Further evidence that recycling tenofovir in second-line treatment is effective

Second-line treatment with dolutegravir and recycled tenofovir and lamivudine is superior to protease inhibitor-based treatment using a new nucleoside backbone, VISEND study investigators reported last week at the Conference on Retroviruses and Opportunistic Infections (CROI 2022).

The study findings add to evidence that retaining tenofovir ('recycling' it) after the failure of first-line treatment rather than replacing it with zidovudine does not raise the risk of treatment failure. Also presented at the conference, 96-week results from the NADIA study showed that recycled tenofovir and lamivudine resulted in superior viral suppression when compared to a new nucleoside backbone.

Current World Health Organization guidelines recommend the use of dolutegravir in second-line treatment in resource-limited settings. They also recommend including a new nucleoside reverse transcriptase inhibitor (NRTI) in the regimen. As most people on first-line treatment take tenofovir, this means switching to zidovudine, which is less well tolerated.

The VISEND study was designed to address several questions regarding second-line treatment in resource-limited settings:

• Is the use of dolutegravir with recycled NRTIs inferior to use of a boosted protease inhibitor with new NRTIs in second-line treatment?
• Is the combination of tenofovir disoproxil (TDF) and lamivudine inferior to the new formulation of tenofovir (TAF) and emtricitabine, when combined with dolutegravir?
• Can tenofovir and lamivudine be recycled in second-line treatment or is this option inferior to switching to zidovudine/lamivudine?

VISEND recruited 1201 participants in Zambia who were taking a failing regimen based on a non-nucleoside reverse transcriptase inhibitor (NNRTI) that contained tenofovir and lamivudine.

Participants with viral load below 1000 (n=418) (arm A) were randomised to receive either TDF and lamivudine with dolutegravir (TLD) or TAF and emtricitabine with dolutegravir (TAFED). This study arm was designed to investigate whether TDF and lamivudine was inferior to TAF and emtricitabine. The study population was restricted to people with low or undetectable viral load at the time of switching to minimise the risk of developing drug resistance.

Participants whose treatment was failing, with viral load above 1000 (arm B) were randomised to either TLD (n=208), TAFED (n=211), zidovudine/lamivudine plus atazanavir/ritonavir (n=167), or zidovudine/lamivudine plus lopinavir/ritonavir (n=197).

During the study, participants underwent viral load testing at weeks 12, 24, 48, 72, 96 and 144. If their viral load was above 50 on two consecutive visits, they received enhanced adherence counselling. If their viral load was above 1000 on two consecutive visits, they underwent resistance testing.

Study participants in arm A had a median age of 44, approximately 80% had viral loads below 50 and just under two-thirds were women. Study participants in arm B had a median age between 36 and 39 according to treatment assignment, between 58% and 67% were women and the proportions with viral load above 100,000 ranged from 20% in the TAFED arm to 31% in the lopinavir/ritonavir arm.

The primary study outcome was the proportion of study participants in each arm with viral load below 1000 at week 144. Dr Lloyd Mulenga of the University Teaching Hospital, Lusaka, presented the 48-week analysis.

In arm A, 86% of those assigned to TAFED and 88% of those assigned to TLD had viral loads below 1000 at week 48, while 76% of those assigned to TAFED and 81% of those assigned to TLD had viral loads below 50 in an intent-to-treat analysis. In a per-protocol analysis, 98% of participants on each regimen had viral loads below 1000; 86% and 90% respectively had viral loads below 50.

In arm B, 88% of those assigned to TAFED, 83% assigned to TLD, 82% assigned to atazanavir/ritonavir and 69% assigned to lopinavir/ritonavir had viral loads below 1000 in an intent-treat analysis. 82% of those taking TAFED, 72% on TLD, 71% on atazanavir/ritonavir and 56% on lopinavir/ritonavir had viral loads below 50 by intent-to-treat analysis.

By per-protocol analysis, 95% of the TAFED group, 93% of the TLD group, 90% of the atazanavir/ritonavir group and 83% of the lopinavir/ritonavir group had viral loads below 1000, while 89% of the TAFED group, 82% of the TLD group, 78% of the atazanavir/ritonavir group and 68% of the lopinavir/ritonavir group had viral loads below 50.

In participants with baseline viral loads above 1000, the non-inferiority analysis showed that both TAFED and TLD regimens demonstrated superiority in viral suppression below 1000 and 50 compared to a boosted protease inhibitor plus zidovudine and lamivudine. TAFED was also superior to TLD in suppressing viral load below 50, but not 1000, in participants in arm B.

In participants with baseline viral loads below 1000 (arm A), TAFED was non-inferior to TLD when assessing viral suppression below 1000 or 50.

The study analysis also looked at changes in weight in arm A, finding that TAFED recipients gained more weight after 48 weeks than TLD recipients (+2.8 vs 1.1kg). Weight gain was more pronounced in arm B, where TAFED and TLD recipients gained 5.4kg and 5kg respectively after 48 weeks, compared to 2.8kg in the atazanavir recipients and 2kg in the lopinavir recipients. But when weight gain in arm B was analysed by sex, TAFED was associated with greater weight gain in women (+5.7kg) compared to other regimens, whereas the greatest weight gain in men occurred in those who received TLD (+4.6kg).

NADIA study

The VISEND study explored similar questions to the NADIA trial, conducted in seven African countries. NADIA compared switching to dolutegravir or darunavir without resistance testing in people experiencing viral rebound above 1000 on an efavirenz-based regimen. It also investigated whether recycling tenofovir and lamivudine in second-line treatment was inferior to switching to zidovudine and lamivudine. The 48-week results presented at CROI 2021 showed that dolutegravir was non-inferior to boosted darunavir and that recycling tenofovir/lamivudine was non-inferior to switching to zidovudine/lamivudine.

Professor Nick Paton reported 96-week results of the NADIA study, showing that dolutegravir remained non-inferior to darunavir/ritonavir at week 96. Whereas at week 48, the tenofovir/lamivudine backbone was non-inferior to zidovudine/lamivudine, by week 96 the tenofovir/lamivudine backbone was superior (+7%, 95% CI 1.2-12.8, p = 0.019). Viral rebound was more frequent in the zidovudine group than the tenofovir group (14.3 vs 5.6%, p = 0.0002) and the development of high-level dolutegravir resistance mutations occurred more frequently after viral rebound in the zidovudine group (5 vs 2 cases).

Dolutegravir resistance after viral rebound had been a concern when the 48-week results of the study were analysed. At this point, four cases of dolutegravir resistance had been identified in people with detectable viral load.

“It looks from our data as if the way to avoid dolutegravir resistance is to stop combining it with zidovudine in second-line,” said Professor Paton.

“Guidelines that recommend switching from tenofovir/lamivudine to zidovudine/lamivudine in the public health approach should be reconsidered,” he concluded.