Differential persistence of transmitted HIV-1 drug resistance mutation classes

Abstract

Background: Transmitted human immunodeficiency virus type 1 (HIV-1) drug resistance (TDR) mutations can become replaced over time by emerging wild-type viral variants with improved fitness. The impact of class-specific mutations on this rate of mutation replacement is uncertain.

Methods: We studied participants with acute and/or early HIV infection and TDR in 2 cohorts (San Francisco, California, and São Paulo, Brazil). We followed baseline mutations longitudinally and compared replacement rates between mutation classes with use of a parametric proportional hazards model.

Results: Among 75 individuals with 195 TDR mutations, M184V/I became undetectable markedly faster than did nonnucleoside reverse-transcriptase inhibitor (NNRTI) mutations (hazard ratio, 77.5; 95% confidence interval [CI], 14.7-408.2; P<.0001), while protease inhibitor and NNRTI replacement rates were similar. Higher plasma HIV-1 RNA level predicted faster mutation replacement, but this was not statistically significant (hazard ratio, 1.71 log(10) copies/mL; 95% CI, .90-3.25 log(10) copies/mL; P=.11). We found substantial person-to-person variability in mutation replacement rates not accounted for by viral load or mutation class (P<.0001).

Conclusions: The rapid replacement of M184V/I mutations is consistent with known fitness costs. The long-term persistence of NNRTI and protease inhibitor mutations suggests a risk for person-to-person propagation. Host and/or viral factors not accounted for by viral load or mutation class are likely influencing mutation replacement and warrant further study.

Figure 1.

Kaplan-Meier plot of cumulative probability of mutation replacement over time in different classes of transmitted drug resistance mutations among 75 patients followed up from early infection. Probabilities of mutation replacement for each of 6 mutation groups are plotted against the number of antiretroviral treatment–free days since the estimated date of HIV infection, as follows: Lamivudine/emtricitabine-associated mutations M184V/I (solid black line), TAMs M41l/D67N/K70R/L210W/T215Y/F/K219Q/E (solid gray line), T215 revertant mutations T215C/D/E/I/S/V (black dotted line), other nucleoside reverse-transcriptase inhibitor (NRTI) mutations (gray dotted line), nonnucleoside reverse-transcriptase inhibitor (NNRTI) mutations (black dashed line), and protease inhibitor (PI) mutations (gray dashed line). TAM, thymidine analog-associated mutations.