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Genes key to personalised medicines

While drugs work in most people who have the same disease symptoms, there are some who do not experience therapeutic benefits because of their race.

Local medical experts now believe that this aspect is one of the reasons why HIV infections and AIDS complications are prevalent among Africans unlike in other races.

A typical case of race-specific drugs is that of Bidil, a drug for heart disease failure.

In medicine one size does not fit all.

In other words the concept of a standard dosage does not necessarily apply to all patients.

The President and Chief Science Officer of the African Institute of Biomedical Science and Technology, AiBST, in Harare Prof Collin Masimirembwa said two people taking the same cancer medication, for instance, have different responses.

One may experience severe or even life threatening side effects while another may not.

Isoniazid, one of the cocktail drugs used in the treatment of TB, the major cause of death in HIV/AIDS patients, was noted to be removed rapidly from some patients while others were slow to release it from their bodies.

If the drug remains too long in the body, its toxic waste compounds harm vital organs.

Professor Collen Masimirembwa, said studies identified the human enzyme that is responsible for breaking down, absorption and disposal of Isoniazid from the body.

The efficacy of this enzyme to breakdown and dispose Isoniazid from the body varies with the different genetic setup of individuals.  

“Before one administers Isoniazid, it is important to look at the patient’s genetic status and determine whether to reduce or increase the standard dose,” said Prof Masimirembwa.

“Such dose adjustments also reduce high incidence of liver toxicity and severity of burning or itching sensation,” he said.

In the late 1980s, Prof Charles Nhachi of the University of Zimbabwe’s Clinical Pharmacology, discovered in his research on genetics that over 60% of Zimbabweans release drugs slowly from their bodies.

Recent studies at AiBST revealed that a particular genetic coding with a prevalence rate of around 80% among Africans is associated with people whose bodies release Isoniazid slowly.

This data is very important in the country’s efforts to combat HIV/AIDS and TB as exposure to Isoniazid at standard doses might result in many cases of liver toxicity and peripheral neuropathy in a significant number of TB patients.

Prof Masimirembwa said there can be further complications in the treatment of HIV/AIDS-TB co-infections which are estimated at over 60% in HIV/AIDS patients taking the combination of Isoniazid and Stavudine, an ARV which also causes severe peripheral neuropathy.  

The major reason for differences in drug response is inherited variations in gene structures which affect the body’s response to medication.

This variation in response to medication has given rise to a specialized field further defined as pharmacogenetics or pharmacogenomics which is the influence of genetic variability to drugs.

This is one of the core reasons why the African Institute of Biomedical Science and Technology was established.

Genomic medicine is therefore driving the current shift in clinical practice from that of one diagnosis and one treatment fits all to a paradigm of individual treatment known as personalized treatment.

Pharmacogenomics currently holds the promise that drugs might one day be tailor made for individuals and adapted to each person’s own genetic makeup.

The environment, diet, age, lifestyle and state of health are all considered to influence a person’s response to medicines but understanding an individual’s genetic setup is now the key to creating personalized drugs that have great efficacy and safety.

The concept that underpins personalized medicine is information about a patient’s protein, genes and the individual’s food conversion factor known as metabolic profile which could be used to tailor medical care suitable for the patient’s needs.

“The aim of personalized medicine or individual treatment is to match the right drug to the right patient and in some cases even design the appropriate treatment for a patient according to their genotypes,” said Prof Masimirembwa.

Efavirenz is one of the highly active antiretroviral therapies that can be used as a substitute to drugs causing side effects in certain patients.

Prof Masimirembwa said Efavirenz is usually used in patients who show severe hypersensitivity reactions to Nevirapine or in patients with HIV/AIDS-TB co-infections in order to avoid the drug to drug interactions that occur between Nevirapine and Rifampicin, an anti-TB drug.

However, Efavirenz has its own problems in certain patients.

Studies carried out at AiBST showed that an enzyme CYP2B6 is responsible for breaking down and eventual removal of nicotine and Efavirenz from the body.

The studies also revealed that the enzyme produced under certain genetic variations results in some patients having a reduced capacity to eliminate Efavirenz.

 Subsequently, drug accumulation associated with increased incidences and severities of central nervous system such as madness and suicidal behavior occurs.

Prof Masimirembwa said, the variants associated with reduced Efavirenz elimination are more prevalent in people of African origin than in Caucasians.

The variant was discovered to be common among African tribes such as the Shona, Ndebele and San of Zimbabwe, the Venda of South Africa, Ibo, Hausa and Yoruba of Nigeria and the Luo, Kikuyu and Masai of Kenya.

This was done to evaluate the clinical impact of the variant as a possible biomarker for the application of effective dosages in Africans.

According to the study, HIV/AIDS co-infected patients showed a strong association between the enzyme and high concentrations of Efavirenz in their bodies.

The study also showed that at standard doses of 600 mg optimized for Europeans, most Zimbabwean patients are over dosing.

“However for patients on Antiretroviral treatment and anti-TB medication, cautious recommendations to increase the dose of Efavirenz to 800mg a day should be considered due to the possible interaction with Rifampicin which could reduce the levels of Efavirenz thereby rendering the drug ineffective,” said Prof Masimirembwa.    

By introducing personalized medicine, pharmaceutical companies will be able to create drugs based on proteins, enzymes and ribonucleic acid (RNA) molecules associated with genes and diseases.

This will facilitate drug discovery and will allow makers to produce a therapy more targeted to specific diseases.

The accuracy will not only maximize therapeutic benefits but also decreases damage to nearby healthy cells.

Current methods of basing dosages on weight and age only will be replaced with the dosage based on a person’s genetics, how well the body processes the medicine and the time it takes to metabolize it.

According to Science and Society Journal, knowing one’s genetic code will allow a person to make adequate lifestyle and environmental changes at an early age so as to avoid or lessen the severity of a genetic disease.

Likewise, advanced knowledge of a particular disease will allow careful monitoring thereby introducing treatment at the most appropriate stage.

Although personalized treatment reduces adverse drug effects in patients, there are disadvantages associated with it.

Prof Charles Nhachi of the University of Zimbabwe’s Clinical Pharmacology said personalized treatment remains a preserve for the rich because it involves genetic testing.

Genetic testing also called DNA-based test is the newest and most sophisticated technique used to test genetic disorders.

It involves direct examination of the DNA molecule itself.

“The other problem associated with personalized treatment at the moment in Zimbabwe includes limited resources,” said Prof Nhachi.    

In the public domain, the problem largely has to do with the handling of the genetic information of an individual.

A University of Zimbabwe biochemist, Dr Tamuka Nhiwatiwa said personalized medicine based on genetic information is undoubtedly a great leap in science.

However the main question with the public is how safe the information of their genetic makeup is.

“If there is no way to really ensure that such information is protected and kept private, genomic medicine will struggle to take off,” said Dr Nhiwatiwa.

In order to accurately diagnose a disease at genetic level, AiBST has established a Biobank of samples from major ethnic groups across Africa.

The samples were collected from specific patient groups, psychiatric patients and HIV/TB patients with respect to ethnic diversity and geographical coverage.

The Biobank being created is an important tool in the discovery of personalized treatment which will take into account the validation of molecular diagnostic tools that have sensitivity and selectivity for variability in African populations.  




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