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. 2024 Feb 10:69:102457.
doi: 10.1016/j.eclinm.2024.102457. eCollection 2024 Mar.

Long-term efficacy and safety of a treatment strategy for HIV infection using protease inhibitor monotherapy: 8-year routine clinical care follow-up from a randomised, controlled, open-label pragmatic trial (PIVOT)

Nicholas I Paton  1   2 , Wolfgang Stöhr  1 , Alejandro Arenas-Pinto  1 , Amanda Clarke  3 , Ian Williams  4 , Margaret Johnson  5 , Chloe Orkin  6 , Fabian Chen  7 , Vincent Lee  8 , Alan Winston  9 , Mark Gompels  10 , Julie Fox  11 , Karen Sanders  1 , David T Dunn  1 ; Protease Inhibitor monotherapy Versus Ongoing Triple therapy (PIVOT) Trial Team
Collaborators, Affiliations

Long-term efficacy and safety of a treatment strategy for HIV infection using protease inhibitor monotherapy: 8-year routine clinical care follow-up from a randomised, controlled, open-label pragmatic trial (PIVOT)

Nicholas I Paton et al. EClinicalMedicine. .

Abstract

Background: Treatment-simplification strategies are important tools for patient-centred management. We evaluated long-term outcomes from a PI monotherapy switch strategy.

Methods: Eligible participants attending 43 UK treatment centres had a viral load (VL) below 50 copies/ml for at least 24 weeks on combination ART. Participants were randomised to maintain ongoing triple therapy (OT) or switch to a strategy of physician-selected PI monotherapy (PI-mono) with prompt return to combination therapy if VL rebounded. The primary outcome, previously reported, was loss of future drug options after 3 years, defined as new intermediate/high level resistance to at least one drug to which the participant's virus was considered sensitive at trial entry. Here we report resistance and disease outcomes after further extended follow-up in routine care. The study was registered as ISRCTN04857074.

Findings: We randomised 587 participants to OT (291) or PI-mono (296) between Nov 4, 2008, and July 28, 2010 and followed them for a median of more than 8 years (100 months) until 2018. At the end of this follow-up time, one or more future drug options had been lost in 7 participants in the OT group and 6 in the PI-mono group; estimated cumulative risk by 8 years of 2.7% and 2.1% respectively (difference -0.6%, 95% CI -3.2% to 2.0%). Only one PI-mono participant developed resistance to the protease inhibitor they were taking (atazanavir). Serious clinical events (death, serious AIDS, and serious non-AIDS) were infrequent; reported in a total of 12 (4.1%) participants in the OT group and 23 (7.8%) in the PI-mono group (P = 0.08) over the entire follow-up period.

Interpretation: A strategy of PI monotherapy, with regular VL monitoring and prompt reintroduction of combination treatment following rebound, preserved future treatment options. Findings confirm the high genetic barrier to resistance of the PI drug class that makes them well suited for creative, patient-centred, treatment-simplification approaches. The possibility of a small excess risk of serious clinical events with the PI monotherapy strategy cannot be excluded.

Funding: The National Institute for Health Research Health Technology Assessment programme.

Keywords: Darunavir; HIV; Protease inhibitor monotherapy; Randomised; Simplification.

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Conflict of interest statement

NP reports grants to institution from Janssen; and honoraria for lectures from Janssen. AA-P reports grants to institution from Janssen, ViiV Healthcare and Gilead Sciences and advisory board fees from ViiV Healthcare. AC reports contracts to run clinical trials with payments to institution from Gilead Sciences, ViiV Healthcare, MSD and GSK; honoraria for lectures from MSD; support for attending meetings from ViiV Healthcare and Gilead Sciences; advisory board fees from Gilead Sciences, ViiV Healthcare and Theratechnologies. CO reports grants to institution from Janssen, Gilead, ViiV Healthcare, MSD and Astrazeneca; honoraria for lectures from Janssen, Gilead, ViiV Healthcare and MSD; and unpaid appointments as President of the Medical Women's Federation and a member of the International AIDS Society governing council. MG reports advisory board fees from Gilead. All other authors declare no competing interests.

Figures

Fig. 1
Fig. 1
a). Kaplan–Meier estimates of the proportion of participants who remained on the treatment allocated by randomisation. The ongoing triple therapy (OT) group is shown in blue; the protease inhibitor monotherapy (PI-mono) group is shown in red. Switch from allocated treatment was defined as discontinuation of all ART for ≥28 days (both groups); or re-introduction of combination therapy (PI-mono group); or initiation of PI monotherapy (OT group). Follow-up was censored at the last clinic visit. b). Kaplan–Meier estimates of the proportion of participants who remained on the treatment allocated by randomization who did not experience viral failure. The ongoing triple therapy (OT) group is shown in blue; the protease inhibitor monotherapy (PI-mono) group is shown in red. Viral failure was defined as a single VL ≥ 200 copies/ml. Follow-up was censored at switch from allocated treatment (defined as above) or at last viral load measurement.
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