Dolutegravir resistance has not risen in Lesotho cohort

Resistance to dolutegravir was seen in 8% of people with repeatedly detectable viral loads who had resistance test results in an ongoing study in Lesotho. Compared to previous rates of dolutegravir resistance in the same cohort from three years ago, there was no increase. Most people with dolutegravir resistance also had resistance to other HIV drugs that it is often combined with.

The findings from Dr Anna Klicpera and colleagues were presented by Professor Niklaus Labhardt of University Hospital Basel at the International Congress on Drug Therapy in HIV Infection (HIV Glasgow 2026) yesterday.

Context

Dolutegravir is a crucial part of the World Health Organization’s (WHO) recommended HIV treatment and is widely used across Africa, usually as the single pill tenofovir / lamivudine / dolutegravir (TLD). It blocks integrase – the enzyme HIV uses to stitch its DNA permanently into our cells’ genome. 

One of the reasons dolutegravir has become so central to HIV treatment is its high genetic barrier to resistance, meaning it’s harder for the virus to become resistant to it compared to many other drugs. Resistance arises when changes in HIV’s genetic code make a drug less effective at suppressing it. While a viral load test can show that treatment is not fully controlling the virus, a resistance test tells us whether the virus carries changes that may explain why some drugs are working less well.

Although resistance to dolutegravir was generally rare in clinical trials, some studies of routine care have found higher levels. That is important because treatment programmes across many low- and middle-income countries rely heavily on the drug, yet have limited access to resistance testing, leaving clinicians without a clear answer about whether there is resistance when HIV becomes detectable. 

The study 

The researchers used data from the Viral Load Cohort North-East Lesotho, which follows people receiving routine viral load monitoring in three districts. 

By April 2026, 26,919 participants had received dolutegravir and had at least a year of follow-up. The resistance analysis focused on people with a viral load of at least 50 copies followed by a later result of at least 500 copies. The results had to be obtained at least three months after starting a dolutegravir-containing regimen. 

With these criteria, 745 participants were selected and resistance results were available for 298, or 40%. Not having written consent to use stored samples and unavailable samples were the main reasons why more resistance results could not be obtained.

The median age of these 298 participants was 37 years and 40% were men. They had been on dolutegravir-containing treatment for a median of 3.6 years. Around one in five participants had started HIV treatment with dolutegravir, while the others had switched from earlier regimens, and 84% were taking dolutegravir as part of TLD. At resistance testing, just over half had a viral load of at least 10,000 copies.

Rates of resistance against two separate criteria 

Of the 298 participants, 24 (8.1%) had genetic changes on their virus predicting at least low-level resistance to dolutegravir. Because these were the participants with any level of resistance, it doesn’t mean that all had a virus that was completely ‘insensitive’ to dolutegravir’s action, although all 24 cases were classified as intermediate- or high-level resistance.

A second layer of analysis was done, this time using WHO’s criteria for virological failure defined as two consecutive viral loads of at least 1,000 copies. Of the 298 participants with sequenced virus, only 96 experienced this. Nine of them or 9.4% had some level of dolutegravir resistance. This means that 15 of the 24 people with dolutegravir resistance did not meet those criteria at the time of testing, suggesting that restricting resistance testing to WHO’s criteria alone could miss cases.

It’s important to note that the 8.1% figure is the rate in a selected group with repeated detectable virus and available resistance results – it is not the rate of dolutegravir resistance in the whole population of people with HIV taking dolutegravir.  

Looking at the whole combination

Dolutegravir resistance was strongly associated with resistance to drugs such as tenofovir and lamivudine, which it is commonly taken with. These belong to a group called nucleoside reverse transcriptase inhibitors or NRTIs. They block the preceding step of the virus’ lifecycle before integration. Before the virus can stitch its DNA into our genome (the step blocked by dolutegravir), the virus has to make a DNA copy of its otherwise RNA genome. Although dolutegravir is difficult for the virus to get around, if resistance has weakened its ‘teammates’, it may be left carrying more of the workload. 

Alongside dolutegravir, the participants took lamivudine and one other drug – tenofovir, abacavir or zidovudine. Among those with the relevant test results, resistance to this other companion drug was found in 12 of 20 people with dolutegravir resistance (60%), compared with 10 of 226 without dolutegravir resistance (4.4%).

For some participants, the treatment history offered clues. Labhardt described one person whose HIV was already resistant to lamivudine before they switched to dolutegravir. Their viral load fell but never became fully suppressed, and dolutegravir resistance was detected about a year and half later. This highlights how resistance can add up, although it does not prove that it was the weakened companion drugs that caused the resistance to dolutegravir.

Also, people with dolutegravir resistance tended to have had detectable viral loads on previous treatments and to be on a regimen without tenofovir. So, in the context of resistance, treatment history plays a significant role.

He explained that, in Lesotho, the combination TLD is available as one pill, while some alternative combinations require at least two pills. He suggested that this extra pill burden might help explain why resistance was more common among people taking regimens without tenofovir (implying adherence issues).

Concluding thoughts 

An earlier analysis of the same cohort, published in the journal Clinical Infectious Diseases, reported dolutegravir resistance in eight of 85 people tested, or 9.4%. 

“The overall prevalence of DTG resistance among viraemic people [with a detectable viral load] in our cohort remains below 10%, and we don’t have evidence it increased,” Labhardt said.

However, the two percentages are not a straightforward measure of change over time. The earlier study focused on people who had switched from older regimens and required a sample taken at least a year and a half after starting dolutegravir. The current analysis used broader eligibility criteria (like at least three months after starting dolutegravir) so that could on paper reduce the resistance estimation. 

Most participants with repeated detectable viral loads did not have detected dolutegravir resistance. Although that’s a positive finding, it does not explain why their viral loads remained detectable. Looking at treatment interruptions, difficulties accessing or taking their treatment, drug interactions and resistance to companion drugs may give a more complete answer.

In addition, only 40% of the selected participants had resistance test results, a gap which limits the confident interpretability of the final resistance estimate. 

“We need access to resistance testing in high-burden settings,” Labhardt told the conference.

References

Klicpera A et al. Dolutegravir resistance among people with repeated viraemia in a prospective routine HIV care cohort in Lesotho. International Congress on Drug Therapy in HIV Infection, Glasgow, abstract O42, 2026.

Tschumi N et al. Emergence of acquired dolutegravir resistance in treatment-experienced people with HIV in Lesotho. Clinical Infectious Diseases 79: 1208–1222, 2024. 

https://doi.org/10.1093/cid/ciae185