AmBisome Monotherapy and Combination AmBisome-Miltefosine Therapy for the Treatment of Visceral Leishmaniasis in Patients Coinfected With Human Immunodeficiency Virus in India: A Randomized Open-Label, Parallel-Arm, Phase 3 Trial.

BACKGROUND: Visceral leishmaniasis (VL) in patients with human immunodeficiency virus (HIV) presents an increasingly important patient cohort in areas where both infections are endemic. Evidence for treatment is sparce, with no high-quality studies from the Indian subcontinent. METHODS: This is a randomized, open-label, parallel-arm, phase 3 trial conducted within a single hospital in Patna, India. One hundred and fifty patients aged ≥18 years with serologically confirmed HIV and parasitologically confirmed VL were randomly allocated to 1 of 2 treatment arms, either a total 40 mg/kg intravenous liposomal amphotericin B (AmBisome; Gilead Pharmaceuticals) administered in 8 equal doses over 24 days or a total 30 mg/kg intravenous AmBisome administered in 6 equal doses given concomitantly with a total 1.4 g oral miltefosine administered through 2 daily doses of 50 mg over 14 days. The primary outcome was intention-to-treat relapse-free survival at day 210, defined as absence of signs and symptoms of VL or, if symptomatic, negative parasitological investigations. RESULTS: Among 243 patients assessed for eligibility, 150 were recruited between 2 January 2017 and 5 April 2018, with no loss to follow-up. Relapse-free survival at day 210 was 85% (64/75; 95% CI, 77-100%) in the monotherapy arm, and 96%, (72/75; 90-100%) in the combination arm. Nineteen percent (28/150) were infected with concurrent tuberculosis, divided equally between arms. Excluding those with concurrent tuberculosis, relapse-free survival at day 210 was 90% (55/61; 82-100%) in the monotherapy and 97% (59/61; 91-100%) in the combination therapy arm. Serious adverse events were uncommon and similar in each arm. CONCLUSIONS: Combination therapy appears to be safe, well tolerated, and effective, and halves treatment duration of current recommendations. CLINICAL TRIALS REGISTRATION: Clinical Trial Registry India (CTRI/2015/05/005807; the protocol is available online at https://osf.io/avz7r).

Diagnostic accuracy of commercially available immunochromatographic rapid tests for diagnosis of dengue in India.

BACKGROUND & OBJECTIVES: There is limited evidence regarding the accuracy of dengue rapid diagnostic kits despite their extensive use in India. We evaluated the performance of four immunochromatographic Rapid Diagnostic Test (RDTs) kits: Multisure dengue Ab/Ag rapid test (MP biomedicals; MP), Dengucheck combo (Zephyr Biomedicals; ZB), SD bioline dengue duo (Alere; SD) and Dengue day 1 test (J Mitra; JM). METHODS: This is a laboratory-based diagnostic evaluation study. Rapid tests results were compared to reference non-structural (NS1) antigen or immunoglobulin M (IgM) enzyme-linked immunosorbent assay (ELISA) results of 241 dengue-positive samples and 247 dengue-negative samples. Sensitivity and specificity of NS1 and IgM components of each RDT were calculated separately and in combination (either NS1 or IgM positive) against reference standard ELISA. RESULTS: A total of 238, 226, 208, and 146 reference NS1 ELISA samples were tested with MP, ZB, SD, and JM tests, respectively. In comparison to the NS1 ELISA reference tests, the NS1 component of MP, ZB, SD, and JM RDTs demonstrated a sensitivity of 71.8%, 85.1%, 77.2% and 80.9% respectively and specificity of 90.1%, 92.8%, 96.1 %, and 93.6%, respectively. In comparison to the IgM ELISA reference test, the IgM component of RDTs showed a sensitivity of 40.0%, 50.3%, 47.3% and 20.0% respectively and specificity of 92.4%, 88.6%, 96.5%, and 92.2% respectively. Combining NS1 antigen and IgM antibody results led to sensitivities of 87.5%, 82.9%, 93.8% and 91.7% respectively, and specificities of 75.3%, 73.9%, 76.5%, and 80.0% respectively. INTERPRETATION & CONCLUSION: Though specificities were acceptable, the sensitivities of each test were markedly lower than manufacturers' claims. These results also support the added value of combined antigen-and antibody-based RDTs for the diagnosis of acute dengue.

Antibiotic susceptibility patterns of pathogens isolated from hospitalized patients with advanced HIV disease (AHD) in Bihar, India.

Objectives: To describe the prevalence of common bacterial pathogens and antibiotic susceptibility patterns amongst advanced HIV disease (AHD) patients admitted between May 2019 and March 2021 to a Médecins Sans Frontières (MSF)-supported AHD inpatient unit in Bihar, India. Methods: A retrospective analysis of routinely collected demographic, clinical and microbiological data. Antibacterial susceptibility testing was done by an accredited referral laboratory using the modified Kirby-Bauer disc diffusion method. Results: A total of 238 isolates from 577 patients were identified through culture testing. Patient median (IQR) age was 38 (31-45) years, and 75% were male. Predominant sample types included blood (600; 38%), urine (266; 17%) and sputum (178; 11%). Of the isolated bacteria, Escherichia coli (80; 13.9%) was the most prevalent, followed by Klebsiella pneumonia (54; 9.4%), Pseudomonas aeruginosa (22; 3.8%), Klebsiella oxytoca (10; 1.7%), Proteus mirabilis (9; 1.6%), and Acinetobacter baumannii (7; 1.2%). The resistance pattern showed that most bacterial isolates were highly resistant to commonly prescribed antibiotics such as third-generation cephalosporins, fluoroquinolones and co-trimoxazole. Most pathogens were moderately resistant to antibiotics from the WHO Watch group, such as meropenem and piperacillin/tazobactam. In contrast, isolates were more susceptible to aminoglycosides, such as amikacin, gentamicin and nitrofurantoin. Conclusions: In Bihar, inpatients with AHD displayed a concerning array of antibiotic-resistant infections. This study provides a starting point from which further work on antimicrobial resistance in this vulnerable cohort of patients can be conducted.

Implementation of point-of-care testing and prevalence of cryptococcal antigenaemia among patients with advanced HIV disease in Mumbai, India.

OBJECTIVES: To describe the implementation of screening for cryptococcal antigenaemia by point-of-care (POC) serum cryptococcal antigen (CrAg) lateral flow assay, measure the prevalence and factors associated with serum cryptococcal antigenaemia in the routine programmatic setting. DESIGN: Cross-sectional study. SETTING: Seventeen publicly funded antiretroviral therapy (ART) centres in Mumbai, India. PARTICIPANTS: Serum CrAg screening was offered to all adolescents (>10 years of age) and adults with advanced HIV disease (AHD) (CD4 <200 cells/mm3 or with WHO clinical stage III/IV) regardless of symptoms of cryptococcal meningitis. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome was to describe the implementation of serum CrAg screening and secondary outcome was to measure the prevalence of serum cryptococcal antigenaemia and its risk factors. RESULTS: A total of 2715 patients with AHD were tested for serum CrAg by POC assay. Of these, 25 (0.9%) had a CrAg positive result. Among CrAg-positive patients, only one had symptoms. Serum CrAg positivity was 3.6% (6/169) and 1.6% (6/520) among those presenting with CD4 <100 cells/mm3 in the treatment naïve and treatment experienced group, respectively. On multivariable analysis, CD4 count <100 cells/mm3 (OR: 2.3, 95% CI 1.01 to 5.3; p=0.05) and people living with HIV who were treatment naïve (OR: 2.5, 95% CI 1.04 to 6.0; p=0.04) were significantly associated with a positive serum CrAg result. Lumbar puncture was obtained in 20/25 patients within 4 days (range: 1-4 days) of positive serum CrAg result and one person was confirmed to have meningitis. All serum CrAg-positive patients who had a negative cerebrospinal fluid CrAg were offered pre-emptive therapy. CONCLUSIONS: Implementation of a POC CrAg assay was possible with existing ART centre staff. Initiation of pre-emptive therapy and management of cryptococcal antigenaemia are operationally feasible at ART centres. The Indian National AIDS Control Programme may consider reflexive CrAg screening of all AHD patients with CD4 <100 cells/mm3.

Prevalence and determinants of asymptomatic Leishmania infection in HIV-infected individuals living within visceral leishmaniasis endemic areas of Bihar, India.

People living with HIV (PLHIV) have an increased risk of developing visceral leishmaniasis (VL) and poor outcomes compared to HIV negative individuals. Here, we aim to establish the prevalence and determinants of asymptomatic Leishmania infection (ALI) in a cohort of PLHIV in Bihar, India. We hoped to evaluate optimal diagnostic algorithms to detect ALI in PLHIV. We conducted a cross-sectional survey of PLHIV ≥18 years of age with no history or current diagnosis of VL or post kala-azar dermal leishmaniasis (PKDL) at anti-retroviral therapy centres within VL endemic districts of Bihar. ALI was defined as a positive rK39 enzyme-linked immunosorbent assay (ELISA), rK39 rapid diagnostic test (RDT) and/or quantitative polymerase chain reaction (qPCR). Additionally, the urinary Leishmania antigen ELISA was evaluated. Determinants for ALI were established using logistic regression and agreement between diagnostic tests calculated using Cohen's Kappa. A total of 1,296 PLHIV enrolled in HIV care, 694 (53.6%) of whom were female and a median age of 39 years (interquartile range 33-46), were included in the analysis. Baseline prevalence of ALI was 7.4% (n = 96). All 96 individuals were positive by rK39 ELISA, while 0.5% (n = 6) and 0.4% (n = 5) were positive by qPCR and rK39 RDT, respectively. Negligible or weak agreement was seen between assays. Independent risk factors for ALI were CD4 counts <100 (OR 3.1; 95% CI 1.2-7.6) and CD4 counts 100-199 (OR = 2.1;95% CI:1.1-4.0) compared to CD4 counts ≥300, and a household size ≥5 (OR = 1.9;95% CI:1.1-3.1). A total of 2.2% (n = 28) participants were positive by Leishmania antigen ELISA, detecting 20 additional participants to the asymptomatic cohort. Prevalence of ALI in PLHIV in VL endemic villages in Bihar was relatively high. Using the Leishmania antigen ELISA, prevalence increased to 9.0%. Patients with low CD4 counts and larger household size were found to have significantly higher risk of ALI. Trial Registration: Clinical Trial Registration CTRI/2017/03/008120.

Evaluation of qPCR on blood and skin microbiopsies, peripheral blood buffy coat smear, and urine antigen ELISA for diagnosis and test of cure for visceral leishmaniasis in HIV-coinfected patients in India: a prospective cohort study.

INTRODUCTION: HIV coinfection presents a challenge for diagnosis of visceral leishmaniasis (VL). Invasive splenic or bone marrow aspiration with microscopic visualisation of Leishmania parasites remains the gold standard for diagnosis of VL in HIV-coinfected patients. Furthermore, a test of cure by splenic or bone marrow aspiration is required as patients with VL-HIV infection are at a high risk of treatment failure. However, there remain financial, implementation and safety costs to these invasive techniques which severely limit their use under field conditions. METHODS AND ANALYSIS: We aim to evaluate blood and skin qPCR, peripheral blood buffy coat smear microscopy and urine antigen ELISA as non-invasive or minimally invasive alternatives for diagnosis and post-treatment test of cure for VL in HIV-coinfected patients in India, using a sample of 91 patients with parasitologically confirmed symptomatic VL-HIV infection. ETHICS AND DISSEMINATION: Ethical approval for this study has been granted by The Liverpool School of Tropical Medicine, The Institute of Tropical Medicine in Antwerp, the University of Antwerp and the Rajendra Memorial Research Institute of Medical Science in Patna. Any future publications will be published in open access journals. TRIAL REGISTRATION NUMBER: CTRI/2019/03/017908.

Lived experiences of palliative care among people living with HIV/AIDS: a qualitative study from Bihar, India.

OBJECTIVES: This study aimed to assess the lived experiences of palliative care among critically unwell people living with HIV/AIDS (PLHA), caregivers and relatives of deceased patients. It also aimed to understand the broader palliative care context in Bihar. DESIGN: This was an exploratory, qualitative study which used thematic analysis of semistructured, in-depth interviews as well as a focus group discussion. SETTING: All interviews took place in a secondary care hospital in Patna, Bihar which provides holistic care to critically unwell PLHA. PARTICIPANTS: We purposively selected 29 participants: 10 critically unwell PLHA, 5 caregivers of hospitalised patients, 7 relatives of deceased patients who were treated in the secondary care hospital and 7 key informants from community-based organisations. RESULTS: Critically ill PLHA emphasised the need for psychosocial counselling and opportunities for social interaction in the ward, as well as a preference for components of home-based palliative care, even though they were unfamiliar with actual terms such as 'palliative care' and 'end-of-life care'. Critically unwell PLHA generally expressed preference for separate, private inpatient areas for end-of-life care. Relatives of deceased patients stated that witnessing patients' deaths caused trauma for other PLHA. Caregivers and relatives of deceased patients felt there was inadequate time and space for grieving in the hospital. While both critically ill PLHA and relatives wished that poor prognosis be transparently disclosed to family members, many felt it should not be disclosed to the dying patients themselves. CONCLUSIONS: Despite expected high inpatient fatality rates, PLHA in Bihar lack access to palliative care services. PLHA receiving end-of-life care in hospitals should have a separate dedicated area, with adequate psychosocial counselling and activities to prevent social isolation. Healthcare providers should make concerted efforts to inquire, understand and adapt their messaging on prognosis and end-of-life care based on patients' preferences.

Refused and referred-persistent stigma and discrimination against people living with HIV/AIDS in Bihar: a qualitative study from India.

OBJECTIVES: This study aimed to explore barriers to accessing care, if any, among people living with HIV/AIDS (PLHA) in two districts of Bihar. We also aimed to assess attitudes towards PLHA among healthcare providers and community members. DESIGN: This qualitative study used an exploratory study design through thematic analysis of semistructured, in-depth interviews. SETTING: Two districts were purposively selected for the study, namely the capital Patna and a peripheral district located approximately 100 km from Patna, in order to glean insights from a diverse sample of respondents. PARTICIPANTS: Our team purposively selected 71 participants, including 35 PLHA, 10 community members and 26 healthcare providers. RESULTS: The overarching theme that evolved from these data through thematic coding identified that enacted stigma and discrimination interfere with each step in the HIV care continuum for PLHA in Bihar, India, especially outside urban areas. The five themes that contributed to these results include: perception of HIV as a dirty illness at the community level; non-consensual disclosure of HIV status; reliance on identifying PLHA to guide procedures and resistance to universal precautions; refusal to treat identified PLHA and referrals to other health centres for treatment; and inadequate knowledge and fear among health providers with respect to HIV transmission. CONCLUSIONS: The continued presence of discriminatory and stigmatising attitudes towards PLHA negatively impacts both disclosure of HIV status as well as access to care and treatment. We recognise a pressing need to improve the knowledge of HIV transmission, and implement universal precautions across all health facilities in the state, not just to reduce stigma and discrimination but also to ensure proper infection control. In order to improve treatment adherence and encourage optimal utilisation of services, it is imperative that the health system invest more in stigma reduction in Bihar and move beyond more ineffective, punitive approaches.

Malnutrition in Chakradharpur, Jharkhand: an anthropological study of perceptions and care practices from India.

BACKGROUND: This study aims to investigate the knowledge, perception and practices related to health, nutrition, care practices, and their effect on nutrition health-seeking behaviour. METHODS: In order to have maximum representation, we divided Chakradharpur block in Jharkhand state into three zones (north, south and centre regions) and purposively selected 2 Ambulatory Therapeutic Feeding Centre (ATFC) clusters from each zone, along with 2 villages per ATFC (12 villages from 6 ATFCs in total). In-depth interviews and natural group discussions were conducted with mothers/caregivers, frontline health workers (FHWs), Medicins Sans Frontieres (MSF) staff, community representatives, and social leaders from selected villages. RESULTS: We found that the community demonstrates a strong dependence on traditional and cultural practices for health care and nutrition for newborns, infants and young children. Furthermore, the community relies on alternative systems of medicine for treatment of childhood illnesses such as malnutrition. The study indicated that there was limited access to and utilization of local health services by the community. Lack of adequate social safety nets, limited livelihood opportunities, inadequate child care support and care, and seasonal male migration leave mothers and caregivers vulnerable and limit proper child care and feeding practices. With respect to continuum of care, services linking care across households to facilities are fragmented. Limited knowledge of child nutrition amongst mothers and caregivers as well as fragmented service provision contribute to the limited utilization of local health services. Government FHWs and MSF field staff do not have a robust understanding of screening methods, referral pathways, and counselling. Additionally, collaboration between MSF and FHWs regarding cases treated at the ATFC is lacking, disrupting the follow up process with discharged cases in the community. CONCLUSIONS: For caregivers, there is a need to focus on capacity building in the area of child nutrition and health care provision post-discharge. It is also recommended that children identified as having moderate acute malnutrition be supported to prevent them from slipping into severe acute malnutrition, even if they do not qualify for admission at ATFCs. Community education and engagement are critical components of a successful CMAM program.

Knowledge, attitudes, and practices related to antibiotic use in Paschim Bardhaman District: A survey of healthcare providers in West Bengal, India.

INTRODUCTION: Antibiotic misuse is widespread and contributes to antibiotic resistance, especially in less regulated health systems such as India. Although informal providers are involved with substantial segments of primary healthcare, their level of knowledge, attitudes, and practices is not well documented in the literature. OBJECTIVES: This quantitative study systematically examines the knowledge, attitudes, and practices of informal and formal providers with respect to antibiotic use. METHODS: We surveyed a convenience sample of 384 participants (96 allopathic doctors, 96 nurses, 96 informal providers, and 96 pharmacy shopkeepers) over a period of 8 weeks from December to February using a validated questionnaire developed in Italy. Our team created an equivalent, composite KAP score for each respondent in the survey, which was subsequently compared between providers. We then performed a multivariate logistic regression analysis to estimate the odds of having a low composite score (<80) based on occupation by comparing allopathic doctors (referent category) with all other study participants. The model was adjusted for age (included as a continuous variable) and gender. RESULTS: Doctors scored highest in questions assessing knowledge (77.3%) and attitudes (87.3%), but performed poorly in practices (67.6%). Many doctors knew that antibiotics were not indicated for viral infections, but over 87% (n = 82) reported prescribing them in this situation. Nurses, pharmacy shopkeepers, and informal providers were more likely to perform poorly on the survey compared to allopathic doctors (OR: 10.4, 95% CI 5.4, 20.0, p<0.01). 30.8% (n = 118) of all providers relied on pharmaceutical company representatives as a major source of information about antibiotics. CONCLUSIONS: Our findings indicate poor knowledge and awareness of antibiotic use and functions among informal health providers, and dissonance between knowledge and practices among allopathic doctors. The nexus between allopathic doctors, pharmaceutical company representatives, and informal health providers present promising avenues for future research and intervention.

"Without antibiotics, I cannot treat": A qualitative study of antibiotic use in Paschim Bardhaman district of West Bengal, India.

BACKGROUND: Misuse of antibiotics is a well-known driver of antibiotic resistance. Given the decentralized model of the Indian health system and the shortage of allopathic doctors in rural areas, a wide variety of healthcare providers cater to the needs of patients in urban and rural settings. This qualitative study explores the drivers of antibiotic use among formal and informal healthcare providers as well as patients accessing care at primary health centers across Paschim Bardhaman district in West Bengal. MATERIALS AND METHODS: We conducted 28 semi-structured, in-depth interviews with four groups of healthcare providers (allopathic doctors, informal health providers, nurses, and pharmacy shopkeepers) as well as patients accessing care at primary health centers and hospitals across Paschim Bardhaman district. Qualitative data was analyzed using the framework method in an inductive and deductive manner. RESULTS: Our results indicate that patients demand antibiotics from healthcare providers and seek the fastest cure possible, which influences the prescription choices of healthcare providers, particularly informal health providers. Many allopathic doctors provide antibiotics without any clinical indication due to inconsistent follow up, lack of testing facilities, risk of secondary infections, and unhygienic living conditions. Pharmaceutical company representatives actively network with informal health providers and formal healthcare providers alike, and regularly visit providers even in remote areas to market newer antibiotics. Allopathic doctors and informal health providers frequently blame the other party for being responsible for antibiotic resistance, and yet both display interdependence in referring patients to one another. CONCLUSIONS: A holistic approach to curbing antibiotic resistance in West Bengal and other parts of India should focus on strengthening the capacity of the existing public health system to deliver on its promises, improving patient education and counseling, and including informal providers and pharmaceutical company representatives in community-level antibiotic stewardship efforts.