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AIDS Treatment News
Combination Treatment and Single Drugs: Interview with
John S. James
July 7, 1995
AIDS TREATMENT NEWS #226, July 7, 1995

Margaret Poscher, M. D., is an internist in private practice with Quest, a five-physician medical group in San Francisco. Dr. Poscher is also Assistant Clinical Professor, University of California Medical Center, and Director of HIV Clinical Services, University of California Mt. Zion.

ATN: Which antiretroviral combinations do you most use or prefer? Dr. Poscher: I am disappointed that there is still not much published information on combination therapy. I was on the fence about combinations for a number of years. But in the last two years, and especially with viral load assays now available, it has become clear that combination treatment is incredibly important. I don't think I have any patients on monotherapy, except for some on d4T.

My favorite combination now is AZT plus 3TC. I foresee that as being initial therapy, when 3TC is approved; patients who have CD4 (T-helper cell) counts below 500, or have a certain threshold level of HIV RNA, will be started immediately on this combination.

At this point, with patients who are asymptomatic and have a relatively high CD4 count, and a moderate viral load, between 10,000 and 100,000 copies of RNA, I am starting those patients on AZT plus ddI, or AZT plus ddC. They make the decision of ddC or ddI, based on my description of the two drugs. I tend to prefer ddI, as I have not been impressed with ddC as an antiviral.

This week I had a patient who recently seroconverted, and in a big way -- with several million copies of HIV RNA, a big dip in his CD4 count, and who continues to have over 100,000 copies of RNA. In 1995 there is concern about people becoming infected with AZT-resistant virus. So we discussed potentially starting him on d4T as initial therapy, and using d4T with either ddI or 3TC. I think that d4T with ddI is a very good combination, especially in people with higher T-cells, who tend not to get neuropathy as easily as advanced patients.

In patients I've had on AZT plus 3TC who have developed complications -- especially anemia, the big complication I have seen, especially in patients with more advanced disease -- I've had success switching them to d4T plus 3TC.

Occasionally I will use the triple combination AZT plus 3TC plus ddI; this is based on Dr. St. Clair's report at the 2nd National Conference on Human Retroviruses and Related Infections (January 29 -- February 2, 1995, in Washington, D. C.) on laboratory studies with this combination. Since then there has been a question raised about possible antagonism between ddI and 3TC, but this is not yet substantiated. With these untested combinations, we do have to be careful about unknown potential antagonisms.

ATN: Any other thoughts about which patients are the best candidates for which treatments? Dr. Poscher: It is probably also important to look at the viral load. People with very high levels of HIV RNA, I would be more likely to put on a triple combination. Some patients may want to start therapy very early; they may only have 15 or 20 thousand copies of RNA, and CD4 counts of 500 or above; you might even consider monotherapy for somebody like that. Or I might put them on AZT plus ddC, as ddC is easier to take that ddI. With high viral loads, I would dose higher, and give more drugs, at least initially, until the viral load drops.

ATN: On doses, do you tend toward the lower end of the standard range? Dr. Poscher: I tend to give low doses. For AZT, I give 300 or 400 mg per day total. With ddC, I refuse to use the 0.75 mg tablet; my experiences with ddC back when it was in parallel track was that higher doses just meant more neuropathy and more anemia when used with AZT. So I tend to stick to 0.375 mg of ddC three times a day.

With ddI I also use low doses, because of problems with pancreatitis which I saw when the drug was parallel track; my cohort of patients had close to a 20 percent incidence of pancreatitis. But that is when we were using total daily doses of 750 to 900 mg. Now I tend to give 250 mg of ddI once per day. I was sad to see the 375 mg sachet taken away, because I had many patients on 375 mg once per day. I dose it once a day for convenience for the patient; most patients cannot find two times in a day when they have an empty stomach, since usually they are trying to eat as much as they can to maintain their weight. To try to fast for an hour to be able to take ddI twice a day usually means missing a meal, at one end of the day or other. So I encourage them to take it in the middle of the night, if they wake up to urinate, as they often do. If you make it easy for people, they are more likely to take the drug; it is better for them to get one good dose in than skip it altogether because it's inconvenient.

ATN: What differences do you see with therapy naive patients, vs. those who have been on AZT for a long time? Dr. Poscher: It's like night and day; it is significantly different. I think 3TC is the one exception, where you can add it to AZT and still get some mileage out of the AZT. I have completely given up on adding either ddI or ddC to a patient who is already on AZT; I think that is a waste of time. When you start a naive patient on antiretroviral treatment early on, that is where those two drugs have a role -- but not in somebody who has been on AZT for three or four years. The only drugs I could see adding then would be 3TC, or potentially a protease inhibitor if that were available.

For patients who are on AZT and not eligible for 3TC today because they have a CD4 count over 100, I usually switch them to d4T, usually to a combination of d4T and ddI.

ATN: Do you switch them all at once to the combination, or do you start one drug first? Dr. Poscher: All at once. Some patients are hesitant; they want to try one drug and start at a low dose and get used to it. But I encourage people to go for it, take both drugs full dose from day one.

Acyclovir ATN: What about other antivirals, such as acyclovir, or oral ganciclovir prophylaxis? Dr. Poscher: I'm pro acyclovir -- absolutely for people who have a known history of herpes, or zoster. I have all of them on suppressive doses of acyclovir, 400 mg twice daily. A few patients don't want to take it; they are usually patients who have never had herpes or zoster outbreaks. Still I encourage them to consider it, as I think there are other herpes viruses which are not clinically apparent which are exerting some effect. And acyclovir is safe; there is no major drawback to using it. In the six years I have been in private practice, I have seen two cases of acyclovir-resistant herpes, after treating many people with acyclovir.

Oral Ganciclovir Oral ganciclovir for CMV prophylaxis, I am still ambivalent about. I am concerned about the potential for resistance; I think it is far more likely with ganciclovir and CMV, than with acyclovir and herpes. I have had a couple patients who have been on protocols for oral ganciclovir prophylaxis and have then developed CMV, and it has been a nightmare. One patient was resistant to everything; oral ganciclovir led to ganciclovir resistance, and before he saw foscarnet he was foscarnet resistant, and he was also resistant to HPMPC.

My thinking now is that there are better therapies coming for CMV, such as local therapies through injection or eye implants. With these we have a better chance of conserving retina, which I think is the important thing, than through years of treatment with oral ganciclovir and its complications. So I am leaning to not using oral ganciclovir in patients who have no CMV whatsoever, and to be careful with ophthalmologic followup -- frequent eye exams, and alerting people to symptoms of CMV retinitis.

I would use oral ganciclovir in patients who had end-organ CMV disease -- CMV esophagitis, colitis, gastritis -- but have not yet developed retinitis. Here you might use oral therapy as secondary prophylaxis essentially -- as those patients will probably develop retinitis within six to 12 months.

For treatment of CMV retinitis, people often do well with oral ganciclovir, after an initial course of IV induction treatment. I have had a couple patients recently who have gone one year without a recurrence, on oral ganciclovir.

Other, Miscellaneous Potential HIV Treatments ATN: Are there other therapies that many of your patients are on, such as experimental immune modulators? Dr. Poscher: I have probably a dozen who continue to use DNCB. Many continue to be on the TP-5 protocol. A few are interested in the Cytolin, a mouse monoclonal antibody; I have not seen enough on that to form an opinion. I think the enthusiasm for IL-2 has diminished; nobody has asked about it in months.

Thalidomide is the newest. I used it several times over the past several years, in patients with oral aphthous ulcers, and found it to be a very easy drug to take. The patients I had who were maintained on thalidomide seemed to do very well; I used to wonder if maybe the thalidomide was doing something for them [vs. HIV disease, not only vs. the ulcers]. So I'm encouraged that we at least have access to it now, as a potential treatment for wasting, and possibly for MAC, since it has been used in the treatment of leprosy for decades now. [See "Thalidomide and HIV: Several Possible Uses," by Denny Smith, AIDS TREATMENT NEWS #221, April 21, 1995.] ATN: What kinds of changes are you seeing in CD4 and viral load with the different combination therapies? Dr. Poscher: One therapy naive patient had avoided starting antiretroviral therapy for years, and his CD4 count kept going down. Finally I insisted that he do the HIV RNA test. His count was greater than 1,600,000. He decided to go into a clinical trial of PMEA; when he finally started that treatment, his viral load was still over a million, and his CD4 count had dropped below 200. He was a perfect example of an antiretroviral naive patient who was put on the mid dose of PMEA, and his viral load went from over a million to 30,000, and his CD4 count went from less than 200 to over 500, after six weeks on PMEA. He is now on AZT plus 3TC, and doing very well.

I have seen at least one log (ten fold) viral load reductions with d4T and 3TC. And when the RNA goes down, the CD4 count goes up. Usually it does not last -- but I find that people often reach a new plateau. They get a big increase, and then it comes down a little, and they stay at that new plateau, a little higher than they originally were, for a good six months, or longer in some cases. I've seen people go from well over 100,000 copies of HIV RNA, to under 10,000 copies.

[Part II of this interview will look at possible side effects of combination treatment, treating a sudden CD4 drop, and reimbursement and managed-care issues.]