CROI 2022: Dolutegravir plus recycled tenofovir rather than switch to AZT: public health approach to second-line ART

Polly Clayden, HIV i-Base

CROI 2022Results from the NADIA and VISEND trials provide further evidence for dolutegravir and recycled tenofovir in second-line adult ART. These findings were presented at CROI 2022. 

Week 48 results from NADIA, presented last year, found both dolutegravir (DTG) and boosted darunavir (DRV/r)-based regimens maintained high levels of viral suppression in second-line – including in combination with NRTIs with no predicted activity. [1, 2]

In the VISEND trial, people failing tenofovir disoproxil fumarate (TDF), lamivudine (3TC) plus NNRTI first-line regimens had better outcomes when switched to DTG with either TDF/3TC or tenofovir alafenamide (TAF)/emtricitabine (FTC) compared to those switched to standard-of-care boosted-PI ART at week 48. [3]

In NADIA, at week 96 DTG remained non-inferior to DRV/r. The results also showed the TDF backbone to be superior to zidovudine (AZT) and this may protect against DTG resistance. DTG resistance did not increase substantially during longer follow-up. [4]

VISEND study

VISEND is an ongoing 144 week, randomised, open-label, phase 3 non-inferiority trial conducted in Zambia.

The study is looking at four second-line regimens in 1201 participants who received TDF/3TC plus efavirenz (EFV) or nevirapine (NVP) first-line. 

In Arm A, participants with viral load <1000 copies/mL were randomised to receive TDF/3TC/DTG (TLD, n=209) or TAF/FTC/DTG (TAFED, n=209).

In Arm B, participants with viral load >1000 copies/mL were randomised to TLD (n=208), TAFED (n=211), or a second-line boosted protease inhibitor (PI/r)-based regimen: lopinavir/ritonavir (LPV/r, n=167) or atazanavir/r (ATV/r, n=197) plus AZT/3TC.

The primary end point is viral load <1,000 copies/mL at week 144 (ITT population). The non-inferiority margin is 10%.

At baseline, participants in arm A were a median age of 44, approximately 60% were women, about 80% had viral loads <50 copies/mL and median CD4 was just over 400 cells/mm3.

In arm B, across the four groups, the participants were a median age of 38, 58–67% were women, 20–31% had viral load above 100,000 copies/mL and median CD4 was about 170 cells/mm3.

Viral load testing was performed at weeks 12, 24, 48, 72, 96 and 144. Participants with two consecutive viral load results >50 copies/mL received enhanced adherence counselling. Those with viral loads >1000 copies/mL on two consecutive visits had resistance testing.

In Arm A, 74% of participants in the TAFED group and 80% in the TLD group had viral load <50 copies at week 48 (ITT).

In Arm B, 82% in TAFED, 72% in TLD, 71% in ATV/r and 56% of participants in LPV/r group had viral loads <50 copies/mL (ITT).

Differences were similar in the <1000 copies/mL analysis with 86% in the TAFED group achieving viral suppression compared with only 69% in the LPV/r group (ITT).

The non-inferiority analyses found TAFED and TLD to be comparable and superior to the PI-based regimens for viral suppression to both <50 and <1000 copies/mL

In arm A, participants in the TAFED group gained more weight from baseline to week 48 than those in TLD (2.8 vs 1.1 kg).

In arm B, participants in the TAFED and TLD groups gained 5.4 kg and 5 kg, compared to 2.8 kg and 2 kg in ATV/r and LPV/r, respectively.

Women in the TAFED group experienced greater weight gain (5.7 kg) compared to the other groups. In men, the greatest weight gain was in those in the TLD group (4.6 kg).

Nadia study

NADIA randomised participants receiving EFV or NVP/TDF/3TC first-line with viral load >1000 copies/mL to receive second-line ART of DTG or DRV/r and TDF or AZT, all with 3TC (2 x 2 factorial randomisation).

The primary endpoint was viral load suppression to <400 copies/mL at 96 weeks (non-inferiority margin 12% for each comparison and separate comparisons for each study question).

Open viral load testing was performed at 24, 48 and 96 weeks (and 72 weeks, if not stable at week 48 and 12 weeks after any result >1000 copies/mL). There was also open resistance testing following confirmed viral load test >1000 copies/mL (and stored batched samples from baseline and for participants with viral load rebound >400 copies/mL).

The study enrolled 464 participants at seven sites in Kenya, Uganda and Zimbabwe: 61% women, 51% CD4 <200 cells/mm3, and 28% viral load >100,000 copies/mL.

At baseline, 58% had intermediate-high level resistance to TDF, 18% to AZT and 92% to 3TC.

At week 96, 89.8% in the DTG group and 86.9% in the DRV/r group achieved <400 copies/mL (ITT analysis): difference 2.9% (95% CI: –3.0 to +8.7%), p=0.332. This showed non-inferiority of DTG, but not superiority.

These results were consistent in sensitivity analyses and at <1000 copies/mL and <50 copies/mL

Approximately 10% of participants had viral rebound >1000 copies/mL. Of these, seven participants had one or more DTG mutation and none had DRV mutations.

Over 90% of participants in both groups with no predicted active NRTIs achieved viral load <400 copies/mL.

In the second comparison, 91.8% in the TDF group and 84.8% in the AZT group were suppressed <400 copies/mL: difference 7.0% (95% Cl: 1.2 to 12.8%), p=0.019.  This indicated superiority of TDF at week 96 (progressing from non-inferiority at week 48).

Again, the various sensitivity analyses for this comparison were consistent with the main results.

Viral load  rebound >1000 copies/mL occurred in 5.6% of participants in the TDF group and 14.3% in the AZT group: difference –8.7% (95% CI: –14.1 to –3.3%), p=0.002.

Of the seven cases of DTG resistance, five were in the AZT group. There were a further two participants with resistance among the retrospective samples from those with rebound >400 copies/mL; one each in the TDF and AZT groups.

In the subgroup of participants with the K65R/N at baseline, 95.7% achieved suppression in the TDF group (93.6% in the AZT group).

Presenting author Nick Paton, suggested that: “The best way to avoid dolutegravir resistance is to simply stop combining it with zidovudine in second-line”


Current World Health Organization (WHO) guidelines recommend optimised NRTIs, including a switch from TDF to AZT for second-line therapy in the public health approach. [5]

These data suggest that this recommendation should be reconsidered and discussions are underway to inform the upcoming guideline revisions.

From both and individual and programmatic standpoint, using TLD second-line after NNRTI with TDF and 3TC would have several advantages.

NADIA data also support upgrading DRV/r to preferred PI second-line. Since the DRV/r pricing agreement, announced last year by Unitaid and CHAI, this has become more feasible in terms of cost. [6]

Remaining questions associated with TDF vs TAF and with weight gain (which may increase risk for non-communicable diseases and/or metabolic complications) still need longer-term follow up.

WHO also recommends enhanced adherence counselling before switching to second-line for people with detectable viral loads.

A sub study of VISEND – also presented at this conference – looked at data from participants with viral load >1000 copies/mL, who received three counselling sessions over three months, according to existing guidance. [7] 

This led to viral suppression rates near the WHO target of 70%, although outcomes varied by sex, education, and other factors. The investigators recommended incorporating this counselling into clinical trials and practice before switching to optimise outcomes.


  1. Clayden P. Dolutegravir with recycled tenofovir and lamivudine performs well second-line: primary results from the NADIA trial. HTB. 12 March 2021.
  2. Paton N et al. Dolutegravir or darunavir in combination with zidovudine or tenofovir to treat HIV. N Engl J Med 2021; 385:330-341. 22 July 2021.
  3. Mulenga L et al. Dolutegravir with recycled NRTIs is noninferior to PI-based ART: VISEND trial. CROI 2022. 12–16 February. Virtual. Oral abstract 135. (abstract) (webcast)
  4. Paton N et al. Nucleosides and darunavir/dolutegravir in Africa (NADIA) trial: outcomes at 96 weeks. (abstract) (webcast)
  5. WHO. Consolidated guidelines on HIV prevention, testing, treatment, service delivery and monitoring: recommendations for a public health approach. 16 July 2021.
  6. Clayden P. Darunavir/ritonavir price now US $210 for global access. HTB. 17 September 2021.
  7. Engamba D et al. Predictors of viral suppression following enhanced adherence counseling: VISEND trial. CROI 2022. 12–16 February. Virtual. Poster abstract 135.

This report was first published in 14 April 2022.

Links to other websites are current at date of posting but not maintained.