Comparison of HIV drug resistance profiles across HIV-1 subtypes A and D for patients receiving a tenofovir-based and zidovudine-based first line regimens in Uganda

Abstract

Background: Resistance to antiretroviral drugs is a major challenge among Human Immunodeficiency Virus (HIV) positive patients receiving antiretroviral therapy (ART). Mutations that arise as a result of this are diverse across the various drugs, drug classes, drug regimens and subtypes. In Uganda, there is a paucity of information on how these mutations differ among the different drug regimens and the predominant HIV-1 subtypes. The purpose of this study was to determine mutation profile differences between first-line drug regimens: TDF/3TC/EFV and AZT/3TC/EFV and HIV-1 subtypes: A and D in Uganda. The study also investigated the potential usage of rilpivirine, doravirine and etravirine in patients who failed treatment on efavirenz. Methods: A retrospective study was conducted on 182 archived plasma samples obtained from patients who were experiencing virological failure between 2006 and 2017 at five Joint Clinical Research Center (JCRC) sites in Uganda. Sanger sequencing of the Reverse Transcriptase (RT) gene from codons 1-300 was done. Mutation scores were generated using the Stanford University HIV Drug Resistance Database. A Chi-square test was used to determine the association between drug resistance mutations (DRMs) and drug regimens or HIV-1 subtypes. Results: The prevalence of DRMs was 84.6% among patients failing a first-line efavirenz (EFV)-based regimen. The most prevalent Nucleoside Reverse Transcriptase Inhibitor (NRTI) mutations were M184V/I (67.3%), K219/Q/E (22.6%) and K65R (21.1%). While K103N (50.8%) and G190A/S/E/G (29.1%) were the most prevalent Non-Nucleoside Reverse Transcriptase Inhibitor (NNTRI) mutations. As expected, discriminatory DRMs such as K65R, L74I, and Y115F were noted in Tenofovir (TDF) containing regimens while the Thymidine Analogue Mutations (TAMs) L210W and T215 mutations were in Zidovudine (AZT)-based regimens. No significant difference (p = 0.336) was found for overall DRMs between HIV-1 subtypes A and D. Among the patients who had resistance to EFV, 37 (23.6%) were susceptible to newer NNRTIs such as Rilpivirine and Etravirine.

Nationwide Study of Drug Resistance Mutations in HIV-1 Infected Individuals under Antiretroviral Therapy in Brazil

“…Strikingly, in our nationwide work in Brazil we found that K65R was the only SDRM that followed an accentuated increase in prevalence over the studied years (2.23% in 2008 to 12.11% in 2017). The increasing and preferential usage of TDF in the clinical practice [ 21 ], including in a context of a failing regimen, could be the primordial reason for the significant expansion of K65R as other studies show a higher prevalence of this mutation in patients failing ART treatment [ 15 , 52 , 53 , 54 , 55 ]. However, although an increasing trend was identified in a cohort from India [ 56 ], several studies report a decrease on K65R levels over the years in other countries [ 48 , 57 , 58 , 59 , 60 ].…”

<p>Doravirine and Its Potential in the Treatment of HIV: An Evidence-Based Review of the Emerging Data</p>

“…When this group was analyzed for crossresistance to the other NNRTIs, only 25.2% (n=36) were susceptible to etravirine and rilpivirine and 15.4% (n=22) were susceptible to doravirine. 22…”

HIV and Drug-Resistant Subtypes

“…Reduced viral sensitivity to zidovudine largely results from an accumulation of mutations, with a mutation at codon 70 (K70R) emerging first, followed by codon 215 substitutions (T215Y or T215F) and mutations at codon 41(M41L) [ 71 , 72 ]. The combination of mutations 215 and 41 confers the highest level of zidovudine resistance.…”