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Mark Siedner, MD, MPH: Pretreatment HIV Drug Resistance and ADVANCE Trial Outcomes

The time is now to put in place comprehensive action plans now to monitor, detect, and respond to treatment failure on dolutegravir.

There is a distinct lack of empiric data in sub-Saharan Africa on the performance of antiretroviral therapy (ART) regimens amid pretreatment HIV drug resistance. To combat this, an international team of investigators has conducted a sub-study of the ADVANCE trial.

The team presented data on pretreatment resistance and 48-week virologic outcomes from the ADVANCE trial at the Annual Conference on Retroviruses and Opportunistic Infections (CROI 2020).

Mark Siedner, MD, MPH, infectious disease clinician and researcher in the Division of Infectious Diseases at Massachusetts General Hospital, and presenting author, discussed the trial highlights with Contagion®.

Contagion®: What was the context for the undertaking of this study?

Mark Siedner, MD, MPH: This was a resistance testing sub-study of the ADVANCE clinical trial, which compared 3 treatment regimens for HIV in South Africa. The parent study compared the prior standard of care HIV regimen, comprised of efavirenz, with 2 regimens containing a newer drug, dolutegravir. The 3 arms were essentially equivalent. Due in part to findings of the ADVANCE study, along with decreases in generic pricing of dolutegravir, and increasing circulating HIV drug resistance, dolutegravir has now replaced efavirenz as the key component of HIV regimens in most sub-Saharan African treatment guidelines. In this sub-study, we sought to support that decision and demonstrate that HIV drug resistance effects efavirenz-based therapy, but largely spares people who are on newer dolutegravir-based therapy.

Contagion®: Can you summarize the key findings?

Siedner: As expected, having drug resistance significantly impacted the success of efavirenz-based therapy, resulting in an approximate 30% reduction in the proportion who achieved documented virologic suppression at 96 weeks. What was unexpected, was that we found similar, if not slightly decreased harmful effects of pre-treatment drug resistance for people starting dolutegravir as well. People in the dolutegravir study arms had approximately 20% decreased rate of documented virologic suppression at 96 weeks. Although the proportions differed slightly, we found these patterns were consistent when we defined treatment success in a number of different ways, and after accounting for clinical and social factors in our models. Perhaps most importantly, HIV drug resistance worsened outcomes for people on dolutegravir even after accounting for treatment adherence, which we believed might be the connection between drug resistance and poor clinical outcomes.

Contagion®: What are the larger clinical takeaways?

Siedner: If these findings are supported by other studies, they should significantly alter our understanding of the effect of circulating drug resistance in sub-Saharan Africa on the success of the dolutegravir roll-out. We know resistance is common. So if it has even a moderate effect on the success of dolutegravir-based treatment, it could result in significant numbers of people with treatment failure for the over 15 million people with HIV who are in the process of switching form efavirenz to dolutegravir in sub-Saharan Africa.

Contagion®: Are there plans for future research on this topic?

Siedner: We are currently investigating whether low level drug resistance (sometimes called minority resistance) to other drugs in the regimens could explain the relationships we saw. We and others have also started large, real-world studies to observe the success of the dolutegravir rollout in practice and see if these patterns are seen in programmatic care. Finally, we have reached out to colleagues who have conducted other trials in sub-Saharan Africa, to see if they have recognized similar patterns in their work. It will be critical to get this right and to not be over-confident in the impact of dolutegravir on the HIV epidemic until we have primary data to support its long-term success. The time is now to put in place comprehensive action plans now to monitor, detect, and respond to treatment failure on dolutegravir. History has taught us that no anti-infective agent is perfect or immune to resistance, so we should be planning now for a future when dolutegravir might not be the long-lasting savior to the epidemic many of us hoped it might be.

The poster, “Pretreatment HIV drug resistance and 48-week virologic outcomes in the ADVANCE Trial,” was virtually presented Monday, March 9, 2020, at CROI 2020.