Switch to long-acting cabotegravir and rilpivirine in virologically suppressed adults with HIV in Africa (CARES): week 48 results from a randomised, multicentre, open-label, non-inferiority trial.

BACKGROUND: Long-acting injectable cabotegravir and rilpivirine is licensed for individualised treatment of HIV-1 infection in resource-rich settings. Additional evidence is required to support use in African treatment programmes where demographic factors, viral subtypes, previous treatment, and delivery and monitoring approaches differ. The aim of this study was to determine whether switching to long-acting therapy with injections every 8 weeks is non-inferior to daily oral therapy in Africa. METHODS: CARES is a randomised, open-label, non-inferiority trial being conducted at eight sites in Uganda, Kenya, and South Africa. Participants with HIV viral load below 50 copies per mL on oral antiretroviral therapy and no history of virological failure were randomly assigned (1:1; web-based, permuted blocks) to receive cabotegravir (600 mg) and rilpivirine (900 mg) by intramuscular injection every 8 weeks, or to continue oral therapy. Viral load was monitored every 24 weeks. The primary outcome was week 48 viral load below 50 copies per mL, assessed with the Food and Drug Administration snapshot algorithm (non-inferiority margin 10 percentage points) in the intention-to-treat exposed population. This trial is registered with the Pan African Clinical Trials Registry (202104874490818) and is ongoing up to 96 weeks. FINDINGS: Between Sept 1, 2021, and Aug 31, 2022, we enrolled 512 participants (295 [58%] female; 380 [74%] previous non-nucleoside reverse transcriptase inhibitor exposure). Week 48 viral load was below 50 copies per mL in 246 (96%) of 255 participants in the long-acting therapy group and 250 (97%) of 257 in the oral therapy group (difference -0·8 percentage points; 95% CI -3·7 to 2·3), demonstrating non-inferiority (confirmed in per-protocol analysis). Two participants had virological failure in the long-acting therapy group, both with drug resistance; none had virological failure in the oral therapy group. Adverse events of grade 3 or greater severity occurred in 24 (9%) participants on long-acting therapy and ten (4%) on oral therapy; one participant discontinued long-acting therapy (for injection-site reaction). INTERPRETATION: Long-acting therapy had non-inferior efficacy compared with oral therapy, with a good safety profile, and can be considered for African treatment programmes. FUNDING: Janssen.

Patient Participant Perspectives on Implementation of Long-Acting Cabotegravir and Rilpivirine: Results From the Cabotegravir and Rilpivirine Implementation Study in European Locations (CARISEL) Study.

INTRODUCTION: CARISEL is an implementation-effectiveness "hybrid" study examining the perspectives of people living with HIV-1 (patient study participants [PSPs]) on cabotegravir (CAB) plus rilpivirine (RPV) long-acting (LA) dosed every 2 months (Q2M) across 5 European countries. METHODS: PSPs completed questionnaires on acceptability (Acceptability of Intervention Measure), appropriateness (Intervention Appropriateness Measure), and feasibility (Feasibility of Intervention Measure) at their first (Month [M] 1), third (M4), and seventh (M12) injection visits. Semistructured qualitative interviews were also conducted. RESULTS: Overall, 437 PSPs were enrolled, of whom 430 received treatment. Median (interquartile range) age was 44 (37-51) years, 25.3% (n = 109/430) were female (sex at birth), and 21.9% (n = 94/430) were persons of color. Across time points, PSPs found CAB + RPV LA highly acceptable, appropriate, and feasible (mean scores ≥4.47/5). Qualitative data supported these observations. CONCLUSIONS: PSPs found CAB + RPV LA Q2M to be an acceptable, appropriate, and feasible treatment option.

Quantifying pediatric patient need for second- and third-line HIV treatment: A tool for decision-making in resource-limited settings.

As national HIV programs across the world mature and continue to scale up towards UNAIDS' 90-90-90 targets, it is increasingly important to accurately estimate HIV treatment needs in pediatric patient populations to prepare for anticipated increases in demand. This is particularly vital in sub-Saharan Africa, where the bulk of the global pediatric HIV burden remains concentrated, and for treatment-experienced populations, for which data are severely limited. This article discusses the conceptual framework behind and application of a five-year country-level quantification and decision-making tool aimed at providing national HIV programs and their partners with a better understanding of their evolving national HIV treatment and programming needs for second-and third-line pediatric populations. The conceptual framework of the algorithm which undergirds the tool is the patient pathway, along which key influencing factors that determine whether pediatric HIV patients are linked to care, remain in treatment, and are appropriately switched to later lines of treatment are accounted for quantitatively. Excel-based and arithmetic, the algorithm is designed to use available national, regional, and global data for factors impacting patient estimates including treatment coverage; routine viral load testing; viral load non-suppression; confirmed treatment failure; and patient loss to follow up-outcomes for which data are generally very limited in this patient population. The ultimate output of the tool is an estimate of the aggregate annual number of patients by treatment line. Given the limitations in available data for pediatric HIV, particularly for patients on second- and third-line treatments, this tool may help fill a data gap by providing a mechanism for policymakers to scenario plan, thus aiding resource allocation decisions for pediatric HIV program scale-up. The tool may be used to streamline national antiretroviral procurement of later lines of treatment, especially in resource-limited settings, and may also be used to add value to broader HIV policy and planning processes at the national level.

Switching at Low HIV-1 RNA into Fixed Dose Combinations: TDF/FTC/RPV is non-inferior to TDF/FTC/EFV in first-line suppressed patients living with HIV.

BACKGROUND: In low- and middle-income countries (LMICs), a substantial unmet need for affordable single-tablet regimen (STR) options remains. Rilpivirine (RPV, TMC278) is formulated in a low-cost STR with tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC). OBJECTIVES: Switching at Low HIV-1 RNA into Fixed Dose Combinations (SALIF) compared RPV with efavirenz (EFV), both as STRs with TDF and FTC, in maintaining virologic suppression. METHODS: SALIF was a phase 3b, randomised, open-label, non-inferiority study in virologically suppressed adults (HIV-1 RNA < 50 copies/mL) on non-nucleoside reverse transcriptase inhibitor (NNRTI)-based first-line antiretroviral therapy (ART) in Cameroon, Kenya, Senegal, South Africa, Uganda and Thailand. Patients (N = 426), stratified by NNRTI use, were randomised 1:1 to receive TDF/FTC/RPV (300/200/25 mg qd) or TDF/FTC/EFV (300/200/600 mg qd). Primary endpoint was proportion of patients with virologic suppression (HIV-1 RNA < 400 copies/mL) at week 48 (intent-to-treat, modified Food and Drug Administration Snapshot, 10% non-inferiority margin). RESULTS: Patients received TDF/FTC/RPV (n = 213) or TDF/FTC/EFV (n = 211). At week 48, virologic suppression was maintained in 200/213 (93.9%) patients in the RPV arm and 203/211 (96.2%) in the EFV arm (difference -2.3%; 95% confidence interval: -6.4, +1.8), demonstrating non-inferiority of TDF/FTC/RPV. One patient in each arm experienced virologic failure without treatment-emergent resistance. Twenty-seven patients discontinued prematurely (8.0% RPV vs. 4.7% EFV), the most frequent reasons being adverse events (3.3% vs. 0.5%, respectively), site closure (1.9% vs. 0.5%), loss to follow-up (0.9% vs. 1.4%) and consent withdrawal (0.9% vs. 1.4%). CONCLUSION: In adults with suppressed viral load on first-line NNRTI-based ART in LMICs, switching to an STR of TDF/FTC/RPV was non-inferior to TDF/FTC/EFV in maintaining high rates of viral suppression with a comparable tolerability profile.

Efficacy of Once Daily Darunavir/Ritonavir in PI-Naïve, NNRTI-Experienced Patients in the ODIN Trial.

Background. An exploratory subanalysis of the ODIN trial was performed to evaluate the efficacy of darunavir/ritonavir (DRV/r) 800/100 mg OD versus 600/100 mg BID in patients who were NNRTI-experienced but PI-naïve. Methods. ODIN was a phase III, 48-week study comparing DRV/r OD versus BID in 590 treatment-experienced patients with no DRV resistance-associated mutations (RAMs) at screening. Patients received DRV/r 800/100 mg OD or DRV/r 600/100 mg BID plus ≥2 NRTIs. Of the 590 patients randomized, 272 (46%) were NNRTI-experienced but PI-naïve. Results. Overall, 272 patients received DRV/r OD (n = 135) or BID (n = 137) plus ≥2 optimised NRTIs. The mean age was 39 years; 35% were female; 27% were Black, 24% Caucasian, 26% Oriental/Asian, and 23% other races; 17% were recruited in South Africa; and 48% had non-B HIV-1 subtypes. Mean baseline plasma HIV-1 RNA load was 4.10 log10⁡ copies/mL; median CD4 cell count was 258 cells/µL. At week 48, 111/135 (82%) of DRV/r OD and 109/137 (80%) of DRV/r BID patients achieved an HIV-1 RNA load <50 copies/mL. No patient developed primary PI RAMs. Conclusion. DRV/r 800/100 mg OD in combination with ≥2 optimised NRTIs led to virological suppression <50 copies/mL in 82% of NNRTI-experienced, PI-naïve patients by week 48.

Can we stop CD4+ testing in patients with HIV-1 RNA suppression on antiretroviral treatment?

BACKGROUND: It is unclear whether regular CD4 testing is necessary for all patients during long-term antiretroviral treatment, after patients achieve full HIV-1 RNA suppression. METHODS: In the AntiRetroviral Therapy with TMC114 Examined in Naïve Subjects (ARTEMIS) trial, 689 treatment-naïve patients were randomized to tenofovir/emtricitabine and either darunavir/ritonavir or lopinavir/ritonavir. The number of patients with CD4 cell counts equal or above 200 copies/ml and HIV-1 RNA below 50 copies/ml at week 48 was assessed. For these patients, we assessed whether CD4 cell counts fell below 200 cells/µl from week 49 to week 192, while HIV-1 RNA suppression was maintained. RESULTS: Of the 520 responders, five (1.0%) progressed to an AIDS-defining event during the first 48 weeks of the trial, whereas 19 of the 169 non-responders (11.2%) developed AIDS-defining events during this time (P = 0.001, Fisher's Exact test). Of the 449 patients with sustained HIV-1 RNA suppression below 400 copies/ml from week 49 to week 192, five patients (1.1%) had reductions in CD4 cell count below 200 cells/µl on two consecutive visits. These were all short-term reductions, with follow-up results equal or above 200 cells/µl. CONCLUSIONS: There was a benefit to testing for CD4 cell count in the first 48 weeks of treatment, to identify patients who have immuno-virological discordance and therefore a higher risk of progression to AIDS. However, after 48 weeks of antiretroviral treatment, for the 'responder' patients in the ARTEMIS trial who had both HIV-1 RNA below 50 copies/ml and rises in CD4 cell count equal or above 200 cells/µl, there appears to be little clinical benefit from continued testing for CD4 cell count.