Antiretroviral resistance testing in people living with HIV

What is the aim of this review?

The aim of this review was to find out whether a drug resistance test for people living with HIV (starting antiretroviral therapy (ART) or already on ART but with unsuppressed HIV) would reduce the number of deaths or improve HIV suppression.

Background

Drug resistance to ART implies that specific antiretroviral drugs will be less effective. This happens either because the virus has changed to become resistant, or because an individual was infected with a resistant virus. To determine which drugs will be less effective, healthcare providers may conduct a resistance test. Two kinds of resistance tests are available: the genotypic test, in which the virus is examined to determine which drugs it is resistant to, and the phenotypic test, in which the virus is exposed to antiretroviral drugs to see which one it is resistant to. Use of resistance tests is common only in high-income countries. Before we prepared this review, we did not know how well the use of resistance tests may reduce the number of deaths and improve HIV suppression.

Main results

Cochrane review authors collected and analysed all relevant studies up to 26 January 2018 to answer this question and included 11 randomized controlled trials (published between 1999 and 2006) with a total of 2531 people. Trials included only people who had detectable HIV despite being on antiretroviral drugs; no trials included patients starting therapy for the first time. 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 probably made little or no difference to the risk of dying (moderate-certainty evidence) or progression to AIDS (moderate-certainty evidence). Resistance testing probably increased the chance of successful suppression of HIV replication (low-certainty evidence) but probably made little or no difference in CD4 cell counts (cells affected by HIV) (moderate-certainty evidence). Resistance testing made little or no difference in the number of people who experience medication side effects (low-certainty evidence). No studies examined how many people developed a new opportunistic infection, and no studies examined patient quality of life.

Conclusion

For people for whom treatment no longer works, the use of resistance tests to select new treatments led to suppression of the HIV virus as measured by a blood test, but probably did not reduce the risk of death or progression to AIDS. Whether or not resistance testing provides any benefit for patients who are starting HIV treatment for the first time remains uncertain because no studies have evaluated this. These conclusions are based on studies conducted up to 12 years ago and included very few participants from low- and middle-income countries.

Authors' conclusions: 

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.

Read the full abstract...
Background: 

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.

Objectives: 

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

Search strategy: 

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.

Selection criteria: 

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.

Data collection and analysis: 

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.

Main results: 

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.

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