African study confirms dolutegravir for second-line treatment and supports recycling of tenofovir

Professor Nicholas Paton (bottom, left) presenting to CROI 2021.
Professor Nicholas Paton (bottom, left) presenting to CROI 2021.

Dolutegravir or darunavir/ritonavir are equally effective in second-line treatment, even in the presence of high-level resistance to NRTIs included in the regimen, a large randomised study carried out in three African countries has found.

Furthermore, tenofovir and lamivudine can be recycled in second-line treatment even in people with high-level resistance to the drugs, without undermining viral control when taking either dolutegravir or darunavir/ritonavir, the study showed.

The results, from the Nucleosides and Darunavir/Dolutegravir in Africa (NADIA) study were presented to the 2021 virtual Conference on Retroviruses and Opportunistic Infections (CROI) by Professor Nicholas Paton of the National University of Singapore.


second-line treatment

The second preferred therapy for a particular condition, used after first-line treatment fails or if a person cannot tolerate first-line drugs.

first-line therapy

The regimen used when starting treatment for the first time.

treatment failure

Inability of a medical therapy to achieve the desired results. 

viral rebound

When a person on antiretroviral therapy (ART) has persistent, detectable levels of HIV in the blood after a period of undetectable levels. Causes of viral rebound can include drug resistance, poor adherence to an HIV treatment regimen or interrupting treatment.

virological suppression

Halting of the function or replication of a virus. In HIV, optimal viral suppression is measured as the reduction of viral load (HIV RNA) to undetectable levels and is the goal of antiretroviral therapy.

The World Health Organization recommends (WHO) that people who experience 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). WHO recommends including a new NRTI in the regimen. As most people on first-line treatment now take tenofovir, this means switching to zidovudine, which is less well tolerated than tenofovir.

However, these recommendations are based on slender evidence. In particular, it’s unclear if switching to dolutegravir without choosing second-line NRTIs by resistance testing leaves people exposed to a higher risk of treatment failure and dolutegravir resistance.

Furthermore, there is no evidence from randomised studies that the strategy of changing 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

The researchers recruited people with viral loads above 1000 copies/ml on a failing NNRTI-based first-line regimen that contained tenofovir and lamivudine (such as efavirenz/tenofovir/lamivudine). They were randomised, firstly, to switch to either dolutegravir or darunavir/ritonavir (800/100mg), and then in a second randomisation, to either retain tenofovir or switch to zidovudine. Everyone took lamivudine. This study design enabled comparison between four strategies for switching.

The study recruited 464 people living with HIV at seven sites in Kenya, Uganda and Zimbabwe. One of the study investigators was Professor James Hakim of the University of Zimbabwe, a leading African HIV researcher, who died of COVID-19 in January 2021.

The study population was 61% female and half had advanced HIV disease (51% had a CD4 count below 200 and the median CD4 count in the study population was 194 cells). Twenty-seven per cent had viral loads above 100,000 copies/ml, indicating advanced failure of HIV treatment and the likelihood of high-level drug resistance. Indeed, 92% had resistance 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 in the world; the TenoRes study found that 57% of people on failing first-line treatment in treatment cohorts in eastern Africa had tenofovir resistance, and a similar proportion in southern Africa. It has been unclear if retaining tenofovir after first-line treatment failure contributes to viral suppression.

The primary outcome of the study was the proportion of people with viral load suppressed below 400 copies/ml at week 48. There was no significant difference in primary outcome between the two study arms at week 48; 90.2% of the dolutegravir arm and 91.7% of the darunavir arm had viral load below 400 copies/ml.

The lack of active NRTIs in the regimen did not lead to differences in response between the dolutegravir and darunavir arms.

There was no significant difference in virological outcome according to NRTI randomisation; 92.3% in the tenofovir group and 89.6% in the zidovudine group had 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 the response to second-line treatment in participants randomised to tenofovir; 94.7% of those in the tenofovir arm with intermediate- or high-level resistance to tenofovir had viral load below 400 copies/ml at week 48, compared to 93.2% in the zidovudine arm. Furthermore, people with low-level or no resistance to tenofovir did no better than those with greater resistance to tenofovir; 88.5% assigned to tenofovir and 83.5% assigned to zidovudine had viral load below 400 copies/ml at week 48.

"The lack of active NRTIs in the regimen did not lead to differences in response between the dolutegravir and darunavir arms."

Turning to dolutegravir resistance, although there was no difference in the rate of viral rebound above 1000 copies/ml after switching (6% in the dolutegravir arm and 5.7% in the darunavir arm), four people in the dolutegravir arm developed resistance to the drug (three high-level and one intermediate-level case). There was no resistance to darunavir among people who experienced rebound in the darunavir arm.

Dolutegravir resistance also occurred in three people in the zidovudine group who experienced rebound compared to one person in the tenofovir group.

Serious adverse events were uncommon and there was no significant difference in the frequency of drug-related serious adverse events according to study arm.


The study investigators concluded that the 48-week results of the NADIA study support the WHO recommendation of a switch to dolutegravir in second-line treatment, even if second-line NRTIs have no predicted activity. They also concluded that darunavir/ritonavir is a robust alternative to dolutegravir in second-line treatment in sub-Saharan Africa, giving excellent viral suppression.

“High-level dolutegravir resistance is a concern, so we need more data on this risk in long-term use,” Paton said. “I don’t think 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 dolutegravir resistance 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-resistance mutations, simplifying the process of switching treatment for treatment programmes. Paton acknowledged that this finding is at odds with normal practice in infectious disease treatment, where treatment failure usually leads to switching of multiple drugs but suggested that predictions of NRTI resistance by algorithms may need to be revised.

Asked if the study findings should change WHO recommendations, he said: “In a public health approach setting, I don’t know why you’d recommend switching to zidovudine with those data that we’ve seen.”


Paton N et al. Nucleosides and darunavir/dolutegravir in Africa (NADIA) trials: 48 wks primary outcome. Conference on Retroviruses and Opportunistic Infections, abstract 94, 2021.

Download the abstract eBook from the conference website.

Update: Following the conference presentation, this research was published in a peer-reviewed journal:

Paton N et al. Dolutegravir or Darunavir in Combination with Zidovudine or Tenofovir to Treat HIV. New England Journal of Medicine, 385:330-341, July 2021.

DOI: 10.1056/NEJMoa2101609