Oral Lipid Nanocrystal Amphotericin B for Cryptococcal Meningitis: A Randomized Clinical Trial.

BACKGROUND: Amphotericin B is the gold standard treatment for severe mycoses. A new orally delivered, less-toxic formulation of amphotericin has been developed. METHODS: In our randomized clinical trial, we tested oral lipid nanocrystal (LNC) amphotericin B (MAT2203, Matinas Biopharma) vs intravenous (IV) amphotericin for human immunodeficiency virus-associated cryptococcal meningitis in 4 sequential cohorts. Two pilot cohorts assessed safety and tolerability (n = 10 each), and 2 cohorts assessed efficacy with/without 2 IV loading doses (n = 40 each). The experimental arm received 1.8 g/d oral LNC amphotericin through 2 weeks with 100 mg/kg/d flucytosine, then 1.2 g/d LNC amphotericin through 6 weeks. The randomized control arm (n = 41) received 7 days of IV amphotericin with flucytosine, then 7 days of fluconazole 1200 mg/d. The primary end point was cerebrospinal fluid (CSF) early fungicidal activity (EFA). RESULTS: We randomized 80 participants to oral LNC amphotericin + flucytosine with (n = 40) and without (n = 40) 2 IV loading doses and 41 control participants to IV amphotericin + flucytosine. Mean EFA was 0.40 log10 colony-forming units (CFU)/mL/d for all-oral LNC amphotericin, 0.42 log10  Cryptococcus CFU/mL/d for oral LNC amphotericin with IV loading doses, and 0.46 log10 CFU/mL/d for IV amphotericin controls. LNC amphotericin groups achieved 2-week CSF sterility in 63% (44 of 70) vs 68% (23 of 34) of controls. The 18-week survival was 85% (34 of 40) with all-oral LNC amphotericin, 90% (36 of 40) with oral LNC amphotericin given IV loading doses, and 85% (35 of 41) with IV amphotericin.Grade 3-4 laboratory adverse events occurred less frequently in LNC amphotericin groups (41%) than the IV amphotericin group (61%, P = .05), particularly for anemia (21% vs 44%; P = .01) and potassium (5% vs 17%; P = .04). CONCLUSIONS: This new oral amphotericin B LNC formulation appears promising for cryptococcal meningitis with antifungal activity, similar survival, and less toxicity than IV amphotericin. CLINICAL TRIALS REGISTRATION: NCT04031833.

Effect of a patient-centered hypertension delivery strategy on all-cause mortality: Secondary analysis of SEARCH, a community-randomized trial in rural Kenya and Uganda.

BACKGROUND: Hypertension treatment reduces morbidity and mortality yet has not been broadly implemented in many low-resource settings, including sub-Saharan Africa (SSA). We hypothesized that a patient-centered integrated chronic disease model that included hypertension treatment and leveraged the HIV care system would reduce mortality among adults with uncontrolled hypertension in rural Kenya and Uganda. METHODS AND FINDINGS: This is a secondary analysis of the SEARCH trial (NCT:01864603), in which 32 communities underwent baseline population-based multidisease testing, including hypertension screening, and were randomized to standard country-guided treatment or to a patient-centered integrated chronic care model including treatment for hypertension, diabetes, and HIV. Patient-centered care included on-site introduction to clinic staff at screening, nursing triage to expedite visits, reduced visit frequency, flexible clinic hours, and a welcoming clinic environment. The analytic population included nonpregnant adults (≥18 years) with baseline uncontrolled hypertension (blood pressure ≥140/90 mm Hg). The primary outcome was 3-year all-cause mortality with comprehensive population-level assessment. Secondary outcomes included hypertension control assessed at a population level at year 3 (defined per country guidelines as at least 1 blood pressure measure <140/90 mm Hg on 3 repeated measures). Between-arm comparisons used cluster-level targeted maximum likelihood estimation. Among 86,078 adults screened at study baseline (June 2013 to July 2014), 10,928 (13%) had uncontrolled hypertension. Median age was 53 years (25th to 75th percentile 40 to 66); 6,058 (55%) were female; 677 (6%) were HIV infected; and 477 (4%) had diabetes mellitus. Overall, 174 participants (3.2%) in the intervention group and 225 participants (4.1%) in the control group died during 3 years of follow-up (adjusted relative risk (aRR) 0.79, 95% confidence interval (CI) 0.64 to 0.97, p = 0.028). Among those with baseline grade 3 hypertension (≥180/110 mm Hg), 22 (4.9%) in the intervention group and 42 (7.9%) in the control group died during 3 years of follow-up (aRR 0.62, 95% CI 0.39 to 0.97, p = 0.038). Estimated population-level hypertension control at year 3 was 53% in intervention and 44% in control communities (aRR 1.22, 95% CI 1.12 to 1.33, p < 0.001). Study limitations include inability to identify specific causes of death and control conditions that exceeded current standard hypertension care. CONCLUSIONS: In this cluster randomized comparison where both arms received population-level hypertension screening, implementation of a patient-centered hypertension care model was associated with a 21% reduction in all-cause mortality and a 22% improvement in hypertension control compared to standard care among adults with baseline uncontrolled hypertension. Patient-centered chronic care programs for HIV can be leveraged to reduce the overall burden of cardiovascular mortality in SSA. TRIAL REGISTRATION: ClinicalTrials.gov NCT01864603.

Uptake, engagement, and adherence to pre-exposure prophylaxis offered after population HIV testing in rural Kenya and Uganda: 72-week interim analysis of observational data from the SEARCH study.

BACKGROUND: Optimal strategies for pre-exposure prophylaxis (PrEP) engagement in generalised HIV epidemics are unknown. We aimed to assess PrEP uptake and engagement after population-level HIV testing and universal PrEP access to characterise gaps in the PrEP cascade in rural Kenya and Uganda. METHODS: We did a 72-week interim analysis of observational data from the ongoing SEARCH (Sustainable East Africa Research in Community Health) study. Following community sensitisation and PrEP education, we did HIV testing and offered PrEP at health fairs and facilities in 16 rural communities in western Kenya, eastern Uganda, and western Uganda. We provided enhanced PrEP counselling to individuals 15 years and older who were assessed as having an elevated HIV risk on the basis of serodifferent partnership or empirical risk score, or who otherwise self-identified as being at high risk but were not in serodifferent partnerships or identified by the risk score. PrEP follow-up visits were done at facilities, homes, or community locations. We assessed PrEP uptake within 90 days of HIV testing, programme engagement (follow-up visit attendance at week 4, week 12, and every 12 weeks thereafter), refills, self-reported adherence up to 72 weeks, and concentrations of tenofovir in hair samples from individuals reporting HIV risk and adherence during follow-up, and analysed factors associated with uptake and adherence. This study is registered with ClinicalTrials.gov, NCT01864603. FINDINGS: Between June 6, 2016, and June 23, 2017, 70 379 community residents 15 years or older who had not previously been diagnosed with HIV were tested during population-level HIV testing. Of these individuals, 69 121 tested HIV-negative, 12 935 of whom had elevated HIV risk (1353 [10%] serodifferent partnership, 6938 [54%] risk score, 4644 [36%] otherwise self-identified risk). 3489 (27%) initiated PrEP, 2865 (82%) of whom did so on the same day as HIV testing and 1733 (50%) of whom were men. PrEP uptake was lower among individuals aged 15-24 years (adjusted odds ratio 0·55, 95% CI 0·45-0·68) and mobile individuals (0·61, 0·41-0·91). At week 4, among 3466 individuals who initiated PrEP and did not withdraw or die before the first visit, 2215 (64%) were engaged in the programme, 1701 (49%) received medication refills, and 1388 (40%) self-reported adherence. At week 72, 1832 (56%) of 3274 were engaged, 1070 (33%) received a refill, and 900 (27%) self-reported adherence. Among participants reporting HIV risk at weeks 4-72, refills (89-93%) and self-reported adherence (70-76%) were high. Among sampled participants self-reporting adherence at week 24, the proportion with tenofovir concentrations in the hair reflecting at least four doses taken per week was 66%, and reflecting seven doses per week was 44%. Participants who stopped PrEP accepted HIV testing at 4274 (83%) of 5140 subsequent visits; half of these participants later restarted PrEP. 29 participants of 3489 who initiated PrEP had serious adverse events, including seven deaths. Five adverse events (all grade 3) were assessed as being possibly related to the study drug. INTERPRETATION: During population-level HIV testing, inclusive risk assessment (combining serodifferent partnership, an empirical risk score, and self-identification of HIV risk) was feasible and identified individuals who could benefit from PrEP. The biggest gap in the PrEP cascade was PrEP uptake, particularly for young and mobile individuals. Participants who initiated PrEP and had perceived HIV risk during follow-up reported taking PrEP, but one-third had drug concentrations consistent with poor adherence, highlighting the need for novel approaches and long-acting formulations as PrEP roll-out expands. FUNDING: National Institutes of Health, President's Emergency Plan for AIDS Relief, Bill & Melinda Gates Foundation, and Gilead Sciences.

Machine Learning to Identify Persons at High-Risk of Human Immunodeficiency Virus Acquisition in Rural Kenya and Uganda.

BACKGROUND: In generalized epidemic settings, strategies are needed to prioritize individuals at higher risk of human immunodeficiency virus (HIV) acquisition for prevention services. We used population-level HIV testing data from rural Kenya and Uganda to construct HIV risk scores and assessed their ability to identify seroconversions. METHODS: During 2013-2017, >75% of residents in 16 communities in the SEARCH study were tested annually for HIV. In this population, we evaluated 3 strategies for using demographic factors to predict the 1-year risk of HIV seroconversion: membership in ≥1 known "risk group" (eg, having a spouse living with HIV), a "model-based" risk score constructed with logistic regression, and a "machine learning" risk score constructed with the Super Learner algorithm. We hypothesized machine learning would identify high-risk individuals more efficiently (fewer persons targeted for a fixed sensitivity) and with higher sensitivity (for a fixed number targeted) than either other approach. RESULTS: A total of 75 558 persons contributed 166 723 person-years of follow-up; 519 seroconverted. Machine learning improved efficiency. To achieve a fixed sensitivity of 50%, the risk-group strategy targeted 42% of the population, the model-based strategy targeted 27%, and machine learning targeted 18%. Machine learning also improved sensitivity. With an upper limit of 45% targeted, the risk-group strategy correctly classified 58% of seroconversions, the model-based strategy 68%, and machine learning 78%. CONCLUSIONS: Machine learning improved classification of individuals at risk of HIV acquisition compared with a model-based approach or reliance on known risk groups and could inform targeting of prevention strategies in generalized epidemic settings. CLINICAL TRIALS REGISTRATION: NCT01864603.

HIV Testing and Treatment with the Use of a Community Health Approach in Rural Africa.

BACKGROUND: Universal antiretroviral therapy (ART) with annual population testing and a multidisease, patient-centered strategy could reduce new human immunodeficiency virus (HIV) infections and improve community health. METHODS: We randomly assigned 32 rural communities in Uganda and Kenya to baseline HIV and multidisease testing and national guideline-restricted ART (control group) or to baseline testing plus annual testing, eligibility for universal ART, and patient-centered care (intervention group). The primary end point was the cumulative incidence of HIV infection at 3 years. Secondary end points included viral suppression, death, tuberculosis, hypertension control, and the change in the annual incidence of HIV infection (which was evaluated in the intervention group only). RESULTS: A total of 150,395 persons were included in the analyses. Population-level viral suppression among 15,399 HIV-infected persons was 42% at baseline and was higher in the intervention group than in the control group at 3 years (79% vs. 68%; relative prevalence, 1.15; 95% confidence interval [CI], 1.11 to 1.20). The annual incidence of HIV infection in the intervention group decreased by 32% over 3 years (from 0.43 to 0.31 cases per 100 person-years; relative rate, 0.68; 95% CI, 0.56 to 0.84). However, the 3-year cumulative incidence (704 incident HIV infections) did not differ significantly between the intervention group and the control group (0.77% and 0.81%, respectively; relative risk, 0.95; 95% CI, 0.77 to 1.17). Among HIV-infected persons, the risk of death by year 3 was 3% in the intervention group and 4% in the control group (0.99 vs. 1.29 deaths per 100 person-years; relative risk, 0.77; 95% CI, 0.64 to 0.93). The risk of HIV-associated tuberculosis or death by year 3 among HIV-infected persons was 4% in the intervention group and 5% in the control group (1.19 vs. 1.50 events per 100 person-years; relative risk, 0.79; 95% CI, 0.67 to 0.94). At 3 years, 47% of adults with hypertension in the intervention group and 37% in the control group had hypertension control (relative prevalence, 1.26; 95% CI, 1.15 to 1.39). CONCLUSIONS: Universal HIV treatment did not result in a significantly lower incidence of HIV infection than standard care, probably owing to the availability of comprehensive baseline HIV testing and the rapid expansion of ART eligibility in the control group. (Funded by the National Institutes of Health and others; SEARCH ClinicalTrials.gov number, NCT01864603.).