Association between hiv-1 subtypes and drug resistance to first line therapy among individuals with advanced disease in Homa bay county, Kenya

Abstract

Human Immunodeficiency Virus-1 remains a public health threat globally, and although antiretroviral therapy has greatly improved the lives of people living with HIV, challenges persist due to high HIV genetic diversity and drug resistance. Analysis of HIV-1 subtypes over time demonstrates high subtype diversity and dynamic changes with variations in drug resistance among different HIV-1 subtypes. Homa Bay County carries one of the highest HIV-1 burdens worldwide, yet up-to-date information on circulating subtypes and subtype-specific drug resistance is lacking. The general objective of this study was to determine the association between HIV-1 subtypes and drug resistance to first-line ART among individuals with advanced disease in Homa Bay County. The study specifically sought to characterize HIV-1 subtypes and recombinants, to determine HIV-1 subtype-specific drug-resistance mutations, and to determine HIV-1 subtype-specific polymorphisms associated with drug resistance among HIV-1 patients on first-line ART in Homa Bay County, Kenya. A facility-based, cross-sectional survey was conducted, enrolling individuals aged 15 years and above, with advanced HIV-1 disease, and who had been on first-line ART for at least 6 months. The sample size determined using Cochran's formula was 70 participants. Plasma samples were analyzed using CAP/CTM real-time PCR for HIV-1 viral load and genotyping was performed on dried blood spots for samples with a viral load ≥1000 copies/mL. A genetic analysis of a 1,084-bp fragment of the HIV-1 pol gene encoding amino acids 6-99 of the protease (PR) and 1-251 of the reverse transcriptase (RT) region from 65 participants was performed using an in-house assay. Drug resistance was determined using the Stanford University HIV Database. Subtypes were identified using phylogenetic analysis and REGA subtyping tool. Fisher’s exact test was used to assess the association between subtypes and drug-resistance mutations. Samples with a significant association were subjected to logistic regression analysis, controlling for regimen. The findings revealed that subtype A1 was most prevalent in 46 patients (70.8%), with lower prevalence rates for subtype D (n=9, 13.8%), recombinants (n=6, 9.2%) and A2 (n=4, 6.2%). No statistically significant association was observed between subtypes and nucleoside reverse transcriptase inhibitor (NRTI) mutations or polymorphisms. However, a notable finding was the lower likelihood of observing NNRTI mutations K101E/H and Y181C/I/V, associated with high-level resistance to Nevirapine (NVP) and Efavirenz (EFV), in subtype A1 than in other subtypes (OR=0.14, 95% CI=0.03-0.60 and OR=0.21, 95% CI=0.06-0.72, respectively). This analysis found that HIV-1 subtypes are associated with resistance mutations, with K101 and Y181 less likely in subtype A. This suggests that areas with a high prevalence of subtype A1 may experience reduced compromised efficacy of NVP and EFV as first-line ART options. This implies that ART choice may need to be tailored to the HIV-1 subtypes. However, further investigations with large sample sizes and longitudinal designs are warranted to confirm this and assess the clinical impact of these subtype-specific differences to inform ART regimen policies effectively.