HIV-1 subtype-specific drug resistance in patients failing dolutegravir-based first-line, second-line or third-line regimens: multiregional study

Dolutegravir (DTG) based antiretroviral therapy is the preferred antiretroviral regimen for initiation among persons with HIV disease. Recent WHO treatment guidelines also recommend Dolutegravir based antiretroviral regimen for failure of first line NNRTIs based regimen. WHO has estimated that around 20 million persons with HIV are receiving dolutegravir antiretroviral regimen globally. Dolutegravir has a high genetic barrier to resist and suppress HIV rapidly. There is a limited data available on the prevalence of dolutegravir resistance mutations among patients failing dolutegravir based antiretroviral regimens. Hence this study is carried out with the following aims and hypotheses.

Aims and hypotheses

Aim #1: To determine the patterns and spectrum of InSTI DRMs in adults and adolescents with virologic failure on DTG-based ART by ART regimen and HIV-1 subtype.

Hypothesis: The patterns and spectrum of InSTI DRMs at the time of virologic failure will differ by HIV-1 subtype and by treatment context.

Objective: (i) To identify the prevalence of InSTI DRMs at the time of virologic failure. (ii) To compare the prevalence of InSTI DRMs at the time of virologic failure between HIV-1subtypes and treatment contexts.

Aim #2: To identify risk factors for virologic failure, InSTI DRMs, and InSTI drug resistance in adolescents and adults on DTG-based ART, including drug, host and health system factors.

Hypothesis: Male sex, younger age, previous exposure to InSTI drugs, 2nd/3rd-line ART or advanced disease, exposure to rifampicin, and lack of routine viral load monitoring are risk factors for virologic failure, and – upon virologic failure – the development of InSTI DRMs, and the emergence of DTG drug resistance.

Objective: To identify risk factors for VF. To identify risk factors for DRMs.

Aim #3: To investigate correlations between novel resistance genotypes and phenotypic DTG resistance across HIV-1 subtypes.

Hypothesis:

The HIV-genotypes identified in patients failing on DTG based ART confer high-level phenotypic resistance. The resistance mutations accumulate along subtype-specific pathways, and their effect on phenotypic DTG resistance will differ by HIV-1 subtype.

Mutations outside the HIV-1 integrase contribute to DTG resistance.

Objectives: (i) To verify the phenotypic relevance of the observed resistance patterns. (ii) To identify the phenotypic effect of mutations in the HIV integrase on the sensitivity to DTG across subtypes. (iii) To determine the patterns of clinically relevant HIV-1 drug resistance mutations across different HIV-1 subtypes, focusing on DTG resistance, and to identify the phenotypic effect of mutations in the 3’ polypurine tract (PPT). (iv) To identify novel pathways or mutations relevant for DTG resistance by exploratory analyses such as a viral Genome-Wide Association Study (GWAS) or Conjunctive-Bayesian-Network (CBN).

Primary and secondary endpoints

For aim #1, the endpoints are (number and type of) InSTI DRMs at the time of failing a DTG- based regimen. For aim #2 we are assessing determinants (HIV-1 subtype, treatment context, sex, age, previous InSTI exposure, disease status, exposure to rifampicin, previous virologic failure, other detected drug resistances, and programmatic factors [routine viral load monitoring] for failing the treatment (VL > 1000 copies/mL), developing InSTI DRMs, or emerging DTG drug resistance. For aim #3 we identify the phenotypic resistance of observed patterns of DRMs quantified as the fold change of IC50 (concentration at which viral replication is reduced by 50%) to DTG.

We will consecutively recruit eligible individuals attending the site Out patient clinic. We will include

• adults aged 18 years or older

• on any DTG-based ART regimen

• who develop virologic failure (VF) defined as a VL >1000 copies/mL (single or confirmed measurement),

• and have signed the informed consent.

The study duration is 3 years.