Resistance profile and cross‐resistance of HIV‐1 among patients failing a non‐nucleoside reverse transcriptase inhibitor‐containing regimen*

Abstract

The objectives were to determine the resistance profile and the rate of cross-resistance in HIV-1 infected patients failing an efavirenz or a nevirapine or a nevirapine then efavirenz containing regimens, and to investigate if zidovudine and more generally thymidine analog nucleosides lead to a particular genotypic pattern in nevirapine failing patients. A study was conducted in 104 patients with virological rebound to a non-nucleoside reverse transcriptase inhibitors (NNRTI) regimen (efavirenz n = 39, nevirapine n = 46 and nevirapine then efavirenz n = 19). Genotypic resistance testing was carried out of detectable plasma HIV-1 RNA (> 200 copies/ml). Among the 104 patients studied, only two patients failed to respond to the nevirapine regimen without selection of a NNRTI resistance mutation. All patients failing an efavirenz regimen harboured mutations conferring cross-resistance to nevirapine (K103N, Y188L, G190S). Among patients failing the nevirapine regimen and presenting with NNRTI mutations, 35 (80%) harboured mutations conferring cross-resistance to efavirenz (K101E, K103N, Y188L) and 9 (20%) harboured mutations conferring resistance to nevirapine alone (V106A and Y181C). In patients failing nevirapine then efavirenz therapy, all NNRTI resistance profile led to cross-resistance to all available NNRTIs. Among patients receiving nevirapine, the selection of mutations associated with a cross-resistance to efavirenz was more frequent statistically when a thymidine nucleoside analog (zidovudine or stavudine) was used in the regimen (P = 0.02). In conclusion, 100% of patients developed cross-resistance to nevirapine and efavirenz after treatment by efavirenz and 80% after treatment by nevirapine. The use of a thymidine analog concomitantly with nevirapine leads to the preferential selection of cross-resistance NNRTI mutations.

Interruption of Nonnucleoside Reverse Transcriptase Inhibitor (NNRTI) Therapy for 2 Months Has No Effect on Levels of Human Immunodeficiency Virus Type 1 in Plasma of Patients Harboring Viruses with Mutations Associated with Resistance to NNRTIs

“…In fact, in all patients, viruses in plasma harbored NNRTI and NRTI resistance mutations (Table 1). These results agree with previous studies that have shown the quasisystematic presence of NNRTI resistance mutations associated with failure of NNRTI regimens (4,5,7). Viral load (Roche Amplicor HIV-1 Monitor assay 1.5), CD4 cell counts (flow cytometric analysis [Coulter]), and genotype (automated population-based full-sequence analysis [ABI System]) were determined at day 0 (the time of NNRTI interruption) and then at days 15, 30, and 60.…”

“…According to these authors, mutations such as V106A, G190C/S/E/Q, P225H, M230L, and P236L can reduce replication capacity to various degrees. However, these mutations are not the most frequently selected or are usually associated with primary substitution in clinical context (4)(5)(6)(7). In fact, depending on the NNRTI compound used, primary mutations such as K103N, Y181C/I, Y188C, and G190A are the most common substitutions selected in NNRTI regimen failure (6).…”

Molecular Mechanism of Antagonism between the Y181C and E138K Mutations in HIV-1 Reverse Transcriptase

“…However, one major limitation of narrow-spectrum NNRTIs is that they have a low genetic barrier for resistance, and a single mutation, such as K103N, is able to cause cross-resistance to all the drugs in this class (12,18). Resistance to narrow-spectrum NNRTIs can develop quickly if low-grade HIV replication is permitted to occur, and this has spurred efforts to discover newer NNRTIs that have improved potency and a higher genetic barrier for resistance.…”

TMC125 Displays a High Genetic Barrier to the Development of Resistance: Evidence from In Vitro Selection Experiments

“…However, the utility of the currently licensed NNRTIs is limited by the relatively easy selection of single mutations that alone can confer large reductions in susceptibility to the drug: i.e., they are characterized by a low genetic barrier to the development of resistance. This disadvantage is compounded by cross-resistance across the class (4,11), which makes sequential therapy with the currently licensed NNRTIs clinically inappropriate (3). Resistance to NNRTIs among HIV-1-positive patients receiving antiretroviral therapy is widespread, and the prevalence of transmitted NNRTI resistance is also increasing in some populations (14,17,26,33).…”