Roger J Pomerantz; David L Horn


Nat Med. 2003;9(7) 

In This Article

1995-1997: HAART; More Protease Inhibitors; Non-NRTIs and Additional NRTIs; Understanding of HIV-1 Viral Dynamics; Plasma Viral Load Testing

In 1995, there was preliminary understanding of the clinical efficacy of using a protease inhibitor in combination with two NRTIs. The subsequent approvals of more potent protease inhibitors, such as indinavir, ritonavir and nelfinavir, rendered feasible the prolonged survival of patients with AIDS and HIV-1 infection. Subsequent landmark studies proved the efficacy of triple combination therapy, or highly active antiretroviral therapy (HAART), in markedly reducing mortality[17] and inducing viral load suppression.[18] Using these new agents, sufficient antiviral potency could be sustained to drive plasma viral load below the detection limits of RT-PCR for plasma HIV-1 RNA. Scientists realized that sustained suppression of HIV-1 titers could minimize viral replication, which would, in turn, deter the development of resistance to the new agents and allow for immune reconstitution. Clinical documentation of the duration of this suppression now exceeds 4 years.[19,20]

In addition, using protease inhibitors and HAART, studies were carried out that showed the very rapid turnover of HIV-1.[21,22] The understanding of HIV-1 viral dynamics laid the foundation for understanding T-cell loss and the benefits and limitations of antiretroviral therapy, including the rapid development of drug resistance associated with incomplete suppression of HIV-1.

Another important development included the creation of quantitative viral assays. These assays were first used in clinical trials, but once they became available in the clinic, they provided critical information for making therapeutic decisions for individual patients.[23] The introduction of plasma viral load assays, which measured viral RNA levels, allowed for the discovery that after several months following the initial infection, a steady-state level of viral RNA is achieved. This steady-state level is determined primarily by host response and secondarily by the virulence of the infecting HIV-1 strain. In addition, time until a diagnosis of AIDS, from initial clinical evaluation, could be accurately predicted based on the initial viral set point.[24]

Other triple combination therapies became possible with the introduction of non-nucleoside reverse transcriptase inhibitors (NNRTIs), which, when combined with two NRTIs, were very effective in suppressing HIV-1 replication.[27] NNRTIs are a group of structurally diverse agents with a reasonable toxicity profile that bind at a region distant from the active site, resulting in conformational changes at the active site of reverse transcriptase, thereby inhibiting its activity[8] (Fig. 2). They are highly specific inhibitors with potent antiviral activity in vitro and in vivo. When these agents are used as monotherapy, however, there is a rapid emergence of resistant viral strains associated with single point mutations in the reverse transcriptase gene.[26] The introduction of abacavir, a potent NRTI, also facilitated the use of triple NRTI regimens that have the advantages of not including a protease inhibitor, which have many adverse side effects, and of requiring fewer pills per day. However, questions about the potency of triple NRTI regimens compared with protease inhibitor-containing regimens have been raised.[27]