EACS 2023: TDF/FTC dual-nuke ART: not supported by ALTAR study

EACS 2023 included an unexpected oral presentation on use of TDF/FTC as dual-NRTI combination, a combination that is not recommended in guidelines and that would risk viral breakthrough due to reduced potency compared to triple combinations.

However, the results from a small number of participants collected before the study was ended early, are much too limited to support dual-NRTI ART.

Several integrase inhibitor-based (INSTI) dual-ART regimens are included in clinical guidelines (DTG/3TC, DTG/RPV and CAB/RPV), but tenofovir does not have the same potency and pharmacokinetic properties as integrase inhibitors.

The randomised open-label ALTAR study aimed to assess non-inferiority for viral suppression at week 48 for participants receiving either DTG/3TC or TDF/FTC. For the TDF/FTC arm, there was a 12-week oral lead-in with triple therapy (TDF/XTC/INSTI) before switch to dual therapy.

The study was approved in 2016 and aimed to enrol 180 participants per arm. However, the trial was halted to await results from GEMINI and then was beset by issues arising from the unfolding COVID-19 pandemic in France. The regulator stopped the trial in 2021 and data out to week 24 were collected for 45 participants only. Participants were female (16%), median age was 32 years (IQR: 26 to 47) and 78% were heterosexual.

Viral suppression rates at week 24 were comparable between groups, with 87% achieving <50 copies/mL. There were comparable improvements in virologic parameters for both arms. Viral load decreased by 0.57 (SE: 0.1) vs 0.32 (SE: 0.11) log copies/mL for the TDF/FTC vs DTG/3TC arms, respectively. Participants on TDF/FTC gained +0.9 kg (SE: 3.9 kg), vs +1.4 kg (SE: 2.7 kg) with DTG/3TC.

One case of virologic failure was reported in each arm. For TDF/FTC, a participant had a viral load increase to 139 copies/mL but resistance mutations were not detected. Following re-introduction of DTG they achieved viral suppression. The case in the DTG/3TC arm was linked to missed clinic visits and likely low adherence. They discontinued from the study and PI- and INSTI-associated resistance mutations were identified. With improved adherence to DTG/3TC they achieved an undetectable viral load.

Comparable virologic success was observed for both dual-ART regimens in this small sample size. Further investigation may lead to identification of alternative dual-ART regimens to reduce drug burden of lifelong ART, and provide alternatives for people with INSTI resistance.

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The rationale for using TDF/FTC in this study was the short- to long-term side effects reported in a minority of people using INSTIs. However, as alternative third drugs are available, participants in the study risked developing NRTI drug resistance.

Although comparable levels of virologic control were observed at week 24 in the DTG/3TC (87%) and TDF/FTC (86.4%), the risk of viral rebound with TDF/FTC would be expected at later timepoints. The low participant numbers mean all results are underpowered to interpret either way.

Historical data using dual nukes showed viral load rebound with dual AZT/3TC took a little longer. Even if tenofovir has a slightly higher genetic barrier to drug resistance compared to AZT, resistance can still develop later with suboptimal combinations, and mutations can be cross-resistant to other NRTIs.