More evidence for recycling tenofovir in second-line ART with dolutegravir: 72-week results from ARTIST study

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. [1] 

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. [2]

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.

comment

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. [7]

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. [8]

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). 

References

1. 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.
   ournals.lww.com/jaids/Abstract/9900/Recycling_tenofovir_in_second_line_antiretroviral.176.aspx
2. 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.
   journals.lww.com/aidsonline/Fulltext/2021/07150/Virologic_efficacy_of_tenofovir,_lamivudine_and.10.aspx
3. Clayden P. Dolutegravir with recycled tenofovir and lamivudine performs well second-line: primary results from the NADIA trial. HTB. 12 March 202
   i-base.info/htb/40165
4. Clayden P. Dolutegravir plus recycled tenofovir rather than switch to AZT: public health approach to second-line ART. HTB. 2 May 2022.
   i-base.info/htb/42725
5. 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.
   www.thelancet.com/journals/lanhiv/article/PIIS2352-3018(22)00092-3/fulltext
6. 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.
   www.croiconference.org/abstract/dolutegravir-with-recycled-nrtis-is-noninferior-to-pi-based-art-visend-trial/ (abstract)
   www.croiwebcasts.org/console/player/50578 (webcast)
7. Clayden P. Better re-suppression after viral rebound with DTG-based ART compared to EFV- or PI-based regimens. HTB. 1 December 2022.
   i-base.info/htb/44399
8. Clinicaltrials.gov. Dolutegravir and Darunavir Evaluation in Adults Failing Therapy (D²EFT).
   clinicaltrials.gov/ct2/show/NCT03017872