Impact of drug resistance genotypes on CD4+ counts and plasma viremia in heavily antiretroviral‐experienced HIV‐infected patients

Abstract

The number of HIV-infected individuals with prior multiple treatment failures is increasing as time passes by. The success of antiretroviral therapy in these patients is often compromised by the selection of drug-resistant viruses. Despite initial concerns, a rebound in AIDS cases among heavily treatment-experienced patients failing virologically their antiretroviral therapy has not occurred yet. In a multicenter study conducted in Spain, HIV-infected patients were assessed with prior failure to antiretrovirals from the three main drug families who presented during the last semester of the year 2003 with plasma HIV-RNA values above 1,000 copies/ml, despite good treatment adherence. The relationships between CD4+ T cell counts, viral loads and drug-resistant genotypes were examined. A total of 273 patients were identified in 12 centers (78% male, median age: 41 years). The mean viral load was 50,438 copies/ml and the mean CD4+ count was 328 cells/mul. Only 19.5% had less than 200 CD4+ T cells/mul. Most patients (95%) were receiving nucleoside reverse transcriptase inhibitors (NRTI) in their last antiretroviral regimen, while 63% were treated with protease inhibitors (PI) and 27% on non-nucleoside reverse transcriptase inhibitors (NNRTI). Overall, 97.4% had at least one drug resistance mutation (87.2% for NRTI, 68.5% for NNRTI, and 92.7% for PI). Using the virtual phenotype, resistance to three or more drugs within each class was recognized in 45.8% for NRTI, 40.7% for NNRTI, and 44.7% for PI. Moreover, cross-resistance to compounds from two or three drug families was recognized in 41% and 19.4% of patients, respectively. Nearly half of the patients had plasma HIV-RNA below 10,000 copies/ml and they showed significantly higher CD4 + counts than those with greater viremia (408 versus 259 cells/mul; P < 0.001). Patients with higher plasma viremia had significantly more drug resistance mutations than those with lower viremia. No favorable effect on viral load could be recognized for individual drug resistance mutations known to reduce viral fitness in vitro (i.e., rtM184V, rtL74V, rtK65R, proD30N, or proI50L). In summary, a large proportion of treatment-experienced patients failing their current antiretroviral regimen carry viruses with broad cross-resistant genotypes. Nearly half of the patients with these multi-drug resistant viruses had < 10,000 HIV-RNA copies/ml and 80% have more than 200 CD4 + T cells/mul. Thus, maintaining treatment HIV-infected individuals failing virologically and harboring drug-resistant viruses might ameliorate immunological deterioration until new drugs became available. J. Med. Virol. 77:23-28, 2005. (c) 2005 Wiley-Liss, Inc.