HIV Treatment as Prevention: Considerations in the Design, Conduct, and Analysis of Cluster Randomized Controlled Trials of Combination HIV Prevention

The rigorous evaluation of the impact of combination HIV prevention packages at the population level will be critical for the future of HIV prevention. In this review, we discuss important considerations for the design and interpretation of cluster randomized controlled trials (C-RCTs) of combination prevention interventions. We focus on three large C-RCTs that will start soon and are designed to test the hypothesis that combination prevention packages, including expanded access to antiretroviral therapy, can substantially reduce HIV incidence. Using a general framework to integrate mathematical modelling analysis into the design, conduct, and analysis of C-RCTs will complement traditional statistical analyses and strengthen the evaluation of the interventions. Importantly, even with combination interventions, it may be challenging to substantially reduce HIV incidence over the 2- to 3-y duration of a C-RCT, unless interventions are scaled up rapidly and key populations are reached. Thus, we propose the innovative use of mathematical modelling to conduct interim analyses, when interim HIV incidence data are not available, to allow the ongoing trials to be modified or adapted to reduce the likelihood of inconclusive outcomes. The preplanned, interactive use of mathematical models during C-RCTs will also provide a valuable opportunity to validate and refine model projections

The effectiveness of mindfulness-based interventions in the perinatal period: a systematic review and meta-analysis

Perinatal mental health difficulties are associated with adverse consequences for parents and infants. However, the potential risks associated with the use of psychotropic medication for pregnant and breastfeeding women and the preferences expressed by women for non-pharmacological interventions mean it is important to ensure that effective psychological interventions are available. It has been argued that mindfulness-based interventions may offer a novel approach to treating perinatal mental health difficulties, but relatively little is known about their effectiveness with perinatal populations. This paper therefore presents a systematic review and meta-analysis of the effectiveness of mindfulness-based interventions for reducing depression, anxiety and stress and improving mindfulness skills in the perinatal period. A systematic review identified seventeen studies of mindfulness-based interventions in the perinatal period, including both controlled trials (n = 9) and pre-post uncontrolled studies (n = 8). Eight of these studies also included qualitative data. Hedge’s g was used to assess uncontrolled and controlled effect sizes in separate meta-analyses, and a narrative synthesis of qualitative data was produced. Pre- to post-analyses showed significant reductions in depression, anxiety and stress and significant increases in mindfulness skills post intervention, each with small to medium effect sizes. Completion of the mindfulness-based interventions was reasonable with around three quarters of participants meeting study-defined criteria for engagement or completion where this was recorded. Qualitative data suggested that participants viewed mindfulness interventions positively. However, between-group analyses failed to find any significant post-intervention benefits for depression, anxiety or stress of mindfulness-based interventions in comparison to control conditions: effect sizes were negligible and it was conspicuous that intervention group participants did not appear to improve significantly more than controls in their mindfulness skills. The interventions offered often deviated from traditional mindfulness-based cognitive therapy or mindfulness-based stress reduction programmes, and there was also a tendency for studies to focus on healthy rather than clinical populations, and on antenatal rather than postnatal populations. It is argued that these and other limitations with the included studies and their interventions may have been partly responsible for the lack of significant between-group effects. The implications of the findings and recommendations for future research are discussed

Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P = 0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P = 0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31). Conclusions: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.

Estimating HIV incidence from surveillance data indicates a second wave of infections in Brazil

Emerging evidence suggests that HIV incidence rates in Brazil, particularly among men, may be rising. Here we use Brazil’s integrated health systems data to develop a mathematical model, reproducing the complex surveillance systems and providing estimates of HIV incidence, number of people living with HIV (PLHIV), reporting rates and ART initiation rates. An age-structured deterministic model with a flexible spline was used to describe the natural history of HIV along with reporting and treatment rates. Individual-level surveillance data for 1,077,295 cases (HIV/AIDS diagnoses, ART dispensations, CD4 counts and HIV/AIDS-related deaths) were used to calibrate the model using Bayesian inference. The results showed a second wave of infections occurring after 2001 and 56,000 (95% Credible Interval 43,000–71,000) new infections in 2015, 37,000 (95% CrI 28,000–54,000) infections in men and 16,000 (95% CrI 10,000–23,000) in women. The estimated number of PLHIV by end-2015 was 838,000 (95% CrI 675,000–1,083,000), with 80% (95% CrI 62–98%) of those individuals reported to the Ministry of Health. Women were more likely to be diagnosed and reported than men; 86.8% of infected women had been reported compared with 75.7% of men. Likewise, ART initiation rates for women were higher than those for men. The second wave contradicts previous estimates of HIV incidence trends in Brazil and there were persistent differences in the rates of accessing care between men and women. Nevertheless, the Brazilian HIV program has achieved high rates of detection and treatment, making considerable progress over the past ten years

Anal intercourse among female sex workers in Côte d’Ivoire: prevalence, determinants, and model-based estimates of the population-level impact on HIV transmission

urrent evidence suggests that anal intercourse (AI) during sex work is common in sub-Saharan Africa, but few studies investigated the contribution of heterosexual AI to HIV epidemics. Using a respondent-driven sampling survey of female sex workers (FSW) in Abidjan (2014), we estimated AI prevalence and frequency. Poisson regressions were used to identify AI determinants. About 20% of FSW (N = 466) engaged in AI during a normal week (95% confidence intervals: 15-26%). Women who performed AI were generally younger, had been selling sex for longer, were born in Côte d'Ivoire, reported higher sex-work income, more frequent sex in public places, and violence from clients than women not reporting AI. Condom use was lower, condom breakage/slippage more frequent, and use of water-based lubricants was less frequently reported for AI than for vaginal intercourse. Using a dynamic transmission model, we estimated that 22% (95% credible intervals: 11-37%) of new HIV infections could have been averted among FSW during 2000-2015 if AI had been substituted for vaginal intercourse acts. Despite representing a small fraction of all sex acts, AI is an underestimated source of HIV transmission. Increasing availability/uptake of condoms, lubricants, and pre-exposure prophylaxis for women engaging in AI could help mitigate HIV risk

Changing dynamics of HIV transmission in Cote d'Ivoire: modeling who acquired and transmitted infections and estimating the impact of past HIV interventions (1976-2015)

Introduction: Understanding the impact of past interventions and how it affected transmission dynamics is key to guiding prevention efforts. We estimated the population-level impact of condom, antiretroviral therapy (ART), and prevention of mother-to-child transmission activities on HIV transmission and the contribution of key risk factors on HIV acquisition and transmission. Methods: An age-stratified dynamical model of sexual and vertical HIV transmission among the general population, female sex workers (FSW), and men who have sex with men was calibrated to detailed prevalence and intervention data. We estimated the fraction of HIV infections averted by the interventions, and the fraction of incident infections acquired and transmitted by different populations over successive 10-year periods (1976–2015). Results: Overall, condom use averted 61% (95% credible intervals: 56%–66%) of all adult infections during 1987–2015 mainly because of increased use by FSW (46% of infections averted). In comparison, ART prevented 15% (10%–19%) of adult infections during 2010–2015. As a result, FSW initially (1976–1985) contributed 95% (91%–97%) of all new infections, declining to 19% (11%–27%) during 2005–2015. Older men and clients mixing with non-FSW are currently the highest contributors to transmission. Men who have sex with men contributed ≤4% transmissions throughout. Young women (15–24 years; excluding FSW) do not transmit more infections than they acquired. Conclusions: Early increases in condom use, mainly by FSW, have substantially reduced HIV transmission. Clients of FSWs and older men have become the main source of transmission, whereas young women remain at increased risk. Strengthening prevention and scaling-up of ART, particularly to FSW and clients of female sex workers, is important

The potential impact of the COVID-19 pandemic on the tuberculosis epidemic: a modelling analysis

Background: Routine services for tuberculosis (TB) are being disrupted by stringent lockdowns against the novel SARS-CoV-2 virus. We sought to estimate the potential long-term epidemiological impact of such disruptions on TB burden in high-burden countries, and how this negative impact could be mitigated. Methods: We adapted mathematical models of TB transmission in three high-burden countries (India, Kenya and Ukraine) to incorporate lockdown-associated disruptions in the TB care cascade. The anticipated level of disruption reflected consensus from a rapid expert consultation. We modelled the impact of these disruptions on TB incidence and mortality over the next five years, and also considered potential interventions to curtail this impact. Results: Even temporary disruptions can cause long-term increases in TB incidence and mortality. We estimated that a 3-month lockdown, followed by 10 months to restore normal TB services, would cause, over the next 5 years, an additional 1.65 million TB cases (Crl 1.49– 1.85) and 438,000 TB deaths (CrI 403 – 483 thousand) in India, 41,400 (28,900–62,200) TB cases and 14,800 deaths (10.5 – 19.2 thousand) in Kenya, and 7,960 (6,250 – 9,880) cases and 2,050 deaths (1,610 - 2,360) in Ukraine. However, any such negative impacts could be averted through supplementary “catch-up” TB case detection and treatment, once restrictions are eased. Interpretation: Lockdown-related disruptions can cause long-lasting increases in TB burden, but these negative effects can be mitigated with targeted interventions implemented rapidly once lockdowns are lifted. Funding Statement: USAID and Stop TB Partnership. Declaration of Interests: The authors declare no conflict of interest