[Electronic distribution for GENA/aegis by GENA/aegis_World_HQ * 714.248.2836]

 Volume 8 no. 9

 Gay Men's Health Crisis: Treatment Issues 
 ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^
 > David Ho on HIV Treatment Strategies and Research
 > Anti-HIV Therapies at Yokohama
 > Immunosuppressive Therapy for HIV Infection
 > OI Update from Yokohama
   >> Cytomegalovirus Infection
   >> Pneumocystis Carinii Pneumonia
   >> Mycobacterium Avium Complex
   >> Tuberculosis
 > Kaposi's Sarcoma Reports at Yokohama
 > New York AIDS Trial Sites Cancelled
 > FDA Reaffirms Support for Accelerated Approval
 > Cryptosporidia and the Water Supply
 > Treatment Briefs 
   >> d4T Trial for Newly Infected
   >> Viral Strain and Long-Term Survivors
   >> Shameful Wait for HIV Testing in NYC
   >> Hospital Water May be MAC Risk
   >> Report on Clinical AIDS Research at NIH
   >> GMHC Treatment Fact Sheets


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David Ho on HIV Treatment Strategies and Research

>> David Ho, M.D., is the Director of The Aaron Diamond AIDS Research
Center in New York City. Dr. Ho is one of the most respected HIV
researchers in the world. In just three and one half years he has
built the Aaron Diamond Center into a world-class AIDS research center
employing over 60 full time staff. David Gold and Dave Gilden of
Treatment Issues spoke with Dr. Ho in his office about the
therapeutic implications of his work on the behavior of the human
immunodeficiency virus.  Protease Inhibitors.<<

Treatment Issues (TI): Given the substantial interest in HIV 
protease inhibitors, where do you think we are in the 
development of this class of compounds?

David Ho: It is nice to have so many compounds from different 
companies in clinical development. They all target the active 
sites of the protease. Many of them are really pretty potent 
against HIV in vitro [in the test tube] and there are several 
that are showing different levels of in vivo [in the body] 
efficacy. The thing that encourages me the most is the fact 
that we have inhibitors with different structures that bind 
differently to the active site, meaning that we might be able 
to combine some of these. And the in vitro observation so far 
is that you could have differences in the patterns of 
resistance, so that combining them might begin to make some 
sense. So I am encouraged by the number of inhibitors that 
are pretty potent, and the fact that the virus cannot make 
one mutation and resist all of them. At this point, looking 
at about ten inhibitors, there are at least two major 
patterns of resistance, and more likely three patterns.

TI: Researchers from Merck report that they have seen one 
patient who is resistant to all the protease inhibitors. Does 
this surprise you?

David Ho: When you are dealing with many different strains of HIV,
given a particular background, and particular set of mutations, you
can find viruses that become more and more resistant. But most of
them do follow the patterns. Resistance to all compounds may occur in
a particular case. But that may not be a general rule.

TI: Your lab is overseeing a clinical trial of the Abbott 
protease inhibitor. Can you tell us about it?

David Ho: We are doing a Phase I study of the compound in 
about two dozen patients and we are many months into it now. 
We would like to present our data on safety and antiviral 
efficacy at the ICAAC [Interscience Conference on 
Antimicrobial Agents and Chemotherapy] meeting. At this 
point, I have been instructed not to comment on the study. 
You could sort of guess that if we are eager to present at 
the October meeting as a late breaker report, we have some 
meaningful data, which would be of interest to the field.

Using Viral Load Measurements

TI: What standards should be used for determining whether the 
FDA should approve the protease inhibitors?

David Ho: It depends on your philosophy about this disease. 
My view is that we are dealing with a viral infection, a 
viral disease. I believe less in the autoimmune mechanism and 
such indirect pathways for pathogenesis. So for me, a very 
potent antiviral effect in vivo goes a long way. But that 
doesn't promise clinical benefit if the in vivo effect lasts 
only for a short period. So in the long run, we certainly 
need clinical endpoints to support the initial antiviral 
observations. 

TI: If a drug is relatively safe and has reasonable antiviral 
activity, should it be considered for accelerated approval?

David Ho: Demonstrating the antiviral's effect is a very 
encouraging piece of data. I have mixed feelings about 
whether the approval should be made on that basis alone. I 
think there is not enough data to make a very conclusive 
statement on that issue [but] as we go through some of these, 
we may get better answers to that question.

TI: When will we be able to know whether and what kind of 
virus load changes are really significant?

David Ho: Over the years, many compounds were touted as 
antivirals, but when you measured viral load, no real changes 
were observed. For example, soluble CD4, compound Q, oral 
interferon and, perhaps, hypericin all had no antiviral 
effect in vivo even though they were developed as antiviral 
agents. This kind of data suggests that a drug should 
probably be dropped or at least modified.

But we now have some idea of the decreases one gets with 
compounds like AZT and ddI and other reverse transcriptase 
inhibitors, like nevirapine. And we have a pretty good idea 
from a couple of the protease inhibitors. With saquinavir 
[Roche's compound], by itself, and at doses tested, the 
antiviral effect is not dramatic. With the Merck compounds, 
the effect, at least short term, could be very dramatic. So 
you begin to get a feel for the magnitude of the antiviral 
effect in vivo. If we could correlate that with clinical 
endpoints, we would have learned quite a bit, which could be 
used in assessing future candidate drugs.

TI: Are you referring to a trial to study whether a specific 
drop in viral load correlates with improvement in people's 
symptoms?

David Ho: Well, a trial would be a more formal way, but I 
think we are getting the impression from these current 
studies that some compounds will be very useful. 

TI: A couple of studies presented in Yokohama looked back to 
see whether reductions in viral load were associated with 
clinical improvement.

David Ho: Yes. The impression is that the antiviral benefit 
correlates with clinical data. The Walter Reed data[1] and the 
Coombs data[2] would be consistent with what we know about 
pathogenesis. The viral load and the biological properties of 
the virus all correlate with the disease progression. So, if 
we could bring viral load down to a level that we find in an 
asymptomatic individual, or better yet, the level in long-
term survivors, we could conclude, based on the available 
evidence, that this would result in a significant clinical 
benefit. But that is putting a lot of different types of data 
together and making a link.

TI: Some physicians are using viral load measurements 
[Roche's PCR or Chiron's branched DNA tests] to get some idea 
about treatment strategies for their patients. Do you have 
any advice for physicians or patients who are spending 
significant amounts of money for these tests?

David Ho: I believe that viral load is a very useful 
parameter and that it is going to be the upcoming trend for 
clinical practice. These quantitative techniques have been 
available for several years in our labs, and I find them 
useful with the few patients that I see. We have a limited 
number of antivirals, but you could at least play with those 
using viral load as a guide. And the tests are becoming 
easier to do. They are pretty accurate. And now with these 
two companies [Roche and Chiron] making a major push, we hope 
the price will continue to drop so that it will be 
affordable. So I find these tests useful.

TI: In what ways?

David Ho: For example, if a patient starts on a new 
antiviral, fairly consistently we see a decrease in viral 
load. And if with time, say six months, three months, that 
creeps up or increases dramatically, assuming the patient is 
taking the drug, it says there is some evidence of virologic 
failure. You could think about adding or switching therapies. 
So I find it particularly useful, and have used that 
information to manipulate the antiviral agents, and try to 
keep it at a level that I am comfortable with. What I find is 
a lot of physicians in the New York area are using [the 
tests], yet they don't know what the values mean. Such as 
what does 25,000 [copies per ml] mean? Or 200,000 mean? The 
companies have not done a good job in educating the 
physicians who are likely to use this test. 

TI: What does it really mean if you have an HIV RNA level of 
200,00?

David Ho: Well, obviously, the lower the better. But let's 
say that it is on the order of 10,000 to 20,000. That is, 
relatively speaking, pretty low. Whereas if you begin to have 
levels of 100,000, that's pretty rampant viral replication, 
and I would do something to control that. 

Initiating Antiviral Therapy

TI: What do you suggest to your patients about whether and 
when to begin antiretroviral therapy?

David Ho: I use the numbers to guide me. CD4 to some extent, 
usually in conjunction with viral load data. So if a 
patient's viral titer is, say, below 10,000, sometimes below 
5,000 - and that is generally in conjunction with a pretty 
decent CD4 cell count - I say, that in most cases, we would 
shoot for levels like this, and you are already there. We 
don't know how low we could go, and the assays are not 
particularly good at monitoring the low levels in a reliable 
way at the present - although a year from now that might be 
different. So we would go through that discussion and 
probably not think about initiating therapy. 

In addition to viral load levels, I also look at the CD4 
trend. If a patient's CD4 count is 450 and if the viral load 
is pretty high, say 100,000 copies, I would be more 
comfortable in initiating something like AZT to bring that 
down to a level more consistent with asymptomatic carriers of 
the virus. So I do use viral load measurements to help me 
make decisions. But in practice today, I am not sure how many 
people have access to viral load tests to guide them.

TI: Let's say you personally were in a situation where you 
had been on AZT for six months to a year, and your viral load 
was going up again. Knowing everything that you know about 
the Roche or Merck protease inhibitors, would you try to get 
your hands on these drugs? 

David Ho: Yes, I would. I know less about saquinavir by 
itself. But I have seen data presented by various 
investigators who are studying the Merck compound to know 
that the antiviral benefit is substantial over a course of a 
few months. And it is something that I would consider very, 
very seriously. I have been impressed by the initial viral 
effect of the Merck protease inhibitors.

TI: Do you think that the whole problem with new AIDS drugs 
is just viral resistance?

David Ho: Yes. Viral resistance and the magnitude of it. Protease
inhibitors are going to have resistance too. But the level of
resistance is more in the order of ten-fold, twenty-, fifty-fold,
not a thousand-fold. So that poses a particular problem. Some suggest
that there are different patterns of resistance in the non-nucleoside
reverse transcriptase inhibitors. Certainly, Upjohn and Boehringer
Ingelheim believe they have inhibitors with different resistance 
patterns. Perhaps in the future they could be combined. 

TI: Could antivirals alone make HIV infection a chronic manageable
infection or will we need some sort of immune therapy? 

David Ho: Antivirals could go a long way for many of the 
infected. I really can't say that for the patients who are 
very, very advanced, whose immune system may be depleted. But 
for a lot of the patients we have been looking at, if you 
show me someone with a two log [100-fold] drop in viral load, 
I will show you consistently a very nice CD4 response. In 
fact, if you see virus go down like that, you almost always 
see CD4 go up [correspondingly]. With AZT and with protease 
inhibitor, we know that the decline [in HIV] is very quick.
Even in patients with 50 CD4 cells, there could be a doubling 
or tripling of CD4 levels, sometimes higher. We have seen 
cases, this is perhaps unusual, that go up to 350 to 400. If 
you look at the production rate of virus, even though the 
patient may have steady viral load for the period preceding 
the treatment, a lot of production is going on. And then with 
the treatment, viral production declines and a new 
equilibrium occurs. And looking at the rapid CD4 cell 
increases, you realize that the regenerative capacity is 
still pretty good. 

TI: Are these functional CD4s?

David Ho: We don't know. But it is telling that when you do 
this and you think about regeneration of CD4, you shift the 
equilibrium to a different level. And what happens is that 
when you go through this calculation, you realize that the 
production rates are actually pretty high. That says you 
haven't totally wiped out the bone marrow storage or whatever 
is responsible for making these cells. And it makes me think 
- this is where my bias comes in - that we have to deal 
with the virus first. 

Long-Term Survivors 

TI: You gave a talk in Yokohama about long-term survivors 
that caused a lot of discussion. And you suggested there may 
be something in CD8 cells that suppresses the virus in some 
patients. Does this represent a change in thinking for you?

David Ho: We looked closely at several different parameters 
in these long-term survivors. The virus in all of them is 
very well controlled. We went on to try to explain why that 
is and the conclusion we are left with today is that it is 
really not some sort of resistance of the host CD4 cell to 
infection, but rather a combination of immune responses to 
the virus and some evidence of attenuation of the virus. And 
the CD8 story is part of that. We found many more of the CD8 
cells that are capable of suppressing virus replication. The 
mere finding of those CD8 cells was described by Jay Levy a 
long time ago. What we did was to quantify that response a 
little bit more, in greater detail, and show that numerically 
speaking, it takes a lot less CD8 cells for long-term 
survivors to see such inhibitory effect. At the same time, we 
also showed that the neutralizing antibody titers in long-
term survivors are great. So that these individuals must be 
seeing the virus at least periodically. Maybe not fully 
infectious, aggressive forms, but at least seeing the viral 
antigen. So I think that information is useful to know as we 
design vaccine strategies and immunotherapeutic strategies. 
The CD8 story is very controversial. Jay Levy's contention is 
that they are not CTLs [cytotoxic lymphocytes]. Yet we know 
the CTLs in vitro could do exactly that. If you stimulate the 
CTLs, some CTLs will certainly kill the cell. Others will 
release various cytokines that are suppressive for virus 
replication. So one of the immediate questions that would 
help the field a lot is to resolve this issue. Are these CD8 
cells simply HIV specific CTLs? And I haven't seen anybody 
doing experiments to answer that question in a more direct 
way. I have encouraged some in our lab to address that in a 
more direct way.

TI: So as far as the long-term survivors go, what would you 
say is a more significant immune response: antibodies or CTL?

David Ho: It would be hard for me to answer that question. In 
each case we have analyzed, we see great neutralizing 
antibody titers. We see, quantitatively speaking, a lot of 
these CD8 cells. And which is more important? I don't really 
know. 

Acute HIV Infection 

TI: Your group has done a lot of work on acute HIV infection. 
Should antiretroviral therapies be used in treating a patient 
with acute infection?

David Ho: A Swiss study suggests that treating reasonably early, in
the first six months of infection, has some short-term benefit in
terms of progression of various parameters. But theoretically it has
always made sense that if you could control the virus really well,
early on, with antivirals, you potentially could decrease the number
of viral variants that first populate the patient. And you should
have less problem in terms of variance and likelihood of developing
drug resistance. 

TI: If you were treating someone with acute infection what 
would you recommend?

David Ho: I personally believe that it makes sense to knock 
the virus down the best we can. If it were me, and I had all 
the currently available drugs in front of me, I would 
probably take multiple drugs over the short course. The ones 
that have been shown to have in vivo activity, say, the Merck 
protease inhibitor, AZT, and nevirapine. Put them all 
together. At least short-term, you know the major toxicity 
problem is not going to be a big issue, and resistance is not 
an issue. So if you could decrease virus very early on, there 
are a lot of theoretical advantages, but I have absolutely no 
empirical data. 

Reinfection in HIV-Positive Individuals

TI: Couples who are both HIV-positive are told to use condoms 
because of the risk of "reinfection." Is the risk of 
"reinfection" real? 

David Ho: There is little evidence to document that an 
additional "super" infection [or "reinfection"] with a second 
strain of HIV occurs at a period of time after initial 
infection. However, there is now plenty of evidence that you 
can have two strains circulating simultaneously. We just 
submitted a paper on an acute seroconverter who had multiple 
partners one night and got multiple strains of HIV. There is 
also a case where multiple units of blood were transfused 
into one person and coinfection occurred. So we know multiple 
strains can occur, at least simultaneously ["coinfection"]. 
Whether it can occur sequentially ["reinfection"], I don't 
know. But aside from HIV, you have to worry about other 
infectious agents and we know that other organisms can affect 
HIV activation and replication. 

HIV Vaccines

TI: Is there any basis to believe that therapeutic vaccines 
will be a useful therapy for HIV.

David Ho: I still need to be convinced. If someone comes up 
with a very original idea to use various viral components to 
induce an immune response, I'm willing to listen. If it is 
suggested that giving the patient a gp120 or gp160 or one 
type of viral particle would stimulate a useful immune 
response, my response would be that the body sees more 
variants on a regular basis, compared to these proteins a few 
times a year. And the major problem seems to be, if you give 
the envelope protein, you are trying to induce primarily an 
antibody response. But that antibody response is very 
ineffective against circulating strains of HIV. 

But I am still optimistic about developing a vaccine for HIV. 
We know vaccines are possible because Ron Derossier has an 
attenuated vaccine that works in animals. It would be nice to 
go and figure out in those monkeys what is mediating the 
protection. 

TI: But they haven't been able to do that?

David Ho: They haven't done that yet. Superficially they have 
looked at neutralizing antibody titers in those protected 
monkeys versus monkeys that were not protected by other forms 
of vaccine. And, in fact, the neutralizing antibody response 
was lower in the protected animals. So, I am encouraged by 
the fact that protection is possible. We just don't know how 
to do it in ways that are more acceptable. So we have to be 
more creative.

TI: Do you think it was a mistake not to initiate a large 
trial of the gp120 vaccines?

David Ho: I was not in favor of pushing ahead, given the 
available information. I do not know whether that decision 
ultimately would be proven right or wrong. I just think that 
these vaccines will only induce an antibody response. So when 
antibodies have no activity against the viruses that are in 
the community, the rationale falls apart.

Beyond Protease Inhibitors 

TI: Is there anything beyond the protease inhibitors that 
interests you and could be available within the next few 
years?

David Ho: This is something that we have talked about on the 
National Task Force on Drug Development. Many large 
pharmaceutical companies had some program on reverse 
transcriptase inhibitors and protease inhibitors. But there 
is precious little beyond those two targets, and that is a 
concern. How do you get the pharmaceutical companies to think 
about all the other targets that are out there? Such as tat, 
rev [HIV proteins needed for replication] and integrase [an 
HIV enzyme needed for infecting new cells]. But there are 
other targets that are less well known that are discussed in 
the basic literature. We know gag [HIV core protein] is a 
requirement for viral activity. And there are assays to 
screen for drugs that would block its interaction. Do you see 
a lot of companies thinking about that? Steve Garth's group 
shows that gag interacting with cyclophilin [a cellular 
transport protein] is a requirement for its activity. And 
there is a good assay that screens for cyclophilin 
inhibitors. Sandoz, because of its position in cyclophilin, 
has an interest in this area. But I see very little interest 
from others.

Similarly, you could go down the line: integrase - you could 
try to block protease dimerization [a step in constructing 
the HIV protease enzyme]. I see very little activity there. 
With protease, everybody is focusing on the catalytic side. 
But you could screen for inhibitors that would block the 
interactive surface. Nobody is working on that, as far as I 
know. And, there is evidence that the integrase must bind to 
a transcriptional factor. That sounds like a nice target. And 
there is a nice assay. 

So we have to create a mechanism for the large pharmaceutical 
companies to use their chemical library on these targets 
using the assays. There is a real gap in anti-viral research, 
and we must try to fill it.

TI: What can government do to encourage companies to do this 
type of research?

David Ho: Government has got to provide incentives for the 
companies to do that. Because AIDS is such a difficult and 
controversial area, some companies just say it's not worth 
it. There is concern that there are too few companies that 
are truly devoted to finding something for AIDS. So, at the 
basic level, government must provide some incentive in terms 
of funding to get the companies with expertise into some of 
these new target areas. Exactly how, I think, is a difficult 
thing. 

Government Sponsored AIDS Research 

TI: Should the NIH be emphasizing targeted or investigator-initiated 
AIDS research?

David Ho: They are always trying to balance the two. The 
example I just gave you about providing incentives sounds 
like targeted research. And so there are situations where a 
targeted approach is useful. But in general, I favor what has 
accounted for most of the American success in science, and 
that is investigators pushing and developing their own ideas. 
A lot of the creativity is going to come from that. But if 
you have one obvious gap, where you see after extensive 
survey, almost nobody working on it, then in those 
situations, a targeted approach is required. 

TI: You were one of the first well-known researchers to 
support the Office of AIDS Research [OAR] reforms at the NIH. 
Are you optimistic about these reforms?

David Ho: I like the new direction that has been taken. Of 
course, the new OAR really will only begin to have an impact 
on the '96 budget and thereafter. But some of the concepts 
that have been discussed by [OAR director] Bill Paul, I 
think, are right on. He's developed the plan after 
substantial input from many people outside NIH.

TI: What specifically do you like? 

David Ho: For one, I like the idea of putting greater 
emphasis on basic research. In the therapeutic area, basic 
research will help generate a greater infusion of new targets 
and new drugs into the developmental pipeline. This pipeline 
goes from drug discovery all the way to clinical trials and 
so on. And the infrastructure needs to be reexamined each 
step of the way. That is what the OAR is doing. Does it make 
sense to have a huge infrastructure to test drugs, with very 
few promising drugs flowing through the developmental 
pipeline? 

TI: How would you make the clinical trials program more 
efficient?

David Ho: In terms of the ACTG [NIH AIDS Clinical Trials 
Group], you have to look at what the accomplishments were 
over the years and what dollars have been consumed by that 
process. And almost go through it program by program. 

TI: And how do you feel about the ACTG?

David Ho: This is a very controversial area. I think they 
have made contributions. There are a lot of groups out there 
that may be doing good work. The question is, does it apply 
to every single area? And that has to be evaluated.

TI: Can what has been done here at the Aaron Diamond Center 
be replicated on a government level?

David Ho: I think it is difficult. Here, they took a chance 
and committed the money and allowed us, with guidance from 
our boards, to go out and pick personnel first. That is not 
how government operates. With government you have to spell it 
out. It is better done as a private enterprise. In San 
Francisco, they have the Gladstone Institute which was 
founded, again, by a foundation. And they were able to go and 
pick people. 

We were also able to do something very few places have been 
able to do - go and pick promising researchers with 
complementary skills and interests to form teams. A lot of 
institutions just put together their AIDS researchers whether 
they fit in with one another or not.

TI: Proposals for a "Manhattan Project for AIDS" focus on 
putting together people in different fields of AIDS. What do 
you think about such proposals?

David Ho: First of all, I would never call any project a 
Manhattan Project. I think teams along this line might be 
reasonable. Huge teams congregating at one site are probably 
not practical or even necessary given how easy it is to 
communicate. So I would not favor the type of arrangement 
that developed the atom bomb. 

TI: In terms of the overall U.S. government AIDS research 
effort, what are we doing right and what could be done 
better?

David Ho: There is a large pool of very talented scientists 
working here. And the esprit de corps among scientists is 
much better now than before and there is a lot more positive 
interaction among scientists. In the journals, there is a lot 
of scientific development about HIV every month. So a good 
deal of incremental knowledge is being generated. Obviously 
we need more to get to a level where the clinical translation 
occurs in terms of therapy. We are fortunate in this country 
that the funding for AIDS research is quite large compared to 
funding in other countries and funding in other areas. So 
many of those things I am pleased with. And I think it is 
just a matter of juggling the priorities. If you say, what 
are we doing wrong, we need, as the OAR is doing, to look at 
the entire research portfolio and examine the priorities. Is 
it appropriate to put, you know, X amount on the front end, Y 
amount in the middle and Z in the back end? All of these need 
to be examined and some priority adjustments are required.

1 Mayers D et al. Tenth international conference on AIDS 
abstract book. Aug 7-12 1994; I(abstract 253B):75.

2 Kahn J. Tenth international conference on AIDS program 
book. Aug 7-12 1994; session RT-1:26.

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Anti-HIV Therapies at Yokohama
 by Gabriel Torres, M.D.

The problem of drug-resistant HIV dominated many of the 
proceedings at the Tenth International Conference on AIDS 
this August. Existing therapies such as the nucleoside 
analogs AZT, ddI, ddC and d4T progressively lose their 
effectiveness when used alone. Many researchers hoped that 
combining therapies will so reduce HIV replication that 
strains resistant to multiple medications will not evolve. 
This article will concentrate on the reports about nucleoside 
analogs as well as some other studies concerning AZT combined 
with another class of similar-acting compounds, the non-
nucleoside reverse transcriptase inhibitors (NNRTIs).

AZT Monotherapy

The debate regarding early treatment with AZT among 
asymptomatic HIV positive persons was rekindled by the 
presentation of the final results of the trial known as ACTG 
019.[1] ACTG 019 is the largest and longest study comparing AZT 
to placebo in HIV-positive, symptomless persons with CD4 
counts greater than 500. It enrolled more than 3,200 
participants from 32 medical centers in the United States.
In August of 1989, analysis of participants with baseline CD4 
counts below 500 revealed slower disease progression among 
those taking zidovudine. Investigators then modified the 
trial so that those with CD4 cells greater than 500 were 
randomized to three groups: The 1,637 trial participants 
either deferred taking AZT until their CD4 count dropped 
below 500 or immediately began therapy with either 500 or 
1,500 mg of AZT. Once CD4 counts dropped under 500, all 
participants were given open-labeled AZT at a dose of 500 mg 
per day.

The results of the study indicated that the rates of disease 
progression (as measured by the occurrence of AIDS-defining 
events or death) were similar for the three groups over the 
mean follow-up period of 2.6 years. The time to a drop in CD4 
cells below 500 was slightly shorter overall in the deferred 
therapy group (1 year) than in the AZT groups (1.5 years), 
but the differences in time to a CD4 count under 500 were not 
significant for those who started with CD4 counts less than 
650. The low intrinsic risk of progression at high CD4 
counts, the brief time on blinded treatment and the drop-out 
rate of approximately 25 percent in this trial may have 
contributed to the inability of detecting much benefit of 
early AZT use in persons with CD4 counts exceeding 500.

In reporting on ACTG 019, Paul Volberding, M.D., of the 
University of California San Francisco concluded that the 
data do not support initiation of AZT while CD4 counts are 
above 500. Still, Dr. Volberding continued to recommend AZT 
for those with CD4 counts under 500. Specific patients with 
high HIV blood levels and CD4 counts below 500 may also 
benefit from therapy, although this remains to be 
demonstrated through clinical trials. 

Sequential Monotherapy

Sequential monotherapy implies switching from one drug to 
another, either after a fixed amount of time or after one 
drug has failed to yield further benefit. Several published 
U.S. studies have indicated a benefit from switching to ddI 
after as little as eight to sixteen weeks on AZT. In 
Yokohama, several more studies supported this idea. 

A study reported by Julio Montaner, M.D., of the Canadian HIV 
Trials Network compared switching to ddI versus continuing on 
AZT in a group of 245 patients with baseline CD4 counts 
between 200 and 500.[2] Those switching to ddI had a higher and 
more sustained elevation in counts at 48 weeks than those 
remaining on AZT. The time to the first AIDS-defining illness 
or death was also significantly longer for those switching to 
ddI than those continuing on AZT after two years of follow-
up. Changing to ddI did not slow the development of AZT 
resistance or the emergence of the more virulent type of HIV 
known as SI (syncytia-inducing).

Another comparative study of sequential monotherapy versus 
combination therapy was described in a poster.[3] In this 
retrospective study, 162 AZT-treated patients (mean baseline 
CD4 of 121) were switched to either ddI or combination 
AZT/ddC and followed for new AIDS-defining infections or 
death. After a mean follow-up of 32 weeks, there was no 
difference in rates of new infections, hospitalizations and 
survival, although there was a trend favoring those switching 
to ddI. 

Douglas Mayers, M.D., of the Walter Reed Army Institute of 
Research presented data on the virologic response to ddI 
after AZT monotherapy in a small group of 32 patients with 
CD4 counts over 400 who had enrolled in an observational 
study.[4] The objective of the study was to observe the impact 
on HIV load of switching from prolonged AZT monotherapy to 
ddI. The average time on AZT in the group was two years, and 
the mean CD4 at the time of switching was 93. Twenty-six 
percent of the study group had significant increases in viral 
burden after switching to ddI, 29 percent had decreases and 
45 percent were stable. Neither baseline HIV level nor any of 
the individual virus characteristics (such as resistance to 
AZT) were predictive of a study member's response.

Patients' experience when switching to second-line 
medications has never been stellar. This continuing problem 
was reflected in the retrospective, observational data 
presented by Marcus Conant, M.D., of 96 patients (mean CD4 
count of 100) he treated with d4T after failure or 
intolerance on both AZT and ddI.[5] He reported an adverse 
effect rate of 53 percent. Half of his patients developed 
peripheral neuropathy, a rate much higher than that reported 
in d4T's phase I and II trials. In addition, 36 percent of 
his patients experienced psychiatric disturbances, ranging 
from insomnia to anxiety and panic reactions. Forty-one 
percent discontinued d4T, though no deaths were attributed to 
the drug. A third had rises in CD4 cells and 62 percent had 
declines in this cell population. 

Combination Therapy with Nucleoside Analogs

Various conference papers supported the claim that 
combination therapy is superior to AZT monotherapy or even 
sequential monotherapy. According to the reports, combining 
treatments yields greater increases in CD4 counts and lower 
HIV levels than monotherapy does.

One of these reports was an analysis from the Multicenter 
AIDS Cohort Study (MACS), which tracked 853 gay men who 
started AZT prior to AIDS.[6] The MACS investigators found that 
the men who at some later point added a second anti-HIV 
medication to their regimen had a 34 percent lower risk of 
dying at any given time than those who remained solely on AZT 
or switched to another monotherapy. The occurrence of AIDS 
also was 23 percent less per year in the combination group, 
although this difference was not statistically significant.

Melanie Thompson, M.D., presented a poster that also 
described the differential impact on survival of AZT 
monotherapy and sequential or combination antiretroviral 
therapy.[7] In her cohort of 2,044 Georgia patients, she found 
combination therapy (mainly AZT plus ddC) to be superior to 
AZT monotherapy in those with CD4 counts below 500 and to 
sequential AZT-ddI therapy in those with CD4 counts below 
100. 

An interesting study from the National Cancer Institute in 
the U.S. examined HIV plasma levels and the development of 
mutations in 26 patients receiving long-term combination or 
alternating AZT-ddI therapy.[8] This study found that AZT is 
more potent in activated, dividing cells, whereas ddI is more 
potent against HIV in resting cells. Study participants had a 
greater initial suppression of virus if the drugs were given 
together than if the drugs were alternated. Virus levels 
remained reduced for at least two years, but by then there 
was little difference between the alternating and combination 
regimens. AZT-ddI combination therapy also prevented the 
emergence of a major mutation related to ddI resistance (at 
codon 74 on the HIV genome), yet did not prevent a similar 
AZT-related mutation at codon 215. In this study, no 
correlation was found between changes in CD4 counts and 
changes in plasma viremia.

A Dutch study examined the safety and efficacy of adding AZT 
to lamivudine (3TC) monotherapy.[9] In the laboratory, a 
mutation at codon 184 confers resistance to 3TC but 
simultaneously reverses resistance to AZT. This led 
investigators to believe that adding AZT could result in 
salutary effects. 

In the phase I/II 3TC study, which was open-labeled and
non-randomized, 30 patients with greater than one year of previous
3TC (either 200 or 600 mg/day) therapy or clinical failure on 3TC
started also taking AZT at a dose of 600 mg/day. Baseline CD4 count
was 110. CD4 counts increased and were above baseline for at least a
year. Plasma HIV RNA viral load had a rapid decrease after adding AZT
(over 90 percent) but had a slow and steady rise towards baseline by
week 36. Side effects included nausea, fatigue and neutropenia. The 
authors concluded that adding AZT to 3TC is effective in patients
with 3TC-resistant virus. ddI and ddC would not be expected to
combine well with 3TC since 3TC-resistant virus has been shown to be
cross-resistant to both ddI and ddC.

Lest one conclude that by adjusting nucleoside analog 
combinations one can easily stay ahead of HIV and its 
evolving resistance to therapy, another National Cancer 
Institute report[10] described how combination therapy using 
AZT plus ddI or ddC can give rise to a set of novel HIV 
mutations. The evolving set of changes in the virus's reverse 
transcriptase make it insensitive to all three drugs (the 
decrease in sensitivity to the drugs was 125-, 16- and 30-
fold to AZT, ddI and ddC, respectively). The mutations appear 
as a successive group of seven changes in the reverse 
transcriptase amino acid sequence. In one patient, virus 
levels increased as the mutations developed over 38 months.
NNRTIs

One class of compounds that could supplement nucleoside 
analog combinations is the so-called non-nucleoside reverse 
transcriptase inhibitors (NNRTIs). Like the nucleoside 
analogs, NNRTIs block HIV's infection of new cells. An NNRTI 
fits into the reverse transcriptase's active site so that the 
enzyme can no longer transcribe the HIV genome into a DNA 
form insertable into the cell's normal genetic machinery. 
(Nucleoside analogs are faulty DNA building blocks that cause 
DNA transcription to terminate prematurely.)

There have been repeated problems with rapid emergence of HIV 
resistant to NNRTIs, however, and their usefulness seemed 
limited in the past. But various reports at Yokohama on these 
compounds' synergism with nucleoside analogs may prompt a 
second look at NNRTIs, especially at the new members of this 
class --delavirdine and loviride.

Bill Freimuth, M.D., from the Upjohn Company presented data 
on the surrogate marker responses in the completed two trials 
of delavirdine.[11] These trials were either open-labeled or 
dose-escalating studies of delavirdine in combination with 
AZT or AZT plus ddI in persons with prior experience on these 
drugs. Both trials found that adding nevirapine to the 
combination gave CD4 counts a boost and decreased HIV levels 
in the blood. One important observation was that the response 
to delavirdine was improved if the virus was sensitive to 
AZT. Resistance to delavirdine was observed over time and was 
associated with baseline AZT resistance and the virulent SI 
virus type. 

Loviride is an NNRTI manufactured by Janssen Pharmaceuticals. 
A double-blind placebo-controlled study was reported by a 
German group.[12] HIV-positive patients with CD4 counts more 
than 400 were randomized to receive either loviride, placebo 
or R18893 (a compound similar to loviride). After 24 weeks of 
follow-up, the loviride group had the best CD4 responses with 
an average increase of approximately twenty percent over 
baseline. None of the known mutations conferring resistance 
to loviride were detected. Further trials are planned for 
this very promising compound. 

Conclusion

For early-stage patients with higher CD4 counts, combination 
therapy may result in greater reductions in viral load, 
improved clinical outcome and perhaps a delay in the 
emergence of resistance. The final word on this issue awaits 
the results of larger trials currently underway. For more 
advanced patients with very low CD4 counts, combination 
therapy still has not proven to be better than monotherapy 
and may be associated with more toxicity.

The NNRTIs seem to have considerable potential, at least in 
combination with two nucleoside analogs. Resistance 
apparently does develop rapidly, but the observed lack of 
resistance to loviride is encouraging.

Protease inhibitors are new agents that will increase the 
number of possible combinations immensely. How the addition 
of one or more such compounds affects the activity of 
combination or sequential drug regimens remains to be 
answered, perhaps at the next international conference.

1 Volberding P et al. Tenth international conference on AIDS 
abstract book. Aug 7-12 1994; II(abstract 355B):16.

2 Ruedy N et al. Tenth international conference. II(abstract 
358B):16.

3 Barr M and Torres RA. Tenth international conference. 
I(abstract PB0266):209.

4 Mayers DL et al. Tenth international conference. 
II(abstract 359B):17.

5 Conant M et al. Tenth international conference. I(abstract 
003B):7.

6 Graham NMH et al. Wellcome satellite symposium at the tenth 
international conference on AIDS. Aug 7 1994; abstract 5.

7 Thompson M et al. Tenth international conference. 
I(abstract PB0279):212.

8 Mitsuya H et al. Tenth international conference. I(abstract 
056B):21.

9 van Leeuwen R et al. Tenth international conference. 
I(abstract 057B):21.

10 Shirasaka T et al. Tenth international conference. 
II(abstract 377A):21.

11 Friemuth B et al. Tenth international conference. 
II(abstract 512B):59.

12 Staszewski S et al. Tenth international conference. 
II(abstract 513B):59.

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Immunosuppressive Therapy for HIV Infection
 by Craig Sterritt

Researchers have long tried to reconcile the fact that while the
activation of CD4 cells is required for effective anti-HIV immune
responses, it also leads to increased HIV replication and the
susceptibility of uninfected CD4 cells to HIV infection. In addition
to facilitating the viral life-cycle, activation of CD4 cells from
people with HIV has been found to lead to a phenomenon called
programmed cell death or apoptosis, which is thought to contribute to
the overall loss of CD4 cells in HIV infection. The overactivation of
CD4 cells in HIV can also lead to other deleterious events, including
aberrant cytokine secretion, the overproduction of antibodies and
chronic inflammation, all of which may also be involved in the
development of HIV-related disease.

Supporting a correlation between CD4 hyperactivation and CD4 
depletion was a presentation at the recent International AIDS 
Conference that described a French study[1] of prednisolone, a 
gluccocorticoid with anti-inflammatory and immunosuppressive 
effects. The French group administered prednisolone to 243 
asymptomatic and twenty mildly symptomatic persons with HIV 
in this non-placebo-controlled trial. Investigators reported 
that they observed a peak gain of over 200 CD4 cells per mm3 
of blood after fifteen days of therapy. One year later, trial 
members still were a median of 100 CD4 cells above their 
baseline counts. HIV p24 antigen as well as viral DNA, RNA 
and mRNA remained stable in all patients over the course of 
the trial, indicating that prednisolone treatment does not 
promote HIV replication. Obviously, too, the increase in CD4 
counts was not caused by reduced virus levels.

Immune system and CD4 cell activation markers in the 
prednisolone recipients decreased significantly, although 
cytotoxic lymphocyte (CD8 cell) counts remained unchanged. In 
addition, swollen lymph nodes (lymphadenopathy) disappeared 
in sixteen of the twenty mildly symptomatic patients, 
indicating reduced lymph node activity. No major side effects 
or opportunistic infections occurred during the course of the 
study.

In vitro (test tube) tests done in conjunction with the trial 
revealed that prednisolone exerts its positive influence on 
CD4 counts by preventing apoptosis. Prednisolone was not 
found to inhibit normal functioning of cells: Cells 
treated with prednisolone could still produce the cytokine 
interleukin-2 and proliferate following exposure to antigen 
(such as HIV protein).

1 Andrieu JM et al. Tenth International conference on AIDS 
abstract book. Aug 7-12, 1994; 1(abstract 157B):46.

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OI Update from Yokohama
 by Gabriel Torres, M.D.

Opportunistic infections may have received less attention at 
the Tenth International Conference on AIDS compared to 
previous conferences, but a number of presentations did yield 
helpful suggestions for managing advanced HIV disease. 
Treatments for cytomegalovirus, pneumocystis pneumonia, MAC, 
TB and bacterial pneumonia all were the subjects of informative 
reports.

Cytomegalovirus Infection

The long-awaited trial using oral ganciclovir to prevent CMV 
disease was not formally presented at the conference, 
although a summary of the data was presented by W. David 
Hardy, M.D., at a satellite symposium sponsored by the UCLA 
AIDS Institute on the day after the conference. The trial 
enlisted 750 HIV-positive patients with CD4 counts below 50 
(or below 100 plus a history of AIDS-related illnesses). 
Subjects were randomized to receive 1,000 mg of oral 
ganciclovir or placebo every eight hours and followed with 
ophthalmologic exams every two months for the development of 
CMV retinitis. An interim analysis found that at ten months, 
only sixteen percent of the oral ganciclovir group had 
contracted CMV retinitis, compared to 30 percent of the 
placebo group. This was a highly statistically significant 
difference.

An on-going trial by the Community Program for Clinical 
Research on AIDS (CPCRA) that followed almost 1,000 patients 
with CD4 counts less than 100 has not observed a delay in the 
onset of symptomatic CMV with oral ganciclovir. Participants 
started with slightly higher CD4 counts on average than in 
the first study, though, and their observational period was 
three months shorter. Also, they did not have the 
ophthalmologic exams, so some asymptomatic CMV infections may 
have been missed. Participants in both trials now will be 
given the option of open-label oral ganciclovir therapy.

Several posters provided helpful data for managing active CMV 
infections:
- A 31-person Spanish study[1] evaluated ganciclovir (ten 
milligrams per kilogram of body weight) or foscarnet (100 
mg/kg) given as thrice weekly infusions for maintenance 
therapy in patients with CMV retinitis. There were seventeen 
relapses (51 percent) and 22 deaths (66 percent) after a mean 
follow-up of seventeen weeks. These rates are similar to 
those seen with the standard daily or five times weekly 
maintenance therapy using either drug. Similarly, a German 
study[2] of gastrointestinal CMV found little difference in 
effectiveness whether induction therapy with foscarnet 
infusions were administered for five or for seven days per 
week over a period of three weeks. The option of skipping 
infusion days, especially on weekends when clinics are 
closed, will reduce the extent of hospitalizations required 
for CMV disease.

- Two posters[3,4] described the use of ganciclovir, foscarnet 
or a combination of both drugs for the treatment of CMV 
polyradiculopathy, a spinal cord and nerve root inflammation. 
CMV polyradiculopathy usually leads to paralysis and 
incontinence. At least half of the patients exhibited 
improvement in neurological function and clearing of CMV from 
blood and cerebrospinal fluid. 

- Various studies also examined the usefulness of the CMV 
blood antigen test to monitor patients with CMV disease 
during antiviral therapy. One poster[5] described how bloodborne 
CMV antigen rose prior to the clinical deterioration 
and also correlated with the appearance of drug-resistant 
CMV. The authors concluded that the CMV antigen test may be 
an important tool for detecting both failing CMV therapy and 
the emergence of ganciclovir- or foscarnet-resistant viral 
strains. 

Pneumocystis Carinii Pneumonia

Many PCP reports at the conference focused on the problem of 
patients' intolerance to available drugs. Some presentations 
looked at the use of desensitization techniques to overcome 
allergies to the sulfa component of Bactrim or Septra: These 
allergic reactions seem to be related to an inability to 
metabolize sulfa breakdown products due to a glutathione 
deficiency common in HIV-positive patients.

One regimen presented by the Conant Medical Group[6] showed an 
84 percent success rate in a retrospective analysis of 100 
sulfa-allergic patients given a standard desensitization 
regimen with trimethoprim/sulfamethoxazole (TMP/SMX, the 
generic name for Bactrim and Septra). Since only one 
successfully desensitized patient (1.2 percent) developed PCP 
and toxoplasmosis, the researchers concluded that 
desensitization should be offered to all sulfa-allergic 
patients. Unfortunately, no comparative prospective study 
comparing desensitization merely to deferred rechallenge with 
a single or double strength tablet of TMP/SMX has been 
reported to date.

A 214-person Italian study[7] compared monthly to twice monthly 
dosage of aerosolized pentamidine (AP) (300 mg) for 
preventing PCP after a first attack (secondary prophylaxis). 
After a median follow-up of 200 or 240 days, depending on the 
group, fourteen episodes of PCP occurred in the once monthly 
group, compared to five in the twice monthly group. The 
researchers concluded that twice monthly aerosolized 
pentamidine is superior to once monthly treatment and 
suggested that the drug be used in cases of sulfa 
intolerance.

Studies conducted by the U.S. AIDS Clinical Trials Group 
(ACTG trials 081 and 021) have demonstrated that aerosolized 
pentamidine is just as effective as dapsone for primary 
prophylaxis, yet significantly less effective than TMP/SMX 
for secondary prophylaxis. For those persons intolerant to 
both dapsone and TMP-SMX, twice monthly aerosol pentamidine 
seems a reasonable alternative.

Dr. Hardy at the UCLA symposium presented a summary of the 
data from ACTG 108, a three-week study comparing three oral 
treatment regimens for mild-to-moderate PCP: 
trimethoprim/sulfamethoxazole, dapsone/trimethoprim and 
clindamycin/primaquine. This study enrolled 247 patients with 
mild PCP and found no difference in efficacy or toxicity 
among the three regimens, a reassuring fact for those who 
treat PCP with alternative regimens in an outpatient setting.

Mycobacterium Avium Complex

Prevention of disseminated MAC infections in patients with 
advanced HIV disease was the subject of two major reports:

- The rifabutin treatment IND data were presented[8] describing 
the experience of 2,560 people on the open-label. The median 
duration of prophylaxis was 260 days. Abdominal pain, nausea 
and diarrhea were common side effects. Breakthrough MAC 
infections occurred most frequently in participants with CD4 
counts below 50 (5.3 percent).

- Preliminary information from an Abbott Laboratories 
placebo-controlled trial of clarithromycin was described in 
an oral presentation.[9] To date, 682 patients have been 
enrolled in the U.S. and Europe, of which 308 have withdrawn, 
many to pursue prophylaxis with rifabutin after its approval. 
Fifty-seven breakthrough MAC infections occurred, of which 48 
remained sensitive to clarithromycin and six were highly 
resistant. The predicted versus observed incidence rate of 
MAC indicated that disseminated MAC has been reduced by 40 
percent, an effect presumed to be related to clarithromycin. 
The efficacy data will be unblinded in October, and this 
inference may be confirmed.

Tuberculosis

The magnitude of the TB problem worldwide remains staggering: 
The World Health Organization estimates a current total of 
700,000 cases of active TB among the HIV-positive population 
and that another ten million HIV-positive individuals have 
latent TB infections.

Relapse rates for treated TB vary throughout the world from 
6.5 percent in Europe and the United States to 16.7 percent 
in Kenya. Some of these relapses may be due to reinfections 
with new strains of TB. The rate of protection using 
isoniazid (INH) was demonstrated in a study from Zambia, 
which showed that the drug reduced the incidence of 
reactivated TB from 16.2 percent to 1.8 percent. Another 
study from Barcelona showed that within an eighteen month 
follow-up period INH reduced the risk of reactivation from 
18.5 percent to 6.7 percent.10

An important TB prophylaxis study was presented as a poster 
by a group from Johns Hopkins University.11 Conducted in 
Haiti, the study compared the effectiveness of two regimens 
for the prevention of initial attacks of active tuberculosis 
in HIV-positive, PPD- (skin test-) positive adults. Seven 
hundred eighty-four participants were randomized to receive 
either twice weekly isoniazid (800 mg twice weekly) for six 
months or a combination of rifampin and pyrazinamide twice 
weekly for two months. During the first ten months of follow-
up, the risk of tuberculosis was 0.8 percent in the INH group 
versus 3.5 percent in the rifampin/pyrazinamide group. After 
the first ten months, no significant differences were noted 
in the rates of TB, nor was there a survival difference. The 
authors concluded that the difference in rates of breakthrough 
TB appeared to be related to different durations of prophylaxis. 

A similar CPCRA study is comparing a year of daily INH to two 
months of daily rifampin/pyrazinamide in the same population. 
However, enrollment in this study is proceeding quite slowly, 
and it appears that conclusive documentation of the best TB 
prevention regimen will take some time.

1 Mallolas J et al. Tenth international conference on AIDS 
abstract book. Aug 7-12 1994; II(abstract PB0587):143.

2 Salzberger B et al. Tenth international 
conferenceII(abstract PB0519):127.

3 Karmochkine M et al. Tenth international conference. 
II(abstract PB0520):127.

4 Espinoza LA et al. Tenth international conference. 
II(abstract PB0521):127.

5 Hansen KK et al. Tenth international conference. 
II(abstract PB0528):128.

6 King C et al. et al. Tenth international conference. 
II(abstract 388B):25.

7 Rizzardi GP et al. Tenth international conference. 
II(abstract PB0612):150.

8 Gordin F et al. Tenth international conference. II(abstract 
557B):70.

9 Pierce M et al. Tenth international conference. II(abstract 
558B):70.

10 Gatell JM. Tenth international conference. II(abstract 
PS26):48.

11 Neal CJ et al. Tenth international conference. II(abstract 
PB0681):166.

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Kaposi's Sarcoma Reports at Yokohama
 by Gabriel Torres, M.D.

One of the most exciting reports on Kaposi's sarcoma came 
from Robert Gallo's laboratory at the U.S. National Cancer 
Institute. As reported in Treatment Issues' August edition, 
Gallo's group observed that nude pregnant mice who had been 
injected with a KS cell line did not develop tumors during 
the first trimester of pregnancy whereas KS lesions 
flourished during the second and third trimester. The 
researchers concluded that the beta subunit of the hormone 
human chorionic gonadotropin (HCG), which is high early in 
pregnancy, was responsible for the anti-tumor effect seen in 
the mice.

Liposomal Chemotherapy

Data on the use of chemotherapeutic agents encapsulated 
within liposomes (tiny fat globules that regulate the passage 
of the entrapped drug from the blood stream to specific sites 
- see April 1994 Treatment Issues), were presented by 
various groups of investigators who have successfully used 
these agents in patients with AIDS-related KS.

- DOX-SL: The best results to date were seen in the 
International DOX-SL Study,[1] a multicenter European and 
Australian phase II/III study of 247 KS patients. DOX-SL is a 
preparation of doxorubicin encapsulated in "stealth" 
liposomes that deliver significantly greater quantities of 
the drug to the KS lesions. "Stealth" liposomes incorporate a 
protective polyethylene glycol (PEG) coating allowing them to 
circulate in the bloodstream for up to 48 hours or more. 
Conventional uncoated liposomes are cleared from the blood in 
a few hours. (By comparison, unencapsulated - "free" - drug 
disappears from blood in a matter of minutes.)

The patients were treated with DOX-SL intravenously using a 
30 minute infusion every two weeks. Patients were started at 
10 or 20 mg/m2 of body area, and the dose was titrated upward 
if KS lesions failed to respond. Two-thirds of the trial 
participants received at least six infusions. Of the 133 for 
whom response data are available, three (1.8 percent) 
attained a complete response, 81 (48.5 percent) a partial 
response and 38 (22.8 percent) had stable disease. Partial or 
complete responses were typically seen within two or three 
cycles of DOX-SL. Side effects included nausea (25 percent), 
vomiting (13.9 percent), stomatitis (11.8 percent), diarrhea 
(24.9 percent) and hair loss (11.8 percent). Significant 
neutropenia occurred in 17.9 percent of all treatmentcycles 
whereas anemia and thrombocytopenia occurred in 21.6 percent 
and 12 percent of all cycles, respectively.

On September 7, 1994, Liposome Technology, Inc., the 
manufacturers of DOX-SL, filed a New Drug Application (NDA) 
with the U.S. Food and Drug Administration for the treatment 
of KS in people with AIDS who cannot tolerate or have failed 
conventional chemotherapy. (Until this application is 
approved, people with KS and intolerant to ABV, a standard 
anti-cancer therapy, can receive DOX-SL through a special 
open-label trial accessible through 30 sites nationwide. Call 
Liposome Technology at 415/323-9011 for more information.)

- Daunoxome: Daunoxome is the drug daunorubicin encapsulated 
by a conventional liposome. The first phase II study of 
daunoxome was presented in Yokohama.[2] Through February 1994, 
42 patients had been treated with Daunoxome every two weeks. 
One-third of the patients had a partial response and the 
other two-thirds had stable disease. The median duration of 
the response with the 40 mg dose was 7.5 to nine weeks, 
depending on the dose. The main side effect was neutropenia, 
which could be managed with G-CSF (Neupogen).

Interleukin-4

The Yokohama Conference heard the first clinical data on the 
use of interleukin-4 (IL-4) in patients with KS.[3] IL-4 
promotes CD4 cell proliferation and also suppresses 
interleukin-6 production - as well as KS cells in culture. 
IL-6 is found in high levels in patients with KS and is 
implicated in the pathogenesis of KS lesions.

The phase I/II study (ACTG 224) enrolled patients with 
biopsy-proven KS who had IL-4 administered subcutaneously in 
escalating doses. So far, thirteen trial participants have 
received one of two dose levels. Side effects such as fever, 
fatigue and headaches were very common. Only three patients 
experienced a partial response. The dose limiting toxicity to 
date has been neutropenia. On the other hand, significant 
decreases (60 percent) in HIV p24 antigen levels were 
observed in all patients, which raises the possibility that 
IL-4 is useful as an anti-HIV drug.

1 Goebel FD et al. Tenth international conference on AIDS 
abstract book. Aug 7-12 1994; I(abstract PB0123):174.

2 Wernz JC et al. Tenth international conference. I(abstract 
046B):18.

3 Miles SA et al. Tenth international conference. I(abstract 
159B):46.

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New York AIDS Trial Sites Cancelled
 by Saundra Johnson

The Terry Beirn Community Programs for Clinical Research on 
AIDS (CPCRA) has defunded three of its four New York City 
sites. This action puts in jeopardy New York's ability to 
offer HIV/AIDS clinical trials to underserved populations, a 
goal included in the CPCRA mission statement. The CPCRA, 
which is sponsored by the National Institute of Allergy and 
Infectious Diseases (NIAID), is a network of sixteen 
community-based organizations that is supposed to carry out 
studies of new treatments within the context of ordinary 
medical care.

The decision is the result of a "recompetition" in which 
participating groups and proposed new groups were evaluated 
to find which can best fulfill the CPCRA's mission. In all, 
four organizations lost their funding. The defunded New York 
City groups are: the Addiction Research and Treatment 
Corporation in Brooklyn, Bronx Lebanon Hospital Center, and 
Clinical Directors Network of Region II, which is based in 
Manhattan and also has sites in Newark.

The canceled New York sites account for 59.6 percent of the 
total number of Latinos, 26.7 percent of the total number of 
African Americans, 39.7 percent of the total number of women, 
and 47.2 percent of the total number of injection drug users 
enrolled in CPCRA trials nationally. Moreover, achieving the 
planned enrollment in the tuberculosis prophylaxis and 
treatment trials will be impossible without further accrual 
at the New York sites. 

NIAID has convened a task force to determine the effect the 
defunding will have on TB trials in New York and nationally. 
In addition, state and local officials have questioned the 
fairness of the peer selection process that reviewed the 
performance of CPCRA units and are demanding an investigation 
of how this process was conducted.

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FDA Reaffirms Support for Accelerated Approval
 by David Gold

Freewheeling and emotional testimony was the order of the day 
during a Food and Drug Administration hearing on the "Early 
Availability of Drugs for Serious or Life-Threatening 
Diseases." The September 12 to 13 event, held under the 
auspices of the FDA's Antiviral Drugs Advisory Committee 
provided a stage for a wide range of activists, researchers 
and pharmaceutical company representatives. 

The backdrop to the hearing was discontent among some 
activists and researchers about the accelerated approval of 
ddC and d4T and a proposal by the New York-based Treatment 
Action Group (TAG) for a "large simple trial" (LST) of HIV 
protease inhibitors. (See Treatment Issues, August 1994, 
pages 10-12.) The FDA acknowledged the need for debate about 
the future evolution of the accelerated approval process.

Many of those who testified at the hearings feared that the 
proposal would delay approval of and impede access to 
protease inhibitors. They gave passionate statements 
supporting accelerated approval and the right to access 
experimental therapies for those with life-threatening 
conditions. In response, FDA director David Kessler, M.D., 
strongly reaffirmed his agency's commitment to accelerated 
approval.

In contrast to accelerated approval, the future of the TAG 
proposal seems far less assured. Hoffmann-La Roche and Merck, 
manufacturers of the two most widely studied protease 
inhibitors, claim that the drugs are far too expensive to 
produce for an LST. Large-scale expanded access programs, 
like those set up for ddI, ddC and d4T, are likewise 
extremely unlikely, company officials said.

Yet the TAG proposal did accomplish something significant. It 
focused attention on the lack of real data from which to make 
treatment decisions concerning anti-HIV therapies. Much of 
this gap stems from the failure of the FDA to require 
adequate post-marketing studies of drugs receiving 
accelerated approval.

One committee member, Donald Abrams, M.D., of the University 
of California at San Francisco argued that there probably was 
no real niche for a large, simple trial in the preapproval 
phase of drug development, other than collecting safety data 
at different dosages. But he said that after a drug was 
approved, LSTs could help answer strategy questions such as 
"when to begin, when to combine, and when to switch."

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Cryptosporidia and the Water Supply
 by the GMHC Nutrition Counseling Department

Cryptosporidia are single-cell intestinal parasites that 
cause chronic profuse diarrhea, dull upper abdominal cramps 
and severe weight loss. This infection can be fatal for 
people with severely suppressed immune systems. (See 
Treatment Issues, September 1994, pages 5-6 for an update on 
cryptosporidiosis.) Removing cryptosporidia from water 
requires a filter that removes particles smaller than two 
microns (less than one ten-thousandth of an inch).

New York City's Water

Chlorine in usual amounts does not kill cryptosporidia, and 
New York City does not comply with Environmental Protection 
Agency regulations concerning correct filtration of public 
water supplies.

Trace amounts of cryptosporidia have been found in New York 
City's water supply. (Recent samples contained about one 
organism per 100 gallons of water). These levels may not be 
high enough to harm people with intact immune systems, but 
they can be dangerous for people with HIV, and especially 
AIDS.

Safer Water Sources

- Distilled water is safe.

- Boil all tap water for at least five minutes to make the 
drinking water safe. Lemon or other flavorings may be added 
to improve the taste. Pour into clean, dry containers. 
Dishes, silverware, pots and pans may be washed with tap 
water as long as they are dry before they are used.

- Some bottled "spring water," is filtered well enough to 
trap cryptosporidiosis. The following brands report that they 
use safe filters: Deer Park, Great Bear, Naya, Poland 
Springs, Saratoga, Vivanti, Wissahichon.

- Wash all fresh fruits and vegetables with boiled (and 
cooled), distilled or properly filtered water before eating 
raw.

- Use only boiled, distilled or properly filtered water to 
make ice cubes, dilute fruit juices from concentrate and 
brush your teeth. Beware of beverages and ice cubes at 
restaurants, where they are usually made with tap water.

- Commercially bottled soft drinks and seltzers are 
considered safe. Bottled juices are safe if they have been 
pasteurized and do not require refrigeration before opening.

- Milk is safe if pasteurized. 

- Be careful not to swallow pool or bath water.

Home Water Filtration Systems

Some home water filtration systems can separate out 
cryptosporidia. The following companies claim that their 
products include sufficiently fine filters:

Multi-Pure Drinking Water Systems, 21339 Nordhoff Street, 
Chatsworth, CA 91311. New York City contact: Krae van Sickle, 
212/242-2317 or 516/329-9205

Multi-Pure's models are tested and certified by the EPA and 
the NSF (National Sanitation Foundation). GMHC clients 
receive a $15-$25 discount, depending upon the model. Prices 
range from $189.95 to $329.95.

Everpure Water Treatment Products, 660 N. Blackhawk Drive, 
Westmont, IL 60559, 800/323-7873. New York City contact: Lee 
Hamer, 212/242-1787.

Everpure's models are certified by the NSF to remove 
particles five microns in size. Prices range from $150 to 
$500. GMHC clients, volunteers, and staff are eligible for a 
discount if they call the contact person listed above.

Neolife, 155 West Eighty-first Street, #6H, New York, New 
York 10024, 212/874-6640. The Neolife Water Dome removes 
particles 0.4 microns and larger. Countertop units cost 
$199.50 and undercounter units $387.50.

Equinox, Tres Jordan, 212/421-4247
Equinox filters particles down to one micron in size.

Above all, don't forget to wash and dry your hands before you 
eat or drink!

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Treatment Briefs 
 by David Gold

d4T Trial for Newly Infected

In an apparent effort to expand the limited market for d4T 
(stavudine), Bristol-Myers Squibb is initiating a trial of 
the drug in individuals who have been infected with HIV 
within the past six months. The trial will enroll up to 40 
patients and will use an initial dose of 80 mg twice daily 
for the first month and then 20 mg for the next eleven 
months.

Viral Strain and Long-Term Survivors

More evidence that long-term survivors may have unique viral 
strains of HIV can be seen in a study published in The Lancet 
(September 10, 1994, p. 719-20). In the study, a Red Cross 
transfusion service in Scotland examined rates of disease 
progression in individuals who were infected through blood 
transfusions and whose corresponding donors could be 
identified. The researchers found that if the donor was a 
slow progressor (no AIDS within ten years of infection), the 
transfusion recipient had a significantly greater chance of 
also not developing AIDS within ten years of infection. A 
more rapid progression to AIDS and death was seen in those 
who were infected from the blood of faster progressing 
donors. 

Shameful Wait for HIV Testing in NYC

New York City residents wishing to be tested for HIV through 
the Department of Health's anonymous testing program may have 
to wait as long as ten weeks for an appointment, according to 
a survey by Chuck Sock of GMHC's Department of Treatment 
Education and Advocacy. The survey found that waiting times 
amounted to eight to ten weeks for an appointment at the 
Chelsea testing site, four to six weeks at the Corona, Queens 
site, three to four weeks at the Flatbush, Brooklyn site, and 
two to three weeks at two Harlem sites. Same day appointments 
are available at other sites in Brooklyn, the Bronx, and 
Staten Island. These waiting periods do not include the 
additional two week delay before receiving the test results. 
For information on New York City's HIV testing program, call 
212/447-8200.

Hospital Water May be MAC Risk

Even before widespread concerns about cryptosporidiosis in 
the water supply appeared, a report in The Lancet (1994; 
343(8906):1137-41) suggested that patients at two hospitals 
(one in Boston, the other in New Hampshire) may have been 
infected with mycobacterium avium complex (MAC) while at the 
hospital. According to the researchers, strains of MAC 
isolated from the patients' blood were identical to those 
recovered from the water systems in the hospitals where the 
patients had been admitted before they were diagnosed with 
MAC. The possible sources of exposure to MAC include tap 
water and ice, showers, water used for administration of 
aerosolized pentamidine, and endoscopes or bronchoscopes 
sterilized using the hospital's hot water system. The authors 
recommend that patients with AIDS and CD4 counts of less than 
100 avoid institutional showers and contact with non-sterile 
potable water. They say that MAC-colonized institutional 
water systems should be sterilized using the same measures 
used for legionella.

Report on Clinical AIDS Research at NIH

Derek Link of GMHC's Department of Treatment Education and 
Advocacy has written a report entitled "Current Directions in 
AIDS Research: An Analysis of AIDS Drug and Vaccine 
Development at the NIH." The report provides a detailed 
analysis of the entire clinical research program in AIDS at 
the National Institutes of Health (NIH). According to the 
report, the National Cancer Institute, which is one of seven 
institutes at NIH involved in clinical studies in AIDS, 
currently spends a total of $47.6 million on clinical "AIDS 
research," but $35.9 million of this sum is spent on 
"research infrastructure." A free copy of this report can be 
obtained from GMHC. Call Wendee Rogerson at 212/337-3693.

GMHC Treatment Fact Sheets

The Department of Treatment Education and Advocacy has 
produced a set of easy-to-read treatment fact sheets in 
English and Spanish. The first fact sheet series covers 
toxoplasmosis, cryptosporidiosis, CMV, and MAC. The fact 
sheets describe the signs and symptoms of these illnesses, 
drugs used to treat them, side effects and possible 
prophylaxis. Copies of these treatment fact sheets can be 
obtained by contacting Wendee Rogerson at 212/337-3693.

