Dolutegravir or darunavir/ritonavir are equally effective in second-line treatment, even in the presence of a high level of resistance to the NRTIs included in the regimen, according to a large randomized study conducted in three African countries.
Furthermore, tenofovir and lamivudine can be recycled into second-line treatment even in people with a high level of drug resistance, without undermining viral control when taken with dolutegravir or darunavir/ritonavir, the study showed.
The results of the Nucleosides and Darunavir/Dolutegravir in Africa (NADIA) study were presented at the 2021 virtual Conference on Retroviruses and Opportunistic Infections (CROI) by Professor Nicholas Paton of the National University of Singapore.
The World Health Organization (WHO) recommends that people experiencing viral rebound on a first-line regimen containing efavirenz or a boosted protease inhibitor can be switched to dolutegravir and two nucleoside reverse transcriptase inhibitors (NRTIs). The WHO recommends adding a new NRTI to the regimen. Since most people on first-line treatment are now taking tenofovir, this would mean switching to zidovudine, which is less well-tolerated than tenofovir.
However, these recommendations are based on limited evidence. In particular, it is unclear whether switching to dolutegravir without choosing a second-line NRTI through resistance testing leaves people at increased risk of treatment failure and dolutegravir resistance.
Furthermore, there is no evidence from randomized studies that the strategy of switching NRTIs is superior to recycling tenofovir in second-line treatment, or that dolutegravir is equivalent to boosted darunavir in second-line treatment.
The NADIA study was designed to answer these questions.
The study
Researchers recruited individuals with viral loads greater than 1000 copies/mL on a failed first-line NNRTI-based regimen containing tenofovir and lamivudine (as efavirenz/tenofovir/lamivudine). They were first randomly assigned to switch to either dolutegravir or darunavir/ritonavir (800/100 mg), and then, in a second randomization, to either retain tenofovir or switch to zidovudine. All participants received lamivudine. The study design allowed for comparison of four switching strategies.
The study recruited 464 people living with HIV at seven sites in Kenya, Uganda, and Zimbabwe. One of the study's researchers was Professor James Hakim of the University of Zimbabwe, a leading African HIV researcher, who died of COVID-19 in January 2021.
Sixty-one percent of the study population was female, and half had advanced HIV disease (51% had a CD4 count below 200, and the mean CD4 count in the study population was 194 cells). Twenty-seven percent had viral loads greater than 100,000 copies/mL, indicating advanced HIV treatment failure and the likelihood of high drug resistance. In fact, 92% were resistant to lamivudine, 58.5% had intermediate- or high-level resistance to tenofovir, and 18% had intermediate- or high-level resistance to zidovudine.
High-level tenofovir resistance is more common in sub-Saharan Africa than in other regions of the world; the tenores study found that 57% of people who failed first-line treatment in treatment cohorts in East Africa had tenofovir resistance, and a similar proportion in Southern Africa. It is unclear whether retaining tenofovir after first-line treatment failure contributes to viral suppression.
The primary outcome of the study was the proportion of people with a suppressed viral load below 400 copies/ml at week 48. There were no significant differences in the primary outcome between the two study arms at week 48; 90.2% of the dolutegravir arm and 91.7% of the darunavir arm had a viral load below 400 copies/ml.
The lack of active NRTIs in the regimen did not result in differences in response between the dolutegravir and darunavir arms.
There were no significant differences in virological outcome according to randomization to NRTIs; 92.3% in the tenofovir group and 89.6% in the zidovudine group had a viral load below 400 copies/ml, and there was no difference in the rate of virological rebound above 1000 copies/ml (4.7% vs 6.9%).
High-level tenofovir resistance at baseline did not compromise response to second-line treatment in participants randomized to tenofovir; 94.7% of those in the tenofovir group with intermediate- or high-level tenofovir resistance had a viral load below 400 copies/mL at week 48, compared with 93.2% in the zidovudine group. Furthermore, individuals with low-level or no tenofovir resistance did not fare better than those with higher tenofovir resistance; 88.5% of those assigned to tenofovir and 83.5% assigned to zidovudine had a viral load below 400 copies/mL at week 48.
"The lack of active NRTIs in the regimen did not result in differences in response between the dolutegravir and darunavir arms."
Regarding dolutegravir resistance, although there was no difference in the viral rebound rate above 1000 copies/ml after switching (6% in the dolutegravir group and 5.7% in the darunavir group), four people in the dolutegravir group developed resistance to the drug (three high-level and one intermediate-level). There was no darunavir resistance among those who experienced a rebound in the darunavir arm.
Resistance to dolutegravir also occurred in three people in the zidovudine group who experienced a rebound compared to one person in the tenofovir group.
Serious adverse events were infrequent and there were no significant differences in the frequency of serious drug-related adverse events by study arm.
Conclusions
The study researchers concluded that the 48-week results of the NADIA study support the WHO recommendation to switch to dolutegravir as second-line treatment, even if second-line NRTIs are not expected to be active. They also concluded that darunavir/ritonavir is a robust alternative to dolutegravir as second-line treatment in sub-Saharan Africa, providing excellent viral suppression.
“High-level resistance to dolutegravir is a concern, so we need more data on this risk with long-term use,” Paton said. “I don’t think that at that level of resistance, it should affect how we implement this regimen,” he said in a question-and-answer session after his presentation. In this study, all four patients who developed resistance to dolutegravir had a history of adherence difficulties.
The study also showed that tenofovir and lamivudine can be recycled in second-line treatment, even in people with drug-resistant mutations, simplifying the treatment switching process for treatment programs. Paton acknowledged that this finding contradicts standard practice in infectious disease management, where treatment failure typically leads to switching to multiple drugs, but suggested that NRTI resistance predictions using algorithms may need to be revised.
When asked if the study's findings should change WHO recommendations, he said: "In a public health focus setting, I don't know why I would recommend switching to zidovudine with the data we've seen." References
Paton N et al. Nucleoside and darunavir/dolutegravir trials in Africa (NADIA): 48-week primary outcome . Conference on Retroviruses and Opportunistic Infections, abstract 94, 2021.