Isoniazid-associated pellagra during mass scale-up of tuberculosis preventive therapy: a case-control study.

BACKGROUND: Pellagra is caused by niacin (vitamin B3) deficiency and patients with pellagra present with a characteristic rash. Isoniazid disrupts intracellular niacin synthesis and might induce niacin deficiency. In 2017, Malawi scaled up continuous isoniazid preventive treatment (IPT) for tuberculosis prevention among people living with HIV. In addition, an under-diversified diet based on subsistence maize, as is commonly the case in Malawi, is a risk factor for pellagra. We aimed to investigate whether large-scale isoniazid exposure in Malawi contributed to the cumulative risk for pellagra in a nutritionally vulnerable population. METHODS: We did a matched case-control study to evaluate the association between daily, continuous isoniazid exposure and pellagra. We matched sequentially enrolled patients with pellagra each with four control participants by sex and age from referral dermatology centres in three IPT scale-up districts in Malawi (Lilongwe, Blantyre, and Zomba) to evaluate isoniazid as a risk for pellagra using multivariable conditional logistic regression. We established a community clinic referral system surrounding the dermatology clinic in each district to enhance case-finding and included all patients with pellagra, regardless of referral status. The primary outcome was dermatologist-diagnosed pellagra. We calculated the interval between isoniazid initiation and rash onset and assessed 30-day clinical outcomes after multi-B vitamin treatment containing 300 mg nicotinamide daily. FINDINGS: Between Feb 5 and Aug 9, 2019, we enrolled 197 patients with pellagra and 781 matched controls. Isoniazid exposure was associated with an increased risk of pellagra (adjusted odds ratio 42·6 [95% CI 13·3-136·6]). Significant covariates included HIV infection, referral status, food insecurity, underweight, excess alcohol consumption, and, among women, lactation. The median time from isoniazid initiation to rash onset was shorter during the season of food scarcity (5 months [IQR 3-7]) compared with the harvest season (9 months [8-11]; hazard ratio 7·2 [95% CI 3·2-16·2], log-rank p<0·0001). Those with isoniazid-associated pellagra who discontinued isoniazid and adhered to multi-B vitamin treatment showed 30-day clinical improvement. INTERPRETATION: Continuous IPT scale-up and the annual period of food scarcity both increased the risk of pellagra in Malawi. Use of shorter rifamycin-based regimens for tuberculosis prevention and food fortification in populations with undernutrition might reduce this risk. Niacin-containing multi-B vitamin co-administration with isoniazid as pellagra prevention is worth exploring further. FUNDING: This study was supported by the President's Emergency Plan for AIDS Relief through the US Centers for Disease Control and Prevention under project 7173.

Uninterrupted HIV treatment for women: Policies and practices for care transitions during pregnancy and breastfeeding in Côte d'Ivoire, Lesotho and Malawi.

Transitions between services for continued antiretroviral treatment (ART) during and after pregnancy are a commonly overlooked aspect of the HIV care cascade, but ineffective transitions can lead to poor health outcomes for women and their children. In this qualitative study, we conducted interviews with 15 key stakeholders from Ministries of Health along with PEPFAR-supported and other in-country non-governmental organizations actively engaged in national programming for adult HIV care and prevention of mother-to-child-transmission of HIV (PMTCT) services in Côte d'Ivoire, Lesotho and Malawi. We aimed to understand perspectives regarding transitions into and out of PMTCT services for continued ART. Thematic analysis revealed that, although transitions of care are necessary and a potential point of loss from ART care in all three countries, there is a lack of clear guidance on transition approach and no formal way of monitoring transition between services. Several opportunities were identified to monitor and strengthen transitions of care for continued ART along the PMTCT cascade.

Sexually transmitted infections (STI) and antenatal care (ANC) clinics in Malawi: effective platforms for improving engagement of men at high HIV risk with voluntary medical male circumcision services.

INTRODUCTION: Voluntary medical male circumcision (VMMC), an effective HIV prevention programme for men, is implemented in East and Southern Africa. Approximately 50% of VMMC clients are aged below 15 years. More targeted interventions to reach older men and others at higher short-term HIV risk are needed. METHODS: We implemented a quality improvement project testing the effectiveness of an active referral-based VMMC recruitment approach, targeting men attending STI clinics and those escorting partners to antenatal care (ANC) clinics, at Bwaila Hospital in Lilongwe, Malawi. We compared the proportions aged older than 15 years among men who received VMMC following referral from STI and ANC clinics with those among men referred from standard community mobilisation. We also analysed referral cascades to VMMC. RESULTS: In total, 330 clients were circumcised after referral from STI (242) and ANC (88) clinics, as compared with 3839 other clients attributed to standard community mobilisation. All clients from ANC and STI clinics were aged over 15 years, as compared with 69% from standard community mobilisation. STI clinics had a higher conversion rate from counselling to VMMC than ANC (12% vs 9%) and a higher contribution to total circumcisions performed at the VMMC clinic (6% vs 2%). CONCLUSIONS: Integrating VMMC recruitment and follow-up in STI and ANC clinics co-located with VMMC services can augment demand creation and targeting of men at risk of HIV, based on age and STI history. This approach can be replicated at least in similar health facilities with ANC and STI services in close proximity to VMMC service delivery.

Protocol for a Case-Control Study to Investigate the Association of Pellagra With Isoniazid Exposure During Tuberculosis Preventive Treatment Scale-Up in Malawi.

Background: Pellagra is caused by niacin (vitamin B3) deficiency and manifested by a distinctive dermatitis. Isoniazid is critical for treating tuberculosis globally and is a component of most regimens to prevent tuberculosis. Isoniazid may contribute to pellagra by disrupting intracellular niacin synthesis. In 2017, Malawian clinicians recognized a high incidence of pellagra-like rashes after scale-up of isoniazid preventive treatment (IPT) to people living with HIV (PLHIV). This increase in pellagra incidence among PLHIV coincided with a seasonal period of sustained food insecurity in the region, which obscured epidemiological interpretations. Although isoniazid has been implicated as a secondary cause of pellagra for decades, no hypothesis-driven epidemiological study has assessed this relationship in a population exposed to isoniazid. We developed this case-control protocol to assess the association between large-scale isoniazid distribution and pellagra in Malawi. Methods: We measure the relative odds of having pellagra among isoniazid-exposed people compared to those without exposure while controlling for other pellagra risk factors. Secondary aims include measuring time from isoniazid initiation to onset of dermatitis, comparing niacin metabolites 1-methylnicotinamide (1-MN), and l-methyl-2-pyridone-5-carboxamide (2-PYR) in urine as a proxy for total body niacin status among subpopulations, and describing clinical outcomes after 30-days multi-B vitamin (containing 300 mg nicotinamide daily) therapy and isoniazid cessation (if exposed). We aim to enroll 197 participants with pellagra and 788 age- and sex-matched controls (1:4 ratio) presenting at three dermatology clinics. Four randomly selected community clinics within 3-25 km of designated dermatology clinics will refer persons with pellagra-like symptoms to one of the study enrollment sites for diagnosis. Trained study dermatologists will conduct a detailed exposure questionnaire and perform anthropometric measurements. A subset of enrollees will provide a casual urine specimen for niacin metabolites quantification and/or point-of-care isoniazid detection to confirm whether participants recently ingested isoniazid. We will use conditional logistic regression, matching age and sex, to estimate odds ratios for the primary study aim. Discussion: The results of this study will inform the programmatic scale-up of isoniazid-containing regimens to prevent tuberculosis.

HIV-positive pregnant and postpartum women's perspectives about Option B+ in Malawi: a qualitative study.

INTRODUCTION: The implementation of lifelong antiretroviral treatment (ART) for all pregnant women (Option B+) in Malawi has resulted in a significant increase in the number of HIV-positive pregnant women initiating treatment. However, research has highlighted the challenge of retaining newly initiated women in care. This study explores barriers and facilitators that affect a woman's decision to initiate and to adhere to Option B+. METHODS: A total of 39 in-depth interviews and 16 focus group discussions were conducted. Eligible women were ≥18 years old, living with HIV and either pregnant and receiving antenatal care from a study site or had delivered a child within the last 18 months, breastfed their child and received services at one of the study sites. Eligible women were identified by healthcare workers (HCWs) in the antenatal clinic and ART unit. Focus groups were also conducted with HCWs employed in these departments. Qualitative data were analyzed using Maxqda version 10 (VERBI Software, Berlin, Germany). RESULTS: The general perception towards the drug regimen used in Option B+ was positive; women reported fewer side effects and acknowledged the positive benefits of ART. Women felt hopeful about prolonging their life and having an HIV-uninfected baby, yet grappled with the fact that ART is a lifelong commitment. Women and HCWs discussed challenges with the counselling services for prevention of mother-to-child HIV transmission under the new Option B+ guidelines, and many women struggled with initiating ART on the same day as learning their HIV status. Women wanted to discuss their circumstances with their husbands first, receive a CD4 count and obtain an HIV test at another facility to confirm their HIV status. HCWs expressed concern that women might just agree to take the drugs to please them. HCWs also discussed concerns around loss to follow-up and drug resistance. CONCLUSIONS: Although Option B+ has significantly increased the number of women initiating ART, there are still challenges that need to be addressed to strengthen initiation, adherence and retention in care. Strategies to strengthen the counselling services upon diagnosis need to be developed to improve same-day initiation of ART and long-term adherence.

Barriers; Facilitators and Recommendations for the Early Infant Diagnosis and Treatment (EIDT) Cascade: A Qualitative Study in Malawi

Background. Identifying and testing all HIV-exposed infants (HEIs) by 2 months of age with rapid antiretroviral therapy (ART) initiation for those infected is critical to survival. Yet in 2009 only 29% of HEIs in need of ART received treatment in Malawi.Objectives. To understand barriers; facilitators and recommendations for five key steps in the early infant diagnosis and treatment (EIDT) cascade: (1) identification of HEIs; (2) infant testing; (3) sample processing and transport; (4) reporting results to mothers; (5) ART initiation for HEI.Methods. Semistructured interviews were conducted through convenience sampling with mothers of infants eligible for EIDT (n=47) and with healthcare workers (HCWs) providing EIDT (n=20) in five facilities; in April 2013. Results. (1) Reliance on the health passport to identify HEIs is both barrier; as women may not attend appointments with their passports; and facilitator; for documentation of HIV-exposure status. Use of trained health surveillance assistants in EIDT enhances cascade steps 1 and 2; but requires increased supervision. (2) Women struggle to accept their own HIV status; yet test results for an HEI is a motivator. Sensitisation through local leadership facilitates EIDT. (3) A reliable transport system is needed. (4) Maintaining appointments to report results to women motivates them. (5) Mothers were reluctant to give ART to young; apparently healthy infants. Conclusion. Both women and healthcare workers are motivated by test results for HEIs. The inclusion of community education can improve all steps in the EIDT cascade; including information that HEIs need ART