      FOCUS: A Guide to AIDS Research and Counseling
      Volume 9, Number 11 - October 1994
      ----------------------------------------------

      Editorial: Beyond Ignorance
      Robert Marks, Editor

      The gloom and doom of the "post-Berlin syndrome," as
Ronald Baker describes it in this issue of FOCUS, has been a
powerful disincentive to pursue HIV-related treatment. It was,
of course, preceded in earlier years by highs and lows following
each international AIDS conference as expectations were either
fulfilled or disappointed. 

      The highs of recent years--apparent progress in vaccine
development, positive reports of zidovudine and its cousins
extending life, and the promise of everything from the protease
inhibitors to compound Q--and the desperate desire for cure and
closure after all this time made the disappointments of Berlin
even more devastating. 

      As prevention researcher Tom Coates, who writes about
psychosocial findings at Yokohama in next month's issue of
FOCUS, said to me, breakthroughs cannot be timed for the AIDS
conferences. And, as many others have said throughout the years,
scientific breakthroughs of any sort are incremental, rarely
making compelling news for the tabloids or the talk shows. The
conferences provide a glorious stage for AIDS research and only
spectacular success or failure is dramatic enough for most
theater-goers. 

      Toward a Universal Theory

      Having said this, it is notable that this year's
conference in Yokohama demonstrated, more than anything else,
the extraordinary value of research that has been going on in
apparent silence for the past few years--so notable that we have
decided to devote both this issue and next month's issue to the
Yokohama conference. 

      Some of this data is applicable immediately; much of it
represents increments toward truly effective treatment. Little
of it will save many lives today, but it seems that all of it
will save lives tomorrow. Baker speaks eloquently of this
progress, outlining an emerging treatment paradigm that is
logically consistent, intellectually compelling, and most
important of all theoretically comprehensive. I am no authority
on HIV-related treatment, but this is the most clear and
compelling example I've seen of the connections between basic
science--the natural history of HIV infection--and HIV-related
diagnosis and treatment. 

      The second article in this issue, by Charles van der
Horst, provides a brief overview of the most important concepts
that clinicians can use to get people with HIV disease--
discouraged by the predictions of recent years--back into
treatment. Both of these articles provide mental health
practitioners with a powerful tool to use in therapy: hope. For
the first time--it seems to me--our knowledge of HIV disease and
HIV-related treatment approaches our ignorance. 


      Prospects for a New Strategy for HIV Treatment 
      Ronald Baker, PhD

      Findings from the 1994 International Conference on AIDS in
Yokohama have effectively counteracted what has been labeled the
"post-Berlin syndrome," named for the pervasive mood of
gloom-and-doom that dominated the proceedings of the 1993
International Conference on AIDS.*  Among the highlights of the
conference included reports on advances in the use of
recombinant human growth hormone therapy to fight HIV-related
wasting (423B); zidovudine (ZDV; AZT) therapy to reduce the rate
of transmission from mother to fetus (PS11, SR2); and acyclovir
co-treatment with other anti-HIV drugs to increase survival time
among people with AIDS.[1] 

      But the Yokohama data have more profound implications,
reshaping notion of early treatment and highlighting an emerging
treatment strategy: Individualized Therapy. The essence of
"Individualized Therapy" is tailored care: designing anti-HIV
therapy for the individual patient based primarily on periodic
measurement of "viral load," coupled with the early initiation
of drug treatment while the immune system is relatively intact
and capable of a strong response. Within the next six months, as
access to new diagnostic technologies and more effective
antiviral regimens increases, a significantly large number of
community physicians will be able to offer at least some
elements of Individualized Therapy to their patients. 

      The Yokohama conference highlighted four ongoing
developments that are particularly important in shaping the
future of Individualized Therapy: continuing progress in
clarifying HIV pathogenesis; broader access agents with
different mechanisms of action, specifically the protease
inhibitor and non-nucleoside reverse transcriptase inhibitor
drugs; wider access to HIV RNA testing; and more widespread use
of three- and four-drug combination therapy. In order to fully
appreciate the change, it is useful to review the Yokohama
presentations on these topics. 

      Viral Load

      HIV infects a huge reservoir of T-helper cells in the
lymph glands. Using the polymerase chain reaction (PCR) to
detect viral RNA, Ashley Haase, of the University of Minnesota,
showed for the first time that in the early stages of HIV
infection, about 25 percent of all T-helper cells are latently
infected (PS16). Only 1 percent of HIV-infected lymphocytes
contains virus that is actively replicating, but continuing HIV
gene expression in the reservoir of latently infected cells
creates a cascade of viral replication and an increased viral
load when latent virus becomes activated. This leads to a slow
but relentless depletion of T-helper cells and could account for
HIV disease progression. 

      In real numbers this translates to 100 billion latently
infected T-helper cells in the lymphoid tissue and one billion
actively infected cells that contribute to viral load in the
blood stream. The total HIV burden, comprised of latently and
actively infected cells in an infected individual, is enormous
and is rapidly established in the earliest stage of infection. 

      While scientists do not yet have a clear understanding
about how HIV causes disease, this finding demonstrates
continuing progress in this area and clarifies three issues. It
explains how an apparently small concentration of HIV in the T-
helper cells in the bloodstream accounts for the gradual
collapse of the immune system. More importantly for treatment,
it confirms the significance of viral load--the amount of both
latent and active virus--in determining the extent and
progression of HIV infection. Finally, it suggests that that
viral load is high early in infection and, therefore, early
treatment with three or four effective antiviral drugs may be
crucial. 

      New York researcher David Ho's intensive study of 10
long-term non-progressors complements Haase's findings: low
viral burden correlates with non-progression (PS10). Ho, of the
Aaron Diamond AIDS Research Center, found that non-progressors--
people who have been healthy and had normal T-helper cell counts
for 12 to 16 years-have extremely low levels of HIV. This
response was not due to an inherent resistance to HIV among
these subjects' T-helper cells, but instead to a potent
T-suppressor cell and neutralizing antibody response. 

      Measuring HIV RNA

      PCR and branched chain DNA (bDNA) tests are effective in
measuring plasma HIV RNA, and thus are useful for estimating
viral load among HIV-infected individuals, and will lead to
better assessment of treatment in patients and faster clinical
trials of experimental drugs (253B, 254B). The new tests measure
the RNA of HIV, which indicates the number of free viral
particles and reflects how much viral replication is going on in
an infected individual. When tested in blood samples, the test
findings are expressed as the number of copies of HIV RNA in
each milliliter of blood plasma. Further studies are necessary
to ensure reliability and accuracy of the tests, define their
range of day-to-day variation, standardize testing across assay,
and clarify the correlation of test results, level of tissue
viral load, and disease stage. 


      The most significant implication of this finding is that
since reducing viral load appears to correlate with clinical
benefit, PCR or bDNA test results may be able to serve as
surrogate markers for disease progression and indicators of drug
efficacy both in individuals and in clinical trials. Using viral
load in this way suggests that physicians and patients will be
able to observe the effects of a failing drug regimen before
patients experience significant T-helper cell loss and clinical
decline, which are relatively late results of viral replication.

      Eventually, these tests will be standardized and approved
by the U.S. Food and Drug Administration (FDA).* Using PCR or
bDNA tests, physicians will be able to determine whether a
patient's viral load is increasing, decreasing, or remaining
stable over time. With this critically important information in
hand, physicians will be able to "individualize" drug treatment
for each patient, making recommendations about continuing,
halting, changing, or adding drug treatment early, before 
patients experience T-helper cell loss. 

      By using HIV RNA testing in clinical trials to assess the
HIV load, researchers may be able to predict which drugs will
work best for a particular patient or subset of patients. Assays
of viral burden may also dramatically shorten the amount of time
necessary to test the effectiveness of experimental therapies.
Therapies with no effective anti-HIV activity could be quickly
identified and abandoned. By significantly decreasing the amount
of time required to evaluate these therapies, promising
treatments will be approved more rapidly and millions of dollars
in research costs may be saved. 

      Drug Development

      There is growing evidence that monotherapy with currently
approved antivirals--all nucleoside analogues like ZDV--cannot
effectively suppress viral activity in the lymph glands during
the earliest stages of HIV infection. While double combination
therapy--the use of two antivirals--is more effective than
monotherapy, reliance on two agents of the same class of drugs
is also unlikely to adequately suppress HIV replication for an
extended period of time due to the rapid mutation of the virus. 

      Three- or four-drug combination therapy holds the greatest
promise, and historically, three- or four-drug combinations have
been necessary for the effective treatment of certain chronic
diseases such as tuberculosis and various cancers. Recent
reports in the medical literature focus on promising treatment
combinations, most prominently nevirapine--a transcriptase
inhibitor-ZDV, and ddC; and saquinavir--a protease inhibitor--
ZDV, and zalcitabine (ddC), a combination that received
attention at the conference (058B). These findings are
particularly exciting because they mean that single agent drugs
to which HIV quickly develops resistance--for example,
nevirapine and the protease inhibitors saquinavir and L-524--
appear to be more effective when used in three- or four-drug
combination regimens . 

      There are currently four FDA-approved nucleoside
analogues: ZDV, ddC, didanosine (ddI), and stavudine (d4T); and
three drugs with anti-HIV activity that are FDA-approved for
other indications: alpha interferon, foscarnet, and ribavirin.
In addition, lamivudine (3TC)--another nucleoside analogue--is
available through the parallel track (expanded access) program.
In addition, protease inhibitors, non-nucleoside reverse
transcriptase inhibitors, and treatment vaccines are emerging
from Phase 11 studies in the coming months, raising the number
of potential three-drug combinations to several thousand. 

      It is imperative to perform research on the most promising
drug combinations and to implement a new, streamlined, HIV-
related drug research program. One such approach is already in
place. The Inter-Company Collaboration for AIDS Drug
Development, a consortium of 15 pharmaceutical companies, will
begin an unprecedented program in the fall of 1994 to test the
efficacy of various three-drug combinations. The collaborators
have designed a "Master Protocol" to quickly evaluate currently
feasible three-drug combinations and to allow for the addition
of new drugs as they become available. These protocols are
designed as pilot Phase 11 studies, but if results show a
clinical benefit, the drugs could be made widely available to
patients through the existing FDA accelerated approval and
parallel track systems. If a study shows negative results, then
that combination would be dropped from the options recommended
for patients. The first four triple combinations are: ZDV, ddC,
and saquinavir; ZDV, ddI, and nevirapine; ZDV, ddI, and 3TC; and
ZDV, ddC, and nevirapine. These combinations were selected
because they demonstrate in vitro evidence of synergistic
anti-HIV activity and no evidence of overlapping toxicities. It
is also important to note that the drugs that constitute these
promising combinations are available now, and could be approved
by FDA for marketing within a matter of months through the
accelerated approval program. 

      The FDA and Accelerated Approval

      The FDA will play a critical role on several levels in
determining how quickly Individualized Therapy becomes a reality
in HIV disease. First, it must collaborate with manufacturers to
ensure the timely design and implementation of studies to test
the reliability of the HIV RNA assays and the potential of these
assays to evaluate treatment regimens. More importantly, the FDA
must continue its policy of granting accelerated approval to
experimental AIDS therapies that show reasonable safety and
reasonable promise of benefit. 

      Recently, the agency considered proposals to make more
stringent requirements for accelerated approval, specifically
for the protease inhibitors. Some activists and researchers have
suggested that we need to apply a new strategy to AIDS drug
evaluation, using a larger number of subjects and more trial
arms. As of late September, it appears that the FDA will not
significantly change existing standards, but current regulations
continue to be controversial. 

      Raising the standard for accelerated approval would limit
access to promising new therapies and send a chilling message to
drug developers, large and small. The end result of a more
difficult, time-consuming, and expensive process might be a
retreat by these companies from AIDS drug development.

      Conclusion

      The current "cookbook" approach to HIV-related treatment
relies almost exclusively on T-helper cell counts and clinical
symptoms to guide treatment decisions. By using powerful new
tests that measure viral load to determine disease stage,
evaluate treatment regimens, and guide the timing and choice of
changing therapy, Individualized Therapy goes beyond this
template. Viral load will revolutionize HIV-related care by
providing earlier in the disease process more precise
information about the progression of HIV infection, and this
will lead to much more flexible and individualized treatment
regimens. This will also benefit patients with advanced AIDS,
who will be able to modify ineffective treatment without waiting
for later signs of failure. 

      Before Individualized Therapy can be widely used, however,
certain ongoing developments require completion: correlation of
PCR and bDNA assay measurements of viral load with clinical
outcome; development of standardized kits of these assays to
ensure consistency among laboratories; availability of new
agents-currently in the research pipeline--to use in three- or
four-drug combination; and maintenance of current standards for
accelerated approval of promising new AIDS drugs. Broader access
to HIV RNA testing and to promising new AIDS drugs, such as the
protease inhibitors, will allow for more effective combination
treatment regimens and result in better care for HIV-infected
individuals. 

      Author

      Ronald Baker, PhD is editor of the Bulletin of
      Experimental Treatments for AIDS (BETA), published
      quarterly by the San Francisco AIDS Foundation. A Personal
      
      **********

      Response to Therapeutic Nihilism 
      Charles van der Horst, MD

      Having taken care of hundreds of people with HIV infection
since 1981, I have grown somewhat philosophical. In Kafka's "The
Doctor", a country doctor visits a patient dying from some
mysterious illness. The doctor lays down beside the man who is 
then miraculously cured. But in response, the physician becomes
ill. Like the country doctor, at times I feel that the only
thing I have to offer my patients is a hug; unfortunately, it
does not result in miracles. At other times, I think that the
limitations of emotional support can lead to burnout similar to
the illness of Kafka's doctor. As caregivers and patients we
need to assess realistically HIV-related treatment and design a
hopeful and concrete plan of action that goes beyond
hand-holding. 

      The mood of caregivers and people living with HIV disease
has bounced from high to low. The 1986 Burroughs Wellcome phase
11 trial reported dramatic results for patients with T-helper
cell counts below 200: 19 deaths in the placebo arm versus only
one in the ZDV arm.[1]  The 1990 AIDS Clinical Trial Group's
(ACTG) 019 study found that ZDV decreased progression to AIDS by
50 percent among asymptomatic patients with T-helper cell counts
below 500.[2] In response, clinicians, researchers, and
activists directed efforts at lowering the price of ZDV,
screening more people for HIV antibody, and developing other
antiviral agents. 

      But ZDV proved to be no magic bullet. The 1993 Concorde
study,[3] the 1992 VA study,[4] and the extended follow-up of
019 showed benefit of ZDV in asymptomatic patients was limited
to one-and-a-half years to two years. New agents such as soluble
CD4, dextran sulfate, and tat inhibitors have proven ineffective
as well. Finally, studies of didanosine (ddI) and zalcitabine
(ddC) use in late-stage patients treated previously with ZDV
have been particularly disappointing. 

      The response of caregivers, patients, and the media to
these findings reflect the epidemic's emotional roller-coaster.
Based on little evidence and often misinterpreted clinical trial
results, people erupt into joy, despair, or fury. As a result of
this disappointing data, ZDV use is down dramatically. In the
western United States, in particular, there has been a decrease
in doctor visits among HIV-infected patients.[5] Many feel that
early intervention is "dead." While some people are using
non-traditional methods of health care, many have lost hope.
This therapeutic "nihilism" has led people not only to stop
taking antiviral drugs, but also to stop prophylactic
medications, postpone HIV antibody testing, and practice unsafe
sex. 

      These emotional responses are not fully justified by the
data, and we clinicians, perhaps suffering from burnout, must
resist sinking into a similar emotional maelstrom. Now, a full
11 years after HIV was discovered, we can make some definitive
and hopeful recommendations to our patients and their health
care providers. We need to be practical, stick to concrete
facts, and work with our patients to counter this fatalism. 

      Knowledge is Power

      It is important to recognize what a difficult disease this
is to study and that, as a result, there are no perfect studies.
There are also no good animal models, so researchers are forced
to test all theories on humans. Since the disease is a chronic
one with extremely variable impact on different patients, it is
simply not feasible to do the huge long-term trials necessary to
prove some of the current hypotheses. 

      To demand perfect studies in an imperfect world is
wrongheaded. Unfortunately, some act as if the findings of
various clinical trials are infallible and overstate them both
in throw-away pharmaceutical-company-sponsored publications and
in official government approved blurbs. To best serve our
patients, however, we should focus on what we know conclusively.

      1. We know that approximately 80 percent of HIV-infected
patients will experience a drop in T-helper cell counts of 80 to
100 per year from the time of infection. Ten percent will have
a more rapid decrease, and 10 percent will remain stable or
experience an increase.[6] 

      2. We know this is an infectious disease. Namely, there is
a large amount of viral RNA present in the bloodstream and in
the lymph nodes from the beginning of the infection until the
end. 

      3. We know that if you give a patient ZDV, didanosine
(ddI), the protease inhibitor saquinavir, or non-nucleoside
analogue drug--for example, nevirapine and delavirdine--you can
decrease the amount of virus in the bloodstream whether in the
plasma or in circulating lymphocytes. Certainly the most
dramatic evidence of an antiviral effect was seen in the
recently completed ACTG 076 study, where ZDV decreased
maternal-child transmission of HIV by two-thirds.[7] 

      4. We know that HIV can become resistant to antiviral
drugs. In some cases, this appears to have clinical
significance. 

      So where do these four facts lead? I want to be a
practical physician and maintain an open mind. Similar to
Kafka's country doctor, I try to put myself in the place of my
patients. What would I do? Although AIDS drugs like ZDV and ddI
are not as effective as penicillin, they do decrease viral
burden and that has to be a good thing. Being a practical
person, I realize that the T-helper cell counts of some
patients-the so-called "long-term survivors"-will not drop for
a prolonged period and that we should not treat these patients
with antivirals. Others do not tolerate these drugs or are
psychologically devastated by taking pills and visiting doctors
when they are well. For everyone else, however, antiviral
therapy is a viable alternative. 

      Responding to Patient Concerns
      
      It is important for caregivers to avoid media-inspired
self-flagellation: focus on the facts, not the hysteria. We must
be aware that burnout may be causing us to be pessimistic and
despairing, and that we may communicate these feelings to our
patients. 

      To respond to our patients' concerns, we should remind
them of our therapeutic successes: the person who started ZDV
and did well; the person who, despite having a low T-helper cell
count, has worked full-time for years. I think about George
McKoy, whose T-helper cell climbed from 320 in 1987 to above 500
today after treatment on ddI and ZDV. Above all, it is important
to tell our patients that it is all right for them to express
their doubts about treatment, to tell us when they get side
effects so that we can work with them, and to talk to us about
alternatives. Only with this kind of interchange can we make
primary care an attractive option. 

      References:

      2. Volberding PA, Lagakos SW, Koch MA, et al. Zidovudine
in asymptomatic human immune deficiency virus infection: A
controlled trial in persons with fewer than 500 CD4 cells. New
England Journal of Medicine. I 990; 3224):941-949. 

      3. Concorde Coordinating Committee. Concorde: MRC/ANRS
randomised doubleblind controlled trial of immediate and
deferred zidovudine in symptom-free HIV infection. Lancet. 1994;
343(8902): 871-880. 

      4. Hamilton JD, Hartigan PM, Simberkoff MS, et al. A
controlled trial of early versus late treatment with zidovudine
in symptomatic human immunodeficiency virus infections. New
England Journal of Medicine. 1992; 326(7):437-443. 

      5. Discussion at the Western AIDS Educational and Training
Center Faculty Development Conference, Monterey, California,
April 1994. 

      6. Kirby AJ, Phair JV, He YD, et al. Longterm survival
with HIV infection. Journal of Acquired Immune Deficiency
Syndromes. In press. 

      7. Boyer PJ, Dillon M, Navaie M, et al. Factors predictive
of maternal-fetal transmission of HIV-1: Preliminary analysis of
zidovudine given during pregnancy and/or delivery. Journal of
the American Medical Association. 1994; 271(24): 1925-1930. 

      Author


      Charles van der Horst, MD is Associate Professor of
      Medicine and Director of the AIDS Clinical Trials Unit at
      the University of North Carolina at Chapel Hill. 

      **************
      Recent Reports

      Recent Findings of ZDV Treatment

      Volberding PA, Lagakos SW, Grimes JM, et al. The duration
      of zidovudine benefit in persons with asymptomatic HIV
      infection: Prolonged evaluation of Protocol 019 of the
      AIDS Clinical Trials Group. Journal of the American
      Medical Association. 1994; 272(6): 437-442. (University of
      California San Francisco and Harvard School of Public
      Health.) 

      Vella S. Giuliano M, Dally LG, et al. Long-term follow-up
      of zidovudine therapy in asymptomatic HIV infection:
      Results of a multicenter cohort study. Journal of Acquired
      Immune Deficiency Syndromes. 1994; 7(1): 31-38. (Instituto
      Superiore di Sanita, Rome.) 

      Cooper DA, Gatell JM, Kroon S. et al. Zidovudine in
      persons with asymptomatic HIV infection and CD4+ cell
      counts greater than 400 per cubic millimeter. New England
      Journal of Medicine. 1993;329(5):297-303. (University of
      New South Wales, Hospital Clinic I Provincial de
      Barcelona, and Bispebjerg University Hospital,
      Copenhagen.) 

      Concorde Coordinating Committee. Concorde: MRC/ANRS
      randomised double-blind controlled trial of immediate and
      deferred zidovudine in symptom-free HIV infection. Lancet.
      1994; 343(8902):871-880. 

      Zidovudine (ZDV; AZT) has been alternately hailed as the
best science can offer and scorned as a cofactor in HIV
progression. Research published over the past year attempts to
clarify the role of ZDV mono-therapy, but scientists continue to
debate the implications of this data. 

      The AIDS Clinical Trials Group (ACTG) has performed the
longest-running studies of ZDV. Two recent publications-one
reporting on ACTG 019 and another on a European replication of
the ZDV treatment arm of 019-offer insights into ZDV use. 

      ACTG 019, the "grandfather" of ZDV monotherapy studies,
included 1,565 patients with T-helper cell counts of less than
500 at entry. The initial study had three treatment groups: one
receiving 500 milligrams of ZDV a day, one receiving 1,500
milligrams of ZDV a day, and one receiving placebo. A
year-and-a-half into the study-after an interim analysis
demonstrated decreased clinical progression in the ZDV treatment
group--researchers made ZDV available to the study's placebo
group. At that time, the higher dose ZDV arm was discontinued
because of increased toxicity without clinical benefit. 

      The follow-up analysis, which extended the results 4.5
years, confirmed the earlier benefit in terms of disease
progression, but found that this benefit lasted only 2.1 years
(Volberding et al.). Slowed progression was more pronounced
among participants with T-helper cell counts ranging from 300 to
500 at entry. There was no benefit in terms of survival rates,
which were the same for both treated and placebo groups. 

      A two-and-a-half year Italian study complements the 019
study (Vella et al.). Following the 019 entry criteria, 936
patients were treated with ZDV for a mean of 124 weeks. The mean
T-helper cell count at entry was 308. Since there was no placebo
arm, the investigators compared the rate of progression to AIDS
of treated participants in this study to the published rate of
progression in the placebo arm of 019. Even at 124 weeks, the
progression rate for those receiving ZDV was lower than the 019
placebo group at 55 weeks. The authors do not discuss deaths in
the study population. They conclude that the clinical benefit of
ZDV in asymptomatic individuals can be sustained for greater
than two years. 

      Two other studies focus on ZDV treatment at the early,
asymptomatic stage of disease. The European-Australian
Collaborative Group study (Cooper et al.) found ZDV treatment to
be beneficial in people with T-helper cell counts of 400 or
higher. The study randomly assigned 933 asymptomatic
HIV-infected people to a treatment group--in which participants
received 500 milligrams of ZDV twice daily--and to a placebo
group. The mean duration of treatment was 94 weeks. 

      Nineteen percent of those receiving ZDV experienced
disease progression as compared to 34 percent in the placebo
group. In the treatment group, progression to severe HIV disease
was reduced by half, and decline in T-helper cell counts to
below 350 was reduced 40 percent. Since the authors do analyze
death rates, it is presumed there were few deaths in the
population during the study period.

      The Concorde study-a collaboration of French and British
researchers-received a great deal of attention in the spring of
1993 when investigators published preliminary results. The study
has been engulfed in controversy, but the publication of more
complete results has helped clarify the issues (Concorde
Coordinating Committee). Investigators randomly assigned 1,749
asymptomatic individuals to a treatment group-receiving 250
milligrams of ZDV four times a day-and to a placebo group. There
was a total of 5,419 person-years of follow-up, or a median of
3.3 years, making Concorde the largest ZDV study. 

      Without "breaking the code," that is, letting participants
know who was in each group, researchers offered access to ZDV
when subjects progressed to AIDS-related complex (ARC) or AIDS.
In addition, in response to interim 019 results, researchers
offered all participants ZDV if they had T-helper cell counts
below 500. Despite this, the study maintained clear differences
between the groups: individuals in the treatment group spent 81
percent of the time on ZDV before progressing to ARC or AIDS
compared to only 16 percent of the placebo group. 

      Although there was a persistent benefit in T-helper cell
count results associated with ZDV use, this did not translate
into clinical benefit. Progression to symptomatic HIV disease
and survival did not differ significantly between the two
groups: 18 percent of patients in each group progressed to AIDS
or death. The authors conclude that these results do not
encourage the early use of ZDV in symptom-free, HIV-infected
adults. 

      So where do these studies leave the clinician and the
asymptomatic HIV-infected patient with "early" disease,
particularly since we know that there is viral activity at this
early stage? Clearly all the authors would agree that early ZDV
monotherapy does not make asymptomatic individuals feel better,
although the incidence of side effects seemed low in all the
studies. All the studies agree that there is no difference in
death rates between treated and untreated individuals. The
studies seem to suggest that there is a transient delay in
progression to clinical disease among those treated with ZDV.
This may persist as long as two years, but it wanes with time
and is undetectable beyond two years. Possibly the higher the T-
helper cell count--but still below 501--the more pronounced the
benefit. 

      The studies suggest that T-helper cell counts alone may
not be the most important parameter for deciding when to
initiate monotherapy. There may be subsets of individuals in
each of these study cohorts who did indeed benefit from ZDV and
may have had a prolonged benefit. Their existence could have
been obscured in the final analyses by the majority of
participants for whom ZDV was not indicated. 

      These studies point out the necessity of further work to
define other markers of disease--such as viral load--that may be
more important in the decision to initiate therapy, whether
monotherapy or combination therapy. This is especially true
given the additional conclusion of the Concorde study that
modest increases in T-helper cell count may not translate into
survival benefit or improved condition.

      ----------
      Vertical Transmission and ZDV Treatment

      Boyer PJ, Dillon M, Navaie M, et al. Factors predictive of
      maternal-fetal transmission of HIV-1: Preliminary analysis
      of zidovudine given during pregnancy and/or delivery.
      Journal of the American Medical Association 1994; 271(24):
      1925-1930. (University of California, Los Angeles; Long
      Beach Memorial Hospital; and Harbor-UCLA Medical Center.)

      A study of 68 HIV-infected pregnant women and their
infants found that ZDV therapy significantly reduces vertical
transmission rates. Pregnant women may be able to prevent HIV
transmission to their fetuses using this regimen. 

      Only one of the 26 mothers treated with ZDV passed the
virus on to her infant compared to 12 out of 42 mothers in the
untreated control group. Treated mothers who had lower mean
T-helper cells transmitted the virus less often than non-treated
mothers with higher T-helper cell counts. 

      Infants were more likely to be vertically infected if they
were exposed to maternal blood during labor or if they were born
to mothers with high levels of immune complex dissociated (ICD)
p24 antigen-a measure that separates p24 antigen from antibody
allowing it to be quantified and that indicates high viral load.

      ************************
      Comments and Submissions

      We invite readers to send letters responding to articles
published in FOCUS or dealing with current AIDS research and
counseling issues. We also encourage readers to submit article
proposals, including a summary of the idea and a detailed
outline of the article. Send correspondence to: 

      Editor
      FOCUS UCSF AIDS Health Project
      Box 0884 
      San Francisco, CA 94143-0884 


      ***********
      Next Month

      Two conferences this year focused attention on
psychosocial issues. AIDS' Impact, the second international
conference on Biopsychosocial Aspects of HIV Infection convened
in Brighton, United Kingdom, in July, and the Tenth
International Conference on AIDS, convened in Yokohama, Japan in
August. The November issue of FOCUS covers both of these
conferences. 

      Thomas Coates, PhD, Director of the Center for AIDS
Prevention Studies and Professor of Medicine at the University
of California San Francisco, reports on the Yokohama conference.
Robert Marks, Editor of FOCUS and Publications Director at the
UCSF AIDS Health Project, reviews the Brighton conference. The
two cover a variety of topics including: counseling and support,
staff burnout, risk behaviors, school-based prevention, issues
for women, cross-cultural dilemmas, and quality of life
research. 

      Copyright (c) 1994 - Reproduced with Permission. 
      Reproduction of FOCUS must be cleared through the Editor,
      FOCUS --UCSF AIDS Health Project, Box 0884, San Francisco,
      CA 94143-0884, (415) 476-6430.  Subscription information:
      12 monthly issues- $36 individuals; $90 institutions.