Antiretroviral resistance testing in HIV-positive people

Resistance to antiretroviral therapy (ART) among people living with human immunodeficiency virus (HIV) compromises treatment effectiveness, often leading to virological failure and mortality. Antiretroviral drug resistance tests may be used at the time of initiation of therapy, or when treatment failure occurs, to inform the choice of ART regimen. Resistance tests (genotypic or phenotypic) are widely used in high-income countries, but not in resource-limited settings. This systematic review summarizes the relative merits of resistance testing in treatment-naive and treatment-exposed people living with HIV.

To evaluate the effectiveness of antiretroviral resistance testing (genotypic or phenotypic) in reducing mortality and morbidity in HIV-positive people.

We attempted to identify all relevant studies, regardless of language or publication status, through searches of electronic databases and conference proceedings up to 26 January 2018. We searched MEDLINE, Embase, the Cochrane Central Register of Controlled Trials (CENTRAL), in the Cochrane Library, the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP), and ClinicalTrials.gov to 26 January 2018. We searched Latin American and Caribbean Health Sciences Literature (LILACS) and the Web of Science for publications from 1996 to 26 January 2018.

We included all randomized controlled trials (RCTs) and observational studies that compared resistance testing to no resistance testing in people with HIV irrespective of their exposure to ART.Primary outcomes of interest were mortality and virological failure. Secondary outcomes were change in mean CD4-T-lymphocyte count, clinical progression to AIDS, development of a second or new opportunistic infection, change in viral load, and quality of life.

Two review authors independently assessed each reference for prespecified inclusion criteria. Two review authors then independently extracted data from each included study using a standardized data extraction form. We analysed data on an intention-to-treat basis using a random-effects model. We performed subgroup analyses for the type of resistance test used (phenotypic or genotypic), use of expert advice to interpret resistance tests, and age (children and adolescents versus adults). We followed standard Cochrane methodological procedures.

Eleven RCTs (published between 1999 and 2006), which included 2531 participants, met our inclusion criteria. All of these trials exclusively enrolled patients who had previous exposure to ART. We found no observational studies. Length of follow-up time, study settings, and types of resistance testing varied greatly. Follow-up ranged from 12 to 150 weeks. All studies were conducted in Europe, USA, or South America. Seven studies used genotypic testing, two used phenotypic testing, and two used both phenotypic and genotypic testing. Only one study was funded by a manufacturer of resistance tests.Resistance testing made little or no difference in mortality (odds ratio (OR) 0.89, 95% confidence interval (CI) 0.36 to 2.22; 5 trials, 1140 participants; moderate-certainty evidence), and may have slightly reduced the number of people with virological failure (OR 0.70, 95% CI 0.56 to 0.87; 10 trials, 1728 participants; low-certainty evidence); and probably made little or no difference in change in CD4 cell count (mean difference (MD) -1.00 cells/mm³, 95% CI -12.49 to 10.50; 7 trials, 1349 participants; moderate-certainty evidence) or progression to AIDS (OR 0.64, 95% CI 0.31 to 1.29; 3 trials, 809 participants; moderate-certainty evidence). Resistance testing made little or no difference in adverse events (OR 0.89, 95% CI 0.51 to 1.55; 4 trials, 808 participants; low-certainty evidence) and probably reduced viral load (MD -0.23, 95% CI -0.35 to -0.11; 10 trials, 1837 participants; moderate-certainty evidence). No studies reported on development of new opportunistic infections or quality of life. We found no statistically significant heterogeneity for any outcomes, and the I² statistic value ranged from 0 to 25%. We found no subgroup effects for types of resistance testing (genotypic versus phenotypic), the addition of expert advice to interpretation of resistance tests, or age. Results for mortality were consistent when we compared studies at high or unclear risk of bias versus studies at low risk of bias.

Resistance testing probably improved virological outcomes in people who have had virological failure in trials conducted 12 or more years ago. We found no evidence in treatment-naive people. Resistance testing did not demonstrate important patient benefits in terms of risk of death or progression to AIDS. The trials included very few participants from low- and middle-income countries.