Virologic and Immunologic Consequences of Discontinuing Combination Antiretroviral-Drug Therapy in HIV-Infected Patients with Detectable Viremia [Deeks SG, et al. NEJM 2001;344:472]: The authors report sequential changes in CD4 cell counts, viral load, and resistance test results in patients taking antiretroviral therapy with viral loads of at least 2500 c/mL. There were 16 patients randomized 2:1 for discontinuation of therapy. Changes in viral load, CD4 count, and susceptibility test results were measured weekly. At 12 weeks, discontinuation of treatment was associated with a median decrease in CD4 cell count of 128/mm3, and a median increase in HIV RNA level of 0.84 log₁₀ c/mL. Loss of PI resistance was initially noted at six weeks. All isolates showed full susceptibility to PIs at 16 weeks. Laboratory tests showed that viral replicative capacity was low at baseline and increased after therapy was stopped. Despite the loss of resistance in HIV isolates in plasma, resistance was found in cultures of PBMC. Controls who continued HAART had stability in CD4 cell counts, HIV RNA levels, and in drug susceptibility test results. The authors conclude that, despite resistance and virologic failure, antiretroviral therapy provides immunologic and virologic benefit.
Comment: This is the report from San Francisco General Hospital that most of us have heard presented at various meetings. The results indicate that, despite virologic failure with resistance, there was rapid virologic rebound and CD4 cell loss when "ineffective therapy" was stopped. Virologic rebound was associated with "wild-type virus" that was usually drug-sensitive and "more fit." Viral fitness refers to the replication capacity of the virus, which was demonstrated in 5 of 9 isolates in vitro, which correlates with the in vivo observations. The presumed mechanism is that the mutations that confer PI resistance also reduce replication capacity, an observation that has been reported previously [J Virol 1999;73:3744; J Virol 1998;72:3300]. There are several practical applications of these data: 1) continued HAART may successfully suppress more fit, drug-sensitive forms of HIV; 2) discontinuation of HAART for virologic failure may result in rapid decline in CD4 cell count and rapid increase in viral load; 3) despite the return of sensitive strains, resistant isolates of HIV persist as minor species, and 4) resistance testing after viral rebound will not detect the resistant minor species. The median time from discontinuation of therapy to reversion from PI resistance to susceptibility was six weeks. Dr. Deeks, and colleagues reported follow-up data on this cohort at the 8th CROI in Chicago, February 2001 [Abstract 292]. Patients who had therapy discontinued started salvage and at 24 weeks had a median increase in CD4 cells of 77/mm³ and a median decrease in VL of 1.9 log₁₀ c/mL.
posted 3/1/2001

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