Emerging resistance to nonnucleoside reverse transcriptase inhibitors: a warning and a challenge.

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TWO DECADES AFTER THE RECOGNITION OF THE HUman immunodeficiency virus (HIV) epidemic, the potential for widespread treatment of HIV infection is now at a pivotal, yet precarious time. In the United States and Europe, patients with HIV infection are living longer without acquired immunodeficiency syndrome (AIDS)–defining illnesses, new highly active antiretroviral therapy (HAART) strategies are being developed and tested, and resistance testing is becoming a new standard for managing therapy after failure with HAART. Yet in much of the developing world, most notably sub-Saharan Africa, HIV and AIDS are devastating innumerable communities. At a time when the introduction of HAART in Africa is in its infancy, 2 articles in this issue of THE JOURNAL illustrate the crucial role the nonnucleoside reverse transcriptase inhibitors (NNRTIs), as well as the implications of NNRTI resistance, will play in the treatment of HIV in both developed and developing countries. The study by Hammer et al is a randomized controlled trial comparing dual vs single protease inhibitor (PI) therapy in 481 patients who failed HAART treatment. The investigators demonstrated that the addition of a second PI to an amprenavir (PI)/efavirenz (NNRTI)–based regimen decreased the HIV-1 RNA level to less than 200 copies/mL in 35% of patients, compared with 23% in the placebo plus an amprenavir/efavirenz-based regimen group at 24 weeks (P=.002), and 30% vs 22% (P=.04), respectively, at 48 weeks. There was a modest increase in the CD4 cell count in the second PI group vs the placebo group at 24 weeks (+34/μL vs +13/μL; P=.048), but the 2 groups had similar increases at 48 weeks. However, a more intriguing finding was the association of virologic failure with NNRTI experience and efavirenz resistance. Forty-three percent of NNRTI-naive patients achieved an HIV-1 RNA level of less than 200 copies/mL at 24 weeks compared with 16% of NNRTIexperienced patients (P .001). Moreover, reduced susceptibility to efavirenz was associated with decreased virologic suppression, and efavirenz hypersusceptibility was associated with virologic response to treatment. This is a striking finding given that all 4 classes of antiretrovirals (ARVs) were used in this study. The effectiveness of the NNRTI class is impressive but not surprising. Patients treated with an NNRTI-based regimen were significantly more likely to achieve an undetectable viral load and had better outcomes at 6 months when compared with PI-based regimens in 888 ARV-naive patients. In a study of 450 patients comparing efavirenz plus 2 nucleoside reverse-transcriptase inhibitors (NRTIs) vs indinavir (a PI) plus 2 NRTIs, the efavirenz-based regimen achieved undetectable HIV-1 RNA levels in 70% of the patients, compared with 48% with the indinavir-based regimen (P .001). The NNRTIs have been used successfully both in combination with PI-based regimens and in multidrug salvage therapy for patients who did not respond to PI-based regimens. Numerous studies also have shown that switching from a PI-based regimen to an NNRTI regimen results in decreased rates of virologic failure, decreased rates of ARV adverse effects, increased rates of adherence, and increased quality of life. However, emerging resistance to the NNRTI class of drugs may be increasing, especially when the drugs are administered in nonsuppressive regimens or as single-dose prophylaxis. In another study in this issue of THE JOURNAL, Grant et al performed genotype and phenotype analysis on HIV isolates obtained from 225 patients in San Francisco with acute HIV infection from 1996 through 2001. The salient observation in this study was the marked increase in NNRTI resistance in HIV isolates even before ARV therapy was initiated. Genotype mutations conferring resistance increased from 0% in 1996-1997 to 13.2% in 2000-2001 (P=.01), and phenotypic resistance increased from 0% to 9.9% (P=.02). In contrast, PI genotypic resistance increased less dramatically and phenotypic resistance to NRTIs actually decreased. A similar study from the United Kingdom demonstrated that primary NNRTI resistance increased from 0 of 22 individuals