A 24-Week, All-Oral Regimen for Rifampin-Resistant Tuberculosis.

BACKGROUND: In patients with rifampin-resistant tuberculosis, all-oral treatment regimens that are more effective, shorter, and have a more acceptable side-effect profile than current regimens are needed. METHODS: We conducted an open-label, phase 2-3, multicenter, randomized, controlled, noninferiority trial to evaluate the efficacy and safety of three 24-week, all-oral regimens for the treatment of rifampin-resistant tuberculosis. Patients in Belarus, South Africa, and Uzbekistan who were 15 years of age or older and had rifampin-resistant pulmonary tuberculosis were enrolled. In stage 2 of the trial, a 24-week regimen of bedaquiline, pretomanid, linezolid, and moxifloxacin (BPaLM) was compared with a 9-to-20-month standard-care regimen. The primary outcome was an unfavorable status (a composite of death, treatment failure, treatment discontinuation, loss to follow-up, or recurrence of tuberculosis) at 72 weeks after randomization. The noninferiority margin was 12 percentage points. RESULTS: Recruitment was terminated early. Of 301 patients in stage 2 of the trial, 145, 128, and 90 patients were evaluable in the intention-to-treat, modified intention-to-treat, and per-protocol populations, respectively. In the modified intention-to-treat analysis, 11% of the patients in the BPaLM group and 48% of those in the standard-care group had a primary-outcome event (risk difference, -37 percentage points; 96.6% confidence interval [CI], -53 to -22). In the per-protocol analysis, 4% of the patients in the BPaLM group and 12% of those in the standard-care group had a primary-outcome event (risk difference, -9 percentage points; 96.6% CI, -22 to 4). In the as-treated population, the incidence of adverse events of grade 3 or higher or serious adverse events was lower in the BPaLM group than in the standard-care group (19% vs. 59%). CONCLUSIONS: In patients with rifampin-resistant pulmonary tuberculosis, a 24-week, all-oral regimen was noninferior to the accepted standard-care treatment, and it had a better safety profile. (Funded by Médecins sans Frontières; TB-PRACTECAL ClinicalTrials.gov number, NCT02589782.).

Chronic high level parasitemia in HIV-infected individuals with or without visceral leishmaniasis in an endemic area in North-West Ethiopia: potential superspreaders?

BACKGROUND: HIV patients with recurrent visceral leishmaniasis (VL) could potentially drive Leishmania transmission in areas with anthroponotic transmission such as East-Africa, but studies are lacking. Leishmania parasitemia has been used as proxy for infectiousness. METHODS: This study is nested within the PreLeish prospective cohort study, following a total of 490 HIV infected individuals free of VL at enrollment for upto 24-37 months in North-West Ethiopia. Blood Leishmania PCR was done systematically. This case series reports on ten HIV-coinfected individuals with chronic VL (≥3 VL episodes during follow-up) for upto 37 months, and three individuals with asymptomatic Leishmania infection for upto 24 months. RESULTS: All ten chronic VL cases were male, on antiretroviral treatment, with 0-11 relapses before enrollment. Median baseline CD4 counts were 82 cells/µL. They displayed three to six VL treatment episodes over a period upto 37 months. Leishmania blood PCR levels were strongly positive for almost the entire follow-up time (median Ct value 26 (IQR 23-30), including during periods between VL treatment. Additionally, we describe three HIV-infected individuals with asymptomatic Leishmania infection and without VL history, with equally strong Leishmania parasitemia over a period of upto 24 months without developing VL. All were on antiretroviral treatment at enrollment, with baseline CD4 counts ranging from 78 to 350 cells/µL. CONCLUSION: These are the first data on chronic parasitemia in HIV-infected individuals from L donovani endemic areas. HIV patients with asymptomatic and symptomatic Leishmania infection could potentially be highly infectious and constitute Leishmania superspreaders. Xenodiagnosis studies are required to confirm infectiousness.

Paromomycin and Miltefosine Combination as an Alternative to Treat Patients With Visceral Leishmaniasis in Eastern Africa: A Randomized, Controlled, Multicountry Trial.

BACKGROUND: This study aimed to determine whether paromomycin plus miltefosine (PM/MF) is noninferior to sodium stibogluconate plus paromomycin (SSG/PM) for treatment of primary visceral leishmaniasis in eastern Africa. METHODS: An open-label, phase 3, randomized, controlled trial was conducted in adult and pediatric patients at 7 sites in eastern Africa. Patients were randomly assigned to either 20 mg/kg paromomycin plus allometric dose of miltefosine (14 days), or 20 mg/kg sodium stibogluconate plus 15 mg/kg paromomycin (17 days). The primary endpoint was definitive cure after 6 months. RESULTS: Of 439 randomized patients, 424 completed the trial. Definitive cure at 6 months was 91.2% (155 of 170) and 91.8% (156 of 170) in the PM/MF and SSG/PM arms in primary efficacy modified intention-to-treat analysis (difference, 0.6%; 97.5% confidence interval [CI], -6.2 to 7.4), narrowly missing the noninferiority margin of 7%. In the per-protocol analysis, efficacy was 92% (149 of 162) and 91.7% (155 of 169) in the PM/MF and SSG/PM arms (difference, -0.3%; 97.5% CI, -7.0 to 6.5), demonstrating noninferiority. Treatments were well tolerated. Four of 18 serious adverse events were study drug-related, and 1 death was SSG-related. Allometric dosing ensured similar MF exposure in children (<12 years) and adults. CONCLUSIONS: PM/MF and SSG/PM efficacies were similar, and adverse drug reactions were as expected given the drugs safety profiles. With 1 less injection each day, reduced treatment duration, and no risk of SSG-associated life-threatening cardiotoxicity, PM/MF is a more patient-friendly alternative for children and adults with primary visceral leishmaniasis in eastern Africa. CLINICAL TRIALS REGISTRATION: NCT03129646.

Population pharmacokinetics of a combination of miltefosine and paromomycin in Eastern African children and adults with visceral leishmaniasis.

OBJECTIVES: To improve visceral leishmaniasis (VL) treatment in Eastern Africa, 14- and 28-day combination regimens of paromomycin plus allometrically dosed miltefosine were evaluated. As the majority of patients affected by VL are children, adequate paediatric exposure to miltefosine and paromomycin is key to ensuring good treatment response. METHODS: Pharmacokinetic data were collected in a multicentre randomized controlled trial in VL patients from Kenya, Sudan, Ethiopia and Uganda. Patients received paromomycin (20 mg/kg/day for 14 days) plus miltefosine (allometric dose for 14 or 28 days). Population pharmacokinetic models were developed. Adequacy of exposure and target attainment of paromomycin and miltefosine were evaluated in children and adults. RESULTS: Data from 265 patients (59% ≤12 years) were available for this pharmacokinetic analysis. Paromomycin exposure was lower in paediatric patients compared with adults [median (IQR) end-of-treatment AUC0-24h 187 (162-203) and 242 (217-328) µg·h/mL, respectively], but were both within the IQR of end-of-treatment exposure in Kenyan and Sudanese adult patients from a previous study. Cumulative miltefosine end-of-treatment exposure in paediatric patients and adults [AUCD0-28 517 (464-552) and 524 (456-567) µg·day/mL, respectively] and target attainment [time above the in vitro susceptibility value EC90 27 (25-28) and 30 (28-32) days, respectively] were comparable to previously observed values in adults. CONCLUSIONS: Paromomycin and miltefosine exposure in this new combination regimen corresponded to the desirable levels of exposure, supporting the implementation of the shortened 14 day combination regimen. Moreover, the lack of a clear exposure-response and exposure-toxicity relationship indicated adequate exposure within the therapeutic range in the studied population, including paediatric patients.

Predictors of virological failure among people living with HIV receiving first line antiretroviral treatment in Myanmar: retrospective cohort analysis.

BACKGROUND: Progress toward the global target for 95% virological suppression among those on antiretroviral treatment (ART) is still suboptimal. We describe the viral load (VL) cascade, the incidence of virological failure and associated risk factors among people living with HIV receiving first-line ART in an HIV cohort in Myanmar treated by the Médecins Sans Frontières in collaboration with the Ministry of Health and Sports Myanmar. METHODS: We conducted a retrospective cohort study, including adult patients with at least one HIV viral load test result and having received of at least 6 months' standard first-line ART. The incidence rate of virological failure (HIV viral load ≥ 1000 copies/mL) was calculated. Multivariable Cox's regression was performed to identify risk factors for virological failure. RESULTS: We included 25,260 patients with a median age of 33.1 years (interquartile range, IQR 28.0-39.1) and a median observation time of 5.4 years (IQR 3.7-7.9). Virological failure was documented in 3,579 (14.2%) participants, resulting in an overall incidence rate for failure of 2.5 per 100 person-years of follow-up. Among those who had a follow-up viral load result, 1,258 (57.1%) had confirmed virological failure, of which 836 (66.5%) were switched to second-line treatment. An increased hazard for failure was associated with age ≤ 19 years (adjusted hazard ratio, aHR 1.51; 95% confidence intervals, CI 1.20-1.89; p < 0.001), baseline tuberculosis (aHR 1.39; 95% CI 1.14-1.49; p < 0.001), a history of low-level viremia (aHR 1.60; 95% CI 1.42-1.81; p < 0.001), or a history of loss-to-follow-up (aHR 1.24; 95% CI 1.41-1.52; p = 0.041) and being on the same regimen (aHR 1.37; 95% CI 1.07-1.76; p < 0.001). Cumulative appointment delay was not significantly associated with failure after controlling for covariates. CONCLUSIONS: VL monitoring is an important tool to improve programme outcomes, however limited coverage of VL testing and acting on test results hampers its full potential. In our cohort children and adolescents, PLHIV with history of loss-to-follow-up or those with low-viremia are at the highest risk of virological failure and might require more frequent virological monitoring than is currently recommended.

Safety and Effectiveness of Short-Course AmBisome in the Treatment of Post-Kala-Azar Dermal Leishmaniasis: A Prospective Cohort Study in Bangladesh.

Background: A safe and effective short-course treatment regimen for post-kala-azar dermal leishmaniasis (PKDL) is considered essential for achieving and sustaining elimination of visceral leishmaniasis (VL) in the Indian subcontinent [1, 2]. Here, single-dose liposomal amphotericin B (AmBisome) has been adopted as a first-line regimen for VL; however the effectiveness and safety of AmBisome for PKDL has not been formally evaluated. Methods: The safety and effectiveness of AmBisome 15 mg/kg, given over 15 days in 5 biweekly infusions of 3 mg/kg on an outpatient basis, was evaluated between April and November 2014 in patients with clinically diagnosed PKDL, aged ≥12 years and residing in a highly VL-endemic area in Bangladesh. This was a prospective cohort observational study, with the objective to assess final cure 12 months after treatment. Clinical response was monitored at 1, 3, 6, and 12 months, and safety during treatment and up to 1 month after treatment. Results: Of the 280 patients meeting the inclusion criteria, 273 were assessed at 12 months. A complete or major improvement of lesions was seen in 245 patients (89.7%); 213 (78.0%) were considered completely cured. Lesions did not improve in 28 (10.3%) and new lesions appeared in 13 (4.8%). All patients completed treatment without severe or serious adverse events. Conclusions: A short-course 15-mg/kg AmBisome regimen proved safe and effective in the treatment of clinically diagnosed PKDL in Bangladesh, and should be considered a treatment option for routine programmatic use in the VL elimination effort in the Indian subcontinent.

Long-term Clinical Outcomes in Visceral Leishmaniasis/Human Immunodeficiency Virus-Coinfected Patients During and After Pentamidine Secondary Prophylaxis in Ethiopia: A Single-Arm Clinical Trial.

Background: We have conducted a single-arm trial evaluating monthly pentamidine secondary prophylaxis (PSP) to prevent visceral leishmaniasis (VL) relapse in Ethiopian human immunodeficiency virus-infected patients. Outcomes at 12 months of PSP have been previously reported, supporting PSP effectiveness and safety. However, remaining relapse-free after PSP discontinuation is vital. We now report outcomes and associated factors for a period of up to 2.5 years after initiating PSP, including 1-year follow-up after PSP discontinuation. Methods: The trial had 3 phases: (1) 12 months of PSP; (2) a 6-month PSP extension period if CD4 count was ≤200 cells/µL at month 12; and (3) 12-month follow-up after stopping PSP. The probability of relapse and risk factors were calculated using Kaplan-Meier methods and Cox regression analysis. Results: For the 74 patients included, final study outcomes were as follows: 39 (53%) relapse-free, 20 (27%) relapsed, 5 (7%) deaths, 10 (14%) lost to follow-up. The 2-year risk of relapse was 36.9% (95% confidence interval, 23.4%-55.0%) and was highest for those with a history of VL relapse and low baseline CD4 count. Forty-five patients were relapse-free and in follow-up at month 12 of PSP. This included 28 patients with month 12 CD4 counts >200 cells/µL, remaining relapse-free after PSP discontinuation. Among the 17 with month 12 CD4 count <200 cells/µL, 1 relapsed and 3 were lost during the PSP extension period. During 1-year post-PSP follow-up, 2 patients relapsed and 1 was lost to follow-up. No PSP-related serious adverse events were reported during the PSP-extension/post-PSP follow-up period. Conclusions: It seems safe to discontinue PSP at month 12 CD4 counts of >200 cells/µL. The management of those failing to reach this level remains to be defined. Clinical Trials Registration: NCT01360762.

The Risk and Predictors of Visceral Leishmaniasis Relapse in Human Immunodeficiency Virus-Coinfected Patients in Ethiopia: A Retrospective Cohort Study.

BACKGROUND: East Africa, where Leishmania donovani is prevalent, faces the highest burden world-wide of visceral leishmaniasis (VL) and human immunodeficiency virus (HIV) coinfection. However, data on the risk and predictors of VL relapse are scarce. Such information is vital to target medical follow-up and interventions to those at highest risk. METHODS: We conducted a retrospective cohort study at a Médecins Sans Frontières-supported health center in northwest Ethiopia. We included adult VL-HIV coinfected patients treated for VL and discharged cured between February 2008 and February 2013. The risk of relapse was calculated using Kaplan-Meier methods, and predictors were determined using Cox regression models. RESULTS: Of the 146 patients included, 140 (96%) were male and the median age was 31 years. At the index VL diagnosis, 110 (75%) had primary VL, 57 (40%) were on antiretroviral therapy (ART), and the median CD4 count was 149 cells/µL. The median follow-up time after cure was 11 months, during which 44 (30%) patients relapsed. The risk of relapse was 15% at 6 months, 26% at 12 months, and 35% at 24 months. Predictors of relapse were: not being on ART at VL diagnosis, ART not initiated during VL treatment, and high tissue parasite load (parasite grade 6+) at VL diagnosis. CONCLUSIONS: The risk of VL relapse in coinfected patients was high, particularly in those not on ART or presenting with a high tissue parasite load. These patients should be preferentially targeted for secondary prophylaxis and/or regular medical follow-up. Timely ART initiation in all coinfected patients is crucial.

Dilution testing using rapid diagnostic tests in a HIV diagnostic algorithm: a novel alternative for confirmation testing in resource limited settings.

BACKGROUND: Current WHO testing guidelines for resource limited settings diagnose HIV on the basis of screening tests without a confirmation test due to cost constraints. This leads to a potential risk of false positive HIV diagnosis. In this paper, we evaluate the dilution test, a novel method for confirmation testing, which is simple, rapid, and low cost. The principle of the dilution test is to alter the sensitivity of a rapid diagnostic test (RDT) by dilution of the sample, in order to screen out the cross reacting antibodies responsible for falsely positive RDT results. METHODS: Participants were recruited from two testing centres in Ethiopia where a tiebreaker algorithm using 3 different RDTs in series is used to diagnose HIV. All samples positive on the initial screening RDT and every 10th negative sample underwent testing with the gold standard and dilution test. Dilution testing was performed using Determine™ rapid diagnostic test at 6 different dilutions. Results were compared to the gold standard of Western Blot; where Western Blot was indeterminate, PCR testing determined the final result. RESULTS: 2895 samples were recruited to the study. 247 were positive for a prevalence of 8.5 % (247/2895). A total of 495 samples underwent dilution testing. The RDT diagnostic algorithm misclassified 18 samples as positive. Dilution at the level of 1/160 was able to correctly identify all these 18 false positives, but at a cost of a single false negative result (sensitivity 99.6 %, 95 % CI 97.8-100; specificity 100 %, 95 % CI: 98.5-100). Concordance between the gold standard and the 1/160 dilution strength was 99.8 %. CONCLUSION: This study provides proof of concept for a new, low cost method of confirming HIV diagnosis in resource-limited settings. It has potential for use as a supplementary test in a confirmatory algorithm, whereby double positive RDT results undergo dilution testing, with positive results confirming HIV infection. Negative results require nucleic acid testing to rule out false negative results due to seroconversion or misclassification by the lower sensitivity dilution test. Further research is needed to determine if these results can be replicated in other settings. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01716299 .

Evaluation of HIV testing algorithms in Ethiopia: the role of the tie-breaker algorithm and weakly reacting test lines in contributing to a high rate of false positive HIV diagnoses.

BACKGROUND: In Ethiopia a tiebreaker algorithm using 3 rapid diagnostic tests (RDTs) in series is used to diagnose HIV. Discordant results between the first 2 RDTs are resolved by a third 'tiebreaker' RDT. Médecins Sans Frontières uses an alternate serial algorithm of 2 RDTs followed by a confirmation test for all double positive RDT results. The primary objective was to compare the performance of the tiebreaker algorithm with a serial algorithm, and to evaluate the addition of a confirmation test to both algorithms. A secondary objective looked at the positive predictive value (PPV) of weakly reactive test lines. METHODS: The study was conducted in two HIV testing sites in Ethiopia. Study participants were recruited sequentially until 200 positive samples were reached. Each sample was re-tested in the laboratory on the 3 RDTs and on a simple to use confirmation test, the Orgenics Immunocomb Combfirm® (OIC). The gold standard test was the Western Blot, with indeterminate results resolved by PCR testing. RESULTS: 2620 subjects were included with a HIV prevalence of 7.7%. Each of the 3 RDTs had an individual specificity of at least 99%. The serial algorithm with 2 RDTs had a single false positive result (1 out of 204) to give a PPV of 99.5% (95% CI 97.3%-100%). The tiebreaker algorithm resulted in 16 false positive results (PPV 92.7%, 95% CI: 88.4%-95.8%). Adding the OIC confirmation test to either algorithm eliminated the false positives. All the false positives had at least one weakly reactive test line in the algorithm. The PPV of weakly reacting RDTs was significantly lower than those with strongly positive test lines. CONCLUSION: The risk of false positive HIV diagnosis in a tiebreaker algorithm is significant. We recommend abandoning the tie-breaker algorithm in favour of WHO recommended serial or parallel algorithms, interpreting weakly reactive test lines as indeterminate results requiring further testing except in the setting of blood transfusion, and most importantly, adding a confirmation test to the RDT algorithm. It is now time to focus research efforts on how best to translate this knowledge into practice at the field level. TRIAL REGISTRATION: Clinical Trial registration #: NCT01716299.

Correction: The increasing incidence of visceral leishmaniasis relapse in South Sudan: A retrospective analysis of field patient data from 2001-2018.

[This corrects the article DOI: 10.1371/journal.pntd.0010696.].

Blood transfusion in the care of patients with visceral leishmaniasis: a review of practices in therapeutic efficacy studies.

Blood transfusion remains an important aspect of patient management in visceral leishmaniasis (VL). However, transfusion triggers considered are poorly understood. This review summarises the transfusion practices adopted in VL efficacy studies using the Infectious Diseases Data Observatory VL clinical trials library. Of the 160 studies (1980-2021) indexed in the IDDO VL library, description of blood transfusion was presented in 16 (10.0%) (n=3459 patients) studies. Transfusion was initiated solely based on haemoglobin (Hb) measurement in nine studies, combining Hb measurement with an additional condition (epistaxis/poor health/clinical instability) in three studies and the criteria was not mentioned in four studies. The Hb threshold range for triggering transfusion was 3-8 g/dL. The number of patients receiving transfusion was explicitly reported in 10 studies (2421 patients enrolled, 217 underwent transfusion). The median proportion of patients who received transfusion in a study was 8.0% (Interquartile range: 4.7% to 47.2%; range: 0-100%; n=10 studies). Of the 217 patients requiring transfusion, 58 occurred before VL treatment initiation, 46 during the treatment/follow-up phase and the time was not mentioned in 113. This review describes the variation in clinical practice and is an important initial step in policy/guideline development, where both the patient's Hb concentration and clinical status must be considered.

Correction: Treatment outcomes among snakebite patients in north-west Ethiopia-A retrospective analysis.

[This corrects the article DOI: 10.1371/journal.pntd.0010148.].

Short oral regimens for pulmonary rifampicin-resistant tuberculosis (TB-PRACTECAL): an open-label, randomised, controlled, phase 2B-3, multi-arm, multicentre, non-inferiority trial.

BACKGROUND: Around 500 000 people worldwide develop rifampicin-resistant tuberculosis each year. The proportion of successful treatment outcomes remains low and new treatments are needed. Following an interim analysis, we report the final safety and efficacy outcomes of the TB-PRACTECAL trial, evaluating the safety and efficacy of oral regimens for the treatment of rifampicin-resistant tuberculosis. METHODS: This open-label, randomised, controlled, multi-arm, multicentre, non-inferiority trial was conducted at seven hospital and community sites in Uzbekistan, Belarus, and South Africa, and enrolled participants aged 15 years and older with pulmonary rifampicin-resistant tuberculosis. Participants were randomly assigned, in a 1:1:1:1 ratio using variable block randomisation and stratified by trial site, to receive 36-80 week standard care; 24-week oral bedaquiline, pretomanid, and linezolid (BPaL); BPaL plus clofazimine (BPaLC); or BPaL plus moxifloxacin (BPaLM) in stage one of the trial, and in a 1:1 ratio to receive standard care or BPaLM in stage two of the trial, the results of which are described here. Laboratory staff and trial sponsors were masked to group assignment and outcomes were assessed by unmasked investigators. The primary outcome was the percentage of participants with a composite unfavourable outcome (treatment failure, death, treatment discontinuation, disease recurrence, or loss to follow-up) at 72 weeks after randomisation in the modified intention-to-treat population (all participants with rifampicin-resistant disease who received at least one dose of study medication) and the per-protocol population (a subset of the modified intention-to-treat population excluding participants who did not complete a protocol-adherent course of treatment (other than because of treatment failure or death) and those who discontinued treatment early because they violated at least one of the inclusion or exclusion criteria). Safety was measured in the safety population. The non-inferiority margin was 12%. This trial is registered with ClinicalTrials.gov, NCT02589782, and is complete. FINDINGS: Between Jan 16, 2017, and March 18, 2021, 680 patients were screened for eligibility, of whom 552 were enrolled and randomly assigned (152 to the standard care group, 151 to the BPaLM group, 126 to the BPaLC group, and 123 to the BPaL group). The standard care and BPaLM groups proceeded to stage two and are reported here, post-hoc analyses of the BPaLC and BPaL groups are also reported. 151 participants in the BPaLM group and 151 in the standard care group were included in the safety population, with 138 in the BPaLM group and 137 in the standard care group in the modified intention-to-treat population. In the modified intention-to-treat population, unfavourable outcomes were reported in 16 (12%) of 137 participants for whom outcome was assessable in the BPaLM group and 56 (41%) of 137 participants in the standard care group (risk difference -29·2 percentage points [96·6% CI -39·8 to -18·6]; non-inferiority and superiority p<0·0001). 34 (23%) of 151 participants receiving BPaLM had adverse events of grade 3 or higher or serious adverse events, compared with 72 (48%) of 151 participants receiving standard care (risk difference -25·2 percentage points [96·6% CI -36·4 to -13·9]). Five deaths were reported in the standard care group by week 72, of which one (COVID-19 pneumonia) was unrelated to treatment and four (acute pancreatitis, suicide, sudden death, and sudden cardiac death) were judged to be treatment-related. INTERPRETATION: The 24-week, all-oral BPaLM regimen is safe and efficacious for the treatment of pulmonary rifampicin-resistant tuberculosis, and was added to the WHO guidance for treatment of this condition in 2022. These findings will be key to BPaLM becoming the preferred regimen for adolescents and adults with pulmonary rifampicin-resistant tuberculosis. FUNDING: Médecins Sans Frontières.

Correction: Viraemic-time predicts mortality among people living with HIV on second-line antiretroviral treatment in Myanmar: A retrospective cohort study.

[This corrects the article DOI: 10.1371/journal.pone.0271910.].

Persistent T cell unresponsiveness associated with chronic visceral leishmaniasis in HIV-coinfected patients.

A large proportion of HIV-coinfected visceral leishmaniasis (VL-HIV) patients exhibit chronic disease with frequent VL recurrence. However, knowledge on immunological determinants underlying the disease course is scarce. We longitudinally profiled the circulatory cellular immunity of an Ethiopian HIV cohort that included VL developers. We show that chronic VL-HIV patients exhibit high and persistent levels of TIGIT and PD-1 on CD8+/CD8- T cells, in addition to a lower frequency of IFN-γ+ TIGIT- CD8+/CD8- T cells, suggestive of impaired T cell functionality. At single T cell transcriptome and clonal resolution, the patients show CD4+ T cell anergy, characterised by a lack of T cell activation and lymphoproliferative response. These findings suggest that PD-1 and TIGIT play a pivotal role in VL-HIV chronicity, and may be further explored for patient risk stratification. Our findings provide a strong rationale for adjunctive immunotherapy for the treatment of chronic VL-HIV patients to break the recurrent disease cycle.

Concomitant malaria among visceral leishmaniasis in-patients from Gedarif and Sennar States, Sudan: a retrospective case-control study.

BACKGROUND: In areas where visceral leishmaniasis (VL) and malaria are co-endemic, co-infections are common. Clinical implications range from potential diagnostic delay to increased disease-related morbidity, as compared to VL patients. Nevertheless, public awareness of the disease remains limited. In VL-endemic areas with unstable and seasonal malaria, vulnerability to the disease persists through all age-groups, suggesting that in these populations, malaria may easily co-occur with VL, with potentially severe clinical effects. METHODS: A retrospective case-control study was performed using medical records of VL patients admitted to Tabarakallah and Gedarif Teaching Hospitals (Gedarif State) and Al`Azaza kala-azar Clinic (Sennar State), Sudan (2005-2010). Patients positively diagnosed with VL and malaria were identified as cases, and VL patients without microscopy-detectable malaria as controls. Associations between patient characteristics and the occurrence of the co-infection were investigated using logistic regression analysis. Confirmation of epidemiological outcomes was obtained with an independently collected dataset, composed by Médecins Sans Frontières (MSF) at Um-el-Kher and Kassab Hospitals, Gedarif State (1998). RESULTS: The prevalence of malaria co-infection among VL surveyed patients ranged from 3.8 to 60.8%, with a median of 26.2%. Co-infected patients presented at hospital with deteriorated clinical pictures. Emaciation (Odds Ratio (OR): 2.46; 95% Confidence Interval (95% CI): 1.72-3.50), jaundice (OR: 2.52; 95% CI: 1.04-6.09) and moderate anemia (OR: 1.58; 95% CI: 1.10-2.28) were found to be positively associated with the co-infection, while severity of splenomegaly (OR: 0.53; 95% CI: 0.35-0.81) and, to a less extent, hepatomegaly (OR: 0.52; 95% CI: 0.27-1.01) appeared to be reduced by concomitant VL and malaria. The in-hospital case-fatality rates did not significantly differ between co- and mono-infected patients (OR: 1.13; 95% CI: 0.59-2.17). Conversely, a significantly increased mortality rate (OR: 4.38; 95% CI: 1.83-10.48) was observed by MSF amongst co-infected patients enrolled at Um-el-Kher and Kassab Hospitals, who also suffered an enhanced risk of severe anemia (OR: 3.44; 95% CI: 1.68-7.02) compared to VL mono-infections. CONCLUSIONS: In endemic VL areas with unstable seasonal malaria, like eastern Sudan, VL patients are highly exposed to the risk of developing concomitant malaria. Prompt diagnosis and effective treatment of malaria are essential to ensure that its co-infection does not result into poor prognoses.

Systematic review on cumulative HIV viraemia among people living with HIV receiving antiretroviral treatment and its association with mortality and morbidity.

BACKGROUND: We performed a systematic review to generate evidence on the association between cumulative human immunodeficiency virus (HIV) viraemia and health outcomes. METHODS: Quantitative studies reporting on HIV cumulative viraemia (CV) and its association with health outcomes among people living with HIV (PLHIV) on antiretroviral treatment (ART) were included. We searched MEDLINE via PubMed, Embase, Scopus and Web of Science and conference abstracts from 1 January 2008 to 1 August 2022. RESULTS: The systematic review included 26 studies. The association between CV and mortality depended on the study population, methods used to calculate CV and its level. Higher CV was not consistently associated with greater risk of acquire immunodeficiency syndrome-defining clinical conditions. However, four studies present a strong relationship between CV and cardiovascular disease. The risk was not confirmed in relation of increased hazards of stroke. Studies that assessed the effect of CV on the risk of cancer reported a positive association between CV and malignancy, although the effect may differ for different types of cancer. CONCLUSIONS: CV is associated with adverse health outcomes in PLHIV on ART, especially at higher levels. However, its role in clinical and programmatic monitoring and management of PLHIV on ART is yet to be established.

Therapeutic Strategies against Leishmania and Trypanosoma.

Human African trypanosomiasis (also known as sleeping sickness, with Trypanosoma brucei gambiense and Trypanosoma brucei rhodesiense as etiological agents), American trypanosomiasis (also known as Chagas disease, with Trypanosoma cruzi as the etiological agent), and leishmaniasis (including cutaneous, mucocutaneous, and visceral forms, with multiple species belonging to the Leishmania genus as etiological agents) are recognized as neglected tropical diseases (NTDs) [...].

Snakebite envenoming at MSF: A decade of clinical challenges and antivenom access issues.

The medical humanitarian organization Médecins Sans Frontières (MSF) provides medical care in more than 70 countries and admits more than 7000 cases of snakebite in its facilities each year. We describe our activities against snakebite in three African countries: Central African Republic, South Sudan and Ethiopia, in which different models of care have been developed. A standard protocol using two different antivenoms depending on the patient's syndrome has been introduced, and a simple blood coagulation test is performed to detect venom-induced coagulopathy. Other services, including surgery for necrotizing wounds, are offered in the facilities where MSF admits a large number of snakebite patients. All services, including provision of antivenom, are offered free-of-charge in MSF-supported facilities. Community-based activities focusing on preventive measures and prompt transport to hospital have been developed in a few MSF projects. The provision of quality care and treatment, including effective antivenoms, without out-of-pocket payments by the patients, probably explains why MSF has admitted an increasing number of snakebite victims over the last years. This model requires significant resources and monitoring, including regular training of healthcare workers on treatment protocols and a considerable budget for antivenom procurement.