Preventing pellagra during isoniazid preventive treatment
Authors: Nathan Kapata, Alimuddin Zumla
Journal: The Lancet Global Health (2022)

An estimated 1·7 billion people globally are latently infected with Mycobacterium tuberculosis.1WHOGlobal tuberculosis report 2021.https://www.who.int/publications/i/item/9789240037021Date: October 14, 2021Date accessed: March 19, 2022Google Scholar Latent M tuberculosis infection is defined by WHO as a state of persistent immune response to M tuberculosis antigens with no clinical evidence of active disease. During their lifetime, up to 10% of people with latent M tuberculosis infection are at risk of progressing to active tuberculosis disease.1WHOGlobal tuberculosis report 2021.https://www.who.int/publications/i/item/9789240037021Date: October 14, 2021Date accessed: March 19, 2022Google Scholar In 2018, the UN General Assembly End TB targets included the specific goal to give tuberculosis preventive treatment for all people with latent M tuberculosis infection.2UN General AssemblyResolution A/RES/73/3: political declaration of the high-level meeting of the General Assembly on the fight against tuberculosis.https://www.un.org/en/ga/search/view_doc.asp?symbol=A/RES/73/3Date: Oct 18, 2018Date accessed: March 17, 2022Google Scholar Proactively screening for and treating this huge reservoir needs to be addressed if the UN End TB targets are to be achieved by 2050. Several treatment regimens to eradicate latent M tuberculosis infection are recommended by WHO, which reduce the risk of reactivating the disease by at least 60%.3WHOWHO consolidated guidelines on tuberculosis: module 1; prevention: tuberculosis preventive treatment.https://www.who.int/publications/i/item/9789240001503Date: March 24, 2020Date accessed: March 15, 2022Google Scholar Giving daily isoniazid preventive treatment (IPT) to immunocompromised people; pregnant or lactating women; and people living with HIV, malnutrition, diabetes, chronic liver disease, or renal failure with latent M tuberculosis infection can prevent progression to active tuberculosis disease and save lives. In countries with a high burden of tuberculosis and HIV, the tuberculosis drug isoniazid is part of the management of people living with HIV taking highly active antiretroviral therapy (HAART).3WHOWHO consolidated guidelines on tuberculosis: module 1; prevention: tuberculosis preventive treatment.https://www.who.int/publications/i/item/9789240001503Date: March 24, 2020Date accessed: March 15, 2022Google Scholar Since the discovery of isoniazid 70 years ago, peripheral neuropathy is a well-documented side-effect that can be prevented by co-administration of vitamin B6 (pyridoxine). However, intermittent clinical reports of an association of isoniazid use with non-vitamin-B6-related severe dermatitis, changes in cognitive, affective, and behavioural states, dementia, and psychosis due life-threatening pellagra, have not attracted global attention.4Zabad M Psychosis with isoniazid therapy.Lancet. 1953; 261: 295Abstract Scopus (2) Google Scholar, 5Kipsang JK Choge JK Marinda PA Khayeka-Wandabwa C Pellagra in isoniazid preventive and antiretroviral therapy.IDCases. 2019; 17e00550Crossref PubMed Scopus (13) Google Scholar, 6Prabhu D Dawe RS Mponda K Pellagra: a review exploring causes and mechanisms, including isoniazid-induced pellagra.Photodermatol Photoimmunol Photomed. 2021; 37: 99-104Crossref PubMed Scopus (8) Google Scholar, 7Coates SJ Blasini AW Musinguzi P LakerOketta M Drug-related pellagra in a Ugandan woman on isoniazid preventative therapy.IDCases. 2020; 20e00750Crossref PubMed Scopus (5) Google Scholar, 8Kabengele C M'hango H Mweemba D Malumani M A peculiarly characterised case of isoniazid-induced pellagra—2 Ds and a C: a case report.Pan Afr Med J. 2021; 39: 73Crossref PubMed Scopus (2) Google Scholar Thus, the diagnosis of pellagra is often overlooked clinically, especially in people living with HIV taking HAART. Ever since WHO recommended fortification of food with vitamin supplements, only sporadic cases of pellagra have been reported,6Prabhu D Dawe RS Mponda K Pellagra: a review exploring causes and mechanisms, including isoniazid-induced pellagra.Photodermatol Photoimmunol Photomed. 2021; 37: 99-104Crossref PubMed Scopus (8) Google Scholar, 7Coates SJ Blasini AW Musinguzi P LakerOketta M Drug-related pellagra in a Ugandan woman on isoniazid preventative therapy.IDCases. 2020; 20e00750Crossref PubMed Scopus (5) Google Scholar, 8Kabengele C M'hango H Mweemba D Malumani M A peculiarly characterised case of isoniazid-induced pellagra—2 Ds and a C: a case report.Pan Afr Med J. 2021; 39: 73Crossref PubMed Scopus (2) Google Scholar which are associated with tuberculosis therapy in people living with HIV or malabsorption disorders, and in populations in sub-Saharan Africa that rely on unfortified maize as their primary food source. Over the past few years, clinical observations in Malawi showed an increasing number of pellagra cases in people living with HIV taking IPT. However, there have been no specific data from clinical trials or epidemiological risk analyses of the association between isoniazid use and pellagra in people living with HIV. To fill this important gap, Scott Nabity and colleagues,9Nabity SA Mponda K Gutreuter S et al.Isoniazid-associated pellagra during mass scale-up of tuberculosis preventive therapy: a case-control study.Lancet Glob Health. 2022; 10: e705-e714Summary Full Text Full Text PDF PubMed Scopus (1) Google Scholar in this issue of The Lancet Global Health, fill this knowledge gap and publish findings from the first ever, large, controlled, epidemiological risk analysis between isoniazid use and dermatologist-confirmed pellagra. Their data show that isoniazid given to people living with HIV in an HIV-endemic setting does have an independent association with the development of pellagra. Importantly, their data show that stopping isoniazid, and adding treatment with multi-B vitamins for 30 days, resolved the rash and other symptoms of pellagra. Given additional stressors of concomitant food shortages, undernutrition, and lactation, pellagra might manifest within a few weeks of isoniazid therapy and the diagnosis can easily be overlooked or delayed. Nabity and colleagues suggest that targeted food supplementation and fortification efforts for people living with HIV starting isoniazid-containing regimens, particularly for those facing food insecurity and lactating women, might be effective in pellagra prevention. Although these findings are important, there are several limitations to the study; key questions remain and need answering before the findings can be included in WHO IPT management guidelines. First, controlling for many covariates might cause imprecise risk estimates. Nearly all of the people living with HIV enrolled in the study were on isoniazid prophylaxis (159 [81%] of 197). As such, further studies across different geographical regions, using adequate numbers of people living with HIV who are not on isoniazid prophylaxis as a comparator group, might provide definitive data for the true independent contribution of HIV. Second, the study was restricted to Malawi only, where other risk factors for pellagra are present. Thus, their findings might not be applicable to other geographical regions. Third, the resulting co-linearity and interpretation of the independent epidemiological association between HIV status and pellagra is not defined accurately. Fourth, B complex vitamins were used instead of niacin to treat pellagra due to the high cost, and pyridoxine dose was empirically increased to 50 mg twice a day for 12 weeks. This strategy, together with the cost-effectiveness of coadministration of B complex vitamins with isoniazid compared with individual vitamin B6 and vitamin B3, needs to be evaluated further. Fifth, community engagement, education, and counselling, especially for the stigma of pellagra rash, should be part of future studies. It is now an opportune time to re-evaluate single-drug isoniazid therapy for latent M tuberculosis infection and focus discussions on non-isoniazid containing regimens for people living with HIV. Using short-course rifamycin-based regimens for latent M tuberculosis infection might help avoid some of the unintended side-effects of isoniazid treatment, including pellagra. Furthermore, the issue of isoniazid prophylaxis for latent M tuberculosis infection in people living with HIV comes at an crucial time in Europe, where the current armed conflict in Ukraine has generated more than 6 million refugees and displaced populations who are particularly susceptible to developing active tuberculosis and will require careful management of latent M tuberculosis infection and all other clinical forms of tuberculosis.10Proença R Mattos Souza F Lisboa Bastos M et al.Active and latent tuberculosis in refugees and asylum seekers: a systematic review and meta-analysis.BMC Public Health. 2020; 20: 838Crossref PubMed Scopus (11) Google Scholar, 11Castro KG Ditiu L Sahu S et al.Optimizing tuberculosis care for refugees affected by armed conflicts.Lancet Respir Med. 2022; (published online March 23.)https://doi.org/10.1016/S2213-2600(22)00104-7Summary Full Text Full Text PDF Scopus (1) Google Scholar Ukraine has the highest rates of tuberculosis and HIV co-infection, multidrug-resistant tuberculosis, and latent drug-resistant M tuberculosis infection in Europe.1WHOGlobal tuberculosis report 2021.https://www.who.int/publications/i/item/9789240037021Date: October 14, 2021Date accessed: March 19, 2022Google Scholar While we await further evidence for updating the WHO guidelines on preventing pellagra in people living with HIV on IPT, given the nutritional and other risk factors refugees face for re-activating the M tuberculosis infection, and for developing pellagra and other nutritional deficiency states, proactive screening in all refugees for all forms of tuberculosis and supplementing their diets empirically with B complex vitamins would be prudent and important. NK and AZ acknowledge support from the Pan-African Network for Rapid Research, Response, Relief and Preparedness for infectious diseases epidemics (PANDORA-ID-NET; funded by the EU European & Developing Countries Clinical Trials Partnership), the Central African Network on Tuberculosis, HIV/AIDS and Malaria (CANTAM-3), and the East African Consortium for Clinical Research (EACCR3) programmes. AZ is in receipt of a UK National Institutes for Health Research Senior Investigator award and is a Mahathir Foundation Science Award and Pascoal Mocumbi Prize laureate. The views expressed in this Comment are entirely those of the authors and do not reflect the views of their respective institutions. We declare no competing interests. Isoniazid-associated pellagra during mass scale-up of tuberculosis preventive therapy: a case-control studyContinuous 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. Full-Text PDF Open Access