Abstract
BackgroundResistance 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.MethodsA 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.ResultsThe 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.ConclusionAccumulation of DRMs between AZT/3TC/EFV and TDF/3TC/EFV is comparable but individual mutations that confer resistance to particular drugs should be considered at virological failure. Having either HIV-1 subtype A or D is not associated with the acquisition of DRMs, therefore HIV diversity should not determine the choice of treatment. Rilpivirine, etravirine and doravirine had minimal benefits for patients who failed on efavirenz.
Highlights
Resistance to antiretroviral drugs is a major challenge among Human Immunodeficiency Virus (HIV) positive patients receiving antiretroviral therapy (ART)
Some of the regimens with a low genetic barrier are used in Uganda’s treatment guidelines, these contain nucleoside backbones in combination with EFV, boosted PIs or Integrase inhibitors [11]. At virologic failure, it appears that TDF/3TCcontaining regimens fail with M184V plus K65R [9] whereas AZT-containing regimens fail with the occurrence of Thymidine Analog Mutations (TAMs) [13, 14]
Findings from this study have shown that 84.6% of the patients had drug resistance mutations (DRMs) conferring resistance to at least one class of drugs and 73.6% had resistance to both Nucleoside Reverse Transcriptase Inhibitor (NRTI) and Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI) classes of drugs
Summary
Resistance to antiretroviral drugs is a major challenge among Human Immunodeficiency Virus (HIV) positive patients receiving antiretroviral therapy (ART). Regimens with a high genetic barrier to resistance [e.g. boosted protease inhibitors (PIs) give sustained viral suppression and resistance to such drugs develops over a prolonged period These drugs may be compromised by other factors such as adverse drug events or other treatment-limiting factors (e.g. lipid alterations)] [9]. Some of the regimens with a low genetic barrier are used in Uganda’s treatment guidelines, these contain nucleoside backbones (such as TDF/3TC or AZT/3TC) in combination with EFV, boosted PIs or Integrase inhibitors [11] Despite their use, at virologic failure, it appears that TDF/3TCcontaining regimens fail with M184V plus K65R [9] whereas AZT-containing regimens fail with the occurrence of Thymidine Analog Mutations (TAMs) [13, 14]
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