The public health approach to identify antiretroviral therapy failure: high-level nucleoside reverse transcriptase inhibitor resistance among Malawians failing first-line antiretroviral therapy

Abstract

Background Over 150 000 Malawians have started antiretroviral therapy (ART), in which first-line therapy is stavudine/lamivudine/nevirapine. We evaluated drug resistance patterns among patients failing first-line ART on the basis of clinical or immunological criteria in Lilongwe and Blantyre, Malawi. Methods Patients meeting the definition of ART failure (new or progressive stage 4 condition, CD4 cell count decline more than 30%, CD4 cell count less than that before treatment) from January 2006 to July 2007 were evaluated. Among those with HIV RNA of more than 1000 copies/ml, genotyping was performed. For complex genotype patterns, phenotyping was performed. Results Ninety-six confirmed ART failure patients were identified. Median (interquartile range) CD4 cell count, log10 HIV-1 RNA, and duration on ART were 68 cells/μl (23–174), 4.72 copies/ml (4.26–5.16), and 36.5 months (26.6–49.8), respectively. Ninety-three percent of samples had nonnucleoside reverse transcriptase inhibitor mutations, and 81% had the M184V mutation. The most frequent pattern included M184V and nonnucleoside reverse transcriptase inhibitor mutations along with at least one thymidine analog mutation (56%). Twenty-three percent of patients acquired the K70E or K65R mutations associated with tenofovir resistance; 17% of the patients had pan-nucleoside resistance that corresponded to K65R or K70E and additional resistance mutations, most commonly the 151 complex. Emergence of the K65R and K70E mutations was associated with CD4 cell count of less than 100 cells/μl (odds ratio 6.1) and inversely with the use of zidovudine (odds ratio 0.18). Phenotypic susceptibility data indicated that the nucleoside reverse transcriptase inhibitor backbone with the highest activity for subsequent therapy was zidovudine/lamivudine/tenofovir, followed by lamivudine/tenofovir, and then abacavir/didanosine. Conclusion When clinical and CD4 cell count criteria are used to monitor first-line ART failure, extensive nucleoside reverse transcriptase inhibitor and nonnucleoside reverse transcriptase inhibitor resistance emerges, with most patients having resistance profiles that markedly compromise the activity of second-line ART.

First and Second Line Highly Active Anti-Retroviral Therapy Failure in HIV Infected Nigerian Children at University of Abuja Teaching Hospital Gwagwalada, Nigeria

“…In adults, the criteria have been shown to be insensitive measures for virologic outcomes [10,11], and a high prevalence of ARV resistance mutations has been documented in HIV-infected adults by the time they progress to meet the WHO criteria for ARV therapy switch [12]. A recent report showed same similarity in pediatric WHO guidelines, where it has been found to offer an insensitive measure of virologic failure [13].…”

Extensive Drug Resistance in HIV-Infected Cambodian Children Who Are Undetected as Failing First-Line Antiretroviral Therapy by WHO 2010 Guidelines

“…Frequent misclassification of virological failure in adult patients has been reported, leading to early ART switch or late failure diagnosis. [3][4][5] In the latter circumstances, by the time treatment failure is recognized, patients may have already accumulated drug resistance mutations and high-level cross-resistance to subsequent antiretroviral regimens. [6][7][8] Minimizing resistance is particularly important in RLS with limited ART options, usually restricted to first-line nonnucleoside reverse transcriptase inhibitor (NNRTI)-based and second-line protease inhibitor (PI)-based regimens.…”

Impact of HIV Type 1 Subtype on Drug Resistance Mutations in Nigerian Patients Failing First-Line Therapy

“…It has been shown that the mutational pathways to drug resistance to nucleoside reverse transcriptase inhibitor (NRTI) drugs may vary among different HIV-1 subtypes. [9][10][11][12][13][14] In addition, non-B subtype HIV genomes carry subtype-specific polymorphisms that act as minor mutations in subtype B, particularly in the protease gene. [15][16][17] The impact of these genetic differences on the clinical response to antiretroviral therapy has yet to be fully assessed.…”