Not one treatment fits all – Fellows’ seminar by Collen Masimirembwa

26 October 2021

Need for precision medicine for Africa highlighted


“One treatment fits all is not appropriate. Treatment should be based on an individual’s genetic make-up,” said STIAS fellow Collen Masimirembwa of the African Institute of Biomedical Science and Technology (AiBST). “We need to understand the genomic diversity of African populations and the opportunities this offers for precision medicine. Africa constitutes 15% of the world population but carries 25% of the global disease burden and allocates the least resources for healthcare – we need a new way of moving forward if the Agenda 2063 for the Africa we want is to be a reality.”

“We know that genes help us to understand our ancestry, solve crimes and find each other but we can also use them for wellbeing and medicine – to keep healthy, determine risk, diagnose and treat diseases,” he continued. “Over the past 25 years we have been studying the genomic diversity of African populations with a focus on pharmacogenes that influence our response to medicines with respect to efficacy and safety.”

STIAS fellow Collen Masimirembwa during his seminar on 21 October 2021

Masimirembwa explained that the genome is the complete nucleic acid (DNA or RNA) composition of a living organism. The complete sequence of the human genome was deciphered in 2003 as being composed of 3 billion base pairs. DNA is composed of chemical units called bases abbreviated as A, T, G, C. These exist in pairs where A pairs with T and G pairs with C. The human genome is the blueprint of our physical and physiological composition and function. This information is organised in units called genes that code for specific proteins that enable our functionality. The genome is the underlying mechanism of how we pass on our traits from generation to generation.

“Overall humans are 99.9% the same,” he said. “There is only a 0.1% difference between people.”

However, the process of reproduction of the genome, and human populations, is associated with the generation of millions of variations in the sequence of DNA bases.

“When information is transferred errors happen – including single-base changes called single nucleotide polymorphisms (SNPS), insertions, deletions and sequence repetition. These all create variation that constitutes the 0.1% we differ in.”

“This variation is key to human evolution as it gives rise to inter-individual and inter-population variation with different performance abilities and survival in different environments. Importantly, the genome gives us insights into human health and disease; how some individuals are at higher risk of some diseases, as well as how we respond to medicines differently.”

Insight into the human race

Since the human genome was decoded in 2003, African scientists were motivated to be involved in this work leading to the establishment of the African Pharmacogenomics Consortium and the African Society of Human Genetics. Five countries – Nigeria, Kenya, Tanzania, South African and Zimbabwe – also created a biobank which now contains 2000 samples from nine ethnic groups.

Analysis of thousands of genetic variants showed a distinct clustering of Caucasians, Asians and Africans on the continent. It also showed conclusively that the African population has a greater genetic diversity than the other groups – up to 25% more variation with big differences across Africa.

“These properties enable us to study and understand human history with respect to migratory patterns over the past 300 000 years in which homo sapiens emerged,” explained Masimirembwa. “This supports the out-of-Africa and bottle-neck-effect model of human evolution and migration – that 100 000 years ago a small group of  homo sapiens left the continent taking with them limited genetic variation compared to the populations that remained on the African continent.”

‘Bad’ medicine for some

Understanding the structure and variation of African genes can tell us which populations have a higher risk of certain illnesses but also how they will respond to the medications available. An example is sickle cell disease (SCD) – particularly prevalent in West Africa – and caused by a single base pair change. Approximately 350 000 people die from SCD annually. “If two people who are carriers of the sickle cell trait marry, they have a 25% chance of giving birth to a child carrying this trait in double dose, hence disease condition,” said Masimirembwa. “For hundreds of diseases, the underlying genetic mechanism is now known and can be determined by analysing a person’s genome. For some diseases, it involves single gene defects whereas for others risk is due to variations in many genes hence more complex and difficult to predict as it also involves the additional role of environmental factors.”

On the other hand, the use of medicines in the treatment of disease can be associated with Adverse Drug Reactions (ADRs) which are more common than we realise. “There are 2.2 million serious ADRs per year,” he said, “59% of drugs cause such reactions and ADRs cause over 100 000 deaths per year. It’s therefore important that we can identify those who are at risk of such ADRs so that we modify their treatment.”

He also pointed out that the efficacy rate of drugs varies dramatically – for some diseases it’s as low as 30% – often based on variation in individuals’ systems that are targeted by the administered drug.  “If we want an optimal therapeutic outcome we need an understanding the effect of genetic variation in the system that handles medicines we take and in systems that are targeted by the medicines.  Specifically we need to ask, will a drug work the same in people of African ancestry as it works in people of other ancestry groups?”

Masimirembwa’s group’s work has resulted in the discovery of genetic variants unique to people of African ancestry with the potential to result in different responses to some medicines on the market.

“In the early 2000s we had major problems with treating HIV/AIDS on the continent. Up to 80% of people taking some of the available antiretrovirals were experiencing side effects. The use of the drug Efavirenz, in particular, was causing more neuropsychiatric ADRs in Africans than in Europeans. We found a higher frequency in African populations of the gene variation associated with the capacity to metabolise and remove the drug. Patience with this variant were not able to efficiently remove the drug from their system meaning we were basically poisoning them with an overdose of the drug.”

“We developed a genetic test and an algorithm for identifying at-risk individuals and implemented dose adjustments for safe outcomes. This work contributed to the World Health Organization reducing the dose of Efavirenz from 600 mg/day to 400 mg/day.”

Currently the group is doing similar work on Tamoxifen used in the treatment of breast cancer. “Besides confounding factors such as late-stage diagnosis and poor treatment adherence, we discovered a genetic variant in African women which we believe significantly contributes to poor treatment outcome,” said Masimirembwa.

“To respond to or activate Tamoxifen you need a properly functioning enzyme system. Our work with a cohort of over 500 breast cancer patients in Johannesburg is showing that 30 % have the genetic variant associated with reduced capacity to activate the drug. These patients are predicted to not effectively respond to the drug requiring that one either increases the drug dose or uses alternative drugs for many women of African ancestry.”

The group has also developed an open-array genetic test for 38 pharmacogenes and 120 genetic variants which are important for guiding the clinical use of over 100 medicines. The test – GenoPharmR – is currently the first and only SAHPRA (South African Health Products Regulatory Authority) registered pharmacogenomics test in Africa and is inclusive of genomic variants unique to Africans. His company, the African Institute of Biomedical Science and Technology (AiBST) is embarking on a programme to establish centres of excellence in genomic medicine in Nigeria, Kenya and Zimbabwe aimed at building critical mass and targeted capacity development in this field, and creating infrastructure for precision medicine. This is being done by the implementing pre-emptive pharmacogenomic testing for effective care and treatment in Africa (iPROTECTA) project.

Describing it as “an ambitious project that will require enormous support from multidisciplinary stakeholders” Masimirembwa pointed to the challenges of persuading governments, the pharmaceutical and biotech industry as well as the health-insurance sector of the importance of pre-emptive genetic testing.

“You have to keep knocking on doors and bothering people with solid evidence of one’s proposition,” he said.

“Governments obviously want to procure the best drugs for their populations but in Africa many drugs may come via donor programmes and may be of no use to the population. This has huge cost implications for individuals and healthcare systems. The knowledge from our research points to the need to be selective on the types and doses of drugs we procure informed by population genomic structures.”

With the price of gene sequencing coming down there is an increased possibility to cost-effectively implement genomic medicine in our setting.

“We must work with pharma and biotech – we can’t keep them out of this shared responsibility,” he said. “They are definitely more accepting of genetic testing. Having to withdraw a drug because patients die from it is a much bigger financial loss – so that’s a major incentive. There is a growing sense that drugs shouldn’t cause more problems than they solve.”

“We are seeing positive signs – for example, Wellcome Trust and the US National Institutes of Health funded the building of biobanks in Africa through the H3Africa program – but there is always a risk that you lose momentum when the funding ends.”

“We need to build a richer tradition around research and innovation on the continent,” he said. “We need to do multicentre studies across Africa to ensure drugs work in the genomically diverse populations – moving from one treatment fits all, to genomics-guided precision medicine.”

Michelle Galloway: Part-time media officer at STIAS
Photograph: Noloyiso Mtembu


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