Classification of Antiretroviral Agents

Antiretroviral agents are synthetic antiviral drugs with activity against human immunodeficiency virus (HIV) and are used to manage HIV infection. Five classes of antiretroviral agents are currently commercially available: nucleoside reverse transcriptase inhibitors (NRTIs), HIV protease inhibitors, non-nucleoside reverse transcriptase inhibitors (NNRTIs), nucleotide reverse transcriptase inhibitors, and HIV fusion inhibitors. These agents are often used in combination to suppress viral replication and reduce the risk of resistance.

Nucleoside reverse transcriptase inhibitors

• abacavir sulfate (ABC)
• didanosine (ddI)
• emtricitabine (FTC)
• lamivudine (3TC)
• stavudine (dT)
• zalcitabine (ddC)
• zidovudine (ZDV, AZT)

NRTIs are synthetic analogues of naturally occurring nucleosides. Seven NRTIs are currently commercially available. These drugs have a broader spectrum of antiviral activity than other currently available antiretroviral agents, and NRTIs are active in vitro against human retroviruses, including HIV type 1 (HIV-1) and HIV type 2 (HIV-2). In addition, abacavir, didanosine, zalcitabine, and zidovudine are active against many animal retroviruses, including feline leukemia virus, Friend leukemia virus, Harvey murine sarcoma virus, murine leukemia virus, and simian T lymphotropic virus. Abacavir, didanosine, lamivudine, zalcitabine, and zidovudine have some activity against hepatitis B virus; however, NRTIs have generally been inactive against other human or animal viruses tested, including herpes simplex virus types 1 and 2, influenza virus, adenovirus, cytomegalovirus, respiratory syncytial virus, varicella-zoster virus, and vaccinia virus.

NRTIs are inactive until they are phosphorylated by cellular enzymes and converted into active triphosphate metabolites. The pharmacologically active triphosphate metabolites then compete with naturally occurring deoxynucleoside triphosphates for the active binding site on viral reverse transcriptase, an enzyme essential for viral replication. Once the triphosphate metabolites are incorporated into viral DNA, synthesis of the viral DNA chain is terminated because the metabolites lack a functional 3-hydroxyl group, which prevents further 5 to 3 phosphodiester linkages. This chain-termination effect is central to their antiviral activity.

HIV protease inhibitors

• amprenavir (VX-478)
• atazanavir sulfate (ATV)
• fosamprenavir calcium
• indinavir sulfate (IDV, MK-639)
• lopinavir and ritonavir (ABT-378/r)
• nelfinavir mesylate (AG1343)
• ritonavir (RTV, ABT-538)
• saquinavir (SQV, RO 31-8959)

HIV protease inhibitors are synthetic antiviral agents that were designed specifically based on the structure of HIV protease, an enzyme that plays an essential role in the HIV replication cycle. Computer models of the enzyme and its binding sites have helped identify a wide variety of compounds as potential inhibitors of HIV protease activity. Eight HIV protease inhibitors are currently commercially available, and many more are under investigation.

HIV protease inhibitors have a very limited spectrum of activity. The drugs are active against HIV-1 and some (but not all) are active, to a lesser extent, against HIV-2. Indinavir and saquinavir have some activity against simian immunodeficiency virus; however, HIV protease inhibitors have generally been inactive against other human and animal viruses tested. On a molar basis, HIV protease inhibitors appear to be more active than either NRTIs or NNRTIs against susceptible HIV-1.

Currently available HIV protease inhibitors have similar mechanisms of action. These drugs inhibit replication of HIV-1 and HIV-2 by directly interfering with HIV protease activity, which results in the formation of non-infectious immature virions. Most of the drugs act as selective, competitive, reversible inhibitors of the enzyme. Unlike NRTIs, the antiretroviral activity of most HIV protease inhibitors does not depend on intracellular conversion to an active metabolite. Because of their potency, these agents are key components of many combination regimens.

Non-nucleoside reverse transcriptase inhibitors

• delavirdine mesylate (DLV)
• efavirenz (EFV, DMP 266)
• nevirapine (NVP)

NNRTIs are a group of structurally diverse antiretroviral agents with a similar mechanism of action. Three NNRTIs are currently commercially available, and many more are under investigation.

NNRTIs have a very specific spectrum of activity. Currently available NNRTIs are active against HIV-1 but are inactive against HIV-2 and have also been inactive against all other human or animal viruses tested to date.

NNRTIs inhibit replication of HIV-1 by interfering with the viral RNA- and DNA-directed polymerase activities of reverse transcriptase. The mechanism of action of NNRTIs differs from that of NRTIs. While NRTIs interfere with reverse transcriptase activity by becoming incorporated into the growing viral DNA chain, NNRTIs interfere with reverse transcriptase function by binding directly to the enzyme in a non-competitive fashion. Unlike NRTIs, the antiretroviral activity of HIV NNRTIs does not depend on intracellular conversion to an active metabolite. This distinction has important implications for resistance patterns and combination therapy.

Nucleotide reverse transcriptase inhibitors

• tenofovir disoproxil fumarate

Nucleotide reverse transcriptase inhibitors are a group of acyclic nucleoside phosphonates with a similar mechanism of action. Tenofovir disoproxil fumarate is currently the only nucleotide reverse transcriptase inhibitor commercially available, but others are under investigation. For the purposes of therapeutic decisions, tenofovir is grouped with the NRTI class of antiretroviral agents.

Tenofovir disoproxil fumarate is inactive until it is hydrolyzed in vivo to tenofovir, then phosphorylated by cellular enzymes and converted into tenofovir diphosphate. The diphosphate competes with naturally occurring deoxyadenosine triphosphate and, after incorporation into viral DNA, synthesis of the viral DNA chain is terminated. This mechanism closely parallels that of other reverse transcriptase chain terminators.

HIV fusion inhibitors

• enfuvirtide (T-20)

HIV fusion inhibitors are synthetic antiviral agents that interfere with fusion of HIV-1 to its target cell. Enfuvirtide is currently the only HIV fusion inhibitor commercially available, but others are under investigation.

HIV fusion inhibitors have a very specific spectrum of activity. HIV fusion inhibitors are active against HIV-1 but are inactive against HIV-2.

HIV fusion inhibitors interfere with entry of HIV-1 into target cells by blocking conformational changes in the HIV-1 glycoprotein that are required for fusion of the virus with the membrane of the host CD4+ T cell. By preventing this fusion step, these agents help block the initial stages of viral infection of new cells.