As the Ugandan Anti-retroviral Therapy (ART) programme matures, new challenges have begun to emerge. Available research indicates that the longer one stays on ART, the more likely for them to develop HIV drug resistance (HIVDR). The emergence of resistance in persons on antiretroviral therapy and transmission of drug-resistant HIV strains to newly infected persons are now major public health concerns.
According to Dr Cissy Kityo, the Deputy Executive Director Joint Clinical Research Centre (JCRC), HIVDR is a situation whereby a client on ART does not respond to the prescribed drugs and therefore, experiences health deterioration despite the fact that he/she takes the drugs efficiently and effectively.
“This means the clients have to be moved from first-line therapy to second line ART, the latter being a more expensive course of treatment,” Kityo explains.
A recent survey by the Health ministry of infected young people in Kampala showed that 8.6% had evidence of the drug-resistant virus, with resistance to all three classes of ARVs currently available in the country.
How drug resistance occurs
According to Prof Tobias Rinke de Wit, the Research and Development Director of PharmAccess – a Dutch foundation that provides HIV treatment services for the private sector in Sub-Saharan Africa – drug resistance is caused by changes (mutations) in the virus’s genetic structure.
“These mutations can lead to changes in certain proteins, most commonly enzymes, that help HIV reproduce (replicate),” he explains.
Prof Rinke adds that mutations are very common in HIV because HIV replicates at an extremely rapid rate and does not contain the proteins needed to ‘correct the mistakes’ it makes during copying. Mutations occur randomly on a daily basis, but many are harmless. In a research conducted by AIDSMEDS, most mutations actually put HIV at a disadvantage because they reduce the virus’s “fitness” and slow its ability to infect CD4 cells in the body.
“However, a number of mutations can actually give HIV a survival advantage when HIV medications are used, because these mutations can block drugs from working against the HIV enzymes they are designed to target,” reports the research.
Accordingly, continued viral replication in the presence of drug pressure allows for the progressive accumulation of mutations that can lead to increased resistance. Some ARVs require only a single-point mutation to have high-level drug resistance, whereas others require multiple-point mutations. The number of mutations required to confer resistance contributes to the genetic barrier to resistance.
Causes of resistance
Prof Rinke says poor treatment adherence to ARVs is the leading cause of drug resistance.
“In order for HIV drugs to work correctly, they must be taken exactly as prescribed. Skipping doses or not taking your medication correctly can cause the amount of an HIV drug to decrease in the bloodstream. If the drug level becomes too low, HIV can reproduce more freely and accumulate additional mutations,” he explains.
Dr Kityo says not only must HIV drugs be taken on schedule; they need to be absorbed effectively into the bloodstream. A drug or combination of drugs that is not absorbed properly can result in levels in the bloodstream that are too low and, ultimately, allow HIV reproduction and the accumulation of drug-resistance mutations.
Effects of drug resistance
According to Prof Pontiano Kaleebu, the Director, Uganda Virus Research Institute (UVRI), drug resistance means that clients on ART that have developed resistance can transmit an HIVDR virus.
“Mothers may pass on this virus to their unborn babies, meaning that by the time a child is born, they resist drugs, which exposes them to high infant mortality,” Kaleebu says.
What has been done?
A number of initiatives have been taken to address challenges presented by HIVDR in ART programmes. One of the critical activities is to monitor emergence of HIVDR among patients that have started ART. Prof Kaleebu says the Uganda Virus Research Institute has established a national HIV drug resistance surveillance programme charged with the duty of monitoring the spread of HIV.
“We have established an HIV technical working group under this programme and its main duty is to monitor and report early warning indicators like drug stock outs, patients’ adherence to the drug and drug resistance in individuals among other roles,” Prof Kaleebu says.
More, the JCRC with other partners have for the last four years carried out research on the emergence of HIVDR in clients on ART over time. Prof Peter Mugyenyi, the Executive Director JCRC, says the research was done in both adults (18 years and above) and children below 12 years with the aim of minimizing HIVDR prevalence in selected geographical settings (Kampala, Fort Portal and Mbale) and other African countries such as Kenya, Nigeria, Zimbabwe, and variations within individuals.
According to Dr Alex Ario, the national coordinator of the ART programme in the ministry of Health, of the 1.2 million people positively living with HIV, 577,000 need ARVs and only 331,000 are on treatment. This is because drug resistant tests are expensive (about Shs 1.3 million).
“While determining the viral load can help you determine if your drugs are not working effectively, it cannot explain why this is happening and hence the need for drug resistance testing,” Dr Ario says.
With budgets for HIV/AIDS treatment already shrinking as a result of the global economic crisis, and second-line ARVs costing at least five times more than first-line drugs, this could stall efforts to expand treatment access.