HIV RNA	  >0.5 log decrease.
       indicative of antiviral
       activity

       Change in HIV RNA that	  Return to (or within 0.3 to 0.5 log
       suggests drug treatment       of) pretreatment value.
       failure

       Suggested frequency of        * At baseline: two measurements,
       HIV RNA measurement             2 to 4 weeks apart.

                                     * Every 3 to 4 months or in
                                       conjunction with CD4 counts.

	                              * Shorter intervals as critical
                                       decision points are neared.

                                     * 3 to 4 weeks after
                                       initiating/changing therapy.


       ------------------------------------
       Azithromycin Approved to Prevent MAC

       On June 17, the FDA approved marketing of the macrolide
antibiotic azithromycin (Zithromax) for preventing disseminated
Mycobacterium avium in persons with advanced HIV. Azithromycin's
advantage is that it need be taken only once weekly (two 600 mg
tablets), compared to daily administration of the other two MAC
prophylaxes, rifabutin and clarithromycin. In trials, azithromycin
reduced the rate of MAC by half in people with AIDS. Azithromycin's
main disadvantage is its common tendency to cause diarrhea and nausea.
See Treatment Issues, April 1996, pages 6-7, 10, for more information
on azithromycin and MAC prevention.


       *******************
       Nevirapine Surprise
       by Theo Smart

       On June 7, in a rare unanimous vote, the Food and Drug
Administration's (FDA) Antiviral Advisory Committee recommended that
the agency grant accelerated approval to Boehringer Ingleheim's
nevirapine (Viramune) for treating HIV-infected adults with evidence
of decline. The committee specified that nevirapine should be combined
with nucleoside analogs. On June 24, the FDA followed the committee's
recommendation, making nevirapine the ninth marketed anti- retroviral,
and the first non-nucleoside reverse transcriptase inhibitor. It will
be on sale in July.

       The ease with which approval occurred stands in stark contrast
to the drug's tortured development. Although potent, the drug has
attracted little interest from either physicians or people with HIV
because of the rapid emergence of nevirapine-resistant HIV in people
treated with the drug. Probably as a result, nevirapine showed only
marginal benefit when combined with AZT or AZT/ddI in trials involving
people with extensive prior AZT. Nevirapine also caused frequent skin
rash (17 percent of patients) which on a few occasions became
life-threatening.

       The case for nevirapine at the committee hearing was buoyed
unexpectedly by interim results from a new study following 151
treatment-naive patients who are receiving either AZT/ddI,
AZT/nevirapine or AZT/ddI/nevirapine (see table). The patient
population is much less advanced than in the earlier studies, with a
mean CD4 count of 376 cells and a mean viral load of 4.41 log (25,704
copies per milliliter of plasma).

       At the week 28 interim analysis, the AZT/ddI and
AZT/ddI/nevirapine arms outperformed the AZT/nevirapine arm in both
CD4 and viral load responses (see table). There was a trend toward
greater viral load and CD4 cell responses in the triple combination.
This combination also reduced viral load to undetectable levels (below
200 copies per ml) in a significantly larger percentage of patients
than in the other arms. Moreover, the CD4 cell response at one year
was sustained for the triple combination arm while CD4 cell counts had
begun to fall in the other two arms.

       A resistance analysis performed on four patients in the
three-drug arm at week 28 found resistance to nevirapine in two who
discontinued one of the nucleoside analogs for more than four weeks,
while isolates from two patients who were compliant to all three
medications remained sensitive to nevirapine. This suggests that the
antiviral effect of nevirapine may be sustained if used consistently
in a potent enough combination.

       Further support for nevirapine came from John Sullivan, M.D.,
of the University of Massachusetts, Worcester, who reported on the
activity of AZT/ddI/nevirapine in eight infants older than two months
and with baseline viral loads ranging between 40,000 and 1,600,000.
All except one child had sustained reductions in viral load and
normalization of CD4 cell counts. Viral load became undetectable in
two children with baseline viral loads close to 300,000 copies per ml.
By the 168th day, these two had begun testing negative on HIV antibody
tests. Such data indicate that the two infants may be eliminating the
HIV in their bodies. Although spontaneous remission has been
previously observed in infants, it is not an everyday occurrence.

       The data in naive patients were so much better than the earlier
experience with nevirapine that many advisory panel members wanted the
drug's labeling to stress that nevirapine should not be added to an
ongoing nucleoside analog regimen, but initiated in combination with
drugs to which the patient has not yet been exposed. Some suggested
that it should not be used with AZT alone except as a last resort,
given that combination's poor performance.

       The FDA approved combining nevirapine with nucleoside analogs
in adults but held off on protease inhibitors because
nevirapine can accelerate the CYP3A liver pathway that
metabolizes these drugs, especially saquinavir. Data released
at the advisory hearing, though, revealed that nevirapine
only lowered saquinavir's blood levels by seventeen percent
(not considered significant) in the first eleven patients in
a drug-interaction study. This bodes well for the potential
use of this drug in combination with indinavir, which has the
lowest rate of elimination by the liver. Complete data from
interaction studies with saquinavir and indinavir should be
available in the fall. Interaction data with ritonavir will
take longer because of difficulty coordinating the study with
Abbott Laboratories, ritonavir's manufacturer.

       -------------------------------------------------
       AZT/ddI/Nevirapine: Trial BI 1046 Interim Results

 Regimen      Week 28       Week 28       Week 28       One Year
              CD4 Cells -   Viral Load -  Viral Load -  CD4 Cells
       	change from   change from   percentage    change from
              baseline      baseline      undetectable  baseline

 AZT/Nev      +10-15 cells  -0.4 log              0%    -2 cells
 AZT/ddI      +70 cells     -1.3 log             40%    +26 cells
 AZT/ddI/Nev  +120 cells    -1.65 log            70%*   +140 cells*

       *statistically significant for the triple combination arm
        compared to the other two arms

       *********************************
       Throw Down Your Crutches and Walk
       by Gregg Gonslaves

       "Can HIV Be Eradicated From An Infected Individual?" was the
brash title of a conference held in Washington, D.C. on June 12 and
13. The new journal Antiviral Therapy and the University of Amsterdam
sponsored the event, while Glaxo- Wellcome, Bristol-Myers Squibb and
Gilead Sciences paid for it. Douglas Richman, M.D., of the University
of California San Diego and Joep Lange, M.D., from the University of
Amsterdam were the conference organizers. "The meeting was convened to
discuss the possibilities of the new therapies eliminating the virus
in infected people," Julio Montaner, M.D., of the University of
British Columbia, and a meeting participant, told The New York Times
(Saturday, June 15). As the conference began, though, Douglas Richman
warned that no one was claiming yet to have achieved that goal. Dr.
Richman did proclaim that with the suppression of viral replication in
some patients for up to two years, we had moved beyond the era of
palliative therapy for HIV infection.

       The symposium gathered together about 75 scientists from
academia and industry, with a high concentration of investigators
affiliated with the AIDS Clinical Trials Group. Many of the
researchers in attendance were people with a long history of
presumptuous optimism about the power of antiretroviral therapy. There
was scant representation of researchers and clinicians who have strong
concerns about defining optimal use of the new generation of anti-HIV
drugs, development of resistance and compliance with dosage schedules.

       At its worst, the proceedings took place in an idealized
world full of antiretroviral-naive patients who could reap
the benefits of a "hit early and hit hard" strategy employing
fresh triple combination regimens to which their HIV had not
had the opportunity to develop resistance. Such patients were
also assumed to all respond to therapy and stay on their
drugs through whatever side effects and drug-drug
interactions they encountered. At its best, the meeting
triggered a thoughtful discussion concerning exactly what is
happening in patients on the potent new combinations, of
exactly how far the new therapies can take us and how much
farther we have to go.

       A lot of the conference consisted of a recapitulation of the
results of studies presented in other forums, broad theoretical
musings or a recitation of studies planned by NIH-sponsored trial
networks or industry. But several key lectures marked considerable
advances in the viral suppression debate.

       The conference began with a presentation by Guiseppe Panteleo,
of the Laboratory of Immunoregulation at the National Institute of
Allergy and Infectious Diseases. Dr. Panteleo discussed the changes in
distribution of virus during the acute and chronic phases of HIV
infection and the implications for therapy. Using macaques acutely
infected with Simian Immunodeficiency Virus, Dr. Panteleo described
how SIV infiltrates the lymph nodes during the first week after
transmission but by the second week is either cleared by the immune
response or exhausts the initial supply of the activated CD4 cells it
targets. By the end of the first month of infection, most of the SIV
in the lymph nodes is composed of virions caught in the network of
follicular dendritic cells (FDCs), where they remain highly
concentrated and infectious.

       The story is largely the same in humans. There are many
individual cells expressing HIV in the lymph nodes during early
infection, but after three months the viral population there consists
mainly of FDC-associated virions. Dr. Panteleo then asked if
peripheral control of HIV infection by antiretroviral therapy in the
blood also indicated control of viral replication in the lymph nodes.
Answering his own question, Dr. Panteleo said that even with complete
suppression of virus in plasma there was still a large pool of virus
trapped in the lymph nodes. Additionally, the decline in blood-borne
free virus did not affect levels of proviral DNA (HIV genetic material
integrated into the cell's chromosomes), from which he surmised the
existence of a large pool of latently infected cells. Dr. Panteleo
thought that it might be possible to achieve full or almost full
clearance of virus in very early acute infection, but once the chronic
phase of the disease has begun, eliminating HIV is not possible.

       The next speaker at the meeting was John Coffin from the Tufts
University School of Medicine, one of the grand old men of
retrovirology. Building on work by David Ho, George Shaw and others,
Dr. Coffin's presentation focused on viral population dynamics. After
describing the steady-state achieved by HIV infection following
primary infection, Dr. Coffin reminded those present of the astounding
reproductive capacity of the virus: within a year HIV has gone through
approximately 180 generations; within five to six years, it has gone
through 1,000 generations. While the new potent therapies have stirred
up a lot of hope, the evolutionary potential of the virus may just
outrun our ability to control it. Indeed, in the HIV steady-state, Dr.
Coffin calculates that there are already 1,000 cells with viral
mutants resistant to any given triple combination regimen. Most of
these mutants may have impaired function, but if one of them has a
selective advantage over other HIV in the presence of therapy, it will
be the basis for creating a new multi-drug resistant viral population.

       Dr. Coffin outlined some of the additional barriers to
eradicating the virus from infected individuals. In what would become
one of the central themes of the meeting, Dr. Coffin expressed
concerns about the population of latently infected or long-lived
productively infected cells, which could easily reseed the body with
HIV should therapy wipe out the active virus-producing cells and then
be discontinued. Probably the most remarkable presentation of the
meeting was by Alan Perelson of the Los Alamos National Laboratory.
Using data from a triple combination study of AZT/3TC and Agouron
Pharmaceutical's protease inhibitor nelfinavir, Dr. Perelson has
developed a complex mathematical model of two-phased viral decline
under antiretroviral therapy. In the first phase, after initiation of
three-drug therapy, there is a one- to two- log (90 to 99 percent)
reduction in virus, which represents the clearance of activated
HIV-producing CD4 T- cells and free virus. The second phase is much
more drawn out (ten- to twenty-fold slower decay) and represents the
clearance of either latently infected cells, in which HIV is not
reproducing, or long-lived infected cells chronically emitting a low
stream of new HIV (these latter cells probably are macrophages).

       Dr. Perelson tried fitting the patient data to a mathematical
model based on either latently infected or long-lived productively
infected cells. He concluded that viral production by long-lived
HIV-producing cells infected before initiation of therapy better
explained the second phase of viral decline. Dr. Perelson then
calculated the length of treatment required to eradicate HIV from
long-lived infected cells. For patients in the AZT/3TC/nelfinavir
study, the clearance of long-lived cells would take anywhere from a
few months to approximately five years. Barring the appearance of drug
resistance in the trial participants, the model brazenly implied that
something close to eradication will be achieved after long-lived cells
are cleared.

       In one of the meeting's last lectures, Anthony Kelleher, M.D.,
from Center for Immunology at St. Vincent's Hospital in Syndey,
Australia, discussed whether or not even the most suppressive
antiretroviral therapy can rebuild immune function. Dr. Kelleher has
observed that protease inhibitor therapy increases CD4 and CD8 T-cell
numbers and restores immune cells' proliferative responses to various
mitogens and recall antigens. But it cannot mend the holes in immune
system response that open up as entire cell subsets disappear.
According to Dr. Kelleher, the increase in CD4 and CD8 T-cell numbers
during protease inhibitor therapy represents a peripheral expansion of
pre-existing memory T- cells with no generation of the new nave
T-cells needed to fight infections to which an individual has no
previous exposure. Based on these findings, Dr. Kelleher recommended
early and potent antiretroviral therapy in order to preserve the
diversity of the immune response.

       He also posed a warning to individuals with symptomatic disease
or very low T-cell counts who have seen their CD4 counts bound upward
on the new triple combination therapies. Any gaps in these people's
immune repertoire are likely to remain despite the higher CD4 count,
and withdrawal of prophylactic therapy for opportunistic infections is
not a good idea.

       The use of the new protease-containing triple combination
regimens is in its infancy. Only time will tell if the dramatic
reductions in viral load are buying people with HIV/AIDS simply a few
months or years or are turning HIV disease into a chronic, manageable
illness. "Can HIV Be Eradicated From An Infected Individual?" Maybe
yes and maybe no. That was the answer from the two-day gathering.

       **************************
       Be Kind to Your Chemokines
       by Dave Gilden

       The rapidly increasing understanding of the way in which HIV
gains access to new cells may lead to new strategies for stopping the
virus. Last month saw the announcement of "fusin," a second receptor
alongside the long-known CD4 receptor to which HIV needs to bind when
infecting cells (see Treatment Issues, May 1996, pages 1-2). Fusin
turns out to be useful only to a restricted variety of HIV strains,
notably lab strains and the strains frequently appearing late in
disease, which are T-cell tropic (they especially bind to and infect
CD4 lymphocytes in test tube cultures). In late June (at Treatment
Issues' press time), no less than five papers appeared in three
journals (the June 20 edition of Nature and the June 28 editions of
Science and Cell) claiming that a related receptor is the co-receptor
for the so-called macrophage-tropic HIV strains present earlier in the
disease process. This new receptor is designated chemokine receptor 5,
or CC-CKR-5.

       CC-CKR-5 normally binds to a class of intercellular messenger
molecules called "b-chemokines." The major known function of
chemokines is to attract immune cells to sites of infection, but
several, RANTES, MIP-1a and MIP-1b, also interfere with HIV
replication, according to recent discoveries made by Robert Gallo's
lab at the National Cancer Institute (see Treatment Issues, January
1996, pages 10-12). It turns out that CC-CKR-5 is a common receptor
for all three of these chemokines. In the experiments described by the
five articles, HIV was able to infect cells bearing both the CD4 and
CC-CKR-5 receptors, but not just CD4. That infectability was
practically eliminated in the joint presence of RANTES and the two
MIPs. When only one of these chemokines was present, infectability was
greatly reduced but not eliminated.

       The simplest explanation seems to be that by binding to CC-
CKR-5, the chemokines block HIV from joining with cell membranes and
entering the cells. One research group, from the Aaron Diamond AIDS
Research Center in New York, also looked at two "exposed but
uninfected" individuals, i.e., persons who have remained HIV-negative
despite a lifestyle that almost certainly exposed them to the virus.
Lo and behold, CD4 cells from these two individuals were not only were
exceptionally resistant to intrusion by HIV. They also produced
abnormally high amounts of the RANTES and MIP-1a and b. The
researchers have not yet determined whether this overexpression of
chemokines or some genetic defect in CC- CKR-5 is at the root of the
cells' resistance to HIV.

       Should the chemokines prove to be the key to protecting cells
from HIV, it is probably not a good idea to just inject large
quantities of these molecules into patients' bloodstreams. High levels
of the b-chemokines are associated with several autoimmune diseases.
Still, it should be possible to develop benign drugs that bind to
either part of CC-CKR-5 or, more likely, to the part of HIV's gp120
envelope protein that attaches itself to this receptor. As Treatment
Issues reported last month when discussing fusin, such drugs might
already exist among the various known compounds (some already under
development as drugs) that block HIV's entry into new cells.

       But there are limits to such an anti-CC-CKR-5 binding strategy:
the cells that the Aaron Diamond group isolated from the two exposed
but uninfected persons were susceptible to infection by HIV that
depends on fusin rather than CC-CKR- 5. More generally in the
experiments, the specific characteristics of the envelope protein on
different HIV strains affected the strains' sensitivity to
b-chemokines, and characteristics of different cell types also seemed
to have a major influence. Researchers at Harvard are proposing two
additional chemokine receptors, CKR-3 and CKR-2b, as alternatives to
CC-CKR-5 or fusin in certain cells. Whether or not this is confirmed,
drugs that might help some people might not help others or might only
protect some types of cells.

       *********************************
       The Correct Amplicor Phone Number

       Last month's Treatment Issues contained an article describing
Roche Diagnostic System's 60-day introductory program that will
provide two free baseline Amplicor viral load tests to anyone who
applies. That program commenced June 17. Note, though, that due to a
last minute change by Roche's long distance telephone company, the
toll-fee phone number printed by Treatment Issues is wrong. The
correct toll-free number is 1-888 TEST PCR. (Do not forget to dial the
"1" first so as to access long-distance service. Several Manhattan
residents who forgot this have complained that they ended up with an
A&P supermarket and not Roche!)

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