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.

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.

Scaling Up Testing for Human Immunodeficiency Virus Infection Among Contacts of Index Patients - 20 Countries, 2016-2018.

In 2017, the Joint United Nations Programme on HIV/AIDS (UNAIDS) estimated that worldwide, 36.9 million persons were living with human immunodeficiency virus (HIV) infection, the virus infection that causes acquired immunodeficiency syndrome (AIDS). Among persons with HIV infection, approximately 75% were aware of their HIV status, leaving 9.4 million persons with undiagnosed infection (1). Index testing, also known as partner notification or contact tracing, is an effective case-finding strategy that targets the exposed contacts of HIV-positive persons for HIV testing services. This report summarizes data from HIV tests using index testing in 20 countries supported by CDC through the U.S. President's Emergency Plan for AIDS Relief (PEPFAR) during October 1, 2016-March 31, 2018. During this 18-month period, 1,700,998 HIV tests with 99,201 (5.8%) positive results were reported using index testing. The positivity rate for index testing was 9.8% among persons aged ≥15 years and 1.5% among persons aged <15 years. During the reporting period, HIV positivity increased 64% among persons aged ≥15 years (from 7.6% to 12.5%) and 67% among persons aged <15 years (from 1.2% to 2.0%). Expanding index testing services could help increase the number of persons with HIV infection who know their status, are initiated onto antiretroviral treatment, and consequently reduce the number of persons who can transmit the virus.

Correction: Pregnancy intention and contraceptive use among HIV-positive Malawian women at 4-26 weeks post-partum: A nested cross-sectional study.

[This corrects the article DOI: 10.1371/journal.pone.0215947.].

Pregnancy intention and contraceptive use among HIV-positive Malawian women at 4-26 weeks post-partum: A nested cross-sectional study.

BACKGROUND: Avoiding unintended pregnancies through family planning is a WHO strategy for preventing mother to child transmission of HIV (PMTCT) and maternal morbidity/mortality. We investigated factors associated with unintended index pregnancy, unmet contraceptive need, future pregnancy intention and current contraceptive use among Malawian women living with HIV in the Option B+ era. METHODS: Women who tested HIV positive at 4-26 weeks postpartum were enrolled into a cross-sectional study at high-volume Under-5 clinics. Structured baseline interviews included questions on socio-demographics, HIV knowledge, partner's HIV status/disclosure, ART use, pregnancy intention and contraceptive use. Logistic regression was used to determine factors associated with outcomes. RESULTS: We enrolled 578 HIV-positive women between May 2015-May 2016; median maternal age was 28 years (y) (interquartile-range [IQR]: 23-32), median parity was 3 deliveries (IQR: 2-4) and median infant age was 7 weeks (IQR: 6-12). Overall, 41.8% women reported unintended index pregnancy, of whom 35.0% reported unmet contraceptive need and 65.0% contraceptive failure. In multivariable analysis, unintended index pregnancy was higher in ≥35y vs. 14-24y (adjusted Odds Ratio [aOR]: 2.1, 95% Confidence Interval [95%CI]: 1.0-4.2) and in women with parity ≥3 vs. primiparous (aOR: 2.9, 95%CI: 1.5-5.6). Unmet contraceptive need at conception was higher in 14-24y vs. ≥35y (aOR: 4.2, 95%CI: 1.8-9.9), primiparous vs. ≥3 (aOR: 8.3, 95%CI: 1.8-39.5), and women with a partner of unknown HIV-status (aOR: 2.2, 95%CI: 1.2-4.0). Current contraceptive use was associated with being on ART in previous pregnancy (aOR: 2.5, 95%CI: 1.5-3.9). CONCLUSIONS: High prevalence of unintended index pregnancy and unmet contraceptive need among HIV-positive women highlight the need for improved access to contraceptives. To help achieve reproductive goals and elimination of MTCT of HIV, integration of family planning into HIV care should be strengthened to ensure women have timely access to a wide range of family planning methods with low failure risk.

Pediatric HIV Treatment Gaps in 7 East and Southern African Countries: Examination of Modeled, Survey, and Routine Program Data.

BACKGROUND: Remarkable success in the prevention and treatment of pediatric HIV infection has been achieved in the past decade. Large differences remain between the estimated number of children living with HIV (CLHIV) and those identified through national HIV programs. We evaluated the number of CLHIV and those on treatment in Lesotho, Malawi, Swaziland, Tanzania, Uganda, Zambia, and Zimbabwe. METHODS: We assessed the total number of CLHIV, CLHIV on antiretroviral treatment (ART), and national and regional ART coverage gaps using 3 data sources: (1) Joint United Nations Programme on HIV/AIDS model-based estimates and national program data used as input values in the models, (2) population-based HIV impact surveys (PHIA), and (3) program data from the President's Emergency Plan for AIDS Relief (PEPFAR)-supported clinics. RESULTS: Across the 7 countries, HIV prevalence among children aged 0-14 years ranged from 0.4% (Uncertainty Bounds (UB) 0.2%-0.6%) to 2.8% (UB: 2.2%-3.4%) according to the PHIA surveys, resulting in estimates of 520,000 (UB: 460,000-580,000) CLHIV in 2016-2017 in the 7 countries. This compared with Spectrum estimates of pediatric HIV prevalence ranging from 0.5% (UB: 0.5%-0.6%) to 3.5% (UB: 3.0%-4.0%) representing 480,000 (UB: 390,000-550,000) CLHIV. CLHIV not on treatment according to the PEPFAR, PHIA, and Spectrum for the countries stood at 48% (UB: 25%-60%), 49% (UB: 37%-50%), and 38% (UB: 24%-47%), respectively. Of 78 regions examined across 7 countries, 33% of regions (PHIA data) or 41% of regions (PEPFAR data) had met the ART coverage target of 81%. CONCLUSIONS: There are substantial gaps in the coverage of HIV treatment in CLHIV in the 7 countries studied according to all sources. There is continued need to identify, engage, and treat infants and children. Important inconsistencies in estimates across the 3 sources warrant in-depth investigation.

Sexually transmitted infections associated with alcohol use and HIV infection among men who have sex with men in Kampala, Uganda.

OBJECTIVES: Few studies have been conducted in Africa to assess prevalence of sexually transmitted infections (STIs) and risk factors among men who have sex with men (MSM). We report findings from the first behavioural survey to include STI testing among MSM in Kampala, Uganda. METHODS: Respondent-driven sampling (RDS) was used to recruit MSM for a biobehavioural survey. Eligible participants were men who reported anal sex with another man in the previous 3 months, were 18 years or older, and resided in Kampala. Information was collected on demographics, sexual behaviour, alcohol and drug use, and STI symptoms. Blood, urine and rectal specimens were tested for syphilis, HIV, rectal and urethral gonorrhoea, and chlamydia. Analyses weighted for RDS were conducted to assess associations with STI diagnosis. RESULTS: A total of 295 MSM participated in the survey. Almost half (weighted percentage: 47.3%) reported STI symptoms in the last 6 months and 12.9% tested HIV-positive. Prevalence of non-HIV STI was 13.5%; syphilis prevalence was 9.0%. Adjusting for age and education, STI was associated with HIV (adjusted OR (AOR)=3.46, 95% CI 1.03 to 11.64), alcohol use before sex (AOR=4.99, 95% CI 1.86 to 13.38) and having sold sex in the last 3 months (AOR=3.17, 95% CI 1.25 to 8.07), and inversely associated with having anonymous sex partners (AOR=0.20, 95% CI 0.07 to 0.61). CONCLUSIONS: We observed high levels of self-reported STI symptoms and STI prevalence associated with alcohol use and HIV among MSM in Kampala. Public health interventions supporting MSM are needed to address STI risk and facilitate access to diagnosis and treatment services.

Correlates of bisexual behaviors among men who have sex with men in El Salvador.

Bisexual behaviors may increase transmission pathways of HIV and sexually transmitted infections (STIs) from a higher prevalence group to lower prevalence groups in El Salvador. In 2008, men who have sex with men (MSM) were recruited in San Salvador and San Miguel using respondent driven sampling. Participants were interviewed and tested for HIV and STIs. Sixteen seeds and 797 MSM participated; 34.9% in San Salvador and 58.8% in San Miguel reported bisexual behavior. Bisexual behavior was associated with drug use (adjusted odds ratio (AOR) = 2.57, 95% CI: 1.30-5.06) and insertive anal sex (AOR = 5.45, 95% CI: 3.01-9.87), and inversely associated with having a stable male partner (AOR = 0.47, 95% CI: 0.26-0.84) and disclosing MSM behavior to family (AOR = 0.41, 95% CI: 0.22-0.75). Bisexual behavior was associated with risk behaviors with male and female partners that may be associated with HIV and STI transmission. Bisexual men displayed a distinct identity calling for tailored interventions.