Review
Antiretroviral therapy of HIV-1 infection: established treatment strategies and new therapeutic options

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Abstract

Recently, studies have shown that non-nucleoside reverse transcriptase inhibitors, such as efavirenz or nevirapine, in combination with two nucleoside analogues have an antiretroviral potency comparable to protease inhibitor containing regimens. Triple combination therapy that includes a non-nucleoside reverse transcriptase inhibitor can therefore be regarded as an effective alternative first-line treatment of HIV-1 infection.

Introduction

For a decade, therapeutic options against HIV-1 infection were limited, consisting only of a single class of drugs, the nucleoside analogue reverse transcriptase inhibitors (nRTIs). The impact of these agents on plasma HIV-1 RNA levels was modest and the development of serious immunodeficiency inevitable. This unsatisfactory situation was dramatically changed with the introduction of inhibitors of the HIV-1 protease. These agents inhibit the cleavage of gag–pol polyproteins. The administration of two nRTIs and a protease inhibitor (PI) in combination resulted in sustained reductions of plasma HIV-1 RNA levels and larger increases of CD4+ T lymphocytes than had been seen with nucleoside analogue therapy [[1], [2]]. Consequently, triple combination therapy using any three drugs was termed highly active antiretroviral therapy (HAART). The widespread use of HAART was associated with an impressive decline in the morbidity and mortality of HIV-1 infected subjects [3], [4], [5]. In the past two years, new antiretroviral drugs have become available and different treatment strategies have been investigated, increasing the number of possible treatment options. In this review, we focus on these new antiretroviral therapeutic options.

Section snippets

Antiviral and immunological effects of HAART

Antiretroviral therapy aims to reduce the viral burden and ultimately, to eradicate HIV-1 infection. Typically, plasma HIV-1 RNA declines in a biphasic pattern in subjects on HAART (Fig. 1), reaching undetectable levels in 50–90% of individuals. The virological response strongly depends on the previous drug history, presumably reflecting the extent of any prior selection of drug-resistant mutants as a result of suboptimal therapy.

Recent studies provided evidence that replication competent virus

Treatment strategies

Currently available classes of antiretroviral drugs include nucleoside reverse transcriptase inhibitors (nRTIs), PIs and non-nucleoside reverse transcriptase inhibitors (nnRTIs) (Table 1). Detailed recommendations on the use associated with these drugs have been provided by several international panels of specialists [24], [25], [26].

Nucleoside analogue reverse transcriptase inhibitors

Mono- or dual regimens of nRTI are now considered to be obsolete, because they usually only lead to transient reductions of plasma HIV-1 RNA and rapid emergence of drug-resistant virus. Several studies have shown that the antiviral response to a combination of two nRTIs, or one protease inhibitor and one nRTI is inferior to that of a regimen consisting of one protease inhibitor and two nRTIs [[1], [2], [27], [28], [29]]. Similarly, sequential combination therapy, starting with one or two drugs

Protease inhibitors

Available protease inhibitors include soft-gel saquinavir, ritonavir, indinavir, nelfinavir and amprenavir. The previous hard-gel formulation of saquinavir showed a poor bioavailability of 4% and should only be used in combination with ritonavir, which inhibits the metabolism of saquinavir to compensate for the poor bioavailability, increasing concentrations up to 20-fold. Clinical data on amprenavir are still very limited. A new protease inhibitor lopinavir (ABT 378) is currently under

Non-nucleoside analogue reverse transcriptase inhibitors

An alternative treatment option is the combination of two nRTIs with an nnRTI such as efavirenz, nevirapine or delavirdine. Efavirenz in combination with zidovudine and lamivudine showed a profound antiviral response in antiretroviral naı̈ve patients, similar to the response seen with indinavir-containing triple therapy [42]. At week 48 of treatment, 64% of subjects treated with the efavirenz-containing triple therapy and 43% of those treated with the indinavir-containing triple therapy had

Initiation of HAART

In view of the rapid evolution of viral diversity and the continuous dissemination of HIV-1 to all body compartments, early aggressive therapy has been promulgated. Certain authorities recommend commencement of therapy during primary HIV-1 infection. An early initiation of HAART leads to sustained antiviral responses and a rapid recovery of the immune system [[48•], [49•]]. On the other hand, it has to be considered that is difficult to maintain good adherence to the drug regimen over many

Salvage regimens

The chance of a good virological response to a second or third drug regimen is considerably lower than to the first therapy, suggesting either that the initial drug regimen should be as potent as possible, providing a durable response, or that the most potent classes of drugs should be saved for later. The selection of salvage regimens may be improved by drug resistance tests. In one study, the reduction of plasma HIV-1 RNA levels was larger and the proportion of subjects with plasma HIV-1 RNA

Induction/maintenance strategy

Three induction/maintenance studies have been published [[55•], [56], [57]]. Induction/maintenance studies involve the use of a potent therapy to induce viral remission (three to four drugs), followed by a less intense therapy (two drugs) to maintain the patient in remission. In two of the studies, triple combinations were used for induction therapy, consisting of indinavir and two nRTIs. In the third study, induction therapy consisted of saquinavir, nelfinavir and two nRTIs. The drugs used in

Limitations of HAART

Drug resistance occurs frequently and is responsible for a large proportion of treatment failures. Poor adherence to the drug regimen has been shown to be an important co-factor for treatment failure and might facilitate the selection of drug resistant HIV-1. Patient counselling, therefore, appears to be crucial to optimise antiretroviral therapy.

Protease inhibitors and nnRTIs are both metabolized by CYP450 enzymes, resulting in complex pharmacokinetic interactions that alter the metabolism of

Conclusions and future trends

The failure to eradicate HIV-1 infection indicates that long-term or even life-long antiretroviral therapy is required. This observation emphasises the need for a well tolerated drug regimen with simple dosage schedules that provides a durable therapeutic response. Current treatment guidelines recommending combinations of protease inhibitors and nRTIs are based on the extensive experience with these therapies. However, recent studies provided evidence that the protease inhibitor may be

Acknowledgements

The National Centre in HIV Epidemiology and Clinical Research is funded by the Commonwealth Department of Health and Aged Care, through the Australian National Council on AIDS and Related Diseases (ANCARD). We thank John Zaunders, Mark Bloch and Don Smith for carefully reading the manuscript.

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • radical dot of special interest

  • radical dotradical dot of outstanding interest

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