The objective of this study was to assess the phenotypic susceptibility of HIV-1 subtype C isolates, with nonnucleoside reverse transcriptase inhibitor (NNRTI) resistance-associated amino acid changes, to newer NNRTIs. A panel of 52 site-directed mutants and 38 clinically derived HIV-1 subtype C clones was created, and the isolates were assessed for phenotypic susceptibility to etravirine (ETR), rilpivirine (RPV), efavirenz (EFV), and nevirapine (NVP) in an in vitro single-cycle phenotypic assay. The amino acid substitutions E138Q/R, Y181I/V, and M230L conferred high-level resistance to ETR, while K101P and Y181I/V conferred high-level resistance to RPV. Y181C, a major NNRTI resistance-associated amino acid substitution, caused decreased susceptibility to ETR and, to a lesser extent, RPV when combined with other mutations. These included N348I and T369I, amino acid changes in the connection domain that are not generally assessed during resistance testing. However, the prevalence of these genotypes among subtype C sequences was, in most cases, <1%. The more common EFV/NVP resistance-associated substitutions, such as K103N, V106M, and G190A, had no major impact on ETR or RPV susceptibility. The low-level resistance to RPV and ETR conferred by E138K was not significantly enhanced in the presence of M184V/I, unlike for EFV and NVP. Among patient samples, 97% were resistant to EFV and/or NVP, while only 24% and 16% were resistant to ETR and RPV, respectively. Overall, only a few, relatively rare NNRTI resistance-associated amino acid substitutions caused resistance to ETR and/or RPV in an HIV-1 subtype C background, suggesting that these newer NNRTIs would be effective in NVP/EFV-experienced HIV-1 subtype C-infected patients. Highly active antiretroviral therapy (HAART), which comprises the concomitant use of multiple potent antiretroviral drugs, has contributed to a significant decrease in the morbidity and mortality of people infected with HIV-1 (1). The failure of HAART through the acquisition of HIV drug resistance-associated substitutions that cause a decrease in viral susceptibility is usually due to poor adherence and insufficient drug concentrations. Although more than two-thirds of the global HIV-1 infections occur in sub-Saharan African countries, where HIV-1 infections are dominated by non-B subtypes, HAART regimens have largely been developed and tested against HIV-1 subtype B isolates (2). Subtype C accounts for almost half of all global infections and dominates the epidemic in southern Africa (3). While HAART agents are effective against all subtypes (4), greatly aiding the global response to HIV infection, specific resistance mutations and disparities in drug susceptibilities can differ by subtype (5). Examples include the K65R (6) and V106M (7) resistance-associated amino acid substitutions, which develop more frequently under drug pressure in HIV-1 subtype C than subtype B.Nonnucleoside reverse transcriptase (RT) inhibitors (NNRTIs) are a component of most first-line HAART regimens. For efavirenz (EF...

Surveillance of human immunodeficiency virus type 1 transmitted drug resistance (TDR) was conducted among pregnant women in South Africa over a 5-year period after the initiation of a large national antiretroviral treatment program. Analysis of TDR data from 9 surveys conducted between 2005 and 2009 in 2 provinces of South Africa suggests that while TDR remains low (<5%) in Gauteng Province, it may be increasing in KwaZulu-Natal, with the most recent survey showing moderate (5%-15%) levels of resistance to the nonnucleoside reverse transcriptase inhibitor drug class.

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