David Ho proposes immunotherapeutic vaccination to help the immune system clear the long-lived “3rd” compartment of HIV-infected cells. These latently infected CD4+ T-cells with integrated HIV DNA currently represent the greatest obstacle to the potential eradication of HIV infection. And a British study may just beat him to the punch: Frances Gotch (London) reported that her group will randomize patients to HAART plus 1) an immunomodulator, 2) the Salk (Immunogen) vaccine, 3) both or 4) placebo.
On the other side of the Atlantic, Dr. Luc Montaigner proposes the use of an HIV-nef vaccine in order to immunize uninfected persons from productive infection with HIV. In an open plenary lecture at the Sixth European Conference on Clinical Aspects and Treatment of HIV Infection in Hamburg, Germany (October 11-15), the official discoverer of HIV explained that HIV’s regulatory proteins nef and tat are responsible for the continual propagation of what would ordinarily be a containable infection with HIV. Montaigner’s goal: by inactivating nef early on, the pool of activated CD4+ cells susceptible to infection would be small enough for — perhaps — the body’s own immune response to clear the initial infection.
Jean-Pierre Sommadossi (UAB) presents compelling evidence of what is being called “pharmacologic resistance” to the entire nucleoside class of drugs after long-term AZT use. Changes in the cellular metabolism of AZT resulted in reduced efficacy of the other nucleoside analogue agents. Whether or not — or to what extent — this sort of pharmacologic resistance develops after prolonged use of the other nukes (and other classes of antiretroviral agents) is not known.
On behalf of the Delta coordinating committee, London’s A. Babiker showed that changes in CD4+ T-cells and HIV plasma RNA levels break down as surrogate markers over the long term. “Similar RNA responses with different treatments do not have similar associations with clinical outcome,” Babiker explained. He speculates that a large part of this dis-association is likely due to the increased toxicity of combination regimens — ill-effects not directly captured by changes in viral load or T-cell counts.
Scott Eastman, speaking at one of the many commercial “satellite” symposia during the two days prior to the Hamburg meeting, presented disturbing data about the variation in blood levels of different antiretroviral drugs. It’s not just indinavir where you see significant variation in plasma drug levels, Eastman explained. While plasma levels of indinavir varied up to 8-fold, plasma levels of 3TC and nevirapine were also found to vary significantly (3-5 fold).
Two-year follow-up of the high-profile Merck 035 study provides both good news and disconcerting news, depending on how carefully you look at the data. While the number that made it into the newspapers was “80% still undetectable at 2 years,” that’s using the bDNA assay with a lower limit of detection of 500 copies/mL. Using the more sensitive Roche UltraDirect assay (with a lower limit of 20 copies/mL), the proportion of 035 patients with “undetectable” plasma HIV RNA fall to 60%. (Which is beginning to look more like INCAS!) While experts disagree on how significant the difference between <500 and <20 copies/mL is, emerging clinical data are becoming more and more convincing that a nadir of <20 assures a significantly more durable response to treatment.
In a French study of similar design called AVANTI 2, which treated drug naïve patients with the same triple combo (AZT+3TC+indinavir), the proportion of study participants with plasma HIV RNA < 20 copies/mL at 52 weeks was also 60% — the same proportion seen at 2 years in 035’s AZT-experienced population.
A study of indinavir in combination with DMP-266 found that 82% of the IDV+DMP recipients whose RNA fell to between 1-400 copies/mL experienced viral rebound (defined as any RNA measurement > 400 copies/mL) within 100 days of initiation of treatment compared to only 25% of patients whose plasma viral load fell to < 1 copy/mL after initiation of the double combination treatment. The ultra, ultra sensitive assay used in this study was the new (experimental) Amplicor assay.
