AIDS Treatment News #160, October 2, 1992
John S. James

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."

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