High Rate of Long-Term Clinical Events After Antiretroviral Therapy Resumption in HIV-Positive Patients Exposed to Antiretroviral Therapy Interruption

Valèria Richart; Irene Fernández; Elisa de Lazzari; Leire Berrocal; Csaba Fehér; Montserrat Plana; Lorna Leal; Felipe García


AIDS. 2021;35(15):2463-2468. 

In This Article

Abstract and Introduction


Objective: We analyzed the incidence rate of long-term events in patients on antiretroviral therapy (ART) previously exposed to therapy interruption.

Design: A single-center cohort study involving participants in ART interruptions (ARTI) clinical trials (n = 10) was conducted.

Methods: Non-AIDS events after ART resumption were analyzed. A control group not exposed to ARTI was randomly selected from the same cohort and a propensity score of belonging to ARTI group was estimated based on age, sex, CD4+ nadir value, time from HIV diagnosis to ARTI, time from HIV diagnosis to starting ART and time of suppressed viral load, and used to adjust effect estimates.

Results: One hundred and eighty-one patients were included, 136 in ARTI and 45 in the control arm. Median time of known HIV-1 infection was 21 years and median time from ART resumption to first non-AIDS event was 5.2 years. A significantly higher proportion of patients with ARTI had an event as compared with control group [raw percentages: 43% (n = 53) vs. 23% (n = 10), P = 0.015]. These differences were confirmed when only the non-AIDS events occurring after ART resumption were analyzed [adjusted hazard ratio (aHR) = 2.43, 95% confidence interval (CI) 1.15–5.12]. The logistic model adjusted for the propensity score indicated that patients with an ARTI had a four-fold higher risk of having at least one non-AIDS event (P = 0.002).

Conclusion: We found a higher risk of having at least one non-AIDS event years after ART resumption in HIV-infected patients exposed to ARTI as compared with controls. These data should be taken into consideration for future functional cure clinical trials.


Antiretroviral therapy (ART) is effective in maintaining viral suppression and reducing morbidity and mortality in patients with HIV infection. Nevertheless, some patients have adherence problems with long-term ART, which could increase the risk of developing drug resistance mutations. ART is a life-long therapy that it is unable to eradicate the virus, which persists indefinitely in latent reservoirs.[1] To date, the only studied strategies that could eliminate the virus reservoir are not well tolerated enough to be scalable, so currently HIV therapeutic research focuses on achieving a functional cure or remission. A functional cure implies sustained viral control in the absence of ART by generating efficient host immunity or reducing viral reservoir size. At present we do not have any nonviral biomarkers of viral control, thus interrupting treatment is required to assess the efficacy of functional cure interventions. Clinical trials including treatment interruption have different designs and different end-points. At first, studies had structured treatment interruptions (STI) that could have lasted years, the stops could be intermittent and treatment resumption was according to CD4+ T-cell count monitoring; at present these interruption periods are referred as analytical treatment interruption (ATI) and last 6 months or less and the viral load dynamics are as important as CD4+ T-cell count for decision-making. Recent ATI consensus guidelines state that researchers should determine if an intervention has achieved predefined goals before treatment interruption but without any nonviral biomarker, assessing viral set-point, peak viral load and time-to-rebound are still the only reliable way to evaluate the efficacy of therapeutic strategies..[2] The safety of antiretroviral therapy interruption (ARTI), in all it various forms, has extensively been analyzed. Rate of non-AIDS and AIDS events in patients included in ARTI trials have been reported during the interruption and short-term.[3–5] The participants of the different studies have reported adverse events, such as acute retroviral syndrome and other cardiovascular, renal or liver-related syndromes. Fortunately, in most cases, the syndromes resolved quickly upon resuming treatment. Other authors have assessed the effect of ARTI in HIV reservoir and have demonstrated that transient viremia does not have a significant impact in total and integrated DNA, and although there could be some increase in proviral DNA levels, these return to baseline no long after treatment resumption.[6–8] Despite all the available evidence about ARTI safety, to our knowledge, it has not yet been described if ARTI during functional cure clinical trials could relate to a higher rate of long-term severe events after ART resumption. To address this issue, we performed a descriptive, retrospective, case–control and single-centered study in a University Hospital. It aimed to describe the incidence rate of long-term events in HIV-infected patients on ART, previously exposed to ATI while participating in 10 different functional cure clinical trials, conducted between 1999 and 2018.[9–18]