Cabotegravir and rilpivirine long-acting injectable antiretroviral therapy for the treatment of HIV-1 infection brings promise of a new mode of delivery and potential solutions to some problems of oral therapy, but also new challenges and unanswered questions. Adding to the increasing body of evidence for newer two-drug combinations, phase II and phase III trial data to date demonstrate cabotegravir and rilpivirine combination injectable therapy to be non-inferior to selected oral triple-therapy alternatives. Most importantly, this therapy is reported to be acceptable to individuals taking the 4-weekly or 8-weekly injections, despite frequent injection-site reactions. Key outstanding questions include management of missed or delayed dosing, drug interactions and management of virological failure, as well as the efficacy of cabotegravir and rilpivirine in all HIV-1 subtypes. We describe clinical evidence to date and efficacy and challenges in selected populations, including women; those with prior virological failure; individuals with a history of difficulty adhering to oral therapy and individuals with co-infections. We await real-world data and longer-term evidence while moving forward to this new era of antiretroviral therapy.

Objectives: We describe isoniazid-related adverse events in Thibela TB, a cluster-randomised study of community-wide isoniazid preventive therapy (IPT) among gold miners in South Africa, where HIV prevalence is estimated at 30%. Methods:Consenting employees were screened prior to IPT for active tuberculosis and increased risk of isoniazid toxicity using a questionnaire and chest radiograph. Study-defined IPT-related adverse events were sought at each study visit: liver function tests were only performed if clinically indicated. In a sub-study, we questioned consecutive participants at baseline and months 1, 3 and 6 concerning minor IPT-related adverse events.Results: Among 24,221 participants (95.2% male, median age 40 years), 130 individuals had 132 study-defined adverse events (0.54%); 61 (0.25%) possible hypersensitivity rash, 50 (0.21%) peripheral neuropathy, 17 (0.07%) clinical hepatotoxicity and 4 (0.02%) convulsions. Four events (two hepatotoxicity, one fatal, and two convulsions) fulfilled criteria for seriousness. Clinical hepatotoxicity was associated with consumption of alcohol (0.11% vs. 0.03% if no alcohol consumed, odds ratio 3.9 [95% confidence interval 1.2-12.1]), but not with sex, age, weight or concurrent antiretroviral therapy. In the sub-study, 324/498 (65.1%) participants reported better health since starting IPT; 180/324 (55.6%) reported that this was because of increased appetite. The frequency of specific minor symptoms was low among those taking IPT, and all symptoms were reported less often than at baseline. Conclusions:The risk of adverse events, particularly hepatotoxicity, was very low in this population.Our data suggest that clinical criteria can safely be used for screening prior to and monitoring during IPT.

TB after recent IPT has prevalence of drug resistance similar to background and treatment outcomes typical of this setting. These data support wider implementation of IPT.

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for the UK Collaborative HIV Cohort (UK CHIC) StudyObjective: The United Kingdom has a low tuberculosis incidence and earlier combination antiretroviral therapy (cART) is expected to have reduced incidence among people with HIV. Epidemiological patterns and risk factors for active tuberculosis were analysed over a 20-year period among people accessing HIV care at sites participating in the UK CHIC observational study.Design: Cohort analysis.Methods: Data were included for individuals over 15 years old attending for HIV care between 1996 and 2017 inclusive, with at least 3 months follow-up recorded. Incidence rates of new tuberculosis events were calculated and stratified by ethnicity (white/Black/ other) as a proxy for tuberculosis exposure. Poisson regression models were used to determine the associations of calendar year, ethnicity and other potential risk factors after cART initiation.Results: Fifty-eight thousand seven hundred and seventy-six participants (26.3% women; 54.5% white, 32.0% Black, 13.5% other/unknown ethnicity; median (interquartile range) age 34 (29-42) years) were followed for 546 617 person-years. Seven hundred and four were treated for active tuberculosis [rate 1.3; 95% confidence interval (CI) 1.2-1.4/1000 person-years). Tuberculosis incidence decreased from 1.3 (1.2-1.5) to 0.6 (0.4-0.9)/1000 person-years from pre-2004 to 2011-2017. The decline among people of Black ethnicity was less steep than among those of white/other ethnicities, with incidence remaining high among Black participants in the latest period [2.1 (1.4-3.1)/1000 person-years]. Two hundred and eighty-three participants [191 (67%) Black African] had tuberculosis with viral load less than 50 copies/ml. Conclusion:Despite the known protective effect of cART against tuberculosis, a continuing disproportionately high incidence is seen among Black African people. Results support further interventions to prevent tuberculosis in this group.