Efavirenz is an antiretroviral medication commonly used to treat the human immunodeficiency virus (HIV), and has helped save millions of lives in sub-Saharan Africa. But it has also caused serious psychiatric disorders in patients, including depression, paranoia, suicidal thoughts and more. While these complications are occasionally seen in AIDS patients of European and Asian origin, we now know that Black Africans are genetically more susceptible to these adverse effects.
The reason for this higher susceptibility is found in an African variant in the CYP2B6 enzyme related to metabolism of efavirenz (EFV) that occurs in half of the sub-Saharan population. Its presence leads to slow absorption and elimination of the antiretroviral, which increases toxicity and triggers potentially harmful psychiatric effects.
One way of avoiding this risk is to reduce the dose — less of the active ingredient is administered when there is a high probability of impaired metabolism of EFV. Another option is to use theoretically safer antiretrovirals such as dolutegravir. This is what Botswana, South Africa and some other countries did in 2019, following a World Health Organization (WHO) recommendation.
Nicola Mulder, a professor of computational biology at the University of Cape Town (South Africa), cites EFV as an example of how much ethnic factors matter when administering medications. “Genetic differences between populations can have a tremendous impact on treatments, sometimes posing significant health problems,” she said. “What works for Europeans doesn’t necessarily work for Africans,” said Ann Daly, a professor of pharmacogenetics at the University of Newcastle, in the U.K.
Pharmacogenetics, a term coined in 1959 by Friedrich Vogel, can be defined in several ways, but it all boils down to humans responding differently to the same drug. This is because of immutable traits, genetic hallmarks embedded in our DNA that are with us for life.
Millions of drugs come into Africa and we have no idea what might happen. We may face serious public health problems in the futurePedro Gil, Karolinska Institute, Stockholm
“Millions of drugs come into Africa and we have no idea what might happen. We may face serious public health problems in the future,” said Pedro Gil, a researcher at the Karolinska Institute in Stockholm (Sweden). While Western countries get plenty of information about drug effects based on extensive trials, this is not so in Africa. This happened with EFV, which was later found to have a high incidence of adverse mental health effects in sub-Saharan Africa.
Gil says the same has happened with some malaria programs that administer amodiaquine, a prophylactic drug widely used against seasonal malaria in the Sahel. It was found to cause severe stomach upset in 30% of children in countries like Mali. The root of that problem was once again genetic. Because of the stomachaches, “many mothers to stop giving the pill to their children,” said Gil, causing a loss in confidence in this drug and maybe future drugs as well.
Pharmacogenetics enables precision medicine — personalized treatments adapted to a patient’s individual characteristics. This approach helps physicians choose medications and modulate dosages with microscopic precision and almost no error margin.
When pharmacogenetics is approached from a broader ethnic or population perspective, it only aims to establish averages. It can provide valuable information on a patient’s probable response to a drug based on ethnicity, but is not as precise as rigorously personalized medicine. Its advocates argue that this approach enables mass drug distribution to be fine-tuned to a specific population since it’s not feasible to do genetic tests on every patient.
Patients with sub-Saharan origins are doubly neglected. They participate minimally in the clinical trials of new drugs and also in the test groups of the pharmacogenetic research that has proliferated in recent decades. In 2020, a meta-analysis (an analysis of multiple studies) dove into hundreds of published studies on potential genetic correlations in 300 drugs. People of African origin were only included in 15 of the drug studies and almost half of these were American descendants of slaves.
The lack of reliable information leads sub-Saharan Africans to take medicines based on blind faith. They must trust that the response expected in Caucasian (and, to a lesser extent, Asian) populations will also apply to them. Ultimately, they are forced to rely on recommendations from Western laboratories and research centers.
Frances Adiukwu, a psychiatrist and researcher at the University of Port Harcourt in Nigeria, told us the problem forced her into a trial-and-error process with patients. She says people in her country with serious pathologies like schizophrenia and bipolar disorder are very reluctant to see a psychiatrist. “They usually go first to a shaman or pastor. When they finally come here and see us continually changing medications and dosages, they lose faith in the system,” she said. The disease then gets worse and the patient’s condition deteriorates. “About 60% of people in northern Nigeria have fast metabolisms,” said Adiukwu. “Perhaps the logical thing would be to start treatments with high doses.”
In Europe, there is little genetic diversity and a lot of money. In Africa, there is little money and a lot of diversityInnocent Assimwe, University of Liverpool (U.K.)
Last year, Adiukwu scoured the scientific literature on pharmacogenetics in psychiatry. Her search yielded 2,550 results between 2020 and 2022. Fewer than 40 studies mentioned African populations. This irked her enough to contact the top experts in the field to see what could be done about the dearth of research. Getting no response, she wrote an article for The Lancet, the world’s highest-impact medical journal. “I felt I had to do something, to do my bit,” she said.
Another facet of drug safety and efficacy in sub-Saharan Africa is the region’s immense genetic diversity. “Gabon alone has more diversity than the entire European Union. While people from Portugal and Finland may look very different, they are almost clones from a pharmacogenetic perspective,” said Gil.
Innocent Assimwe, a Ugandan researcher at the University of Liverpool Center for Personalized Medicine (U.K.), neatly sums up the problem: “In Europe, there is little genetic diversity and a lot of money. In Africa, there is little money and a lot of diversity.” The conclusion seems obvious — there is very little research on ethnic differences in drug response where it’s most needed. Assimwe says this profound asymmetry in the pharmaceutical industry reflects colonialist thinking. “If a drug is safe for whites, it’s safe for Blacks.”
Assimwe extensively analyzed the ethnic factor in studies on warfarin, the world’s most widely used anticoagulant, and found a clear pattern of Caucasian bias. The evidence from the existing research on warfarin is useful for patients of European origin and, to some extent, patients from parts of Asia. But they are of little use to those with African ancestry or the indigenous peoples of Latin America.
PCR equipment can also be used for genetic testing, which is a very useful pandemic byproduct for genotyping the sub-Saharan ethnic melting pot
Pedro Gil has found a ray of light in all this darkness: genotyping the sub-Saharan ethnic melting pot with a focus on the variants that most influence drug metabolism. This ambitious undertaking is no longer an impossible dream because of Covid-19. “The technology transfer of the last few years is an incredible opportunity,” he said. In a twist of fate, the equipment for polymerase chain reaction (PCR) testing can also be used for genetic testing, a fortuitous outcome of the pandemic.
Still, PCR testing machines have limitations, says Assimwe. “They can genotype according to certain variants, but can’t discover new ones that may be important for understanding how Black populations respond to drugs like warfarin.” The technology needed to dive into the labyrinths of the human genome (with its complex puzzles of polymorphisms, alleles and other technicalities) is much more expensive, says Assimwe.
The H3Africa project was launched in 2010 to focus on genotyping the African continent’s populations while searching for new variants. Funded by donors from the U.S. and U.K., the project established a collaborative research network with the shared mission of narrowing the gap between Africa and the global genetic-health revolution. So far, it has genotyped 50,000 Africans from 30 countries, a modest number considering the continent’s overwhelming DNA heterogeneity.
The H3Africa project will shut down shortly when its funding dries up. Professor Nicola Mulder, who has been coordinating the project’s bioinformatics work, is confident that the collaborative research will carry on somehow. “We are considering various options, including becoming an NGO.”
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