A study published in the journal Human Genetics used data from participants in the Regional Prospective Observational Research in Tuberculosis in Brazil consortium to analyze associations between genetic ancestry and the risk for moderate adverse reactions attributed to antituberculosis treatment.

The research included 930 adults with newly diagnosed, culture-confirmed pulmonary tuberculosis who were followed at five centers in three regions of the country: three in Rio de Janeiro, one in Salvador, and one in Manaus.

Genetic ancestry was analyzed using 46 ancestry‑informative markers, based on data from a large Brazilian cohort, and proportions of African, European, and Amerindian ancestry were inferred with the software ADMIXTURE.

Adverse reactions were graded for severity according to the Division of AIDS Table for Grading the Severity, and the likelihood that an event was drug-related was assessed with the Naranjo algorithm. The outcome analyzed was the occurrence of grade ≥ 2 adverse reactions attributed to tuberculosis treatment — ie, events assessed as “possibly,” “probably,” or “definitely” related to the medications.

Ancestry Predicts Reactions

The results show that a higher proportion of African ancestry was associated with a lower risk for grade ≥ 2 adverse reactions attributed to treatment, whereas a higher proportion of European ancestry was associated with a higher risk for those reactions. In standard epidemiologic terms, a 10% increase in African ancestry was associated with an odds ratio of 0.41 for this outcome (95% CI, 0.20-0.85; P = .02), and for every 10% increase in European ancestry, there was a 2.33 increase in the odds ratio (95% CI, 1.14-4.76; P = .02). There was no consistent association with Amerindian ancestry or with other outcomes evaluated, such as treatment-attributed hepatotoxicity, grade ≥ 3 adverse reactions, or treatment failure/recurrence.

In an interview with Medscape Medical News, Bruno de Bezerril Andrade, Laboratory of Clinical and Translational Research, Gonçalo Moniz Institute, Oswaldo Cruz Foundation, Salvador, Brazil, and one of the study authors, noted that grade ≥ 2 adverse reactions attributed to treatment occurred in a minority of the patients studied. “Even so, these reactions have a clinically relevant impact because they can lead to interruptions, drug changes, and poorer adherence, and increase the risk of unfavorable outcomes,” he stressed.

HIV Interaction Analysis

The researchers also evaluated interaction with HIV, since coinfection with tuberculosis and HIV increases the risk for adverse events because of combined regimens and comorbidities. In interaction analyses, there was statistical evidence of effect modification, and when stratified by HIV status, the association with African ancestry appeared mainly among people without HIV; among people living with HIV, the association was not statistically significant — possibly because of smaller sample size and the complexity of concomitant treatment.

Ancestry and Metabolism

The present study grew out of an initial line of research that investigated how Brazilians metabolize antituberculosis drugs. Valeria Rolla, head of the Clinical Research Laboratory on Mycobacterioses at the Evandro Chagas National Institute of Infectious Diseases, Fiocruz, Brazil, and an author of the study, said that in addition to analyzing the risk for adverse reactions the group also investigated whether genetic ancestry influences how the drugs are metabolized.

In an interview with Medscape Medical News, Rolla, explained that metabolism can affect treatment outcome: “In theory, a person who metabolizes a drug very quickly, clears it from the blood and, therefore, the drug does not have an effect, so treatment failures tend to occur. Conversely, a slow metabolizer tends to accumulate the drug in the blood, which can generate side effects.”

To investigate the issue, the group also genotyped N‑acetyltransferase 2, a gene important in the metabolism of some drugs. However, they did not identify a correlation between genetic ancestry and this marker, unlike the finding for risk for adverse reactions.

Implications for Practice

The standard regimen for tuberculosis treatment involves rifampin, isoniazid, pyrazinamide, and ethambutol in phased schedules. Adverse reactions can range from mild, manageable symptoms such as gastrointestinal complaints and itching to less frequent events that require immediate evaluation, such as drug‑related hepatotoxicity or visual changes associated with ethambutol.

For Andrade, the main value of the findings is that they open the way to risk stratification and smarter monitoring strategies — combining genetics, clinical data, and behavioral factors — with the potential to reduce interruptions and loss of adherence to treatment. But he emphasized that the study does not recommend changing the treatment regimen based on ancestry, and the results should not be used as a social marker. This is a population‑level association that needs to be validated in other cohorts and investigated mechanistically, with rigor to avoid stigma.

For Rolla, the findings reinforce the need for clinicians to be more alert to possible adverse reactions during tuberculosis treatment, especially in the first 15 days of therapy. She said this period is important because of rifampin’s pharmacokinetics: It reaches high concentrations in the first days and then stabilizes.

This story was translated from Medscape’s Portuguese edition.