Durable Efficacy of Switching From a 3- or 4-Drug Tenofovir Alafenamide-Based Regimen to the 2-Drug Regimen Dolutegravir/Lamivudine in the TANGO Study Through Week 196.

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.

A Comprehensive Literature Review of Treatment-Emergent Integrase Resistance with Dolutegravir-Based Regimens in Real-World Settings.

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.

Virologic Response to Dolutegravir Plus Lamivudine in People With Suppressed Human Immunodeficiency Virus Type 1 and Historical M184V/I: A Systematic Literature Review and Meta-analysis.

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.

Body mass index trends and its impact of under and overweight on outcome among PLHIV on antiretroviral treatment in rural Tanzania: A prospective cohort study.

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.

Persistent High Burden and Mortality Associated With Advanced HIV Disease in Rural Tanzania Despite Uptake of World Health Organization "Test and Treat" Guidelines.

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.

Evaluating Diversity in Randomized Clinical Trials of Dolutegravir-Based Antiretroviral Therapy Regimens: Pooled 48-Week Analyses by Race, Sex, and Regional Subgroups.

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.

Minimally Invasive Tissue Sampling: A Tool to Guide Efforts to Reduce AIDS-Related Mortality in Resource-Limited Settings.

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.

Minimally Invasive Tissue Sampling: A Tool to Guide Efforts to Reduce AIDS-Related Mortality in Resource-Limited Settings

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.

Improved detection and management of advanced HIV disease through a community adult TB-contact tracing intervention with same-day provision of the WHO-recommended package of care including ART initiation in a rural district of Mozambique.

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.

Improved detection and management of advanced HIV disease through a community adult TB­contact tracing intervention with same­day provision of the WHO­recommended package of care including ART initiation in a rural district of Mozambique

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.

High prevalence and mortality due to Histoplasma capsulatum in the Brazilian Amazon: An autopsy study.

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.

Tuberculosis-HIV Co-Infection: Progress and Challenges After Two Decades of Global Antiretroviral Treatment Roll-Out / Coinfección tuberculosis-VIH: avances y retos 2 décadas después de la implementación del tratamiento antirretroviral a nivel global

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

A pesar de que el uso de antirretrovirales ha aumentado en uso y difusión durante las 2 últimas décadas, lo que ha resultado en la disminución de nuevas infecciones y de la mortalidad global, la tuberculosis asociada al VIH sigue siendo un importante problema de salud pública. La tuberculosis es la principal infección oportunista asociada al VIH y la principal causa de muerte a nivel mundial, particularmente en el marco de situaciones de recursos limitados. Existen varios retos con respecto al diagnóstico, la implementación global del tratamiento de la tuberculosis latente, el manejo de la tuberculosis activa, el proporcionar una prevención óptima de la tuberculosis y el VIH centrada en el paciente y la atención en países de alta carga. En este artículo revisamos los avances en la patogénesis, el diagnóstico y el tratamiento después de casi 2 décadas de implementación global de la terapia antirretroviral y comentamos los retos actuales para el control global de la coinfección tuberculosis-VIH

Tuberculosis-HIV Co-Infection: Progress and Challenges After Two Decades of Global Antiretroviral Treatment Roll-Out.

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.

Short-course amphotericin B in addition to sertraline and fluconazole for treatment of HIV-associated cryptococcal meningitis in rural Tanzania.

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

Mortality due to Cryptococcus neoformans and Cryptococcus gattii in low-income settings: an autopsy study.

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.

Cryptococcal Meningitis Diagnostics and Screening in the Era of Point-of-Care Laboratory Testing.

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.

Laboratory-Reflex Cryptococcal Antigen Screening Is Associated With a Survival Benefit in Tanzania.

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.

Effect of schistosomiasis on the outcome of patients infected with HIV-1 starting antiretroviral therapy in rural Tanzania.

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.

Brief Report: No HIV Transmission From Virally Suppressed Mothers During Breastfeeding in Rural Tanzania.

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.