Drug Susceptibility and Resistance Mutations after First-Line Failure in Resource Limited Settings

Carole Wallis, Evgenia Aga, Heather Ribaudo, Shanmugam Saravanan, Michael Norton, Wendy Stevens, Nagalingeswaran Kumarasamy, John Bartlett, David Katzenstein, on behalf of the A5230 team
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Background. The development of drug resistance to nucleoside (NRTI) and non-nucleoside reverse transcriptase inhibitors (NNRTI) has been associated with baseline HIV-1 RNA level (VL), CD4 cell counts (CD4), subtype, or treatment failure duration. This study describes drug resistance and levels of susceptibility after first-line virologic failure in subjects from Thailand, South Africa, India, Malawi and Tanzania.

Methods. CD4 and VL were captured at ACTG5230 study entry, a study of lopinavir/ritonavir (LPV/r) monotherapy after first-line virologic failure on a NNRTI regimen. HIV drug resistance mutation associations with subtype, site, study entry VL and CD4 were evaluated by Fisher's exact and Kruskall-Wallis tests.

Results. Of the 207 individuals that were screened for A5230, sequence data were available for 148 subjects. Subtypes observed were subtype C (n=97, 66%) followed by AE (n=27, 18%); A1 (n=12, 8%) and D (n=10, 7%). Of the 148 subjects, 93% (n=138) and 96% (n=142) had at least one RT mutation associated with NRTI and NNRTI resistance, respectively. The number of NRTI mutations was significantly associated with a higher study screening VL and lower study screening CD4 (p<0.001). Differences in drug resistant patterns in both NRTI and NNRTI were observed by site.

Conclusions. The degree of NNRTI and NRTI resistance after first-line virologic failure was associated with higher VL at study entry; only 32% of subjects remained fully susceptible to etravirine and rilpivirine, protease inhibitor resistance was rare. Some level of susceptibility to NRTI remained; however, VL monitoring and earlier virologic failure detection may result in lower NRTI resistance.