More evidence for recycling tenofovir in second-line ART with dolutegravir: 72-week results from ARTIST study
1 February 2023. Related: Antiretrovirals, Treatment strategies.
Polly Clayden, HIV i-Base
Recycling NRTIs with dolutegravir (DTG) was effective for most participants up to 72 weeks in the ARTIST study – conducted in Khayelitsha, South Africa. These findings were published ahead of print in JAIDS, January 2023. 
In this study the majority of participants with viraemia did not develop virologic failure and later suppressed with extra adherence counselling or continued their treatment with low-level viraemia.
ARTIST (AntiRetroviral Therapy In Second-line: investigating Tenofovir-lamivudine-dolutegravir trial) is a single arm, prospective study, which switched 62 adults with two viral load test results >1000 copies/mL from first-line tenofovir disoproxil fumarate (TDF)/lamivudine or emtricitabine (XTC) and an NNRTI to TDF/XTC/DTG (TLD).
The authors previously reported week 24 results. 
At this timepoint, 85% participants (51/60) achieved viral load <50 copies/mL (primary endpoint), despite having baseline resistance to either or both TDF and XTC (88%, 48/54). No one had virologic failure and there was no detectable integrase inhibitor resistance in the one participant who met the criteria for resistance testing.
Median (95%CI) rates of virologic suppression <50 copies/mL were 86% (74 to 93%), 74% (61 to 84%) and 75% (63 to 86%) at week 24, 48 and 72 respectively. Eighty-nine per cent of participants (50/56) were resistant to TDF and/or XTC at baseline. No participants developed integrase inhibitor resistance.
A post hoc analysis of the 20 participants with detectable viral load at week 24 and/or 48 revealed: two had virologic failure, one switched ART (adverse event), two were lost to follow up, one missed the clinic visit, one transferred, nine resuppressed <50 copies/mL with enhanced adherence counselling and four remained viraemic (three with <200 copies/mL) at week 72.
The authors reported no integrase-inhibitor resistance despite low-level viraemia in a minority of participants.
Recycling TDF after failure of NNRTI-based first-line ART, as in ARTIST, is simpler and more tolerable than DTG plus switching the NRTI backbone to AZT/3TC (as recommended in current WHO guidelines).
Two larger randomised studies have produced similar results. [4,5,6]
The NADIA study randomised participants failing first-line ART of NNRTI/TDF/XTC to darunavir/ritonavir DRV/r or DTG, and secondly (in a factorial design) to TDF or AZT plus 3TC. This showed DTG to be non-inferior to DRV/r at 48 and 96 weeks, and recycling TDF was non-inferior at week 48 and superior at week 96.
In the VISEND trial, TLD or a regimen of DTG with tenofovir alafenamide (TAF) and FTC, were both superior to boosted protease inhibitor regimens with AZT and 3TC at week 48.
Recent findings from a meta-analysis of four African first- and second-line studies (including VISEND) showed that people receiving DTG-based ART were significantly more likely to re-suppress after initial viraemia compared to those on efavirenz (EFV)- or PI-based regimens, with enhanced adherence counselling. 
Results from D2FT (another second-line ART optimisation study) are expected at CROI 2023. This will give us further information on DTG and DRV/r, as well as recycling TDF. 
Putting all this together suggests WHO recommendations need to revisit:
- Switching NRTIs in second-line (recycled TDF was notably superior to switching to AZT in NADIA at week 96).
- Increased adherence counselling and re-suppression with DTG.
- DRV/r as alternative for people that cannot take DTG and preferred PI (NADIA makes a good case and it will be interesting to look at this once D2FT results are available).
- Keene CM et al. Recycling tenofovir in second-line antiretroviral treatment with dolutegravir: outcomes and viral load trajectories to 72 weeks. JAIDS. Publish ahead of print. 25 January 2023.
- Keene CM et al. Virologic efficacy of tenofovir, lamivudine and dolutegravir as second-line in adults failing a tenofovir-based first-line regimen: a prospective cohort study. AIDS. 2021;35(9):1423-1432.
- Clayden P. Dolutegravir with recycled tenofovir and lamivudine performs well second-line: primary results from the NADIA trial. HTB. 12 March 202
- Clayden P. Dolutegravir plus recycled tenofovir rather than switch to AZT: public health approach to second-line ART. HTB. 2 May 2022.
- Paton NI et al. Efficacy and safety of dolutegravir or darunavir in combination with lamivudine plus either zidovudine or tenofovir for second-line treatment of HIV infection (NADIA): week 96 results from a prospective, multicentre, open-label, factorial, randomised, non. Lancet HIV. 20 April. 2022.
- 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.
- Clayden P. Better re-suppression after viral rebound with DTG-based ART compared to EFV- or PI-based regimens. HTB. 1 December 2022.
- Clinicaltrials.gov. Dolutegravir and Darunavir Evaluation in Adults Failing Therapy (D²EFT).