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Introduction In low? and middle?income settings, more than a third of HIV?positive individuals starting antiretroviral therapy (ART) present with advanced disease (CD4 ? 200 cells/mm[sup.3] ); over half of these [...], : Introduction: Many HIV?positive individuals in Africa have advanced disease when initiating antiretroviral therapy (ART) so have high risks of opportunistic infections and death. The REALITY trial found that an enhanced?prophylaxis package including fluconazole reduced mortality by 27% in individuals starting ART with CD4 Methods: The REALITY trial enrolled from June 2013 to April 2015. A decision?analytic model was developed to estimate the cost?effectiveness of six management strategies in individuals initiating ART in the REALITY trial countries. Strategies included standard?prophylaxis, enhanced?prophylaxis, standard?prophylaxis with fluconazole; and three CrAg testing strategies, the first stratifying individuals to enhanced?prophylaxis (CrAg?positive) or standard?prophylaxis (CrAg?negative), the second to enhanced?prophylaxis (CrAg?positive) or enhanced?prophylaxis without fluconazole (CrAg?negative) and the third to standard?prophylaxis with fluconazole (CrAg?positive) or without fluconazole (CrAg?negative). The model estimated costs, life?years and quality?adjusted life?years (QALY) over 48 weeks using three competing mortality risks: cryptococcal meningitis; tuberculosis, serious bacterial infection or other known cause; and unknown cause. Results: Enhanced?prophylaxis was cost?effective at cost?effectiveness thresholds of US$300 and US$500 per QALY with an incremental cost?effectiveness ratio (ICER) of US$157 per QALY in the CD4 Conclusions: The REALITY enhanced?prophylaxis package in individuals with advanced HIV starting ART reduces morbidity and mortality, is practical to administer and is cost?effective. Efforts should continue to ensure that components are accessed at lowest available prices.

Background We evaluated the efficacy, pharmacokinetics (PK), and safety of clofazimine (CFZ) in patients living with human immunodeficiency virus (HIV) with cryptosporidiosis. Methods We performed a randomized, double-blind, placebo-controlled study. Primary outcomes in part A were reduction in Cryptosporidium shedding, safety, and PK. Primary analysis was according to protocol (ATP). Part B of the study compared CFZ PK in matched individuals living with HIV without cryptosporidiosis. Results Twenty part A and 10 part B participants completed the study ATP. Almost all part A participants had high viral loads and low CD4 counts, consistent with failure of antiretroviral (ARV) therapy. At study entry, the part A CFZ group had higher Cryptosporidium shedding, total stool weight, and more diarrheal episodes compared with the placebo group. Over the inpatient period, compared with those who received placebo, the CFZ group Cryptosporidium shedding increased by 2.17 log2 Cryptosporidium per gram stool (95% upper confidence limit, 3.82), total stool weight decreased by 45.3 g (P =.37), and number of diarrheal episodes increased by 2.32 (P =.87). The most frequent solicited adverse effects were diarrhea, abdominal pain, and malaise. One placebo and 3 CFZ participants died during the study. Plasma levels of CFZ in participants with cryptosporidiosis were 2-fold lower than in part B controls. Conclusions Our findings do not support the efficacy of CFZ for the treatment of cryptosporidiosis in a severely immunocompromised HIV population. However, this trial demonstrates a pathway to assess the therapeutic potential of drugs for cryptosporidiosis treatment. Screening persons living with HIV for diarrhea, and especially Cryptosporidium infection, may identify those failing ARV therapy. Clinical Trials Registration NCT03341767. [ABSTRACT FROM AUTHOR]

Pneumococcal carriage is the primary reservoir for transmission and a prerequisite for invasive pneumococcal disease. Pneumococcal Conjugate Vaccine 13 (PCV13) showed a 62% efficacy in protection against experimental Streptococcus pneumoniae serotype 6B (Spn6B) carriage in a controlled human infection model (CHIM) of healthy Malawian adults. We, therefore, measured humoral responses to experimental challenge and PCV-13 vaccination and determined the association with protection against pneumococcal carriage. We vaccinated 204 young, healthy Malawian adults with PCV13 or placebo and nasally inoculated them with Spn6B at least four weeks post-vaccination to establish carriage. We collected peripheral blood and nasal lining fluid at baseline, 4 weeks post-vaccination (7 days pre-inoculation), 2, 7, 14 and > 1 year post-inoculation. We measured the concentration of anti-serotype 6B Capsular Polysaccharide (CPS) Immunoglobulin G (IgG) and IgA antibodies in serum and nasal lining fluid using the World Health Organization (WHO) standardised enzyme-linked immunosorbent assay (ELISA). PCV13-vaccinated adults had higher serum IgG and nasal IgG/IgA anti-Spn6B CPS-specific binding antibodies than placebo recipients 4 to 6 weeks post-vaccination, which persisted for at least a year after vaccination. Nasal challenge with Spn6B did not significantly alter serum or nasal anti-CPS IgG binding antibody titers with or without experimental pneumococcal carriage. Pre-challenge titers of PCV13-induced serum IgG and nasal IgG/IgA anti-Spn6B CPS binding antibodies did not significantly differ between those that got experimentally colonised by Spn6B compared to those that did not. This study demonstrates that despite high PCV13 efficacy against experimental Spn6B carriage in young, healthy Malawian adults, robust vaccine-induced systemic and mucosal anti-Spn6B CPS binding antibodies did not directly relate to protection. [ABSTRACT FROM AUTHOR]

Background: Despite strong evidence-based strategies for prevention and management, global efforts to reduce deaths from postpartum haemorrhage (PPH) have failed, and it remains the leading cause of maternal mortality. We conducted a detailed review of all maternal deaths from 33 facilities in Malawi to identify health system weaknesses leading to deaths from PPH., Methods: Data were collected regarding every maternal death occurring across all district and central hospitals in Malawi. Deaths occurring from August 2020 to December 2022 were reviewed by multidisciplinary facility-based teams who compiled case narratives from clinical notes and then subsequently reviewed by obstetricians to confirm the cause of death according to international criteria. Data were summarised using proportions/frequencies, comparisons made using χ 2 or Wilcoxon rank sum tests, and logistic regression conducted to calculate ORs with CIs., Results: PPH was the cause of 20.4% of maternal deaths. Most deaths from PPH occurred within 24 hours of birth (80.0%), among women who had been referred to a higher-level facility (57.0%) and were admitted in stable condition (60.0%). Vacuum births carried an increased risk of death from PPH (OR 4.25 (95% CI 1.15 to 20.13, p=0.039)). Detailed reviews identified that deaths from PPH were more likely to be associated with factors such as 'lack of obstetric lifesaving skills' (26.7% vs 10.1%, p<0.001), 'inadequate monitoring' (51.5% vs 40.7%, p=0.012) and 'communication problems between facilities' (11.5% vs 6.2%, p=0.019) than deaths from other causes., Conclusions: Our analysis represents the largest published review of maternal deaths from PPH. We demonstrate that key health system weaknesses are contributing to these preventable maternal deaths. Case reviews conducted by multidisciplinary facility-based teams identified common and recurrent avoidable factors associated with deaths from PPH. Global efforts must now be focused on strategies that address these weaknesses, strengthening health systems and empowering healthcare workers to reduce maternal deaths from PPH., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2025. Re-use permitted under CC BY. Published by BMJ Group.)

Background: Caesarean section (CS) is the most common major surgery conducted globally, with rates rising. CS also contributes to maternal morbidity and mortality, with increased risks in low-resource settings. We conducted a detailed review of maternal deaths from 2020 to 2022 in Malawi to determine the burden of deaths related to CS, avoidable health system factors, and causes of death associated with this procedure., Methods: Data were collected regarding every maternal death occurring across all district and central hospitals in Malawi, alongside facility-level aggregated birth data. Maternal deaths were reviewed by facility-based multidisciplinary teams with subsequent confirmation of cause of death by obstetricians according to international criteria. Logistic regression was applied to estimate the odds of associations of leading causes of death with CS while adjusting for potential confounders., Results: Despite a low national CS rate, most deaths occurred following CS (51.8%, 276/533). Women who delivered by CS were five times (OR 5.60, 95% CI 4.74 to 6.67) more likely to die than women who delivered vaginally. The leading causes of death following CS were postpartum haemorrhage (26.0%, 68/277), eclampsia (15.6%, 41/277) and infection (14.1%, 37/277). Deaths from pregnancy-related infection were more often associated with CS (OR 2.03, 95% CI 1.12 to 3.72). Health system factors more frequently associated with deaths following CS than vaginal birth included 'prolonged abnormal observations without action' (p=0.006), 'delay in starting treatment' (p=0.006) and 'lack of blood transfusion' (p=0.03)., Conclusions: We found a high burden of maternal death following CS in this low-resource setting. Until now, international attention and many clinical trials have been focused on improving the safety of vaginal birth. Our findings highlight the need to ensure the safe and appropriate use of this potentially life-saving intervention to reduce maternal deaths. To avoid the high burden of death following CS we highlight, there is urgent need to develop and trial CS-specific interventions., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Salmonella was isolated from 23/79 (29.1%) pooled gecko stool samples from households in southern Malawi. Whole genome sequencing of 47 individual isolates within this collection revealed 27 Salmonella serovars spanning two subspecies. Our results demonstrate that geckos play an important role in the carriage of Salmonella within households., Competing Interests: None., (© 2024 Published by Elsevier B.V.)

Background: In Malawi, the national pneumococcal conjugate vaccine (PCV13) demonstrated less herd immunity than the USA, likely due to higher natural pneumococcal carriage rates. We assessed PCV13 efficacy against experimental pneumococcal carriage in healthy Malawian adults. We explored how natural carriage (pneumococcal carriage of any other serotype apart from 6B) influenced experimental carriage rates and vaccine efficacy., Methods: Healthy adults aged 18-40 were randomly assigned PCV13 (n=98) or saline (n=106), followed by intranasal SPN 6B inoculation at 20,000 (n=40), 80,000 (n=74), or 160,000 (n=90) CFU/100µl, 28 days post-vaccination. We evaluated natural and experimental pneumococcal carriage before and after vaccination on days 2, 7, and 14 post-inoculation using culture and multiplex qPCR targeting lytA/cpsA genes and compared carriage rates by vaccination status., Results: Of 204 participants, 19.6% (40) exhibited experimental carriage, detected by culture and 25.5% (52) by qPCR. Vaccinated individuals had lower experimental carriage rates (10.2%, n=10/98) compared to the placebo group (28.3%, n=30/106). This difference in vaccine efficacy was more pronounced in participants without natural carriage (PCV13=8% n=6/75 vs. placebo=25.9%, n=21/81) compared to those with natural carriage (PCV13=14.8%, n=4/27 vs. placebo=26.5%, n=9/34). Using a log-binomial model, vaccine effectiveness (VE) was 62%, whether assessed by culture or qPCR. Natural carriers had a lower VE of 52% compared to participants with no natural carriage (VE=69%)., Conclusion: We have shown that PCV13 VE estimate (62%) is robust whether carriage is assessed by culture or qPCR. PCV13 had lower VE in natural carriers compared to those without natural carriage at the inoculation visit., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: As well as suffering a high burden of pneumococcal disease people living with HIV (PLHIV) may contribute to community transmission in sub-Saharan African (sSA) settings. Pneumococcal vaccination is not currently offered to PLHIV in sSA but may prevent disease and reduce transmission. More evidence of vaccine effectiveness against carriage in PLHIV is needed. An Experimental Human Pneumococcal Carriage model (EHPC) has been safely and acceptably used in healthy adults in Malawi to evaluate pneumococcal vaccines against carriage and to identify immune correlates of protection from carriage. This study will establish the same model in PLHIV and will be the first controlled human infection model (CHIM) in this key population. Methods: Healthy participants with and without HIV will be inoculated intranasally with Streptococcus pneumoniae serotype 6B. Sequential cohorts will be challenged with increasing doses to determine the optimal safe challenge dose to establish experimental carriage. Nasal fluid, nasal mucosal, and blood samples will be taken before inoculation and on days 2, 7, 14, and 21 following inoculation to measure pneumococcal carriage density and identify immune correlates of protection from carriage. The vast majority of natural pneumococcal carriage events in PLHIV do not result in invasive disease and no invasive disease is expected in this study. However, robust participant safety monitoring is designed to identify signs of invasive disease early should they develop, and to implement treatment immediately. Participants will complete a Likert-style questionnaire at study-end to establish acceptability. Interpretations: We expect the EHPC model to be safely and acceptably implemented in PLHIV. The CHIM can then be used to accelerate pneumococcal vaccine evaluations in this population, and an evidence-based pneumococcal vaccination policy for PLHIV in sSA., Competing Interests: No competing interests were disclosed., (Copyright: © 2024 Doherty K et al.)

Background: The effect of childhood pneumococcal conjugate vaccine implementation in Malawi is threatened by absence of herd effect. There is persistent vaccine-type pneumococcal carriage in both vaccinated children and the wider community. We aimed to use a human infection study to measure 13-valent pneumococcal conjugate vaccine (PCV13) efficacy against pneumococcal carriage., Methods: We did a double-blind, parallel-arm, randomised controlled trial investigating the efficacy of PCV13 or placebo against experimental pneumococcal carriage of Streptococcus pneumoniae serotype 6B (strain BHN418) among healthy adults (aged 18-40 years) from Blantyre, Malawi. We randomly assigned participants (1:1) to receive PCV13 or placebo. PCV13 and placebo doses were prepared by an unmasked pharmacist to maintain research team and participant masking with identification only by a randomisation identification number and barcode. 4 weeks after receiving either PCV13 or placebo, participants were challenged with 20 000 colony forming units (CFUs) per naris, 80 000 CFUs per naris, or 160 000 CFUs per naris by intranasal inoculation. The primary endpoint was experimental pneumococcal carriage, established by culture of nasal wash at 2, 7, and 14 days. Vaccine efficacy was estimated per protocol by means of a log-binomial model adjusting for inoculation dose. The trial is registered with the Pan African Clinical Trials Registry, PACTR202008503507113, and is now closed., Findings: Recruitment commenced on April 27, 2021 and the final visit was completed on Sept 12, 2022. 204 participants completed the study protocol (98 PCV13, 106 placebo). There were lower carriage rates in the vaccine group at all three inoculation doses (0 of 21 vs two [11%] of 19 at 20 000 CFUs per naris; six [18%] of 33 vs 12 [29%] of 41 at 80 000 CFUs per naris, and four [9%] of 44 vs 16 [35%] of 46 at 160 000 CFUs per naris). The overall carriage rate was lower in the vaccine group compared with the placebo group (ten [10%] of 98 vs 30 [28%] of 106; Fisher's p value=0·0013) and the vaccine efficacy against carriage was estimated at 62·4% (95% CI 27·7-80·4). There were no severe adverse events related to vaccination or inoculation of pneumococci., Interpretation: This is, to our knowledge, the first human challenge study to test the efficacy of a pneumococcal vaccine against pneumococcal carriage in Africa, which can now be used to establish vaccine-induced correlates of protection and compare alternative strategies to prevent pneumococcal carriage. This powerful tool could lead to new means to enhance reduction in pneumococcal carriage after vaccination., Funding: Wellcome Trust., Competing Interests: Declaration of interests DF declares grant funding from Pfizer to her institution for separate projects and consulting fees from Pfizer, MSD, and Sanofi. All other authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: An effective drug to treat cryptosporidial diarrhea in HIV-infected individuals is a global health priority. Promising drugs need to be evaluated in endemic areas which may be challenged by both lack of resources and experience to conduct International Committee of Harmonisation-Good Clinical Practice (ICH-GCP)-compliant clinical trials., Methods: We present the challenges and lessons learned in implementing a phase 2A, randomized, double-blind, placebo-controlled trial of clofazimine, in treatment of cryptosporidiosis among HIV-infected adults at a single site in Malawi., Results: Primary challenges are grouped under study initiation, study population, study implementation, and cultural issues. The lessons learned primarily deal with regulatory system and operational barriers, and recommendations can be applied to other human experimental trials in low- and middle-income countries, specifically in sub-Saharan Africa., Conclusion: This study demonstrated that initiating and implementing human experimental trials in sub-Saharan Africa can be challenging. However, solutions exist and successful execution requires careful planning, ongoing evaluation, responsiveness to new developments, and oversight of all trial operations.