Major advances have been made during the past few years in the understanding of the complex pathogenetic mechanisms leading to the propagation of HIV infection overtime and to the progression of HIV disease and AIDS.
Initial infection with HIV is characterized by a relatively brief period of high level acute virus replication. This is sometimes marked by the development of a flu like illness with fever, malaise, enlarged lymph nodes, sore throat, skin rash or joint pains. This acute febrile illness is accompanied by widespread dissemination of the virus to different tissues especially the lymphoid system that is extensively involved. HIV blood tests that are designed to detect presence of HIV antibodies (ELISA, Rapid immunoassays etc) are usually not yet positive at this point in time. However such patients are highly infectious although they test negative for HIV using the common tests that depend on detection of antibodies against HIV. The high level of viraemia present at the time of sero-conversion may persist for about three months but eventually stabilizes at an individual "set point". The number of RNA copies/unit virus (viral load) is an indicator of disease activity. Nevertheless most patients are clinically asymptomatic in spite of this ongoing extensive immunological battle.
During this asymptomatic phase of the infection, levels of CD4+ T-lymphocytes, the prime target cell for HIV gradually decline although the rate of decline varies substantially among patients. Major factors that are known to influence the rate of CD4+ T-lymphocyte decline include:
Patient genetic factors
Viral load (number of HIV-RNA copies/unit volume) at the "set point"
Studies of cohorts of patients over long periods both clinically and biologically have demonstrated the value of measuring viral load (expressed as number of copies/ml) as the most powerful predictive indicator of disease progression. Viral load and number of circulating CD4+ T-lymphocytes/mm³ are the two most important parameters to consider in deciding to start evaluating treatment. Viral load is the measure of disease activity and can be used to evaluate the rate of the immune system deterioration before and during treatment and the risk for development of resistance during treatment. The CD4 count can be used to evaluate the risk for complications including the development of opportunistic infections.
A high ‘set point’ has been shown to be associated with rapid disease progression than a low "set point". Infection with syncytium forming viruses is associated with rapid rate of disease progression compared to none-syncytium forming viruses. Development of severe immuno-suppression could occur within 2-4 years but may be delayed for more than 15 years. In the "typical" HIV infected patient however it takes 8-10 years. Activation of the immune system for example by infections such as tuberculosis and worm infestation accelerates onset of immuno-suppression. Consequently, institution of preventive therapy to opportunistic infections, early detection and administration of effective and appropriate treatment of infective conditions in persons with HIV infection do minimize the risk of rapid onset of immuno-suppression. Preventive therapies currently used include those for TB, bacterial infections, Pneumocystis carinii pneumonia, (PCP), toxoplasmosis and cryptoccocal meningitis.
Comprehensive clinical care of persons with HIV disease therefore requires the health care personnel to have appropriate clinical knowledge, experience and laboratory support to identify patients with subtle as well as those with gross features of HIV disease. Once diagnosis of HIV infection is made, the goal of any treatment aims at limiting or delaying progression and onset of AIDS for as long as possible to reduce morbidity and to increase survival.
Theoretically the multiple steps in replication of HIV provide opportunities for intervention. Therapeutic regimens may be directed at one or several of the following stages essential for viral replication: (See Chapter 11 for more details).
Attachment of HIV to host cell
Reverse transcription of viral RNA to DNA
Intergration of the proviral DNA into the host cells’ DNA
Expression of the viral gene after it has been integrated into host cell DNA including the process of transcription of more viral RNA and the translation of viral proteins
Processing and post-translational modification of protein products of the virus
In addition, delay of disease progression can be achieved in three ways:
Prolonging amount of time it takes for the virus to replicate
Lowering the viral load
Increasing CD4+ cell count