When Should Antiretroviral Therapy Be Started for HIV Infection?
When Should Antiretroviral Therapy Be Started for HIV Infection?
The point during the course of HIV infection at which antiretroviral therapy (ART) should be initiated remains uncertain. This is reflected in the extent of recent changes in recommendations for treatment guidelines. After a shift in the mid to late 1990s towards earlier initiation of ART - with the most aggressive guidelines suggesting initiation of ART in the overwhelming majority of people diagnosed with HIV - the more recent trend has been for later starting, with a delay in initiation until the CD4 cell count has fallen to 200 x 10 cells/l in the most conservative versions. The time difference between starting ART according to the most aggressive and the most conservative criteria is on average over 5 years, and for some people could mean a potential ART delay of over 10 years; consequently, this issue is of major relevance.
In the absence of any ongoing randomized trial to address the issue directly, it has been necessary to assemble various pieces of evidence from prospective studies to estimate which is likely to prove the best strategy. Interpretation of the relevance and contribution of each study analysis is, however, not straightforward. In this article, we review the key findings and provide a framework for their use in deciding in a person with CD4 cell count ~ 350 x 10 cells/l whether immediate or deferred ART is likely to most delay AIDS and death. This CD4 cell count level is chosen because it is an area of most uncertainty for ART initiation. Although the key ultimate endpoints of importance are AIDS and death, the effectiveness of current ART is such that relatively few people will develop them within a 5 year time span. Since we have not followed people on triple ART regimens for longer time periods than this, we have also, therefore, to consider an intermediate endpoint - virological failure - which, as outlined below, is a key determinant of who is more likely to develop AIDS or die over much longer time periods.
We consider in the following section the risk of AIDS and death before starting ART in those who defer. In the subsequent two sections we then focus on the comparison of the risk of AIDS and death according to whether ART is started immediately or deferred. We separately consider the short-term perspective, for which we have direct estimates of risk of AIDS and death, and the longer-term perspective, for which we must use evidence on risk of virological failure. Finally, we briefly discuss some other issues for consideration and draw some conclusions.
The point during the course of HIV infection at which antiretroviral therapy (ART) should be initiated remains uncertain. This is reflected in the extent of recent changes in recommendations for treatment guidelines. After a shift in the mid to late 1990s towards earlier initiation of ART - with the most aggressive guidelines suggesting initiation of ART in the overwhelming majority of people diagnosed with HIV - the more recent trend has been for later starting, with a delay in initiation until the CD4 cell count has fallen to 200 x 10 cells/l in the most conservative versions. The time difference between starting ART according to the most aggressive and the most conservative criteria is on average over 5 years, and for some people could mean a potential ART delay of over 10 years; consequently, this issue is of major relevance.
In the absence of any ongoing randomized trial to address the issue directly, it has been necessary to assemble various pieces of evidence from prospective studies to estimate which is likely to prove the best strategy. Interpretation of the relevance and contribution of each study analysis is, however, not straightforward. In this article, we review the key findings and provide a framework for their use in deciding in a person with CD4 cell count ~ 350 x 10 cells/l whether immediate or deferred ART is likely to most delay AIDS and death. This CD4 cell count level is chosen because it is an area of most uncertainty for ART initiation. Although the key ultimate endpoints of importance are AIDS and death, the effectiveness of current ART is such that relatively few people will develop them within a 5 year time span. Since we have not followed people on triple ART regimens for longer time periods than this, we have also, therefore, to consider an intermediate endpoint - virological failure - which, as outlined below, is a key determinant of who is more likely to develop AIDS or die over much longer time periods.
We consider in the following section the risk of AIDS and death before starting ART in those who defer. In the subsequent two sections we then focus on the comparison of the risk of AIDS and death according to whether ART is started immediately or deferred. We separately consider the short-term perspective, for which we have direct estimates of risk of AIDS and death, and the longer-term perspective, for which we must use evidence on risk of virological failure. Finally, we briefly discuss some other issues for consideration and draw some conclusions.