Incidence, prevalence and outcome of extensive virologic failure in over 60,000 patients with HIV (PLATO ll)

Over 40 million people in the world have HIV infection. Around 2.5 million are being given drugs to combat the infection. More and more people are being given these drugs, particularly in Africa where the proportion of people with HIV is very high. When taken in combination these drugs are effective at stopping the HIV virus from reproducing itself in a person?s body. When this happens people with HIV tend to get better and are at less risk of getting sick with an AIDS disease. Unfortunately, however, some drugs lose their benefit because the virus develops resistance to them. When this happens, doctors will change the drugs to ones that should still work. So far, the drugs we have available mainly belong to one of three classes. Some patients have reached a point where they have used up all the drugs and there are no drugs left in these three classes that are effective against their virus. While we know this happens, we don?t know how rapidly. This is important for us to understand, particularly because people with HIV in Africa and other developing countries do not have access to any drugs apart from these. Patients who have no more drugs available to control their virus will eventually develop AIDS and die. In developed countries like the UK, we have three newer drug classes available. This means that the people who have failed the original drugs may still have drug options left to control their virus. But we do not know much about these drugs as they are very new. It is likely that the virus will often eventually become resistant to these new drugs also. At that point patients in developed countries would also be in severe danger of AIDS and death. Our project will bring together data from over 60,000 people with HIV in Europe in order to examine how long it takes before all available drugs have stopped working, and what happens to patients for whom this has occurred. Besides obviously being important for doctors and their patients our research is likely to help those planning future health care services, those planning to try to develop new drugs and other researchers that are thinking of new studies to do in these kinds of patients.

Antiretroviral therapy (ART) is highly effective against HIV, but its beneficial effects can be time-limited. Our project aims to assess how rapidly patients are likely to exhaust available drug options, and what happens to patients that do so. ART is currently being used by over 2.5 million people in developed and developing countries and major efforts to scale up use of therapy to more of the 40 million people worldwide with HIV are ongoing. ART induces benefit by reducing HIV viral load to below detectable levels. However, drugs do not always maintain their activity indefinitely ? resistance mutations can appear which lead to raised viral load (?virologic failure?). In such situations regimens are switched to drugs which are still fully active. Until now, drugs have almost all been from three original main classes (nucleos(t)ides, non-nucleoside reverse transcriptase inhibitor and protease inhibitors). In some patients virological failure of drugs from all three classes eventually occurs. It is important that we reliably estimate this rate with which this occurs and understand the factors associated with a higher rate. This has particular relevance for sub-saharan Africa and other developing countries (even though switches are not made on the basis of viral load testing as this is not available) where the available drugs are likely to be restricted to those from these three classes for some time. In developed countries, we have three newer classes available (fusion inhibitors, integrase inhibitors and CCR5 inhibitors). It is unclear how rapidly those that have failed the initial three classes will also fail these new classes. Our project will take advantage of a unique opportunity to bring together data from over 60,000 people with HIV in Europe from several well-established cohort studies in order to study how rapidly triple class virologic failure occurs and what factors predict this. The use of new classes of drugs in patients with triple class failure and the viral load, CD4 count and clinical outcomes will also be examined. In both developing and developed country settings, failure of all available drugs leads to CD4 count decline and eventual clinical disease and death, so the implications of the work are considerable. Our findings are likely to be important for clinicians, patients, drug regulatory authorities, health care planners (including WHO), the pharmaceutical industry and for researchers planning randomized trials.