The World Health Organization (WHO) recently reported drug resistance to the world’s gold-standard antiretroviral medicine, dolutegravir  “exceeding levels observed in clinical trials” – with resistance ranging from 3.9% to 19.6%.

This was potentially very bad news as dolutegravir has been the recommended first- and second-line HIV treatment for all population groups since 2018 – but the WHO told Health Policy Watch this week that the drug resistance was largely related to patients not adhering to treatment properly rather than growing resistance to the medicine.

Dolutegravir is “more effective, easier to take, and has fewer side effects than other drugs currently in use” with “a high genetic barrier to developing drug resistance”, according to the WHO.

It is used in antiretroviral therapy (ART) in combination with tenofovir and lamivudine, and its use has led to “very high levels of viral load suppression at the population level, often in excess of 90% or even 95%”, according to WHO. 

Country reports on resistance

The reports on resistance come from country surveys in Uganda, Ukraine, Malawi and Mozambique, WHO told Health Policy Watch.

In Uganda, Ukraine and Malawi, the levels of resistance to dolutegravir ranged from 3.9% to 8.6% in adults, ranging from those who had never taken ART to those with some exposure to the drugs.

But in Mozambique, the survey involved people experienced with treatment who had transitioned to a dolutegravir-containing regimen while having high HIV viral loads. And in this instance, resistance reached 19.6%. 

“Overwhelmingly, data suggest that non-adherence to treatment is the primary reason for viral non-suppression in people taking dolutegrivar, not drug resistance,” said the WHO spokesperson.

“Levels of HIV drug resistance observed to the integrase inhibitor dolutegravir are much lower than resistance levels observed in populations failing non-nucleoside reverse transcriptase inhibitors (NNRTIs)-based antiretroviral therapy,” added WHO.

NNRTIs refer to a class of ARVs that block an HIV enzyme called reverse transcriptase, which prevents the virus from replicating. Efavirenz, the previous WHO-recommended first-line HIV treatment regimen, was an NNRTI.

“In populations not achieving viral suppression on NNRTI-based ART, we saw levels of resistance from 70-90%. The combination of higher levels of viral load suppression and the much lower levels of acquired drug resistance affirm the global guidelines’ change from NNRTI- to dolutegravir-based treatment,” the WHO added.

The WHO official noted that there was still “much to learn about dolutegravir resistance”, with “very early and limited data” suggesting that “very large proportions of people not achieving viral suppression” on the dolutegravir would do so with “enhanced adherence support”. 

Dolutegravir and TB medication 

Meanwhile, a new clinical trial has found that people newly diagnosed with HIV fared well when given preventative treatment for tuberculosis at the same time as dolutegravir.

These results were released at the recent Conference on Retroviruses and Opportunistic Infections in Denver, Colorado.

“Each year, there are an estimated 670,000 new TB cases among people living with HIV and an estimated 167,000 deaths from TB-related HIV,” according to a media release from the Aurum Institute, one of the research partners in the trial.

The trial – called DOLPHIN-TOO – focused on whether the efficacy of dolutegravir in people living with HIV who had never previously been treated with ARVs was affected by prophylactic TB treatment – either the standard isoniazid (6H) or the newer regimen comprising of a weekly dose of isoniazid and rifapentine for three months referred to as 3HP.

The results showed that, while people in the 3HP group did have lower levels of dolutegravir in their bloodstream than people in the 6H group, they were able to achieve an undetectable level of HIV virus in blood by eight weeks and maintain this for the length of the six-month study. 

Minimal side effects were seen, none were severe, and the majority were resolved with continuation of therapy. 

Previous research released at the Union World Conference on Lung Health in November of 2023, had provided information on the safety and efficacy of the use of 3HP and dolutegravir  together, but without data on the drug levels in the blood.

“This study points to the use of short course TB preventive treatment in people who are newly diagnosed with HIV and are at highest risk of active TB disease,” according to a media release from Aurum.