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: Introduction: Lifelong antiretroviral therapy (ART) improves health outcomes for HIV‐positive individuals, but is jeopardized by irregular clinic attendance and hence poor adherence. Loss to follow‐up (LTFU) is typically defined retrospectively but this may lead to biased inferences. We assessed incidence of and factors associated with LTFU, prospectively and accounting for recurrent LTFU episodes, in the Kilombero and Ulanga Antiretroviral Cohort (KIULARCO) of HIV‐positive persons in rural Tanzania. Methods: We included adults (≥15 years) enrolled in 2005 to 2016, regardless of ART status, with follow‐up through April 2017. LTFU was defined as >60 days late for a scheduled appointment. Participants could experience multiple LTFU episodes. We performed analyses based on the first (prospective) and last (retrospective) events observed during follow‐up, and accounting for recurrent LTFU episodes. Time to LTFU was estimated using cumulative incidence functions. We assessed factors associated with LTFU using cause‐specific proportional hazards, marginal means/rates, and Prentice, Williams and Peterson models. Results: Among 8087 participants (65% female, 60% aged ≥35 years, 42% WHO stage 3/4, and 47% CD4 count Conclusions: LTFU episodes were common and prompt tracing efforts are urgently needed. We identified socio‐demographic and clinical characteristics associated with LTFU that can be used to target tracing efforts and to help inform the design of appropriate interventions. Incidence of and risk factors for LTFU differed based on the LTFU definition applied, highlighting the importance of appropriately accounting for recurrent LTFU episodes. We recommend using a prospective definition of LTFU combined with recurrent event analyses in cohorts where repeated interruptions in care are common., Introduction Lifelong antiretroviral therapy (ART) is crucial to optimize health outcomes for people living with HIV. Retention in care is a critical component to reaching the second and third UNAIDS [...]

Background: Poor adherence to antiretroviral drugs and viral resistance are the main drivers of treatment failure in HIV-infected patients. In sub-Saharan Africa, avoidance of treatment failure on second-line protease inhibitor therapy is critical as treatment options are limited. Methods: In the prospective observational study of the Kilombero & Ulanga Antiretroviral Cohort in rural Tanzania, we assessed virologic failure (viral load ≥1,000 copies/mL) and drug resistance mutations in bio-banked plasma samples 6–12 months after initiation of a protease inhibitor-based treatment regimen. Additionally, viral load was measured before start of protease inhibitor, a second time between 1–5 years after start, and at suspected treatment failure in patients with available bio-banked samples. We performed resistance testing if viral load was ≥1000 copies/ml. Risk factors for virologic failure were analyzed using logistic regression. Results: In total, 252 patients were included; of those 56% were female and 21% children. Virologic failure occurred 6–12 months after the start of a protease inhibitor in 26/199 (13.1%) of adults and 7/53 of children (13.2%). The prevalence of virologic failure did not change over time. Nucleoside reverse transcriptase inhibitors drug resistance mutation testing performed at 6–12 months showed a positive signal in only 9/16 adults. No cases of resistance mutations for protease inhibitors were seen at this time. In samples taken between 1–5 years protease inhibitor resistance was demonstrated in 2/7 adults. In adult samples before protease inhibitor start, resistance to nucleoside reverse transcriptase inhibitors was detected in 30/41, and to non-nucleoside reverse-transcriptase inhibitors in 35/41 patients. In 15/16 pediatric samples, resistance to both drug classes but not for protease inhibitors was present. Conclusion: Our study confirms high early failure rates in adults and children treated with protease inhibitors, even in the absence of protease inhibitors resistance mutations, suggesting an urgent need for adherence support in this setting. [ABSTRACT FROM AUTHOR]

Summary: Background: Cryptococcal meningitis accounts for 15% of all AIDS mortality globally. Most cases in low‐ and middle‐income countries are treated with fluconazole monotherapy, which is associated with a high mortality. New available therapies are needed. Short‐course amphotericin B has been shown to be a safe and efficient therapeutic option. Sertraline has in vitro fungicidal activity against Cryptococcus and bi‐directional synergy with fluconazole. Methods: We conducted an open‐label clinical trial to assess the safety and efficacy of sertraline 400 mg/day and fluconazole 1200 mg/day (n = 28) vs sertraline, fluconazole and additional 5 days of amphotericin B deoxycholate 0.7‐1 mg/kg (n = 18) for cryptococcal meningitis. Results: Two‐week survival was 64% (18/28) without amphotericin and 89% (16/18) with amphotericin, and 10‐week survival was 21% (6/28) vs 61% (11/18), respectively (P = .012). The cerebrospinal fluid (CSF) Cryptococcus clearance rate was 0.264 log10 colony‐forming units (CFU)/mL of CSF/day (95% CI: 0.112‐0.416) without amphotericin and 0.473 log10 CFU/mL/day (95% CI: 0.344‐0.60) with short‐course amphotericin (P = .03). Sertraline was discontinued in one participant due to side effects. Four participants receiving amphotericin B experienced hypokalemia <2.4 mEq/L. Conclusions: Short‐course amphotericin substantially increased CSF clearance and 10‐week survival. Adjunctive sertraline improved 2‐week CSF fungal clearance but did not improve 10‐week mortality compared with published data using fluconazole 1200 mg/day monotherapy (early fungicidal activity 0.15 log10 CFU/mL/day). [ABSTRACT FROM AUTHOR]

Background: Cryptococcal antigen (CrAg) screening in persons with advanced HIV/AIDS is recommended to prevent death. Implementing CrAg screening only in outpatients may underestimate the true CrAg prevalence and decrease its potential impact. Our previous 12-month survival/retention in CrAg-positive persons not treated with fluconazole was 0%., Methods: HIV testing was offered to all antiretroviral therapy-naive outpatients and hospitalized patients in Ifakara, Tanzania, followed by laboratory-reflex CrAg screening for CD4 <150 cells/μL. CrAg-positive individuals were offered lumbar punctures, and antifungals were tailored to the presence/absence of meningitis. We assessed the impact on survival and retention-in-care using multivariate Cox-regression models., Results: We screened 560 individuals for CrAg. The median CD4 count was 61 cells/μL (interquartile range 26-103). CrAg prevalence was 6.1% (34/560) among individuals with CD4 ≤150 and 7.5% among ≤100 cells/μL. CrAg prevalence was 2.3-fold higher among hospitalized participants than in outpatients (12% vs 5.3%, P = 0.02). We performed lumbar punctures in 94% (32/34), and 31% (10/34) had cryptococcal meningitis. Mortality did not differ significantly between treated CrAg-positive without meningitis and CrAg-negative individuals (7.3 vs 5.4 deaths per 100 person-years, respectively, P = 0.25). Independent predictors of 6-month death/lost to follow-up were low CD4, cryptococcal meningitis (adjusted hazard ratio 2.76, 95% confidence interval: 1.31 to 5.82), and no antiretroviral therapy initiation (adjusted hazard ratio 3.12, 95% confidence interval: 2.16 to 4.50)., Conclusions: Implementing laboratory-reflex CrAg screening among outpatients and hospitalized individuals resulted in a rapid detection of cryptococcosis and a survival benefit. These results provide a model of a feasible, effective, and scalable CrAg screening and treatment strategy integrated into routine care in sub-Saharan Africa.

Background: To what extent antiretroviral therapy (ART) reduces mother-to-child HIV transmission (MTCT) during breastfeeding remains unclear. We assessed the MTCT risk from mothers on ART to their infants during breastfeeding., Setting: Ifakara, rural Tanzania., Methods: We included infants born between January 2013 and May 2016 to mothers who initiated ART before delivery, had a negative HIV DNA polymerase chain reaction at 4-12 weeks and exclusively breastfed for ≥6 months. Mothers' plasma HIV-RNA viral loads (VLs) were measured up to 11 months postdelivery. Infants were tested for HIV following national guidelines., Results: Among 214 women with 218 pregnancies and 228 infants (10 twins), the median age at delivery was 33 years (interquartile range 28-36 years), and the mean time on ART was 23 months (interquartile range, 4-52 months). VL was measured twice in 53% (113/218) of pregnancies. During breastfeeding, 91% of mothers (199/218) had VL of <1000 copies per milliliter, and 75% (164/218) had <100 copies per milliliter. To November 2017, 8% (19/228) of infants were lost to follow-up (LTFU), 2% (5/228) transferred, and 8% (18/228) died before the determination of final HIV serostatus. Among the remaining 186 infants, 2 (1%; 95% confidence interval: 0.3% to 4%) were HIV positive: 1 born from a mother with high VL 1-month postdelivery and 1 from a mother who interrupted ART. Assuming a 15% MTCT risk through breastfeeding among the 42 infants LTFU, transferred, or dead, the overall MTCT risk would be 4%., Conclusions: We found no MTCT from mothers who were retained in care and had suppressed VL. Breastfeeding signifies a very low risk when mothers adhere to ART. Adherence counseling, VL monitoring, and strategies to trace back those LTFU should be a priority.