Data published over the last two years in Europe and North America, from clinical trials and observational cohorts, provide convincing evidence of the beneficial impact of combination antiretroviral therapy on the morbidity and premature mortality from HIV infection. This benefit is mainly due to a reversal of the progressive immune deficiency that is characteristic of HIV infection and to effective restoration of the immune system’s reactivity to HIV induced opportunistic infections (OIs).
The course of many OIs has been altered by widespread use of effective ART. Previously untreatable OIs like cryptosporidiosis and AIDS defining illnesses like Kaposi’s sarcoma may resolve without specific treatment and the clinical progression of complicated OIs like cytomegalovirus and atypical mycobacterial infections may be halted and/or reversed. As an extension of the benefits of effective ART, criteria for the discontinuation of chemoprophylaxis against pneumocystis carinii pneumonia, which in the past was a lifelong intervention, have been introduced into current practice guidelines. In time, HIV infection may therefore be considered as a chronic disease manageable over the course many years.
The approach to antiretroviral therapy and the design of therapeutic regimens has been influenced by the following key findings from studies on the pathogenesis of HIV infection:
• demonstration that a continuous high-level of replication of HIV is present from the early stages of infection (at least 1010 particles are produced and destroyed each day)
• demonstration that a specific immune response to HIV occurs in HIV infected subjects during “primary” infection but begins to decline after the first months of infection.
The strength of this primary immune response may be predictive of subsequent concentrations of HIV in the body as measured by the plasma HIV-RNA or “viral load”.
• demonstration that the measured concentration of plasma viral load is predictive of the subsequent risk of disease progression and death.
• proof that combination antiretroviral therapy is not only able to consistently suppress HIV replication, but also able to induce a significant delay in progression to AIDS; this survival benefit is particularly marked in previously untreated patients.
• elucidation of the molecular, functional and clinical impact of resistance to antiretroviral drugs.
Since ongoing replication of HIV drives the disease process, causing progressive immunological damage, an ideal target of antiretroviral treatment is to obtain timely and sustained suppression of viral replication. Many ART regimens that achieve this target to some degree have already become available. Reliable techniques for quantifying HIV in plasma, measured as the amount of HIV-RNA or the “viral load” are also available and have allowed clinical researchers to compare the relative antiviral potency of various antiretroviral drug regimens, while providing a rational tool for monitoring the efficacy of ART in clinical practice. Measurement of the numbers of CD4+ cells in the blood are a reliable indicator of the extent of immunological damage caused by HIV infection and provide further rationale for clinical decisions on antiretroviral therapy.
While the progress so far has been impressive, there is a growing appreciation of some of the difficulties associated with ART and much work still remains to be done. Difficulties with adherence to treatment, long-term toxicity and cross-resistance among antiretroviral drugs have become major drawbacks of current ART strategies. Even with the most potent antiretroviral drug regimens available today, there exists a proportion of patients who fail to have complete and durable virologic responses to therapy for a myriad of reasons. These shortcomings of the current regimens are particularly evident in patients whose baseline levels of plasma “viral load” are high, who have had extensive prior treatment and in whom the stage of disease is advanced.