The emergence and impact of HIV resistance-associated mutations under the public health approach to ART

AIDS is one of the major killers worldwide. The epidemic is growing by the day, and some of the poorest countries are being decimated by deaths amongst young adults and children. Meanwhile, the use of antiretroviral therapy in the resource-rich areas of the world has had enormous benefits to those living with the infection. HIV is no longer a death sentence, and rather has become a chronic disease, requiring daily medication to maintain wellbeing. Until recently, the costs of such treatment have precluded it being available to those areas of the resource-poor world which host the huge bulk of the epidemic. However, a roll out of therapy, funded from a number of initiatives has now started to make such therapy available. The WHO has developed a simple template for the implementation of such treatment. However, the use of sophisticated laboratory monitoring of treatment, as routinely occurs in the West, is not realistic. Such monitoring is typically used in the West to measure the amount of virus in the blood in those receiving treatment. Since effective treatment reduces the levels of virus to very low levels, an increase in such levels suggests that the treatment is working less well. In such situations, the virus is tested to detect resistance to one or more of the drugs being taken, and this can guide the appropriate 2nd line of therapy to start. In this way, high level resistance is minimised. By contrast, in the resource-poor world, these sophisticated and expensive laboratory tests will not be available, and therefore there is a distinct risk that people starting on treatment will end up with highly drug resistant virus, which may not respond well to further treatment.

We aim to investigate the extent of this problem, within a large group of patients treated for HIV in Uganda and Zimbabwe. Our research will identify simple and cheap methods to monitor those receiving treatment in this environment, in order to minimise the risk of such resistance, such that improvements in survival due to antiretroviral therapy can be maintained over a long period of time. Our results will directly inform WHO policy regarding the manner in which treatment is made available to the resource-poor world.

Rollout of antiretroviral therapy (ART) in resource-limited countries, where HIV prevalence is highest, has been identified as a priority by the World Health Organisation (WHO), bilateral donors, multilateral agencies and the countries themselves. The number of people receiving therapy has more than doubled in the last 2 years, most notably in sub-Saharan Africa where approximately 500,000 people started ART in 2005. In the resource-rich world, ART use is accompanied by intensive virological monitoring , to identify early stages of viral rebound at which time treatment is switched. This reduces the risk of extensive drug resistance, as well as prolonging the efficacy of ART, through subsequent treatment switches. By contrast, in the resource poor world, there is neither the infrastructure, nor resource to undertake such testing, and the public health approach to ART rollout is based on the use of standard 1st and 2nd line drug regimens, with treatment switch determined by clinical disease progression. This carries with it risks for development of high level resistance. There is thus need for an evidence-based approach to public-health based rollout of ART in resource-limited environments in order to maximise the potential benefit of ART on long-term survival (first and second line therapy), given that resistance to antiretroviral drugs will inevitably develop.

The quantification of both the risk and determinants of resistance and delineation of the relationship between disease progression, virological and immunological changes and the development of resistance in resource-limited settings in Africa is the focus of this application. Specifically we aim to fully explore disease progression (clinical, immunological and virological) in patients with ongoing viraemia during first-line treatment with three different combivir-based regimens, within the DART Trial, in order to: a) determine the evolution of resistance in the absence of virological monitoring, and therefore identify the implications for NRTI use within a boosted PI-containing second-line ART b) identify simple markers of extensive and clinically relevant resistance during 1st line therapy which can be implemented in a resource-limited environment to guide treatment switch to second-line therapy c) study virological determinants of disease progression during 1st line therapy in the absence of virological monitoring