Resistance Testing for Management of HIV Virologic Failure in Sub-Saharan Africa : An Unblinded Randomized Controlled Trial

Abstract

Background: Virologic failure in HIV predicts the development of drug resistance and mortality. Genotypic resistance testing (GRT), which is the standard of care after virologic failure in high-income settings, is rarely implemented in sub-Saharan Africa.

Objective: To estimate the effectiveness of GRT for improving virologic suppression rates among people with HIV in sub-Saharan Africa for whom first-line therapy fails.

Design: Pragmatic, unblinded, randomized controlled trial. (ClinicalTrials.gov: NCT02787499).

Setting: Ambulatory HIV clinics in the public sector in Uganda and South Africa.

Patients: Adults receiving first-line antiretroviral therapy with a recent HIV RNA viral load of 1000 copies/mL or higher.

Intervention: Participants were randomly assigned to receive standard of care (SOC), including adherence counseling sessions and repeated viral load testing, or immediate GRT.

Measurements: The primary outcome of interest was achievement of an HIV RNA viral load below 200 copies/mL 9 months after enrollment.

Results: The trial enrolled 840 persons, divided equally between countries. Approximately half (51%) were women. Most (72%) were receiving a regimen of tenofovir, emtricitabine, and efavirenz at enrollment. The rate of virologic suppression did not differ 9 months after enrollment between the GRT group (63% [263 of 417]) and SOC group (61% [256 of 423]; odds ratio [OR], 1.11 [95% CI, 0.83 to 1.49]; P = 0.46). Among participants with persistent failure (HIV RNA viral load ≥1000 copies/mL) at 9 months, the prevalence of drug resistance was higher in the SOC group (76% [78 of 103] vs. 59% [48 of 82]; OR, 2.30 [CI, 1.22 to 4.35]; P = 0.014). Other secondary outcomes, including 9-month survival and retention in care, were similar between groups.

Limitation: Participants were receiving nonnucleoside reverse transcriptase inhibitor-based therapy at enrollment, limiting the generalizability of the findings.

Conclusion: The addition of GRT to routine care after first-line virologic failure in Uganda and South Africa did not improve rates of resuppression.

Primary funding source: The President's Emergency Plan for AIDS Relief and the National Institute of Allergy and Infectious Diseases.

Figure 1.. Study flow diagram.

ART = antiretroviral therapy; GRT = genotypic resistance testing; ITT = intention-to-treat; SOC = standard of care.

Figure 2.. Progress through the study by arm.

Diagram showing progress through the study from enrollment through completion of recommended laboratory testing and results reporting in the SOC group (left) and GRT group (right). The figures move from left to right across the study timeline from enrollment and randomization to completion of a repeated viral load test after adherence counseling and viral load results reporting in the SOC group, or from results of the initial resistance test and results reporting in the resistance testing group. The red bars signal high viral loads or the presence of genotypic resistance, whereas the green bars signify low viral loads or the absence of genotypic resistance. In the final column, light blue bars represent participants who continued to receive first-line therapy, whereas yellow bars represent those who changed to second-line therapy. Black bars signal participants who were lost to follow-up or died. GRT = genotypic resistance testing; SOC = standard of care.

Figure 3.. Primary and secondary outcomes, by study group.

Proportion of participants achieving primary and secondary outcomes in the SOC (black boxes) and GRT (green boxes) groups. Error bars represent 95% CIs and were calculated using stratum-level frequency weighting, analogous to estimation of the Cochran–Mantel–Haenszel test statistic. P values were estimated using conditional logistic regression with each outcome as the dependent variable, group as the dependent variable, and strata as matching variables. GRT = genotypic resistance testing; SOC = standard of care.

Figure 4.. Effect of GRT on virologic resuppression in total cohort and subgroups.

Forest plot showing the association between the study intervention (GRT) and primary outcomes, defined as achievement of a viral load of <200 copies/mL 9 mo after enrollment. Results are shown for the overall cohort and prespecified subgroups. Odds ratios were estimated from conditional logistic regression models, which include randomization strata in the model structure. GRT = genotypic resistance testing; SOC = standard of care.