Abstract
HIV-Integrase (IN) has proven to be a viable target for highly specific HIV-1 therapy. We aimed to characterize the HIV-1 IN gene in a South African context and identify resistance-associated mutations (RAMs) against available first and second generation Integrase strand-transfer inhibitors (InSTIs). We performed genetic analyses on 91 treatment-naïve HIV-1 infected patients, as well as 314 treatment-naive South African HIV-1 IN-sequences, downloaded from Los Alamos HIV Sequence Database. Genotypic analyses revealed the absence of major RAMs in the cohort collected before the broad availability of combination antiretroviral therapy (cART) and INSTI in South Africa, however, occurred at a rate of 2.85% (9/314) in database derived sequences. RAMs were present at IN-positions 66, 92, 143, 147 and 148, all of which may confer resistance to Raltegravir (RAL) and Elvitegravir (EVG), but are unlikely to affect second-generation Dolutegravir (DTG), except mutations in the Q148 pathway. Furthermore, protein modeling showed, naturally occurring polymorphisms impact the stability of the intasome-complex and therefore may contribute to an overall potency against InSTIs. Our data suggest the prevalence of InSTI RAMs, against InSTIs, is low in South Africa, but natural polymorphisms and subtype-specific differences may influence the effect of individual treatment regimens.
Highlights
HIV-Integrase (IN) has proven to be a viable target for highly specific HIV-1 therapy
CART has led to the development of resistance-associated mutations (RAMs) and transmitted drug resistances (TDRs), which are associated with a higher rate of virological failure[3,4,5]
Being in concordance with the World Health Organisations (WHO) guidelines, the recommended first-line combination antiretroviral therapy in South Africa consists of a non-nucleoside reverse transcriptase inhibitor (NNRTI) backboned regimen of Efavirenz (EFV), combined with two nucleoside reverse transcriptase inhibitors (NRTIs), namely Lamivudine (3TC) and either Tenofovir Disoproxil Fumarate (TDF) for adults or Abacavir (ABC) for children, respectively
Summary
HIV-Integrase (IN) has proven to be a viable target for highly specific HIV-1 therapy. In 2007, the first INSTI RAL was approved for the treatment of patients infected with HIV-1, followed by EVG in 2012 These first-generation InSTIs are highly effective in the treatment of HIV-1-infected patients, but have a low barrier to resistance, resulting in the rapid emergence of RAMs14,15. DTG is a second-generation InSTI that was approved by the FDA in 201416 It has a higher resistance barrier than that of RAL and EVG17. When compared to an EFV based first-line regimen, patients receiving DTG have shown to be superior regarding viral suppression rates and had stabilized CD4+ T-Cell counts[20]. This is mainly attributed to better adherence and fewer discontinuation rates under treatment. The recommended second-line cART consists of the nucleoside reverse transcriptase inhibitors (NRTIs) Zidovudine (AZT) and Lamivudine (3TC) and a Ritonavir-boosted (/r) Protease Inhibitor (PI), usually Atazanavir[23]
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