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Guillem Deus,1 Silvia Gómez-Zorrilla,1 Daniel Echeverria-Esnal,2 Ana Siverio,3 Robert Güerri-Fernandez,1 Jesús Ares,4 Nuria Campillo,2 Emili Letang,1,5 Hernando Knobel,1 Santiago Grau,2 Juan Pablo Horcajada1 1Infectious Diseases Service, Hospital del Mar, Infectious Pathology and Antimicrobials Research Group (IPAR), Institut Hospital del Mar d’Investigacions Mèdiques (IMIM), Universitat Autònoma de Barcelona (UAB), CEXS-Universitat Pompeu Fabra, Barcelona, Spain; 2Pharmacy Service, Hospital del Mar, Infectious Pathology and Antimicrobials Research Group (IPAR), Institut Hospital del Mar d’Investigacions Mèdiques (IMIM), Universitat Autònoma de Barcelona (UAB), Barcelona, Spain; 3Microbiology Service, Laboratori de Referència de Catalunya, Hospital del Mar, Barcelona, Spain; 4Department of Radiology, Hospital del Mar, Universitat Autònoma de Barcelona (UAB), Barcelona, Spain; 5ISGlobal, Barcelona Institute for Global, Universitat de BarcelonaHealth, Barcelona, SpainCorrespondence: Silvia Gómez-ZorrillaHospital del Mar, Infectious Diseases Department, Passeig Maritim 25-29 I, Barcelona, 08003, SpainTel +34 932483468Fax +34 93248325Email sgomezzorrilla@psmar.catBackground: Skeletal involvement of Cryptococcus neoformans is infrequent and usually associated with disseminated cryptococcosis or underlying predisposing conditions. We present an atypical case of osteoarticular cryptococcosis in an immunocompetent patient.Case Presentation: We herein report a case of bone and soft tissue cryptococcal infection in a 42-year-old male from Pakistan with well-controlled diabetes without other associated immunodeficiencies treated with antifungal therapy without surgical debridement. Furthermore, the patient developed toxidermia due to fluconazole use, so a fluconazole desensitization was performed. Therapeutic management also included the performance of therapeutic drug monitoring of fluconazole plasma concentrations.Conclusion: To our knowledge, this is the first case of osteoarticular cryptococcosis treated with this treatment regimen. This strategy may be of interest to try to reduce hospital stay and associated complications.Keywords: Cryptococcus neoformans, osteoarticular cryptococcosis, immunocompetent, liposomal amphotericin B, fluconazole desensitization

Background: Information about the relationship between HIV-associated immune suppression and COVID-19 outcomes is scarce. We aimed to characterize the epidemiological and clinical features, and impact of immunosuppression on COVID-19-related outcomes [...]

Objectives: Few studies have assessed cognitive impairment among healthy people living with HIV (PLWH) who are stable on antiretroviral treatment (ART) in sub‐Saharan Africa. Methods: We conducted a cross‐sectional study among a random sample of stable adult PLWH from rural Tanzania on ART for more than 1 year and without immunological failure or pre‐existing neurological disease. We evaluated the prevalence and risk factors for neurocognitive impairment (NCI), assessed through neuropsychological tests, functional and depression questionnaires and defined as a mean Z‐score ≤ −1 in two or more cognitive domains. Results: Among 243 participants [median age = 44.3 years (interquartile range: 36–52] and 71% female] we found a rate of NCI of 19.3% (95% confidence interval: 14.8–24.8%). Memory and psychomotor domains demonstrated the highest impairment. Independent predictors of NCI were age and self‐reported alcohol use. Other classical risk factors were not associated with HIV‐associated NCI. Conclusion: Despite effective ART roll‐out, NCI remained a prevalent condition in this healthy rural Tanzanian population of PLWH on ART. Age and alcohol use were key risk factors. [ABSTRACT FROM AUTHOR]

Background: Switching to the 2-drug regimen dolutegravir/lamivudine demonstrated durable non-inferior efficacy vs continuing 3- or 4-drug tenofovir alafenamide-based regimens for maintaining virologic suppression in people with HIV-1 through Week 144 in TANGO., Setting: 134 centers, 10 countries., Methods: Adults with HIV-1 RNA <50 copies/mL for >6 months and no history of virologic failure were randomized to switch from stable tenofovir alafenamide-based regimens to dolutegravir/lamivudine on Day 1 (early-switch group) for 196 weeks. Those randomized to continue tenofovir alafenamide-based regimens on Day 1 who maintained virologic suppression at Week 144 switched to dolutegravir/lamivudine at Week 148 (late-switch group). Efficacy, safety, and tolerability (including weight and biomarker changes) of dolutegravir/lamivudine in early-switch and late-switch groups were assessed through Week 196., Results: Overall, 369 participants switched to dolutegravir/lamivudine on Day 1 (early-switch) and 298 switched at Week 148 (late-switch). In the early-switch group, 83% (306/369) maintained virologic suppression through Year 4, and 3% (11/369) reported new adverse events between Weeks 144 and 196. The late-switch group at Week 196 and early-switch group at Week 48 had comparable proportions with virologic suppression (93% each) and similar safety profiles. No late-switch participants and 1 early-switch participant met confirmed virologic withdrawal criteria through Week 196, with no resistance-associated mutations observed. Treatment continued to be well tolerated long-term., Conclusion: Switching from tenofovir alafenamide-based regimens to dolutegravir/lamivudine showed durable efficacy, high barrier to resistance, and good tolerability through 4 years. These results support dolutegravir/lamivudine as a robust treatment for maintaining virologic suppression., Competing Interests: Conflicts of Interest and Source of Funding: SDW has received funding from ViiV Healthcare paid to his institution. FBonnet has served as a consultant, invited speaker, and/or received grants from Gilead and ViiV Healthcare. OO has served as a consultant for Gilead and ViiV Healthcare and received honoraria from ViiV Healthcare. FBisshop has participated in advisory boards for Gilead. JOlalla has served as a consultant, invited speaker, and/or received grants from Gilead, GSK, Janssen, Merck, and ViiV Healthcare. J-PR has served as a consultant, invited speaker, and/or received grants from AbbVie, Gilead, GSK, Merck, and ViiV Healthcare. CW has no conflicts to disclose. RM, KP, RW, JOyee, EL, BW, BJ, KYS, and MA-K are employees of ViiV Healthcare or GSK and own stock in GSK. PS is a complimentary worker on behalf of GSK. This study was funded by ViiV Healthcare., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

After a decade of dolutegravir (DTG) use in various antiretroviral therapy combinations and in diverse populations globally, it is critical to identify HIV strains with reduced drug susceptibility and monitor emergent resistance in people living with HIV who experience virologic failure while on DTG-based regimens. We searched the PubMed, Embase, and Cochrane databases to identify studies that reported DTG resistance-associated mutations (RAMs) emerging under selection pressure. Our review showed that RAMs conferring resistance to DTG were rare in 2-drug and 3-drug regimens used in real-world cohorts, corroborating data from clinical trials. The potency of DTG in maintaining virologic suppression was demonstrated, even in cases of pre-existing resistance to companion drugs in the regimen. Estimates of DTG RAMs depended on the population and certain risk factors, including monotherapy, baseline resistance or lack of genotypic testing, treatment history and prior virologic failure, and suboptimal treatment adherence. The RAMs detected after virologic failure, often in heavily treatment-experienced individuals with prior exposure to integrase strand transfer inhibitors, were G118R, E138K, G140A/C/R/S, Q148H/K/R, N155H, and R263K. Overall, these data highlight the durable effectiveness and high barrier to resistance of DTG as part of combination antiretroviral therapy in a wide variety of settings.

Background: To investigate the impact of the M184V/I mutation on virologic response to dolutegravir plus lamivudine (DTG + 3TC) in suppressed-switch populations, a meta-analysis was performed using virologic outcomes from people with human immunodeficiency virus type 1 (PWH) with and without M184V/I before DTG + 3TC switch in real-world studies identified via systematic literature review. Sensitivity analyses were performed using data from PWH with M184V/I in interventional studies identified via targeted literature review., Methods: Single-arm meta-analyses using common- and random-effects models were used to estimate proportions of PWH with virologic failure (VF) among real-world populations with and without M184V/I and interventional study participants with M184V/I at 24, 48, and 96 weeks., Results: Literature reviews identified 5 real-world studies from 3907 publications and 51 abstracts meeting inclusion criteria and 5 interventional studies from 1789 publications and 3 abstracts. All time points had low VF incidence in PWH with M184V/I (real-world: 1.43%-3.81%; interventional: 0.00%) and without (real-world: 0.73%-2.37%). Meta-analysis-estimated proportions (95% confidence interval) with VF were low at weeks 24, 48, and 96, respectively, for PWH with M184V/I (real-world: 0.01 [.00-.04], 0.03 [.01-.06], and 0.04 [.01-.07]; interventional: 0.00 [.00-.02], 0.00 [.00-.01], and 0.00 [.00-.03]) and without (real-world: 0.00 [.00-.02], 0.02 [.01-.04], and 0.02 [.00-.05]). One real-world study (n = 712) reported treatment-emergent M184V at VF in 1 of 652 (0.15%) PWH without prior M184V/I., Conclusions: Results suggest that prior M184V/I has minimal impact on virologic suppression after switching to DTG + 3TC and provide reassurance when considering switching regimens in virologically suppressed PWH with incomplete treatment history or limited treatment options., Competing Interests: Potential conflicts of interest. M. K. was a complimentary worker for ViiV Healthcare at the time of the analysis. G. V. is an employee of ViiV Healthcare. C. M. P., B. J., C. O., J. Pr., and E. L. are employees of ViiV Healthcare and own stock in GSK. T. J. B. has received grants from Gilead, MSD, Roche, and ViiV Healthcare; consulting fees and honoraria from Gilead, GSK, Janssen, MSD, Roche, Theratechnologies, and ViiV Healthcare; and travel support from Gilead and ViiV Healthcare. C. A. has received honoraria from Gilead, MSD, and ViiV Healthcare; has received travel support from Gilead and MSD; and is a member of the CPP Ouest IV Ethics Committee. A.-G. M. has received grants and honoraria from Gilead, MSD, and ViiV Healthcare; consulting fees from GSK; and travel support from Gilead. J. Pa. has received honoraria from Gilead, Janssen-Cilag, MSD, and ViiV Healthcare and travel support from Gilead and Janssen-Cilag. N. G. has received grants, honoraria, and travel support from Gilead, Janssen-Cilag, MSD, and ViiV Healthcare. J. M. L. has received grants from Gilead and ViiV Healthcare; has received speaker honoraria from Gilead, Janssen-Cilag, and ViiV Healthcare; and is a member of the Spanish Antiretroviral Treatment Guidelines panel. D. R.-C. has received honoraria from Gilead and ViiV Healthcare and travel support from Gilead. R. D. M.-B. has received speaker fees from Gilead and ViiV Healthcare and travel support from ViiV Healthcare. G. B. has received honoraria and travel support from ViiV Healthcare. M. T., C. H., and T. W. are employees of HEOR Ltd, which received funding from ViiV Healthcare to support this analysis. S. D. G. reports no potential conflicts., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Introduction: Increased body weight is an important risk factor for cardiovascular disease and is increasingly reported as a health problem in people living with HIV (PLHIV). There is limited data from rural sub-Saharan Africa, where malnutrition usually presents with both over- and undernutrition. We aimed to determine the prevalence and risk factors of underweight and overweight/obesity in PLHIV enrolled in a cohort in rural Tanzania before the introduction of integrase inhibitors., Methods: This nested study of the prospective Kilombero and Ulanga Antiretroviral Cohort included adults aged ≥19 years initiated on antiretroviral therapy between 01/2013 and 12/2018 with follow-up through 06/2019. Body Mass Index (BMI) was classified as underweight (<18.5 kg/m2), normal (18.5-24.9 kg/m2), or overweight/obese (≥25.0 kg/m2). Stratified piecewise linear mixed models were used to assess the association between baseline characteristics and follow-up BMI. Cox proportional hazard models were used to assess the association between time-updated BMI and death/loss to follow-up (LTFU)., Results: Among 2,129 patients, 22,027 BMI measurements (median 9 measurements: interquartile range 5-15) were analysed. At baseline, 398 (19%) patients were underweight and 356 (17%) were overweight/obese. The majority of patients were female (n = 1249; 59%), and aged 35-44 years (779; 37%). During the first 9 months, for every three additional months on antiretroviral therapy, BMI increased by 2% (95% confidence interval 1-2%, p<0.0001) among patients underweight at baseline and by 0.7% (0.5-0.6%, p<0.0001) among participants with normal BMI. Over a median of 20 months of follow-up, 107 (5%) patients died and 592 (28%) were LTFU. Being underweight was associated with >2 times the hazard of death/LTFU compared to participants with normal BMI., Conclusion: We found a double burden of malnutrition, with underweight being an independent predictor of mortality. Monitoring and measures to address both states of malnutrition among PLHIV should be integrated into routine HIV care., Competing Interests: I have read the journal’s policy and the author of this manuscript has the following competing interests: Emilio Letang is a full-time employee ViiV Healthcare since May 2021. This does not alter our adherence to PLOS ONE policies on sharing data and materials. Other authors have declared that no competing interests exist., (Copyright: © 2023 Kalinjuma et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Competing Interests: We declare no competing interests.

Background: Information about burden, characteristics, predictors, and outcomes of advanced human immunodeficiency virus disease (AHD) is scarce in rural settings of sub-Saharan Africa. Human immunodeficiency virus (HIV) infections and associated deaths remain high despite specific guidelines issued by the World Health Organization (WHO)., Methods: Burden of AHD and 6-month death/loss to follow-up (LTFU) were described among 2498 antiretroviral therapy (ART)-naive nonpregnant people with HIV (PWH) aged >15 years enrolled in the Kilombero Ulanga Antiretroviral Cohort in rural Tanzania between 2013 and 2019. Baseline characteristics associated with AHD and predictors of death/LTFU among those with AHD were analyzed using multivariate logistic and Cox regression, respectively., Results: Of the PWH, 62.2% had AHD at diagnosis (66.8% before vs 55.7% after national uptake of WHO "test and treat" guidelines in 2016). At baseline, older age, male sex, lower body mass index, elevated aminotransferase aspartate levels, severe anemia, tachycardia, decreased glomerular filtration rate, clinical complaints, impaired functional status, and enrollment into care before 2018 were independently associated with AHD. Among people with AHD, incidence of mortality, and LTFU were 16 and 34 per 100 person-years, respectively. WHO clinical stage 3 or 4, CD4 counts <100 cells/µL, severe anemia, tachypnea, and liver disease were associated with death/LTFU., Conclusions: More than 50% of PWH enrolled in our cohort after test and treat implementation still had AHD at diagnosis. Increasing HIV testing and uptake and implementation of the WHO-specific guidelines on AHD for prevention, diagnosis, treatment of opportunistic infections, and reducing the risks of LTFU are urgently needed to reduce morbidity and mortality., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: In HIV clinical trials, proportions of Black and female participants achieving virologic suppression (VS) are often lower compared with White and male participants. As the antiretroviral therapy (ART) landscape continues to evolve, addressing existing challenges in clinical trial diversity will be critical to effectively translate results into clinical practice. Here, we pooled data to evaluate the efficacy and safety of dolutegravir (DTG)-containing regimens by race, sex, and regional subgroups., Methods: Three pooled analyses were conducted using 48-week results from phase 3/3b trials: DTG 3-drug vs non-DTG-containing 3- or 4-drug regimens in ART-naive participants (ARIA, FLAMINGO, SINGLE, SPRING-2), DTG-containing 2-drug vs 3-drug regimens in ART-naive participants (GEMINI-1, GEMINI-2), and DTG 3-drug vs non-DTG-containing 3- or 4-drug regimens in ART-experienced participants (SAILING, DAWNING). Proportions of participants with VS, safety, and change from baseline in CD4+ cell count were analyzed., Results: Proportions of participants achieving VS were high among those receiving DTG vs comparator regimens. Proportions of participants achieving VS were generally lower in Black (vs non-Black), female (vs male), and US (vs non-US) subgroups. No new safety signals emerged from any subgroup in pooled analyses., Conclusions: These analyses confirm that, across subgroups, DTG has robust efficacy and a good safety profile at week 48 relative to comparator regimens. Achieving VS may vary by participant characteristics, highlighting the urgent need for enrollment to reflect the demographics of global HIV populations more accurately. Future studies should strive to support participants throughout the trial to ensure optimal representation, inclusion, and retention., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Available information on the causes of death among people living with human immunodeficiency virus (PLHIV) in low- and middle-income countries (LMICs) remains scarce. We aimed to provide data on causes of death in PLHIV from two LMICs, Brazil and Mozambique, to assess the impact of clinical misdiagnosis on mortality rates and to evaluate the accuracy of minimally invasive tissue sampling (MITS) in determining the cause of death in PLHIV., Methods: We performed coupled MITS and complete autopsy on 164 deceased PLHIV (18 children, 36 maternal deaths, and 110 adults). HIV antibody levels and HIV RNA viral loads were determined from postmortem serum samples., Results: Tuberculosis (22.7%), toxoplasmosis (13.9%), bacterial infections (13.9%), and cryptococcosis (10.9%) were the leading causes of death in adults. In maternal deaths, tuberculosis (13.9%), bacterial infections (13.9%), cryptococcosis (11.1%), and cerebral malaria (8.3%) were the most frequent infections, whereas viral infections, particularly cytomegalovirus (38.9%), bacterial infections (27.8%), pneumocystosis (11.1%), and HIV-associated malignant neoplasms (11.1%) were the leading cause among children. Agreement between the MITS and the complete autopsy was 100% in children, 91% in adults, and 78% in maternal deaths. The MITS correctly identified the microorganism causing death in 89% of cases., Conclusions: Postmortem studies provide highly granular data on the causes of death in PLHIV. The inaccuracy of clinical diagnosis may play a significant role in the high mortality rates observed among PLHIV in LMICs. MITS might be helpful in monitoring the causes of death in PLHIV and in highlighting the gaps in the management of the infections., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America.)

Background: Factors affecting outcomes of SARS-CoV-2 infection in people living with HIV are unclear. We assessed the factors associated with SARS-CoV-2 diagnosis and severe outcomes among people living with HIV., Methods: We did a retrospective cohort study using data from the PISCIS cohort of people with HIV in Catalonia (Spain) between March 1 and Dec 15, 2020. We linked PISCIS data with integrated health-care, clinical, and surveillance registries through the Public Data Analysis for Health Research and Innovation Program of Catalonia (PADRIS) to obtain data on SARS-CoV-2 diagnosis, chronic comorbidities, as well as clinical and mortality outcomes. Participants were aged at least 16 years in care at 16 hospitals in Catalonia. Factors associated with SARS-CoV-2 diagnoses and severe outcomes were assessed using univariable and multivariable Cox regression models. We estimated the effect of immunosuppression on severe outcomes (hospital admission for >24 h with dyspnoea, tachypnoea, hypoxaemia, asphyxia, or hyperventilation; or death) using Kaplan-Meier survival analysis., Findings: We linked 20 847 (72·8%) of 28 666 participants in the PISCIS cohort with PADRIS data; 13 142 people had HIV. 749 (5·7%) people with HIV were diagnosed with SARS-CoV-2: their median age was 43·5 years (IQR 37·0-52·7), 131 (17·5%) were female, and 618 (82·5%) were male. 103 people with HIV (13·8%) were hospitalised, seven (0·9%) admitted to intensive care, and 13 (1·7%) died. SARS-CoV-2 diagnosis was more common among migrants (adjusted hazard ratio 1·55, 95% CI 1·31-1·83), men who have sex with men (1·42, 1·09-1·86), and those with four or more chronic comorbidities (1·46, 1·09-1·97). Age at least 75 years (5·2, 1·8-15·3), non-Spanish origin (2·1, 1·3-3·4), and neuropsychiatric (1·69, 1·07-2·69), autoimmune disease (1·92, 1·14-3·23), respiratory disease (1·84, 1·09-3·09), and metabolic disease (2·59, 1·59-4·23) chronic comorbidities were associated with increased risk of severe outcomes. A Kaplan-Meier estimator showed differences in the risk of severe outcomes according to CD4 cell count in patients with detectable HIV RNA (p=0·039) but no differences were observed in patients with undetectable HIV RNA (p=0·15)., Interpretation: People living with HIV with detectable HIV viraemia, chronic comorbidities, and some subpopulations could be at increased risk of severe outcomes from COVID-19. These groups should be prioritised in clinical management and SARS-CoV-2 vaccination programmes., Funding: Fundació "la Caixa"., Translations: For the Catalan, Spanish and Russian translations of the Summary see Supplementary Materials section., Competing Interests: Declaration of interests JMM reports receiving a personal 80:20 research grant from Institut d'Investigacions Biomèdiques August Pi I Sunyer, Barcelona, Spain, during 2017–21. EL reports receiving honoraria for lectures and presentations from ViiV Healthcare, Gilead Sciences, and Jansen Therapeutics; travel support for attending meetings from ViiV Healthcare and Jansen Therapeutics; payments for participating in the data safety monitoring and advisory board of ViiV Healthcare; being a full time employee of ViiV Healthcare since May 3, 2020; and payments made from Juan Rodés to the Spanish Government on his behalf. PD reports that his institution received grants from Gilead Sciences, Janssen-Cilag, and ViiV Healthcare; and he personally received honoraria from Gilead Sciences, Janssen-Cilag, Merck Sharp & Dohme, ViiV Healthcare, Roche, and Thera Technologies. AI reports that his institution received grants from Gilead Sciences and Merck Sharp & Dohme; and he personally received consultation fees from Gilead Sciences, ViiV Healthcare, and Thera Technologies; honoraria for lectures and presentations from Gilead Sciences, Merck Sharp & Dohme, Jansen Therapeutics, and ViiV Healthcare; and travel support for attending meetings from Gilead Sciences, Jansen, and ViiV Healthcare. VF reports that his institution received grants from Gilead Sciences, ViiV Healthcare, and Merck Sharp & Dohme; and he personally received consultation fees from ViiV Healthcare; honoraria for lectures and presentations from ViiV Healthcare, Gilead Sciences, Jansen Therapeutics, and Merck Sharp & Dohme; and travel support for attending meetings from Gilead Sciences. All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Introduction: AIDS-mortality remains unacceptably high in sub-Saharan Africa, largely driven by advanced HIV disease (AHD). We nested a study in an existing tuberculosis (TB) contact-tracing intervention (Xpatial-TB). The aim was to assess the burden of AHD among high-risk people living with HIV (PLHIV) identified and to evaluate the provision of the WHO-recommended package of care to this population., Methods: All PLHIV ≥14 years old identified between June and December 2018 in Manhiça District by Xpatial-TB were offered to participate in the study if ART naïve or had suboptimal ART adherence. Consenting individuals were screened for AHD. Patients with AHD (CD4 < 200 cells/μL or WHO stage 3 or 4) were offered a package of interventions in a single visit, including testing for cryptococcal antigen (CrAg) and TB-lipoarabinomannan (TB-LAM), prophylaxis and treatment for opportunistic infections, adherence support or accelerated ART initiation. We collected information on follow-up visits carried out under routine programmatic conditions for six months., Results: A total of 2881 adults were identified in the Xpatial TB-contact intervention. Overall, 23% (673/2881) were HIV positive, including 351 TB index (64.2%) and 322 TB contacts (13.8%). Overall, 159/673 PLHIV (24%) were ART naïve or had suboptimal ART adherence, of whom 155 (97%, 124 TB index and 31 TB-contacts) consented to the study and were screened for AHD. Seventy percent of TB index-patients (87/124) and 16% of TB contacts (5/31) had CD4 < 200 cells/µL. Four (13%) of the TB contacts had TB, giving an overall AHD prevalence among TB contacts of 29% (9/31). Serum-CrAg was positive in 4.6% (4/87) of TB-index patients and in zero TB contacts. All ART naïve TB contacts without TB initiated ART within 48 hours of HIV diagnosis. Among TB cases, ART timing was tailored to the presence of TB and cryptococcosis. Six-month mortality was 21% among TB-index cases and zero in TB contacts., Conclusions: A TB contact-tracing outreach intervention identified undiagnosed HIV and AHD in TB patients and their contacts, undiagnosed cryptococcosis among TB patients, and resulted in an adequate provision of the WHO-recommended package of care in this rural Mozambican population. Same-day and accelerated ART initiation was feasible and safe in this population including among those with AHD., (© 2021 The Authors. Journal of the International AIDS Society published by John Wiley & Sons Ltd on behalf of International AIDS Society.)

Background: Histoplasmosis is acquired by inhalation of spores of the dimorphic fungus Histoplasma spp. Although this pathogen is distributed worldwide, it is more prevalent in the Americas. However, the real burden of histoplasmosis remains undefined in many endemic regions., Methodology: We conducted a series of 61 autopsies to individuals who died in a hospital in the Brazilian Amazon focused on infectious diseases. We performed a detailed histological and microbiological evaluation with genetic characterization of Histoplasma strains with the aim to evaluate the contribution of histoplasmosis to morbidity and mortality. Additionally, we assessed the clinicopathological correlation., Principal Findings: Evidence of Histoplasma infection was detected in 21 patients (34%). Eight cases were disseminated infections, all of them occurred in HIV-positive patients. Six cases were localized histoplasmosis, limited to the lungs. In seven patients Histoplasma DNA was detected by PCR in patients with no histological lesions. Histoplasma infection was detected in 38% of HIV-positive patients and was a major contributor to death in 22% of them. Lungs, liver and spleen were affected in all cases of disseminated histoplasmosis. Phylogenetic analysis of the strains suggested a high diversity of Histoplasma species circulating in the Brazilian Amazon. Histoplasmosis was clinically missed in 75% of the disseminated infections., Conclusions: The high incidence of histoplasmosis, the low index of clinical suspicion, and the severity of the disseminated disease highlight the need of proactively implementing sensitive routine screening methods for this pathogen in endemic areas. Antifungal prophylaxis against Histoplasma should be encouraged in the severely immunocompromised HIV patients in these areas. In conclusion, substantial mortality is associated with disseminated histoplasmosis among HIV-positive patients in the Brazilian Amazon., Competing Interests: The authors have declared that no competing interests exist.

Despite wide antiretroviral scale-up during the past two decades resulting in declining new infections and mortality globally, HIV-associated tuberculosis remains as a major public health concern. Tuberculosis is the leading HIV-associated opportunistic infection and the main cause of death globally and, particularly, in resource-limited settings. Several challenges exist regarding diagnosis, global implementation of latent tuberculosis treatment, management of active tuberculosis, delivery of optimal patient-centered TB and HIV prevention and care in high burden countries. In this article we review the advances on pathogenesis, diagnosis, and treatment after nearly two decades of global roll-out of antiretroviral therapy and discuss the current challenges for the global control of tuberculosis-HIV co-infection., (Copyright © 2020. Published by Elsevier España, S.L.U.)

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 log 10 colony-forming units (CFU)/mL of CSF/day (95% CI: 0.112-0.416) without amphotericin and 0.473 log 10 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 log 10 CFU/mL/day)., (© 2019 Blackwell Verlag GmbH.)

Background: Clinico-pathological discrepancies are more frequent in settings in which limited diagnostic techniques are available, but there is little information on their actual impact., Aim: We assessed the accuracy of the clinical diagnoses in a tertiary referral hospital in sub-Saharan Africa by comparison with post-mortem findings. We also identified potential risk factors for misdiagnoses., Methods: One hundred and twelve complete autopsy procedures were performed at the Maputo Central Hospital (Mozambique), from November 2013 to March 2015. We reviewed the clinical records. Major clinico-pathological discrepancies were assessed using a modified version of the Goldman and Battle classification., Results: Major diagnostic discrepancies were detected in 65/112 cases (58%) and were particularly frequent in infection-related deaths (56/80 [70%] major discrepancies). The sensitivity of the clinical diagnosis for toxoplasmosis was 0% (95% CI: 0-37), 18% (95% CI: 2-52) for invasive fungal infections, 25% (95% CI: 5-57) for bacterial sepsis, 34% (95% CI: 16-57), for tuberculosis, and 46% (95% CI: 19-75) for bacterial pneumonia. Major discrepancies were more frequent in HIV-positive than in HIV-negative patients (48/73 [66%] vs. 17/39 [44%]; p = 0.0236)., Conclusions: Major clinico-pathological discrepancies are still frequent in resource constrained settings. Increasing the level of suspicion for infectious diseases and expanding the availability of diagnostic tests could significantly improve the recognition of common life-threatening infections, and thereby reduce the mortality associated with these diseases. The high frequency of clinico-pathological discrepancies questions the validity of mortality reports based on clinical data or verbal autopsy., Competing Interests: The authors have declared that no competing interests exist.

Cryptococcosis is a major opportunistic infection and is one of the leading causes of death in adults living with HIV in sub-Saharan Africa. Recent estimates indicate that more than 130,000 people may die annually of cryptococcal meningitis in this region. Although complete diagnostic autopsy (CDA) is considered the gold standard for determining the cause of death, it is seldom performed in low income settings. In this study, a CDA was performed in 284 deceased patients from Mozambique (n = 223) and Brazil (n = 61). In depth histopathological and microbiological analyses were carried out in all cases dying of cryptococcosis. We determined the cryptococcal species, the molecular and sero-mating types and antifungal susceptibility. We also described the organs affected and reviewed the clinical presentation and patient management. Among the 284 cases included, 17 fatal cryptococcal infections were diagnosed. Cryptococcus was responsible for 16 deaths among the 163 HIV-positive patients (10%; 95%CI: 6-15%), including four maternal deaths. One third of the cases corresponded to C. gattii (VGI and VGIV molecular types, Bα and Cα strains) and the remaining infections typed were caused by C. neoformans var. Grubii (all VNI and Aα strains). The level of pre-mortem clinical suspicion was low (7/17, 41%), and 7/17 patients (41%) died within the first 72 hours of admission. Cryptococcosis was responsible for a significant proportion of AIDS-related mortality. The clinical diagnosis and patient management were inadequate, supporting the need for cryptococcal screening for early detection of the disease. This is the first report of the presence of C. gattii infection in Mozambique.

Objective: Causes of morbidity and mortality of people living with HIV are changing with access to antiretroviral therapy and increased life expectancy. Age-related data on comorbidities and their impact on mortality in sub-Saharan Africa are scarce., Design: This prospective analysis evaluated comorbidities, assessed by means of International Classification of Diseases and Related Health problems 10th revision codes and clinical variables, derived from data collected from the Kilombero & Ulanga antiretroviral cohort of people living with HIV in rural Tanzania., Methods: We calculated prevalences and incidences of comorbidities in patients enrolled from 2013 to 2017 and evaluated their association with a combined endpoint of death and loss to follow-up (LTFU) in various age groups (15-29, 30-49 and ≥50 years) using Cox regression analysis., Results: Of 1622 patients [65% females, median age 38 years (interquartile range 31-46)], 11% were at least 50 years. During a median follow-up of 22.1 months (interquartile range 10.6-37.3), 48 (2.9%) patients died and 306 (18.9%) were LTFU. Anaemia was the most prevalent comorbidity (66.3%) irrespective of age and was associated with increased mortality/LTFU [hazard ratios 2.02 (95% confidence interval (CI) 1.57-2.60); P < 0.001]. In patients aged at least 50 years, arterial hypertension was highly prevalent (43.8%), but not associated with mortality/LTFU [hazard ratios 1.04 (95% CI 0.56-1.93), P = 0.9]. Undernutrition ranged from 25.5% in the youngest to 29.1% in the oldest age group and contributed to mortality/LTFU [hazard ratios 2.24 (95% CI 1.65-3.04); P < 0.001]. Prevalence of tuberculosis was 21.4% with hazard ratios of 2.54 (95% CI 1.72-3.75, P < 0.001) for mortality/LTFU., Conclusion: We show that anaemia, arterial hypertension and undernutrition are the most relevant comorbidities with different age-associated frequencies and impact on death/LTFU in this population.

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.

Over the past ten years, standard diagnostics for cryptococcal meningitis in HIV-infected persons have evolved from culture to India ink to detection of cryptococcal antigen (CrAg), with the recent development and distribution of a point-of-care lateral flow assay. This assay is highly sensitive and specific in cerebrospinal fluid (CSF), but is also sensitive in the blood to detect CrAg prior to meningitis symptoms. CrAg screening of HIV-infected persons in the blood prior to development of fulminant meningitis and preemptive treatment for CrAg-positive persons are recommended by the World Health Organization and many national HIV guidelines. Thus, CrAg testing is occurring more widely, especially in resource-limited laboratory settings. CrAg titer predicts meningitis and death and could be used in the future to customize therapy according to burden of infection., (Copyright © 2019 American Society for Microbiology.)

Background: It has been hypothesized that schistosomiasis negatively influences immune reconstitution in people living with HIV starting antiretroviral therapy (ART). In this study, we investigated the effect of schistosomiasis on the course of HIV infection in patients starting ART in a rural part of Tanzania., Methodology: Retrospective study including patients prospectively enrolled in a HIV cohort in Ifakara, south-central Tanzania between January 1, 2013 and April 1, 2015. Schistosomal circulating anodic antigen (CAA) was assessed in pre-ART cryopreserved plasma. Regression models were utilized to estimate the effect of CAA positivity on virological and immunological failure and a composite outcome of death/loss to follow-up (LFU)., Principal Findings: At ART-initiation 19.1% (88/461) of patients were CAA-positive. A tendency of higher CD4 increases was seen in CAA-positive patients (+182 cells/μl, interquartile range (IQR), 87-285 cells/μl) compared to CAA-negative patients (+147 cells/μl, IQR, 55-234 cells/μl, p = 0.09) after 10 months of follow-up. After adjustment for baseline risk factors, CAA-positivity showed no association with virological or immunological failure. In CAA-positive patients, 22.7% (20/88) died or were LFU, compared to 29.5% (110/373) of CAA-negative patients (hazard ratio (HR): 0.76, 95% confidence interval (CI), 0.47-1.22, p = 0.25). After adjustment for age, sex, body mass index, educational attainment, WHO-stage, tuberculosis status, and year of ART initiation, CAA-positivity showed a trend of a decreased hazard of death/LFU (HR: 0.58, 95% CI: 0.32-1.05, p = 0.07), while CD4 count at baseline (HR: 0.86, 95% CI: 0.76-1.00, p = 0.02) and MXD (sum of eosinophils, basophils, and monocytes counts) >1,100 cells/μl (HR: 0.56, 95% CI: 0.34-0.93, p = 0.03) were identified as independently protective factors., Conclusions/significance: Schistosomiasis is prevalent in this HIV cohort and may be beneficial for immunological reconstitution, while no effect on virological failure was apparent. A positive effect of schistosomiasis-induced immunomodulation on survival and retention in care needs confirmation in future studies., Competing Interests: The authors have declared that no competing interests exist.

Objectives: We evaluated whether dried blood spots (DBS) are suitable to monitor combined ART when samples are collected in rural Tanzania and transported over a long distance to a specialized bioanalytical laboratory., Methods: Plasma and DBS samples were collected in Tanzania from study patients treated with nevirapine, efavirenz or lopinavir. In addition, plasma, whole blood and DBS samples were obtained from a cohort of HIV patients at the site of the bioanalytical laboratory in Switzerland. DBS samples were analysed using a fully automated LC-MS/MS method., Results: Comparison of DBS versus plasma concentrations of samples obtained from the bridging study in Switzerland indicated an acceptable bias only for nevirapine (18.4%), whereas for efavirenz and lopinavir a pronounced difference of -47.4% and -48.1% was found, respectively. Adjusting the DBS concentrations by the haematocrit and the fraction of drug bound to plasma proteins removed this bias [efavirenz +9.4% (-6.9% to +25.7%), lopinavir +2.2% (-20.0% to +24.2%)]. Storage and transportation of samples from Tanzania to Switzerland did not affect the good agreement between plasma and DBS for nevirapine [-2.9% (-34.7% to +29.0%)] and efavirenz [-9.6% (-42.9% to +23.8%)]. For lopinavir, however, adjusted DBS concentrations remained considerably below [-32.8% (-70.4% to +4.8%)] corresponding plasma concentrations due to decay of lopinavir in DBS obtained under field conditions., Conclusions: Our field study shows that the DBS technique is a suitable tool for therapeutic drug monitoring in resource-poor regions; however, sample stability remains an issue for certain analytes and therefore needs special consideration.

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.

Background: We assessed the prevalence, incidence, and predictors of renal impairment among people living with HIV (PLWHIV) in rural Tanzania., Methods: In a cohort of PLWHIV aged ≥15 years enrolled from January 2013 to June 2016, we assessed the association between renal impairment (estimated glomerural filtration rate < 90 mL/min/1.73 m 2 ) at enrollment and during follow-up with demographic and clinical characteristcis using logistic regression and Cox proportional hazards models., Results: Of 1093 PLWHIV, 172 (15.7%) had renal impairment at enrollment. Of 921 patients with normal renal function at baseline, 117 (12.7%) developed renal impairment during a median follow-up (interquartile range) of 6.2 (0.4-14.7) months. The incidence of renal impairment was 110 cases per 1000 person-years (95% confidence interval [CI], 92-132). At enrollment, logistic regression identified older age (adjusted odds ratio [aOR], 1.79; 95% CI, 1.52-2.11), hypertension (aOR, 1.84; 95% CI, 1.08-3.15), CD4 count <200 cells/mm 3 (aOR, 1.80; 95% CI, 1.23-2.65), and World Health Organization (WHO) stage III/IV (aOR, 3.00; 95% CI, 1.96-4.58) as risk factors for renal impairment. Cox regression model confirmed older age (adjusted hazard ratio [aHR], 1.85; 95% CI, 1.56-2.20) and CD4 count <200 cells/mm 3 (aHR, 2.05; 95% CI, 1.36-3.09) to be associated with the development of renal impairment., Conclusions: Our study found a low prevalence of renal impairment among PLWHIV despite high usage of tenofovir and its association with age, hypertension, low CD4 count, and advanced WHO stage. These important and reassuring safety data stress the significance of noncommunicable disease surveillance in aging HIV populations in sub-Saharan Africa.

Background: Differences in rural and urban settings could account for distinct characteristics in the epidemiology of tuberculosis (TB). We comparatively studied epidemiological features of TB and helminth co-infections in adult patients from rural and urban settings of Tanzania., Methods: Adult patients (≥ 18 years) with microbiologically confirmed pulmonary TB were consecutively enrolled into two cohorts in Dar es Salaam, with ~ 4.4 million inhabitants (urban), and Ifakara in the sparsely populated Kilombero District with ~ 400 000 inhabitants (rural). Clinical data were obtained at recruitment. Stool and urine samples were subjected to diagnose helminthiases using Kato-Katz, Baermann, urine filtration, and circulating cathodic antigen tests. Differences between groups were assessed by χ 2 , Fisher's exact, and Wilcoxon rank sum tests. Logistic regression models were used to determine associations., Results: Between August 2015 and February 2017, 668 patients were enrolled, 460 (68.9%) at the urban and 208 (31.1%) at the rural site. Median patient age was 35 years (interquartile range [IQR]: 27-41.5 years), and 454 (68%) were males. Patients from the rural setting were older (median age 37 years vs. 34 years, P = 0.003), had a lower median body mass index (17.5 kg/m 2 vs. 18.5 kg/m 2 , P <  0.001), a higher proportion of recurrent TB cases (9% vs. 1%, P <  0.001), and in HIV/TB co-infected patients a lower median CD4 cell counts (147 cells/μl vs. 249 cells/μl, P = 0.02) compared to those from urban Tanzania. There was no significant difference in frequencies of HIV infection, diabetes mellitus, and haemoglobin concentration levels between the two settings. The overall prevalence of helminth co-infections was 22.9% (95% confidence interval [CI]: 20.4-27.0%). The significantly higher prevalence of helminth infections at the urban site (25.7% vs. 17.3%, P = 0.018) was predominantly driven by Strongyloides stercoralis (17.0% vs. 4.8%, P <  0.001) and Schistosoma mansoni infection (4.1% vs. 16.4%, P <  0.001). Recurrent TB was associated with living in a rural setting (adjusted odds ratio [aOR]: 3.97, 95% CI: 1.16-13.67) and increasing age (aOR: 1.06, 95% CI: 1.02-1.10)., Conclusions: Clinical characteristics and helminth co-infections pattern differ in TB patients in urban and rural Tanzania. The differences underline the need for setting-specific, tailored public health interventions to improve clinical management of TB and comorbidities.

Objectives: Our objectives were to describe trends in enrolment and clinical outcomes in the open, prospective Kilombero and Ulanga Antiretroviral Cohort (KIULARCO) in the Morogoro region of southern Tanzania, and identify strengths and areas for improvement in the care of HIV-positive individuals in rural Tanzania., Methods: We included adults (≥15 years) and children (<15 years) enrolled in the cohort in 2005-2014. The cohort underwent significant changes from autumn 2012 to optimise care. We evaluated mortality and loss to follow-up (LTFU) using competing risks methods, ART usage, opportunistic infections (OI), co-infections and laboratory abnormalities., Results: Overall, 7010 adults and 680 children were enrolled; enrolment peaked in 2008 but has increased steadily since 2011. Among adults (65% female; median age 37 [interquartile range 31-45] years), the proportion referred from hospital wards quadrupled in 2013-14 versus earlier years. 653 (9%) adults died and 2648 (38%) were LTFU; the five-year cumulative probabilities of death and LTFU were 10.3% and 44.0%, respectively. Among children, 69 (10%) died and 225 (33%) were LTFU. The corresponding five-year probabilities were 12.1% and 39.6%. Adult ART use (regardless of eligibility) increased from 5% in 2005 to 89% in 2014 (similarly among children), with 9% on second-line therapy in 2014 (17% of children). OI diagnoses increased over time; tuberculosis prevalence at enrolment quadrupled from 6% in 2011 to 26% in 2014. The proportion of newly-enrolled participants assessed for laboratory abnormalities peaked at nearly 100% in 2014 (from a minimum of 24%), yet abnormality prevalences remained fairly constant., Conclusions: In this cohort, ART usage improved dramatically and is approaching targets of 90%. Improved screening led to increases in detection of OIs and laboratory abnormalities, suggesting that a large number of these co-morbidities previously went undetected and untreated. Further work will address the high LTFU rates and implications for mortality estimates, and the management and outcomes of co-morbidities.

Background: Strategies to improve the uptake of Prevention of Mother-To-Child Transmission of HIV (PMTCT) are needed. We integrated HIV and maternal, newborn and child health services in a One Stop Clinic to improve the PMTCT cascade in a rural Tanzanian setting., Methods: The One Stop Clinic of Ifakara offers integral care to HIV-infected pregnant women and their families at one single place and time. All pregnant women and HIV-exposed infants attended during the first year of Option B+ implementation (04/2014-03/2015) were included. PMTCT was assessed at the antenatal clinic (ANC), HIV care and labour ward, and compared with the pre-B+ period. We also characterised HIV-infected pregnant women and evaluated the MTCT rate., Results: 1,579 women attended the ANC. Seven (0.4%) were known to be HIV-infected. Of the remainder, 98.5% (1,548/1,572) were offered an HIV test, 94% (1,456/1,548) accepted and 38 (2.6%) tested HIV-positive. 51 were re-screened for HIV during late pregnancy and one had seroconverted. The HIV prevalence at the ANC was 3.1% (46/1,463). Of the 39 newly diagnosed women, 35 (90%) were linked to care. HIV test was offered to >98% of ANC clients during both the pre- and post-B+ periods. During the post-B+ period, test acceptance (94% versus 90.5%, p<0.0001) and linkage to care (90% versus 26%, p<0.0001) increased. Ten additional women diagnosed outside the ANC were linked to care. 82% (37/45) of these newly-enrolled women started antiretroviral treatment (ART). After a median time of 17 months, 27% (12/45) were lost to follow-up. 79 women under HIV care became pregnant and all received ART. After a median follow-up time of 19 months, 6% (5/79) had been lost. 5,727 women delivered at the hospital, 20% (1,155/5,727) had unknown HIV serostatus. Of these, 30% (345/1,155) were tested for HIV, and 18/345 (5.2%) were HIV-positive. Compared to the pre-B+ period more women were tested during labour (30% versus 2.4%, p<0.0001). During the study, the MTCT rate was 2.2%., Conclusions: The implementation of Option B+ through an integrated service delivery model resulted in universal HIV testing in the ANC, high rates of linkage to care, and MTCT below the elimination threshold. However, HIV testing in late pregnancy and labour, and retention during early ART need to be improved.

Background: The Kilombero and Ulanga Antiretroviral Cohort (KIULARCO) is a single-site, open and ongoing prospective cohort of people living with human immunodeficiency virus (PLWHIV) established in 2005 at the Chronic Diseases Clinic of Ifakara (CDCI), within the Saint Francis Referral Hospital (SFRH) in Ifakara, Tanzania. The objectives of KIULARCO are to (i) provide patient and cohort-level information on the outcomes of HIV treatment; (ii) provide cohort-level information on opportunistic infections and comorbidities; (iii) evaluate aspects of human immunodeficiency virus (HIV) care and treatment that have national or international policy relevance; (iv) provide a platform for studies on improving HIV care and treatment in sub-Saharan Africa; and (v) contribute to generating local capacity to deal with the challenges posed by the HIV/AIDS pandemic in this region. Moreover, KIULARCO may serve as a model for other healthcare settings in rural sub-Saharan Africa., Methods: Since 2005, all patients diagnosed with HIV at the Saint Francis Referral Hospital are invited to participate in the cohort, including non-pregnant adults, pregnant women, adolescents, children and infants. The information collected includes demographics, baseline and follow-up clinical data, laboratory data, medication history, drug toxicities, diagnoses and outcomes. Real-time data are captured during the patient encounter through an electronic medical record system that allowed transition to a paperless clinic in 2013. In addition, KIULARCO is associated with a biobank of cryopreserved plasma samples and cell pellets collected from all participants before and at different time-points during antiretroviral treatment., Results: Up to the end of 2016, 12 185 PLWHIV have been seen at the CDCI; 9218 (76%) of whom have been enrolled into KIULARCO and 6965 (76%) of these have received ART from the clinic. Patients on ART attend at least every 3 months, with laboratory monitoring every 6 months. KIULARCO data have been used to generate relevant information regarding ART outcomes, opportunistic infections, non-AIDS comorbidities, prevention of mother-to-child transmission of HIV, paediatric HIV, and mortality and retention in care. Requests for collaborations on analyses can be submitted to the KIULARCO scientific committee., Conclusions: KIULARCO provides a framework for improving the quality of care of people living with HIV in sub-Saharan Africa, to generate relevant information to evaluate ART programmes and to build local capacity to deal with HIV/AIDS. The comprehensiveness of the data collected, together with the biobank spanning over ten years has created a unique research platform in rural sub-Saharan Africa.

Objectives: To assess viral suppression rates, to assess prevalence of acquired HIV drug resistance and to characterize the spectrum of HIV-1 drug resistance mutations (HIV-DRM) in HIV-1-infected patients in a rural Tanzanian HIV cohort., Methods: This was a cross-sectional study nested within the Kilombero and Ulanga Antiretroviral Cohort. Virological failure was defined as HIV-1 RNA ≥50 copies/mL. Risk factors associated with virological failure and with the development of HIV-DRM were assessed using logistic regression., Results: This study included 304 participants with a median time on ART of 3.5 years (IQR = 1.7-5.3 years); 91% were on an NNRTI-based regimen and 9% were on a boosted PI-based regimen. Viral suppression was observed in 277/304 patients (91%). Of the remaining 27 patients, 21 were successfully genotyped and 17/21 (81%) harboured ≥1 clinically relevant HIV-DRM. Of these, 13/17 (76.5%) had HIV-1 plasma viral loads of >1000 copies/mL. CD4 cell count <200 cells/mm(3) at the time of recruitment was independently associated with a close to 8-fold increased odds of virological failure [adjusted OR (aOR) = 7.71, 95% CI = 2.86-20.78, P  <   0.001] and with a >8-fold increased odds of developing HIV-DRM (aOR = 8.46, 95% CI = 2.48-28.93, P  =   0.001)., Conclusions: High levels of viral suppression can be achieved in rural sub-Saharan Africa when treatment and care programmes are well managed. In the absence of routine HIV sequencing, the WHO-recommended threshold of 1000 viral RNA copies/mL largely discriminates virological failure secondary to HIV-DRM., (© The Author 2017. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Introduction: Scarce data are available on the epidemiology of hypertension among HIV patients in rural sub-Saharan Africa. We explored the prevalence, incidence and risk factors for incident hypertension among patients who were enrolled in a rural HIV cohort in Tanzania., Methods: Prospective longitudinal study including HIV patients enrolled in the Kilombero and Ulanga Antiretroviral Cohort between 2013 and 2015. Non-ART naïve subjects at baseline and pregnant women during follow-up were excluded from the analysis. Incident hypertension was defined as systolic blood pressure ≥ 140 mmHg and/or diastolic blood pressure ≥ 90 mmHg on two consecutive visits. Cox proportional hazards models were used to assess the association of baseline characteristics and incident hypertension., Results: Among 955 ART-naïve, eligible subjects, 111 (11.6%) were hypertensive at recruitment. Ten women were excluded due to pregnancy. The remaining 834 individuals contributed 7967 person-months to follow-up (median 231 days, IQR 119-421) and 80 (9.6%) of them developed hypertension during a median follow-up of 144 days from time of enrolment into the cohort [incidence rate 120.0 cases/1000 person-years, 95% confidence interval (CI) 97.2-150.0]. ART was started in 630 (75.5%) patients, with a median follow-up on ART of 7 months (IQR 4-14). Cox regression models identified age [adjusted hazard ratio (aHR) 1.34 per 10 years increase, 95% CI 1.07-1.68, p = 0.010], body mass index (aHR per 5 kg/m2 1.45, 95% CI 1.07-1.99, p = 0.018) and estimated glomerular filtration rate (aHR < 60 versus ≥ 60 ml/min/1.73 m2 3.79, 95% CI 1.60-8.99, p = 0.003) as independent risk factors for hypertension development., Conclusions: The prevalence and incidence of hypertension were high in our cohort. Traditional cardiovascular risk factors predicted incident hypertension, but no association was observed with immunological or ART status. These data support the implementation of routine hypertension screening and integrated management into HIV programmes in rural sub-Saharan Africa.

Objective: To investigate the prevalence and determinants of virologic failure and acquired drug resistance-associated mutations (DRMs) in HIV-infected children and adolescents in rural Tanzania., Design: Prospective cohort study with cross-sectional analysis., Methods: All children 18 years or less attending the paediatric HIV Clinic of Ifakara and on antiretroviral therapy (ART) for at least 12 months were enrolled. Participants with virologic failure were tested for HIV-DRM. Pre-ART samples were used to discriminate acquired and transmitted resistances. Multivariate logistic regression analysis identified factors associated with virologic failure and the acquisition of HIV-DRM., Results: Among 213 children on ART for a median of 4.3 years, 25.4% failed virologically. ART-associated DRM were identified in 90%, with multiclass resistances in 79%. Pre-ART data suggested that more than 85% had acquired key mutations during treatment. Suboptimal adherence [odds ratio (OR) = 3.90; 95% confidence interval (CI) 1.11-13.68], female sex (aOR = 2.57; 95% CI 1.03-6.45), and current nonnucleoside reverse transcriptase inhibitor-based ART (aOR = 7.32; 95% CI 1.51-35.46 compared with protease inhibitor-based) independently increased the odds of virologic failure. CD4 T-cell percentage (aOR = 0.20; 0.10-0.40 per additional 10%) and older age at ART initiation (aOR = 0.84 per additional year of age; 95% CI 0.73-0.97) were protective (also in predicting acquired HIV-DRM). At the time of virologic failure, less than 5% of the children fulfilled the WHO criteria for immunologic failure., Conclusion: Virologic failure rates in children and adolescents were high, with the majority of ART-failing children harbouring HIV-DRM. The WHO criteria for immunologic treatment failure yielded an unacceptably low sensitivity. Viral load monitoring is urgently needed to maintain future treatment options for the millions of African children living with HIV.

Background: Strategies to improve HIV diagnosis and linkage into care, antiretroviral treatment coverage, and treatment outcomes of mothers and children are urgently needed in sub-Saharan Africa., Methods: From December 2012, we implemented an intervention package to improve prevention of mother-to-child transmission (PMTCT) and pediatric HIV care in our rural Tanzanian clinic, consisting of: (1) creation of a PMTCT and pediatric unit integrated within the reproductive and child health clinic; (2) implementation of electronic medical records; (3) provider-initiated HIV testing and counseling in the hospital wards; and (4) early infant diagnosis test performed locally. To assess the impact of this strategy, clinical characteristics and outcomes were compared between the period before (2008-2012) and during/after the implementation (2013-2014)., Results: After the intervention, the number of mothers and children enrolled into care almost doubled. Compared with the pre-intervention period (2008-2012), in 2013-2014, children presented lower CD4% (16 vs. 16.8, P = 0.08) and more advanced disease (World Health Organization stage 3/4 72% vs. 35%, P < 0.001). The antiretroviral treatment coverage rose from 80% to 98% (P < 0.001), the lost-to-follow-up rate decreased from 20% to 11% (P = 0.002), and mortality ascertainment improved. During 2013-2014, 261 HIV-exposed infants were enrolled, and the early mother-to-child transmission rate among mother-infant pairs accessing PMTCT was 2%., Conclusions: This strategy resulted in an increased number of mothers and children diagnosed and linked into care, a higher detection of children with AIDS, universal treatment coverage, lower loss to follow-up, and an early mother-to-child transmission rate below the threshold of elimination. This study documents a feasible and scalable model for family-centered HIV care in sub-Saharan Africa., Competing Interests: The authors have no conflicts of interest to disclose.

Background: Extrapulmonary tuberculosis (EPTB) is associated with high rates of morbidity and mortality. Diagnosis of EPTB is challenging in resource-limited settings due to difficulties in obtaining samples, as well as the paucibacillarity of the specimens. Skeletal tuberculosis accounts for 10-35 % of EPTB cases, with vertebral osteomyelitis (Pott's disease) representing 50 % of the cases. We present two cases of suspected Pott's disease, diagnosed through GeneXpert MTB/RIF assay in urine at a rural Tanzanian hospital., Case Presentation: Case I A 49-year old male, HIV-1 positive, on co-formulated tenofovir disoproxil fumarate/lamivudine/efavirenz since 2009 and CD4 counts of 205 cells/μL (13 %). He presented with lower back pain and progressive lower limb weakness for two weeks prior to admission. The physical examination revealed bilateral flaccid paraplegia with reduced reflexes, but otherwise unremarkable findings. A lateral lumbar X-ray showed noticeable reduction of intervertebral space between L4 and L5, and a small calcification in the anterior longitudinal ligament between L4 and L5, being compatible with focal spondylosis deformans but inconclusive with regard to tuberculous spondylitis. An abdominal ultrasound showed normal kidneys, bladder and prostate gland. The urinalysis and complete blood counts (CBC) were normal. M. Tuberculosis was detected through GeneXpert MTB/RIF in centrifuged urine, with no resistance to rifampicin. Case II A 76-year old female, HIV-1 negative, presented with lower back pain and progressive weakness and numbness of the lower limbs for two months prior to admission. The physical examination revealed paraplegia, but otherwise unremarkable findings. The lumbosacral X-ray findings were compatible with spondylosis deformans of the lumbar spine and possible tuberculous spondylitis in L3-L4. The abdominal and renal ultrasound showed normal kidneys and bladder. The urinalysis and CBC were normal. M. Tuberculosis was detected through GeneXpert MTB/RIF in centrifuged urine, with no resistance to rifampicin., Conclusion: We report two cases of suspected tuberculous spondylitis diagnosed through Xpert MTB/RIF in urine samples from a rural Tanzanian hospital. Urine testing using Xpert MTB/RIF reflects disseminated disease and renal involvement, and may offer a feasible additional diagnostic approach for Pott's disease in rural Africa.

Background: Immune reconstitution inflammatory syndrome associated with dermatophytoses (tinea-IRIS) may cause considerable morbidity. Yet, it has been scarcely reported and is rarely considered in the differential diagnosis of HIV associated cutaneous lesions in Africa. If identified, it responds well to antifungals combined with steroids. We present two cases of suspected tinea-immune reconstitution inflammatory syndrome from a large HIV clinic in rural Tanzania., Cases Presentation: A first case was a 33 years-old female newly diagnosed HIV patient with CD4 count of 4 cells/μL (0 %), normal complete blood count, liver and renal function tests was started on co-formulated tenofovir/emtricitabine/efavirenz and prophylactic cotrimoxazole. Two weeks later she presented with exaggerated inflammatory hyperpigmented skin plaques with central desquamation, active borders and scratch lesions on the face, trunk and lower limbs. Tinea-IRIS was suspected and fluconazole (150 mg daily) and prednisolone (1 mg/Kg/day tapered down after 1 week) were given. Her symptoms subsided completely after 8 weeks of treatment, and her next CD4 counts had increased to 134 cells/μL (11 %). The second case was a 35 years-old female newly diagnosed with HIV. She had 1 CD4 cell/μL (0 %), haemoglobin 9.8 g/dl, and normal renal and liver function tests. Esophageal candidiasis and normocytic-normochromic anaemia were diagnosed. She received fluconazole, prophylactic cotrimoxazole and tenofovir/emtricitabine/efavirenz. Seven weeks later she presented with inflammatory skin plaques with elevated margins and central hyperpigmentation on the trunk, face and limbs in the frame of a good general recovery and increased CD4 counts (188 cells/μL, 6 %). Tinea-IRIS was suspected and treated with griseofulvin 500 mg daily and prednisolone 1 mg/Kg tapered down after 1 week, with total resolution of symptoms in 2 weeks., Conclusion: The two cases had advanced immunosuppression and developed de-novo exaggerated manifestation of inflammatory lesions compatible with tinea corporis and tinea facies in temporal association with antiretroviral treatment initiation and good immunological response. This is compatible with unmasking tinea-IRIS, and reminds African clinicians about the importance of considering this entity in the differential diagnosis of patients with skin lesions developing after antiretroviral treatment initiation.

Background.  We evaluated the prevalence of chronic hepatitis B virus (HBV) infection and liver fibrosis/cirrhosis in human immunodeficiency virus (HIV)-infected individuals enrolled in a rural Tanzanian prospective cohort and assessed hepatic fibrosis progression 12-24 months after antiretroviral treatment (ART) initiation. Methods.  All ART-naive HIV-infected adults ≥15-year-old enrolled in the Kilombero and Ulanga Antiretroviral Cohort who started ART between 2005 and 2015 were included. Pre-ART factors associated with significant liver fibrosis (aspartate aminotransferase-to-platelet ratio index [APRI] >1.5) and cirrhosis (APRI > 2.0) were identified using logistic regression. Results.  Of 3097 individuals screened, 227 (7.3%; 95% CI, 6.4-8.2) were hepatitis B surface antigen (HBsAg) positive. Before ART initiation, 9.1% individuals had significant liver fibrosis and 5.3% had cirrhosis. Human immunodeficiency virus/HBV-coinfected individuals were more likely to have an APRI score indicating significant fibrosis (14.2% vs 8.7%, P = .03) and cirrhosis (9.2% vs 4.9%, P = .03) than HBV-uninfected patients. CD4 cell count <200 cell/μL and alcohol consumption were independently associated with pre-ART APRI score, indicating significant fibrosis and cirrhosis in multivariable analyses. Among individuals with elevated APRI measurements pre- and 12-24 months post-ART initiation, 53 of 57 (93.0%) of HIV-monoinfected and 4 of 5 (80.0%) of HIV/HBV-coinfected had a regression to APRI < 1.5. Conclusions.  Hepatic fibrosis and cirrhosis were common in our cohort, especially among HIV/HBV-coinfected individuals. The APRI improved in most patients. Pre-ART HBsAg screening and early onset of tenofovir-based ART for HIV/HBV-coinfection should be prioritized in sub-Saharan Africa.

Background: The Kato-Katz technique is recommended for the diagnosis of helminth infections in epidemiological surveys, drug efficacy studies and monitoring of control interventions. We assessed the comparability of the average amount of faeces generated by three Kato-Katz templates included in test kits from two different providers., Methods: Nine hundred Kato-Katz thick smear preparations were done; 300 per kit. Empty slides, slides plus Kato-Katz template filled with stool and slides plus stool after careful removal of the template were weighed to the nearest 0.1 mg. The average amount of stool that was generated on the slide was calculated for each template, stratified by standard categories of stool consistency (i.e. mushy, soft, sausage-shaped, hard and clumpy)., Results: The average amount of stool generated on slides was 40.7 mg (95 % confidence interval (CI): 40.0-41.4 mg), 40.3 mg (95 % CI: 39.7-40.9 mg) and 42.8 mg (95 % CI: 42.2-43.3 mg) for the standard Vestergaard Frandsen template, and two different templates from the Chinese Center for Disease Control and Prevention (China CDC), respectively. Mushy stool resulted in considerably lower average weights when the Vestergaard Frandsen (37.0 mg; 95 % CI: 34.9-39.0 mg) or new China CDC templates (37.4 mg; 95 % CI: 35.9-38.9 mg) were used, compared to the old China CDC template (42.2 mg; 95 % CI: 40.7-43.7 mg) and compared to other stool consistency categories., Conclusion: The average amount of stool generated by three specific Kato-Katz templates was similar (40.3-42.8 mg). Since the multiplication factor is somewhat arbitrary and small changes only have little effect on infection intensity categories, it is suggested that the standard multiplication factor of 24 should be kept for the calculation of eggs per gram of faeces for all investigated templates.