Treatment of chronic adult infection

In the mid 1990s, several large clinical endpoint studies demonstrated a strong association between falls in plasma HIV RNA levels (plasma viral load) in the first few weeks on therapy and clinical outcome at one year.

Studies have also shown an association between the plasma viral load nadir on therapy and both the risk of subsequent viral load rebound, and the emergence of viral genotypic mutations associated with reduced drug susceptibility. Where possible an objective of antiretroviral therapy is to reduce and sustain plasma viral load levels to below the level of detectability of the current ultra-sensistive viral load assays ((< 50 copies/ml) for three years or more, discontinuation of antiretroviral therapy results in rapid rebound of plasma viral load to pretreatment levels.

Sustained inhibition of viral replication does however result in substantial immune reconstitution, even in those patients with advanced disease who start antiretroviral therapy at very low CD4 counts. Reduction in immune activation markers, increases in both memory and naive CD4 and CD8 T cells and development of improved lymphoproliferative responses to antigens such as CMV and mycobacteria occur in patients on HAART. Immune responses to HIV are generally not regained, and it remains uncertain what levels of immune reconstitution can be achieved over time. This may depend on any residual thymic function or the ability of extrathymic pathways to facilitate immune reconstitution.

To achieve sustained falls in plasma viral load it is standard of care in patients starting antiretroviral therapy for the first time to use a triple drug regimen containing two NRTIs in combination with either one NNRTI or one or two protease inhibitors. In clinical trials, a combination of two NRTls and a protease inhibitor has been shown to reduce the risk of progression to AIDS or death compared to treatment with two NRTIs alone.

The efficacy of antiretroviral therapy has improved over the last few years, however only approximately 50—70% of patients will have sustained plasma viral loads to in favour of slower disease progression on discontinuation of HAART

Cons:

• Longterm toxicity associated with drug treatment, potential for therapy failure and emergence of drug resistance

• Uncertainty of improved longterm clinical benefit compared to initiating treatment during established chronic HIV infection

• Probably need to treat within a few weeks of exposure to HIV infection to gain immunological benefit. therapy is lower than might have occurred in patients who were not treated during primary infection is not known. Antiretroviral therapy should be considered in patients presenting with acute primary HIV infection, however the immunological arguments need to be balanced against the unknown long-term efficacy of such a strategy, the risk of drug toxicity over time and the development of drug resistance.