CAPE TOWN – A new antiretroviral drug was supposed to be a game-changer for South Africa, which has one of the largest HIV-positive populations in the world. The drug, dolutegravir, was cheap, had few side effects, and – most importantly – it suppressed the virus quickly.

But after a few months on the treatment, many African women began experiencing significant weight gain. A clinical study published in The Lancet in October this year showed that one in five were clinically obese after 96 weeks of treatment, running the risk of cardiovascular problems and diabetes.

These unexpected side effects were in patients that had been excluded from the initial clinical trials, as historically, medicines have been optimised for people in the Global North.

To address this bias and improve the treatment outcomes for millions of African people, Professor Kelly Chibale, founder and director of the Holistic Drug Discovery and Development (H3D) Centre at the University of Cape Town (UCT) in South Africa, is turning his attention to how African populations metabolize drugs.

Dosing regimens are optimised for Caucasians

One of the things Chibale is doing is ‘collecting’ livers. Specifically, he is assessing the livers of African patients for the African Liver Project, which is investigating the African microbiome – the microorganisms in various parts of the body or the combined genetic material of all the microbes, including bacteria and viruses, that live inside people on his continent.

“Africans account for 15% of the world’s population, and 25% of the global disease burden,” he says. “But they are involved in less than 2% of clinical trials that happen here.”

Dosing regimens – meaning the dosage and the frequency a medicine is taken – are optimized for the populations involved in the trial: typically caucasians.

This is a trend that exists across nearly all medical sciences, from treatment design to vaccine development. Although the COVID-19 crisis that has gripped the whole world has highlighted the need for diversity in clinical trial research, the conversation goes beyond COVID-19 and it is only just beginning. And even as awareness grows, three-quarters of COVID-19 treatment trials still exclude pregnant women.

“African patient responses to the medicines are varied and accompanied by suboptimal treatment outcomes in some instances,” adds Chibale, who is also the Neville Isdell Chair in African-centric Drug Discovery and Development and a professor of organic chemistry at UCT.

One of the reasons for such variable responses is down to genetic polymorphism: genetic differences in the activity of enzymes that metabolize drugs in the liver.

For example, for one of the five drug-metabolizing enzymes there is a variation between Africans and Caucasians in its gene coding. The liver is the major organ where metabolism occurs, and five drug-metabolizing enzymes in the liver are responsible for metabolizing 90% of all medicines.

People are either slow, normal or fast metabolizers. Slow metabolizers have too much of the drug in their system which leads to adverse effects, and likely poor patient adherence.

Ultra-fast metabolizers have suboptimal levels of the drug in their system, which leads to poor efficacy and disease-related morbidity.

In a number of cases where African patients have experienced unexpected side effects, the participants in the drug trials had normal or fast metabolisms, whereas the Africans were slower metabolizers. They experienced more drug toxicity because they were unable to process the drug fast enough.

Look at the drug efavirenz, a first-line treatment for HIV/AIDS, for example. Its main route of metabolism involves the cytochrome P450 2B6 (CYP2B6) enzyme. Mutations of this enzyme may lead to reduced metabolism leading to higher efavirenz exposures. These CYP2B6 mutations are more common in patients with African heritage.

“One way to address these variations is to have more clinical trials in Africa. Our people have to understand that taking part in clinical trials will help them,” Chibale rationalises. “It is a necessary sacrifice to be part of the solution. The safety of the medicines we take has been established because someone else sacrificed and took part in a clinical trial.”

Creating a liver ‘bank’

Chibale’s solution is to do more pre-clinical work even before getting to the clinical trials.

“In the past, 40% of the failures in clinical trials were due to suboptimal drug metabolism and pharmacokinetics, which is basically what the body does to the medicine,” he says.

“This was until the pharmaceutical industry realised that we needed to front-load drug metabolism and pharmacokinetics pre-clinical studies much earlier on, to gain an understanding of what the human body is likely to do to a drug,” says Chibale.

‘Front-loading’ involves incubating potential drugs with liver fractions that contain drug-metabolising enzymes. Researchers are then able to examine how human livers process the drugs. By the time drugs get to human trials, scientists are able to make much better predictions about what doses to use.

This is done in conjunction with laboratory test-tube testing the drug, then ethically on animals like rodents and non-human primates to understand its efficacy and safety.

Chibale aims to refine this further, developing tools that will help to identify which drugs are more likely to perform well in African patients, predict what the optimal human dose is likely to be in specific African populations, provide useful data for targeted clinical trial design and eventually for the establishment of better-directed dosing regimens.

The African Liver Project objectives include creating a unique and novel biobank of well-characterised African human liver tissue, generating liver cells (known as hepatocytes) and subcellular liver fractions, and investigating the metabolism of study drugs across different tissue in matching African populations in the same way as has been done for the Caucasian derived human livers and tissue.

This would create a platform for hypothesis testing before clinical trials are carried out.

The proposed in vitro (test tube) experiments would be cheaper to design and perform to get data that can be extrapolated to pharmacokinetics in humans using mathematical models.

To do this, the H3D team needs to get access to diverse African livers to see how their drug-metabolising enzymes work – but most of the liver fractions available have been donated by Caucasians in the Global North and need to be bought for large amounts of money from Western companies.

To address the lack of African liver fractions, the H3D Centre has formed a partnership with the UCT Liver Transplant Centre and has ethical approval to process African human liver tissue from discarded or diseased livers, and examine how the drug-metabolising enzymes present in the liver fractions process drugs.

But Chibale would love to have similar arrangements with liver transplant centres throughout the continent to increase the samples from which to derive robust data and because there are many genetic differences between populations on the continent.

“To do this at scale, we need more transplant hospitals in South Africa and other regions of Africa to collect enough samples. Then, with enough African-derived human liver tissue samples collected, we want to then start generating metabolism data, starting with existing medicines for any disease, whether it’s diabetes or cancer,” says Chibale.

“You know why? Because then this data can help any company really look at their own medicine that they’ve been giving out to African patients, and reformulate it in terms of the right dose,” says Chibale.

Studying the effects of antibiotics 

But drug-metabolising enzymes aren’t the only factors in determining how patients process drugs. Research has shown that the microorganisms that live in the body, including bacteria, viruses and fungi – known as the microbiome – are also important.

“Literally in the last decade, there has been an accumulation of evidence of the involvement of the gut microbiome in the metabolism of medicines, including having an impact on what happens in the liver,” says Chibale. “This means if we just optimise medicine for liver metabolism, we will not necessarily get it right. Why the microbiome is so important is, first of all, clearly genetic differences and there is overwhelming evidence of this.”

H3D’s more recent initiative, the African Gut Microbiome project, is aimed at investigating the impact of microorganisms found in various parts of the body on the metabolising of drugs. It is also aimed at studying the effect of antibiotics on the gut microbiome and the resultant changes in drug metabolism of a range of commonly used medicines.

The idea is that these initial in vivo (human) studies will inform subsequent studies around the African gut microbiome, with the goal of establishing relevant preclinical research tools that mimic those aspects of Africa-specific microbiomes that are involved in variable drug responses.

But socio-economic and physical environments in which patients live also affect how a patient can process drugs. The diet of a person has a major role to play in how the body functions, while the physical environment affects a person’s resilience.

Chibale’s centre is unique in that it is based at a university rather than being a stand-alone company or being part of a drug company. He hopes it can become an example for other parts of the world, such as South America.

Funding comes from a variety of sources from the South African government to philanthropic organisations and innovative pharmaceutical companies.

H3D has the strategic advantage for developing Africa-specific pharmaceutical research tools because of its location on the African continent providing easy access to African patients and researchers who are interested in addressing global health and health inequality issues.

Chibale has built a network of collaboration involving the chemistry, biology and pharmacology departments at the university, and has an 80-person staff, that includes post-doctoral scientists and students from all over the world.

It’s been a long journey for Chibale from a village in northern Zambia and townships in the Zambian Copperbelt, to a PhD at Cambridge University, then research positions at Liverpool University and the Scripps Research Institute in San Diego. For the past 24 years, he has been in Cape Town with his wife and three sons.

Always up for new lessons, Chibale confides that he has recently joined Twitter and realised that he needs to be part of the push-back against misinformation.

“Life is about taking risks and sacrifice. We can never achieve anything if we live in fear. Look what the world has been able to achieve in the face of COVID-19, a vaccine in an unprecedented time,” he says.

Image Credits: Kerry Cullinan.