HIV therapy guidelines.

Abstract

Over the past few months guidelines for the treatment of HIV infection in adults have been published by groups in the United Kingdom (British HIV Association)' and the United States (US Department of Health and Human Services2 and the IAS-USA panel3). These have been prepared in response to rapidly emerging evidence from clinical trials of the clinical benefits of combination regimens for the treatment of HIV infection. On initial review the British group appears to have taken a more conservative therapeutic approach than its United States counterparts. However, in defining the principles of therapy there are major similarities particularly in the use of plasma HIV RNA levels (viral load) for initiating and monitoring therapy. Furthermore, guidelines are only as good as the current data on which they are based. Since the BHIVA guidelines were completed at the end of 1996 two large clinical endpoint studies have reported improved benefit of triple combination regimens compared with double nucleoside analogue combinations. Based on data from natural history studies and clinical endpoint treatment trials all three groups emphasise the importance of measuring plasma HIV RNA and CD4 counts for determining both the risk of disease progression and response to therapy. In addition, the reduction of plasma HIV RNA to below the levels of detection of a sensitive assay is viewed as the optimal treatment response by all groups. This stems from the observation that suppression of HIV replication limits potential for selection of HIV variants that are resistant to antiretroviral drugs. Failure to suppress HIV replication adequately is likely to lead to virological and clinical failure of the treatment regimen. Each of the guidelines discusses treatment regimens that are best able to achieve this treatment goal and in the light of current data few would argue with this principle of therapy although many acknowledge that this may not be achievable in all patients. There are, however, differences in the recommendations for initiating treatment (table) and choice of drug regimens. No clinical trial has determined the optimal time to start treatment and similar magnitudes of clinical benefit have been demonstrated at different stages of disease. In the absence of definitive data clinicians need to draw upon other levels of evidence to determine when to start treatment. Differences lie within the intepretation of this evidence and the expectation of long term benefit from current treatment regimens with the United States groups favouring earlier intervention and a heavier emphasis on the importance of plasma HIV RNA levels. If the main goal of therapy is to limit the risk of clinical progression to symptomatic disease then it seems reasonable for treatment to be offered before substantial immunodeficiency ensues and before the level of risk becomes too high. Recommendations of when to start treatment have therefore been based on studies of the natural history of HIV infection and the value ofCD4 count and viral load to predict disease progression. The most influential of these have been data from the Multicentre AIDS Cohort study which demonstrated a strong association between the level of plasma HIV RNA level in early infection and long term disease progression.4 As the US DHHS guidelines state the potential benefits of early intervention include: (1) control of viral replication and mutation (2) prevention of progressive immunodeficiency with a potential maintenance of a normal immune system (3) decreased risk of selection of resistant virus and (4) a decreased risk of drug toxicity. Alternatively the potential risks include: (1) a reduction in the quality of life from adverse drug effects (2) earlier development of drug resistance (3) limitation in future choices of antiretroviral agents (4) unknown long term toxicity of certain drugs (5) unknown duration of effectiveness of current antiretroviral therapies. Although the potential benefits are admirable it remains unclear whether the complexity and potency of the current treatment regimens will achieve these goals. It is plausible that early intervention with potent and simpler treatment regimens may result in sustained clinical benefit for many years. The US DHHS guidelines encapsulate this problem of risk and benefit in the following statement: "A major dilemma confronting patients and practitioners is that the antiretroviral regimens currently available that have the greatest potency in terms of viral suppression, CD4 T cell preservation are medically complex, are associated with a number of specific side effects and drug interactions and pose a substantial challenge for adherence." For many United Kingdom physicians the current level of evidence supporting early intervention is not sufficient and is outweighed by the potential risks. The protagonist of early intervention would argue that delaying therapy allows cumulative damage to the immune system and increasing diversity of the viral population, the possible prevention of both have the potential for long term benefit of treatment.