CROI 2021: Dolutegravir with recycled tenofovir and lamivudine performs well second-line: primary results from the NADIA trial

Polly Clayden, HIV i-Base

Second-line treatment with dolutegravir (DTG) plus two NRTI led to good viral suppression at week 48 in the Nucleosides and Darunavir/Dolutegravir in Africa (NADIA) Trial – according to data shown at CROI 2021. [1]

NADIA included many participants with substantial resistance and no predicted NRTI activity. The results suggest that tenofovir (TDF) can be maintained in second-line therapy instead of switching to zidovudine (AZT).

After first-line NNRTI-based ART failure, WHO currently recommends switching to DTG plus two NRTI. People with HIV who previously received TDF/lamivudine (3TC) are recommended to change to AZT/3TC. As well as standardised first- and second-line regimens, the public health approach includes simplified monitoring: sparse viral load and safety checks and no resistance testing.

These WHO recommendations were based on one randomised controlled trial that used resistance testing to select NRTI, excluded people with no predicted active NRTIs and had frequent viral load monitoring.[2] How generalisable these findings are to public health approach was uncertain, particularly the performance of DTG when it was not protected by NRTIs with predicted activity.

The aim of NADIA was to investigate whether second-line ART with DTG is non-inferior to once-daily ritonavir-boosted darunavir (DRV/r, using 800 mg /100 mg) and TDF/3TC non-inferior to AZT/3TC, in people with considerable baseline NRTI resistance with a public health approach (including no resistance tests and sparse viral load monitoring).

NADIA is a two-by-two factorial, open-label, non-inferiority trial. Participants failing an NNRTI/TDF/3TC first-line regimen with confirmed viral load of above 1000 copies/mL received DTG vs DRV/r with a second randomisation of AZT/3TC vs TDF/3TC. The primary endpoint is viral load less than 400 copies/mL at week 48 using FDA snapshot algorithm (non-inferiority margin 12%).

Participants had viral load testing at 24 and 48 weeks, in accordance with WHO guidelines. Real-time resistance testing was performed for participants with confirmed viral load 1000 copies/mL and above.  Batched resistance testing was on stored samples (results blinded).

There were 464 participants enrolled at seven sites in Kenya, Uganda and Zimbabwe. Five died before week 48 and one was lost to follow up. They attended 99% of scheduled visits and remained on their assigned regimen for 96% of follow up.

Baseline characteristics overall included: 61% women; 51% with CD4 of 200 cells/mm3 or less and 28% viral load above 100,000 copies/mL. There was extensive baseline resistance: 50% had K65R/N and 87% M184V/I. Participants were similar across all treatment groups.

Week 48 viral load was less than 400 copies/mL in 90.2% in the DTG group and 91.7% in the DRV/r group: difference –1.49%; (95% CI:−6.7 to 3.7%), p=0.576. This indicated non-inferiority of DTG (but not superiority).

The proportion with confirmed viral rebound above 1000 copies/mL was around 6% in each group with no difference between groups (p=0.897). Four participants with viral rebound in the DTG group had major DTG resistance mutations associated with intermediate or high-level resistance, but none of the participants who rebounded in the DRV/r group had DRV mutations.

When the investigators looked at responses in pre-specified subgroups, those with baseline viral load above 100,000 copies/mL had similar suppression rates to the overall population: 89.4% DTG and 90.3% DRV/r.

Importantly in the subgroup with no predicted NRTI activity these proportions were: 92.4% DTG and 93.7% DRV/r.

In the TDF vs AZT comparison, the results were: 92.3% TDF and 89.6% AZT; difference 2.7% (95% CI −2.6 to 7.9), p=0.317. Also indicating non-inferiority but not superiority of TDF.

In the subgroup with the K65R/N mutation, suppression rates were: 94% TDF and 96% DRV/r. And for those with the M184V/I mutation: 94% DTG and 92% DRV/r.

Grade 3/4 adverse events were uncommon and similar in frequency DTG vs DRV/r and TDF vs AZT.

Presenting author Nick Paton remarked: “This finding is at variance with the traditional approach to infectious disease treatment where there is a long-standing aversion to switching just one drug in a failing regimen.”

“It also suggests we may need to revise the nucleoside prediction algorithm” he added.


These findings fill the evidence gap for use of DTG with compromised NRTIs (no predicted active NRTIs), which was the high-risk evidence-free group left behind by DAWNING.

They are important for people switching from NNRTI to DTG second-line, after known treatment failure, as well as programmes switching stable people routinely from NNRTI to DTG-based regimens in settings without pre-switch viral load and resistance testing.

WHO guidelines currently recommend switching NRTIs based on rather sketchy evidence. Here is an opportunity to change this recommendation based on good quality evidence that will make things easier – people can just use the TDF/3TC/TLD fixed dose combination ( TLD) rather than twice-daily NRTIs.

The findings also make the argument to reposition DRV/r in the hierarchy of PIs. Currently once-daily DRV/r 800/100 mg second-line (as in the study) is rarely used in African countries. Its use is mainly in third-line dosed at 600/100 mg twice daily, largely due to the lack of affordable, co-formulated, heat stable, generic products. Two 400/50 mg versions (two pills once daily as 800/100 mg not possible) from Hetero and Mylan are on the way and awaiting FDA tentative approval and WHO prequalification.

NADIA data plus wider availability should lead to an upgrade to “preferred” rather than “alternative” in WHO recommendations and increased use of this PI. Although TLD is likely to be widely used for people failing EFV-based first-line, those who receive TLD first-line will need a PI second-line.       

NADIA is continuing to 96 weeks which, among other things, will mean the study can monitor further for major resistance among participants with viral rebound in the DTG group.

Longer follow-up is also important in case reduced antiviral pressure due to partial drug resistance might mean that it just takes longer for rebound to occur.


  1. Paton N et al. Nucleosides and darunavir/dolutegravir in Africa (NADIA) trial: 48 wks primary outcome.  CROI 2021 (virtual). 6–10 March 2021. Oral abstract 94. (abstract) (webcast session oral O2)
  2. Clayden P. Dolutegravir outperforms lopinavir/ritonavir second-line: interim results from the DAWNING study. HTB. 10 August 2017.

This report was first posted on 10 March 2021.

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