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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]

Comprehensive information on combined antiretroviral therapy (cART) regimens in rural Sub‐Saharan Africa over time is scarce, particularly on the use of stavudine (d4T) and second‐line regimens. Since 2010, World Health Organization (WHO) guidelines discourage using stavudine in first‐line regimens due to frequent and severe side‐effects. This study examined the practical adaption of this phasing‐out and described trends in use of various cART combinations in a rural Tanzanian setting. We analyzed longitudinal, prospectively collected data of HIV‐1‐infected adults initiating cART within the Kilombero Ulanga Antiretroviral Cohort (KIULARCO) in Ifakara, Tanzania from 2007–2011. This analysis included data of 3068 patients over a 5‐year period. Of these subjects, 1997 (66.9%) were female, median age was 37 (interquartile range [IQR] 31–44) years and median CD4 cell count at enrollment was 178 cells/µl (IQR 88‐291). The percentage of prescriptions containing stavudine in initial regimens (Table 1) fell from a peak of 75% in 2008 to 12.2% in 2011 (p for trend Initial cART with stavudine declined to low levels according to recommendations but the overall use of stavudine remains substantial. The usage of second‐line treatment is unusually low in view of expected therapeutic failure rates, indicating potential difficulties in management of suspected treatment failure cases. Monitoring of prescription trends is a simple and feasible approach to identify deficits in the implementation of treatment guidelines for optimal outcomes., Abbreviations DOI: [...]

Presents a letter to the editor commenting on thrombotic manifestations that are the clinical hallmark of antiphospholipid syndrome.

Background: Approximately 46 million of the estimated 60 million deaths that occur in the world each year take place in developing countries. Further, this mortality is highest in Sub-Saharan Africa, although causes of mortality in this region are not well documented. The objective of this study is to describe the most frequent causes of mortality in children under 15 years of age in the demographic surveillance area of the Manhiça Health Research Centre, between 1997 and 2006, using the verbal autopsy tool.Methods: Verbal autopsy interviews for causes of death in children began in 1997. Each questionnaire was reviewed independently by three physicians with experience in tropical paediatrics, who assigned the cause of death according to the International Classification of Diseases (ICD-10). Each medical doctor attributed a minimum of one and a maximum of 2 causes. A final diagnosis is reached when at least two physicians agreed on the cause of death.Results: From January 1997 to December 2006, 568,499 person-year at risk (pyrs) and 10,037 deaths were recorded in the Manhiça DSS. 3,730 deaths with 246,658 pyrs were recorded for children under 15 years of age. Verbal autopsy interviews were conducted on 3,002 (80.4%) of these deaths. 73.6% of deaths were attributed to communicable diseases, non-communicable diseases accounted for 9.5% of the defined causes of death, and injuries for 3.9% of causes of deaths. Malaria was the single largest cause, accounting for 21.8% of cases. Pneumonia with 9.8% was the second leading cause of death, followed by HIV/AIDS (8.3%) and diarrhoeal diseases with 8%.Conclusion: The results of this study stand out the big challenges that lie ahead in the fight against infectious diseases in the study area. The pattern of childhood mortality in Manhiça area is typical of developing countries where malaria, pneumonia and HIV/AIDS are important causes of death. [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.)