The Impact of Emerging Dolutegravir Resistance on Global HIV Treatment and Prevention

Obiageli Okafor, MD, DrPH, MPH is senior manager of medical and scientific affairs for Global Health Business at Thermo Fisher Scientific. Her career and research focus on improving health outcomes for highneed, high-risk populations. As a clinician, she provided care for people living with HIV and worked with NGOs to implement HIV programs in Nigeria. In her current role, Dr. Okafor spearheads efforts that enhance the understanding and accessibility of HIV drug resistance testing on a global scale.

Q: What are the main factors driving variation in reported resistance rates to dolutegravir, and how might these affect both pre-exposure prophylaxis (PrEP) and antiretroviral therapy (ART) programs?

A: When dolutegravir (DTG) was recommended by the WHO as part of first-line treatment in 2018, some lowand middle-income countries (LMICs) transitioned to this drug without conducting viral load tests for people living with HIV (PLHIV). Studies now show that DTG resistance-associated mutations are more likely to emerge in treatment-experienced clients, particularly in those not virally suppressed at the time of transition. Therefore, the observed variations in resistance data may reflect how the switch to DTG-based treatment was implemented in the various countries and the proportions of treatment-experienced versus treatment-naïve clients in the population.

People receiving DTG-based treatment can still achieve viral load suppression in the presence of dolutegravir resistance-associated mutations. Identifying which mutations render DTG truly ineffective remains an area of active research, and the findings will help determine the true impact of DTG resistance on ART programs.

Long-acting cabotegravir (CAB-LA) for PrEP is promising, offering an injection every eight weeks instead of daily pills. However, as both CAB-LA and DTG are second-generation integrase strand transfer inhibitors (INSTIs), there is a risk of cross-resistance. If HIV develops during CAB-LA use for PrEP, its long half-life can expose the virus to subtherapeutic levels of the drug increasing the risk of resistance to other integrase inhibitors used for treatment.

Q: Why is dolutegravir resistance emerging as a critical public health concern, and what are the potential impacts on HIV treatment programs worldwide?

A: We cannot afford to lose DTG. It is a drug of choice in LMICs for many reasons. DTG is well-tolerated, safe for diverse populations like pregnant women and children, and now widely available. It also has a high barrier to resistance, requiring multiple mutations to occur before it loses efficacy. Additionally, DTG is potent, capable of effectively suppressing viral loads in PLHIV. Other similar integrase inhibitor drugs in the same class, like Bictegravir, are rarely accessible in LMICs, while protease inhibitors—though potent—can cause significant side effects that reduce adherence. Losing DTG would set global treatment efforts back significantly, particularly in achieving the goal of reducing viral loads in 95 percent of PLHIV on treatment.

Q: Sanger sequencing has been a widely used method for HIV drug resistance (HIVDR) testing. How does it compare to newer methods like next-generation sequencing (NGS)?

A: Sanger sequencing is the most widely adopted and accessible testing method for HIVDR testing. It is costeffective for small sample volumes, widely validated, and supported by extensive literature. It’s particularly useful in LMICs, where established infrastructure makes it the most feasible option. However, Sanger sequencing detects mutations only at a threshold at or above 20 percent, which can miss low-level resistance mutations. NGS, on the other hand, can detect mutations at thresholds as low as 1–5 percent, which may have clinical implications for people who develop HIV while on PrEP and have low-frequency mutations that may contribute to cross-resistance described earlier.

NGS is more efficient for processing large numbers of samples but less cost-effective for smaller studies. It also requires bioinformatics expertise, which is not always available in resource-limited settings.

Q: What are the main challenges in implementing widespread HIVDR testing in LMICs, and how might these be addressed?

A: A major challenge is associated with the WHO HIVDR testing guidelines which recommend resistance testing only after first- and second-line treatment failure, and only after adherence is confirmed. Stigma can cause PLHIV to withhold their treatment history and in the absence of an objective adherence measure, HIVDR testing guidelines become difficult to implement. Interpreting test results also requires specialized knowledge which healthcare teams may lack. Lastly, many laboratories are equipped for surveillance, but resources are often insufficient to handle test volumes required for clinical care. Expanding laboratory capacity and educating providers in test interpretation can improve access and outcomes.

Q: As HIVDR testing continues to evolve, what advancements or emerging testing technologies could have the greatest impact?

A: Tools to objectively track adherence could drastically improve access to HIVDR testing for people who need it most, eliminating the need to rely on incomplete self-reported histories.

Artificial intelligence (AI) and machine learning can advance HIVDR testing. AI could analyze large datasets to identify resistance mutations, recommend treatment options, and eliminate much of the manual work involved in data analysis. This would provide physicians with actionable insights and help standardize treatment approaches globally.

Global collaboration is also critical. Harmonizing access to HIVDR testing and treatment options across countries is essential for addressing disparities and ensuring equitable care.