Antiretroviral Therapy: Current Drugs

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Key points

  • To date, 28 antiretroviral drugs have been approved by the Food and Drug Administration.

  • Effective combination antiretroviral therapy can durably suppress human immunodeficiency virus (HIV) viremia and has dramatically improved HIV-associated morbidity and mortality.

  • For antiretroviral treatment-naïve patients, a combination regimen typically consists of 2 nucleoside reverse transcriptase inhibitors plus a third drug.

  • Because of the increased number of options, the selection of an antiretroviral

Goals and principles of antiretroviral therapy

The key goals of antiretroviral therapy are to

  • Achieve and maintain suppression of plasma viremia to less than the current assays’ level of detection

  • Improve overall immune function as demonstrated by increases in CD4+ T-cell count

  • Prolong survival

  • Reduce HIV-associated morbidity

  • Improve overall quality of life

  • Reduce risk of transmission of HIV to others

In order to achieve these goals, the clinicians and patients must recognize several key principles:

  • Current antiretroviral regimens do not eradicate

HIV life cycle and targets of antiretroviral drug therapy

Fig. 1 illustrates the different steps of the HIV life cycle and drug targets (adapted from http://www.niaid.nih.gov/topics/HIVAIDS/Understanding/Biology/pages/hivreplicationcycle.aspx).7 HIV virions enter the CD4+ T cells and use the CD4 cells as the machinery for reproduction of new virions. The currently approved antiretroviral drugs aim at halting viral replication at 6 different stages of the HIV life cycle. Table 2 lists the drugs approved by the Food and Drug Administration (FDA) within

Rationale for combination antiretroviral therapy

As described earlier, HIV replication requires a multistep process. Using a combination of different agents targeting different steps within the HIV life cycle provides either a synergistic or additive antiviral effect, thus enhancing the efficiency in which viral replication is suppressed. Based on data from large randomized clinical trials, 4 different combinations are commonly prescribed to treatment-naïve patients. All these combinations include a backbone of 2-NRTIs, plus one of these

NRTIs

The NRTIs are the first class of antiretroviral drugs approved for use in the United States and remains as a key component of most combination regimens.8 The NRTIs are phosphorylated intracellularly to their active diphosphate or triphosphate metabolites, which then inhibit the enzymatic action of the HIV reverse transcriptase by incorporating into the nucleotide analogue causing DNA chain termination or by competing with the natural substrate of the virus. This process in turn halts the

NNRTIs

NNRTIs are different from NRTIs in that they do not require intracellular phosphorylation to exert their pharmacologic action. NNRTIs are noncompetitive inhibitors of reverse transcriptase, which results in a conformational change and, thus, decreases the action of this enzyme.

NNRTIs are potent agents for virologic suppression but are limited by drug interactions, selected side effects, and overall low threshold for the emergence of resistant mutants (exception is etravirine). All of the NNRTIs

PI

PIs exhibit their pharmacologic action late in the HIV replication cycle by binding to HIV proteases, leading to blockage of the proteolytic activities of the enzyme, resulting in the inability to form mature, infectious virions. In combination with 2-NRTIs, certain ritonavir-boosted PI regimens are considered preferred therapies in treatment-naïve patients. PI plus NRTI combination regimens have shown to be effective not only in treatment-naïve patients but also with other antiretroviral

Integrase inhibitors

A decade after the introduction of then novel compounds, such as PI and NNRTI, raltegravir was introduced to the US market as the first INSTI with a novel mechanism of action (see Fig. 1 step 4). Integrase inhibitors block the integrase enzyme from catalyzing the formation of covalent bonds between the host and viral DNA; this in turn prevents the incorporation of viral DNA into the host chromosome. Currently, there are 3 licensed INSTIs (raltegravir, elvitegravir, and dolutegravir) on the US

CCR5 antagonist

Maraviroc is the only CCR5 antagonist approved for use in treatment-naïve or treatment-experienced patients with CCR5-using virus. It selectively binds to the human CCR5 receptor on the cell membrane, thus, blocking the interaction of the HIV gp120 and the CCR5 receptor for CCR5-tropic HIV. However, it does not block the viral entry of CXCR4-tropic HIV or HIV that uses both CCR5 and CXCR4 for cell entry. Before the prescription of maraviroc, viral tropism testing must be performed to confirm

Fusion inhibitor

The fusion inhibitor enfuvirtide interferes with this fusion process by binding to the first heptad-repeat (HR1) in the viral envelope glycoprotein gp41, thus, preventing conformational changes necessary for the fusion of the viral and cellular membrane.60 Because of its unique mechanism of action, there is no cross resistance with other antiretroviral drugs; thus, most patients who have not received enfuvirtide have found virologic benefit when enfuvirtide is added as part of a salvage regimen

Summary

The advances in antiretroviral drug development have dramatically changed the face of HIV infection worldwide from a deadly disease to a manageable chronic condition. Currently available antiretroviral drugs have greater potency, tolerability, and less pill burden than earlier agents. Understanding the potency of the drugs and drug regimens, toxicity profile, drug interaction potential, and resistance potential will help clinicians select a regimen most suitable for a specific patient.

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    Financial Disclosure: None.

    Jomy M. George is now with Virology US Medical Strategy, US Pharmaceuticals Medical Affairs, Bristol-Myers Squibb, 777 Scudders Mill Road, Plainsboro Township, NJ 08536, USA.

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