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Three HIV-treating physicians in Houston, Texas, express their professional opinions regarding a case scenario.

SCENARIO: A 33-year-old African American female is on her first antiretroviral regimen, which consists of nelfinavir (Viracept), stavudine (Zerit) and lamivudine (Epivir). She has no history of an AIDS-defining illness, is asymptomatic and reports excellent adherence to the drugs. Over the last 2 years, her CD4 T cell count has averaged 400-500 cells/[mm.sup.3] and her viral load has been undetectable (less than 400 copies/mL); however, at the two most recent visits, her viral load has rebounded to 5955 copies/mL and 7384 copies/mL. You request genotypic resistance testing, which shows resistance to lamivudine only, as evidenced by the M184V mutation.

What changes, if any, would you make to this patient's treatment regimen and why?

"This patient is on her first regimen of antiretroviral therapy and now has low-ish detectable viral loads and stable absolute CD4 counts on 2 separate occasions. It is unclear how far apart these tests were done, but there was not a significant rise in the last 2 viral load measurements. If her CD4% values are stable or are increasing, I would hesitate to make any changes. Why? First, resistance testing for HIV is still in its infancy even though it has come a long way. These results show the presence of the M184V mutation, which could have been expected. Also, was a reputable lab performing this test? Should phenotyping be considered before changing out just one drug in this regimen? Would changing only one drug without proving phenotypic resistance breed a more resistant virus? At this point, I favor continuing her current medications."

--Natalie Vanek, MD Baylor College of Medicine

"The first step in assessing a patient who has developed viral rebound after responding to treatment with effective antiretrovirals is to try to discover the reason. Failure can result from drug resistance or decreased drug exposure (usually due to decreased adherence to the drug regimen, but also malabsorption of drug). Therefore, a careful history on drug adherence along with discussions on how to improve adherence is an important first step. Assuming that the patient was adherent, she will need to change her antiretroviral regimen. Since she has only failed a single regimen, there are many options fi)r the next line of therapy. Since the genotype does not show resistance to nelfinavir or stavudine, there is a temptation to continue these medications and switch the lamivudine. I do not think that there is enough published literature on this approach to justify its widespread use, and there is a wealth of data suggesting that changing a single drug may predispose the patient to further relapses.

"I would be particularly reluctant to continue nelfinavir. There are several trials of salvage therapy for patients like this who are early failures with nelfinavir. The regimens that have been best documented to work in this context are built on a backbone of ritonavir (Norvir) and saquinavir (Fortovase) along with nucleoside reverse transcriptase inhibitors (NRTIs). However, combinations of ritonavir with either amprenavir (Agenerase) or indinavir (Crixivan) should also be very potent. I probably would encourage the use of ritonavir/saquinavir or ritonavir/amprenavir and reserve ritonavir/indinavir for the third regimen. Nonnucleoside reverse transcriptase inhibitors (NNRTIs) are a potent component in salvage therapy. However, I would tend to avoid them at this particular stage because of the fairly good chance that the patient will eventually require a third regimen and the limited effectiveness of third regimens for patients who are NNRTI and protease inhibitor (PI) experienced.

"In terms of the NRTIs, the patient's virus is lamivudine resistant and this drug should be changed. However, the genotypic sensitivity suggests that the stavudine may still offer some effectiveness. Other NRTI combinations to consider at this point include: stavudine/didanosine (Videx), stavudine/abacavir (Ziagen), didanosine/zidovudine (Retrovir) and zidovudine/abacavir. My preference would be for one of the abacavir containing regimens. A key to successful therapy at this point is to design a regimen that the patient will take. Therefore, it is critically important to involve the patient in the choice of medication. She would need to know the major side effects of each of the medications as well as the pill burden, food restrictions and fluid requirements."

--Clinton White, MD Baylor College of Medicine

"I can think of several options. I am sure that I would discuss them with the patient before taking the final one. Lately, I have become more conservative and may wait before making changes in the antiretroviral regimen, assuming the CD4 counts are maintained. How long to wait? I would not let the viral load go beyond 10,000 copies/mL. I think that it is easier to rescue failing patients with low viral loads (less than 10,000 copies/mL). Another option is to intensify the regimen since the viral load is below 10,000 copies/mL. Abacavir or didanosine could be one option. There is only one pilot study exploring the combination of nelfinavir 500 or 750 mg with ritonavir 400 mg. Thus, ritonavir could potentially be used to enhance nelfinavir's PK [pharmacokinetics], yet it has to be explored further and I would not use this combination until more clinical data are available. Finally, I would consider changing all antiretroviral drugs to a new regimen. Which combination? Efavirenz (Sustiva) plus zidovudine/didanosine or plus zidovudine/abacavir is a good and easy-to-take option. I would reserve a dual PI combination for the future."

--Roberto Arduino, MD The University of Texas Medical School
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Publication:Research Initiative/Treatment Action!
Date:Jun 1, 2000
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