Resistance patterns selected by nevirapine vs. efavirenz in HIV-infected patients failing first-line antiretroviral treatment: a bayesian analysis

Abstract

Background: WHO recommends starting therapy with a non-nucleoside reverse transcriptase inhibitor (NNRTI) and two nucleoside reverse transcriptase inhibitors (NRTIs), i.e. nevirapine or efavirenz, with lamivudine or emtricitabine, plus zidovudine or tenofovir. Few studies have compared resistance patterns induced by efavirenz and nevirapine in patients infected with the CRF01_AE Southeast Asian HIV-subtype. We compared patterns of NNRTI- and NRTI-associated mutations in Thai adults failing first-line nevirapine- and efavirenz-based combinations, using bayesian statistics to optimize use of data.

Methods and findings: In a treatment cohort of HIV-infected adults on NNRTI-based regimens, 119 experienced virologic failure (>500 copies/mL), with resistance mutations detected by consensus sequencing. Mutations were analyzed in relation to demographic, clinical, and laboratory variables at time of genotyping. The Geno2Pheno system was used to evaluate second-line drug options. Eighty-nine subjects were on nevirapine and 30 on efavirenz. The NRTI backbone consisted of lamivudine or emtricitabine plus either zidovudine (37), stavudine (65), or tenofovir (19). The K103N mutation was detected in 83% of patients on efavirenz vs. 28% on nevirapine, whereas Y181C was detected in 56% on nevirapine vs. 20% efavirenz. M184V was more common with nevirapine (87%) than efavirenz (63%). Nevirapine favored TAM-2 resistance pathways whereas efavirenz selected both TAM-2 and TAM-1 pathways. Emergence of TAM-2 mutations increased with the duration of virologic replication (OR 1.25-1.87 per month increment). In zidovudine-containing regimens, the overall risk of resistance across all drugs was lower with nevirapine than with efavirenz, whereas in tenofovir-containing regimen the opposite was true.

Conclusions: TAM-2 was the major NRTI resistance pathway for CRF01_AE, particularly with nevirapine; it appeared late after virological failure. In patients who failed, there appeared to be more second-line drug options when zidovudine was combined with nevirapine or tenofovir with efavirenz than with alternative combinations.

Figure 1. Frequency of resistance mutations observed in subjects failing nevirapine- or efavirenz (EFV)-based treatment.

(a) NNRTI resistance mutations and (b) NRTI resistance mutations observed in 89 subjects failing nevirapine- and 30 failing efavirenz (EFV)-based treatment.

Figure 2. Posterior distributions of the log odds ratios of analyzed parameters for each resistance mutation.

Median posterior distributions, 50%- and 90%-credibility intervals are represented. Distributions are based on 1000 simulations using WinBUGS software. In parentheses are reported the number of patients for which the mutation was observed. A. Distributions of the log odds ratios of efavirenz vs. nevirapine-based HAART. Points to the left of the zero vertical line indicate a greater frequency of the indicated mutation in NVP-based regimens, and points to the right of the zero vertical line in EFV-based regimens. B. Distributions of the log odds ratios of tenofovir (TDF) vs. d4T-based backbone. Points to the left of the zero vertical line indicate a greater frequency of the indicated mutation in d4T-based regimens, and points to the right of the zero vertical line in TDF-based regimens. C. Distributions of the log odds ratios of zidovudine (ZDV) vs. d4T-based backbone. Points to the left of the zero vertical line indicate a greater frequency of the indicated mutation in d4T-based regimens, and points to the right of the zero vertical line in ZDV-based regimens. D. Effect of duration of failure. Distributions of the log odds ratios of one additional month spent on failure. Points to the left of the zero vertical line indicate a greater frequency of the indicated mutation when failure is one-month shorter, and points to the right when failure is one-month longer. E. Effect of viral load at genotype. Distributions of the log odds ratios of each resistance mutation for one additional log of HIV RNA copy/mL. Points to the left of the zero vertical line indicate a greater frequency of the indicated mutation when viral load at genotype is one log lower, and points to the right when viral load is one log higher.

Figure 3. Dendrograms showing correlations between resistance mutations for both nevirapine- and efavirenz-based HAART groups.

The distance between clusters is defined as 1-Pearson correlation adjusted for backbone treatment, and failure duration. Smaller distance indicates greater correlation between mutations (clustering). A. Correlations between NNRTI resistance mutations. B. Correlations between NRTI resistance mutations. Asterisks (*) and (**) indicate respectively TAM-1 and TAM-2 mutations.

Figure 4. Posterior distribution estimates of the probabilities to belong to resistant subpopulation after virologic failure.

Probabilities of resistance to 3TC, ABC, EFV, NVP, TDF, ZDV, d4T and ddI are shown. Based on a simulated sample (n = 5000), boxplots display median (solid square with circle), 25th and 75th percentiles (wide horizontal line), 90% credibility interval (narrow line), and outliers (small circles) for nevirapine (blue boxplots) vs. efavirenz (red boxplots). A. Failure on treatment with d4T-based backbone, B. Failure on treatment with zidovudine-based backbone. C. Failure on treatment with tenofovir-based backbone.