International Conference and Clinical Practice: Interview with Kenneth Mayer, M. D.

Kenneth H. Mayer, M. D., an infectious disease specialist,
is the director of the Brown University AIDS program, and
research director at the Fenway Community Health Center in
Boston. We asked Dr. Mayer to outline some of the clinical
"bottom lines" of the Eighth International Conference on
AIDS (in Amsterdam, July 1992), information that can help
physicians today in treating persons with HIV. [To make
this interview easier for non-physicians, AIDS Treatment
News added explanatory notes in brackets.]

JJ: Looking back after two months, what do you see as the
most important information from the International Conference for
physicians treating HIV disease today?

KM: "What the general media didn't report about Amsterdam
is that certain clinical questions are closer to being resolved,
but there are still many questions related to standards of care.
Two major pragmatic issues are: combination antiretrovirals,
given the drugs that are currently approved; and when to
prophylax specific opportunistic infections.

"Much of how you change your practice is nuance. I function
as a specialist, I am not doing primary care; I generally see
patients in consultation and advise their primary care doctors.
I try to individualize recommendations for each person; some
patients want to be on as few drugs as possible, and others want
to pursue all possible leads, depending on how symptomatic the
persons are and their perception of where they are with their
infection. You have to respect these choices and work with
people on each issue. Much of the data that informs clinical
practice is fragmentary and evolving, often more slowly than we
would like."

JJ: What is most important now in anti-HIV treatments?

KM: "One change will be parallel-track access for
stavudine, or d4T. [This program will be for persons without
approved treatment options; for more information about d4T, see
AIDS Treatment News #159, September 18, 1992]. Several of us at
Brown did a phase I trial, and were impressed early on that while
the neuropathy could be problematic, we could cut back on doses
and at times restart people after we had to stop. Eventually, we
are all looking forward to new kinds of drugs, such as protease
and tat inhibitors, but we can't bank on them yet, given the
paucity of human trial data. With later- phase studies of d4T
looking good, we will have another option for now. The long-term
T-helper data that Lisa Dunkle, M. D., presented on this drug
looks promising for many individuals. We hope this will be a
nucleoside analog that is not associated with pancreatitis and
may have better efficacy than others. It may be one of the more
important nucleoside analogs by itself."

KM: "Then we have the concern raised by the presentation of
David Cooper, M. D., on treating people with much higher T-
helper counts than when we are accustomed to begin therapy.
Should we start nucleoside analogs even before the T-helper count
drops to 500? Because there weren't many deaths or disease
progressions in that study, what he reported was time to drop of
T-helper count. Those with T-helper counts over 500 who were
randomized to AZT did have a delay in their T- helper drop.

"This one study does not make me start putting everybody
with T-helper counts over 500 on AZT. But we should be open to
the possibility that in the future, standard of care might be
single-drug treatment initially [at any T-helper count], then
starting to add drugs as the counts decline. But that is a leap
of faith. Some people have already made that leap; I am not
there. But it is hard to reject drug intervention out of hand.
If a patient came to me and wanted to start AZT at a higher T-
helper count, at least we have this promising data, but concerns
about resistance, cost, possible chronic toxicities, and whether
it really gives any clinical benefit in the long term, have to be
considered as well.

"Regarding combinations, multi-arm studies are now ongoing;
we are waiting for results of ACTG 155 and ACTG 175 [clinical
trials conducted by the AIDS Clinical Trials Group of the U. S.
National Institute of Allergy and Infectious Diseases] to get a
better feel for how and when to start combining. Robert Yarchoan,
M. D., presented data comparing combination treatment with AZT
plus ddI, vs. alternating treatment with those drugs [the
combination seemed to work better]. I don't think it puts the
nail in the coffin on alternating these drugs, but it makes me
feel more comfortable combining them.

"I still recommend monotherapy on AZT if people do not want
to participate in trials and are asymptomatic and have T-helper
counts less than 500. If the T-helper count does not stay stable
over the next few months, I have a lower and lower threshold for
adding another nucleoside analog. Depending on where their T-
helper count is at that time and their clinical status, there are
a number of people I put on ddC per indication, but there are
times when peoples' counts have dropped rapidly and I put them on
AZT plus ddI, now that this combination is prescribable. Their
rate of change, their clinical history, makes me decide to use
one drug or the other."

JJ: Do you usually prefer ddC or ddI for combination with
AZT?

KM: "I feel frustrated that there is not enough data yet to
make the decision. If there is any concern with the pancreas,
the data would push me toward ddC. On the other hand, if there's
a fairly rapid drop in T-helper counts, I have extrapolated from
the data to add ddI instead of ddC at times, since ddI is looking
so promising as monotherapy. There isn't enough data because
there have not been adequate studies. When ACTG and CPCRA [the
Community Program for Clinical Research on AIDS, which conducts
community-based trials sponsored by the U. S. National Institute
of Allergy and Infectious Diseases] results are available, I will
feel more strongly about using one or the other.

JJ: What about adding acyclovir to HIV treatment? That
seems to be continually controversial.

KM: "The acyclovir issue is a tricky one. The study which
got so much press at first in the Times of London [in December
1991] and was reported by Mike Youle, M. D., at the International
Conference found a survival benefit but not a decrease in CMV
retinitis. The question is what is the acyclovir doing? Perhaps
it is stopping subclinical reactivation of members of the
herpesvirus family, and therefore reducing transactivation of
HIV. [See "Activation of Human Immunodeficiency Virus by Herpes
Simplex Virus," The Journal of Infectious Diseases, September
1992, pages 494-499.] It is also possible that subclinical CMV
disease may cause organ dysfunction or susceptibility to other
opportunistic infections; maybe we are not detecting it because
we are using such an advanced endpoint, CMV retinitis. There
have been studies with different doses of acyclovir that have not
shown clear-cut benefit; here we see survival benefit. The drug
continues to impress me; aside from the cost, it is well
tolerated, and I have not seen it impede peoples' care. There is
the issue of how many pills people are willing to take, but now
that there is an 800-mg acyclovir pill, this is less of a
problem, taking three or four or even five of those pills a day.

"One question that remains is whether the new acyclovir
prodrug can have a role in CMV prophylaxis; it is going into a
trial in the ACTG. [A prodrug is a pharmaceutical that turns into
an effective drug inside the body. The advantage of the
acyclovir prodrug, BW 256U87, is that it allows larger doses to
be given orally than would be possible with acyclovir itself.
Acyclovir may have a very small anti-CMV effect.]

"We still don't understand the biology [of acyclovir's
benefit with HIV disease], but if something nontoxic has survival
benefit I am happy to use it, but not entirely clear when to. If
somebody's T-helper count is down and they have been on maximal
antiretroviral therapy, or if acyclovir is something the patient
requests, I increasingly add it in to the regimen. But it is
hard to base a standard of care on one study with a survival
benefit but not a clear-cut mechanism. There is biological
plausibility, and we want to maximize quality of life, and how
well people do over the long haul."

JJ: What are the most important conference results on
opportunistic infections?

KM: "Some of the most useful information at the
International Conference was on macrolide antibiotics and MAC.
Also, Lowell Young, M. D., and colleagues had a paper in The
Lancet [November 2, 1991] on azithromycin and MAC. R. E.
Chaisson, M. D., and colleagues had particularly interesting data
on clarithromycin at 500, 1000, and 2000 mg twice a day. The
decrease in MAC bacteremia [in the blood] was impressive, and it
happened quickly. The sobering data is that resistance did
develop fairly quickly, so I do not think that single-drug
therapy with either of the newer macrolides [clarithromycin or
azithromycin] is a good idea. It is certainly important to treat
this infection; data from Stephen Nightingale, M. D., showed that
there are very many MAC cases. People with low T-helper counts
are living longer, and therefore this disease is a major source
of illness and death. Aggressive treatment with macrolides is
clearly indicated. The question is, is it macrolide plus one
drug? Chaisson said ethambutol; many of us would also use other
oral agents. One thing the macrolides have done is to make it
less likely for clinicians to use amikacin or other injectable
aminoglycosides.

"You can easily give a four-drug regimen with azithromycin
or clarithromycin, ethambutol, ciprofloxacin, and then either
rifampin or clofazimine. One of the issues on which drugs to use
is whether to hold some in reserve because of the emergence of
multidrug resistant MAC; that will be a hard one to sort out.
There is also the issue of cross-resistance when people are at
risk of getting tuberculosis; there is concern about using any
rifamycin in that situation.

"Concerning MAC prophylaxis [as opposed to treatment], one
of the concerns of the FDA and its advisory committee has been
that rifabutin might increase the probability of developing
rifampin-resistant TB. The data is not at all clear; it is a
theoretical concern." [Note: the Antiviral Drug Products
Advisory Committee recommended approval of rifabutin for MAC
prophylaxis on September 24, 1992, the day before this interview
was conducted; the FDA will almost certainly approve the drug.]

JJ: What is your practice now when somebody needs to start
clarithromycin or azithromycin for MAC? What other drugs do you
use?

KM: "I would always add ethambutol and ciprofloxacin; when
it was hard to get clofazimine I was adding rifampin, now I am
adding clofazimine. At least those four. With five or more
drugs, it gets onerous in cost and toxicity. Many physicians
feel three would be enough; I would be happy to cut back. Studies
of optimum combinations are underway. The other things you have
to consider are which other drugs the patient has used or is
currently using.

"One important value of the data from Adria Laboratories
[which conducted trials on rifabutin for MAC prophylaxis] is the
good epidemiological information, showing, for example, at which
T-helper counts people are likely to get MAC bacteremia. Very
few above 100 developed it. But people with T-helper counts
below 100 were also likely to be on multiple other medications,
or to have other complications. If somebody has abnormal liver-
function tests, for example, I certainly will not give them
rifampin. And I do not think it would be wise to give full-dose
ethambutol to somebody who had CMV retinitis, because the drug
can cause ocular toxicity; even though it is a different kind of
toxicity [than the damage CMV retinitis causes], one would not
want to take any chance of impairing somebody's vision. You
balance the regimen according to these kinds of considerations."

JJ: What about rifabutin, which will probably be approved
for prophylaxis soon?

KM: "I put a couple people on the treatment IND [for early
access to rifabutin before its marketing approval] in the past,
and will use the drug when it is approved. I have been concerned
that some physicians, even without a positive blood culture for
MAC, have put people on clarithromycin or azithromycin because of
the low T-helper count and the ease of writing a prescription.
These are broad-spectrum and very useful drugs, but resistance
can develop rapidly.

"In the rifabutin trials, for ethical reasons, people were
not kept on placebo after they developed MAC bacteremia. Because
they were offered rifabutin and could also use other drugs, these
trials would not show differences in survival. And unless you
have autopsies, you may not be able to prove that MAC was the
cause of death. But MAC bacteremia often indicates that people
are severely ill, so I do not feel that I would be treating a
laboratory value [meaning that people should start treatment for
MAC (with more than one drug) if a positive blood culture is
found, even if there are no MAC symptoms yet].

"The idea of MAC prophylaxis is that you would like to start
early [before a positive blood culture]. In my mind, early
enough is when the T-helper count is close to 100. I tend not to
put many people on rifabutin with T-helper counts between 150 and
200. Again it would depend on the individual case, e.g. the
presence of otherwise unexplained constitutional symptoms or
laboratory abnormalities [which might justify rifabutin
prophylaxis at higher T-helper counts]."

JJ: What about other opportunistic infections?

KM: "One concern is the intestinal parasites. There was
data at the International Conference about better diagnostic
techniques for microsporidiosis. One question is how much of the
AIDS-related intestinal disease may be caused by undiagnosed
infectious agents.

"For cryptosporidiosis, there was some promising data on
albendazole. And for patients with higher T-helper counts, many
have had good experience with paromomycin [Humatin, a readily
available prescription drug]. But not everybody responds to this
drug; we clearly need better ones. Macrolides may be helpful
here.

"On toxoplasmosis, there was data suggesting that
sulfonamide drugs used for pneumocystis prophylaxis or for other
purposes seemed to have some protective effect against toxo. A
European study looked at dapsone plus weekly pyrimethamine, an
interesting approach. The pyrimethamine issue is still
confusing, because there are people who are sulfonamide or
sulfone intolerant and cannot be desensitized, so we want to know
how effective pyrimethamine could be alone or in combination.
There was a CPCRA study which suggested that pyrimethamine for
toxo prophylaxis could be detrimental, but the mechanism was not
clear. Perhaps use of folinic acid (leucovorin) might be helpful
there. We need more information on toxoplasmosis prophylaxis;
trials are looking at it both in the U. S. and in Europe.

"The big issue in opportunistic infections is that we need
large-scale multi-site trials of multiple OI prophylaxis
regimens. Which ones give the broadest spectrum of prevention
with the best tolerance, also considering drug interactions, and
real-world issues of ease of administration and cost?

"The other group of infections that need much more study are
fungi. At what T-helper count should one consider fluconazole
prophylaxis? Should the recommendation be gender-specific?

"We are studying fluconazole prophylaxis of mucosal fungal
infections in HIV-infected women. The CPCRA network is also
doing a study; they are looking at a once-weekly dose, and we are
trying smaller doses three times a week, 50 mg Monday, Wednesday,
and Friday. It might be that antifungal prophylaxis should begin
when T-helper counts are low, but the optimal starting point is
unclear. This issue needs to be sorted out. Also, when should
fluconazole be used to prevent cryptococcal disease -- or other
disseminated mycoses?"

JJ: Such as histoplasmosis, in some areas? In San
Francisco we seldom see it.

KM: "We rarely see cases in Boston, but in the South, and
parts of the Midwest, it is a big problem. And in Arizona and
some parts of California, coccidioidomycosis [valley fever] is a
big issue as well."

JJ: What else from the international conference comes to
mind?

KM: "The therapeutic vaccine data looked promising to me,
as an adjunctive therapy in keeping peoples' T-helper counts
higher. There were several good presentations. The followup [on
people using some of the vaccines] is getting to be long enough
that I am looking forward to expanded-access trials. We are very
eager to participate in community-based therapeutic vaccine
studies, based on the Amsterdam data.

"The other treatment I thought was very promising -- I have
prescribed it occasionally on an individual basis -- is
pentoxifylline. Bruce Dezube, M. D., and colleagues did show
reduction in viral load. That was impressive. I think quality
of life measurements are important. We want people to feel
better, even if we are only palliating them, as long as we are
not causing any detriment immunologically. That pentoxifylline
made a difference in HIV replication was important; I am looking
forward to seeing more intensive studies and a better definition
of the population where it will be beneficial. [For more
information on pentoxifylline and the report at the conference,
see AIDS Treatment News #156, August 7, 1992, pages 4-5.]

"I think ICAAC will be a good conference for information on
followup to Amsterdam." [For information on ICAAC, the
Interscience Conference on Antimicrobial Agents and Chemotherapy,
which will be held October 11-14 in Anaheim, California, see AIDS
Treatment News #159, September 18, 1992].

"Progress has been incremental -- slower than we would like,
but there were more practical developments at the conference than
were generally reported. Hopefully a new U. S. administration
will be able to mobilize the resources and cooperation needed for
a more efficient process to get treatments from the lab to the
patient."