Antiretroviral Classes

Currently, there are four classes of andretroviral agents available in the United States for clinical use  

Nucleoside analogue reverse transcriptase inliibitors (NRHs), Nounucleoside analogue reverse ti ansciiptase inliibitors (NNRTIs), Protease inliibitors (Pis), 

NRTIs are phosphorylated and converted into diphosphate forms by nucleoside kinases. These acdvated forms have high levels of afdnity for HTV-1 reverse d anscriptase and compete with the natural deoxynucleoside diphosphates. Once incorporated into the growing chain of DNA, lack of a 3 -hydroxyl group that can form a phosphodiester bond with the incoming nucleoside causes chain terminadon. Tenofovir is an exception in this group as it is a nucleotide analogue rather than nucleoside and, as such, requires only tw o phosphorylation steps instead of three to become the active form. Pharmacological characteristics of FDA approved NRTIs are presented in Table 41.3. 

NNRTIs are drugs of diverse chemical sdructure that act by non-competitive inhibition of HTV-1 reverse d anscriptase. They do not require ind acellular phosphorylation to be activated. NNRTIs inhibit the enzyme aliosterically by binding 

Generic/hade name (abbreviation) How supplied Usual adult dose Major adverse effects Ratio of CSF level to 

Nucleoside analogue reverse transcriptase inhibitors (NRTIs), Nonnucleoside analogue reverse transcriptase inhibitors (NNRTls), Protease inhibitors (Pis), 

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Manfredi R, Sabbatani S. 2006. A novel antiretroviral class (fusion inhibitors) in the management of HIV infection. Present features and future perspectives of enfuvirtide (T-20). Curr Med Chem. 13 2369-2384. 

So far, five different protease inhibitors have been approved by the FDA for the treatment of HIV infection [3, 4]. Clinical trials in which protease inhibitors were evaluated in monotherapy demonstrated the potency of this class of inhibitors (decrease in HIV RNA levels, increase in CD4 cell counts). Treatment regimens were subsequently broadened to include reverse transcriptase inhibitors in combination with protease inhibitors. The result of these clinical trials has led to a list of guidelines with recommendations for the optimal treatment options. Prolonged control of the infection with combination therapy (highly active antiretroviral therapy, HAART ) could be shown. 

Two classes of entry inhibitors have been developed. The first entry inhibitor approved as HIV therapy was enfuvirtide, a fusion inhibitor. In contrast with aU other antiretrovirals, this drug must be administered subcutaneously and twice a day, which represent important disadvantages to the patient. It is very potent and generally reserved for heavily antiretroviral-experienced patients with virologic failure. Unfortunately enfuvirtide shows a low genetic barrier for resistance (Fig. 2) and should be administered in combination with at least one other active drug. 

D/C all antiretrovirals as well as any other possible cause aggressive symptom support do not rechallenge patient with offending agent if caused by NVP, avoid NNRTI class, if possible... 

Balzarini J, Holy A, Jindrich J, Dvorakova H, Hao Z, Snoeck R, Herdewijn P, Johns DG, De Clercq E. 9-[(2RS,)-3-Fluoro-2-phosphonylmcthoxypropyl] derivatives of purines a class of highly selective antiretroviral agents in vitro and in vivo. Proc Natl Acad Sci USA 1991 88 4961-4965. 

The development of antiretroviral therapy has been a major challenge since the discovery of the human inununodeficiency virus (HIV). Early successes with nucleoside and non-nucleoside reverse transcriptase (RT) inhibitors, as well as the development of protease inhibitors have facilitated, in recent years, a highly active antiretroviral therapy (HAART), where a combination of drugs is simultaneously administered. In spite of significant improvements in the morbidity and mortality of HIV-infected patients, the rapid appearance of resistant HIV-variants, as well as adverse effects and high cost of contemporary drugs necessitate the continuous development of independent classes of anti-HIV agents. ... 

Protease inhibitors, a class of antiretroviral drugs used in the management of HIV infection, are associated with a high risk of drug interactions largely... 

This class of antiretrovirals may be considered the most potent therapeutic agents for HIV to date. Protease inhibitors are used in combination regimens and combinations of reverse-transcriptase inhibitors and protease inhibitors have been proven most effective to decrease viral load and prolong survival. However, the protease inhibitors generally show poor penetration into the CNS and thus have no effect on aids dementia. The present Pis available for the treatment of HIV are indinavir, ritonavir, nel-finavir, saquinavir and (fos)amprenavir, atazanavir and lopinavir (in combination with ritonavir as ritonavir improves the bioavailability of lopinavir by inhibiting its metabolism in the liver by CYP3A). 

Resistance to enfuvirtide can occur as a result of mutations in gp41 codons the frequency and significance of this phenomenon are being investigated. However, enfuvirtide lacks cross-resistance to the other currently approved antiretroviral drug classes. 

Although virologic failures have been uncommon in clinical trials of raltegravir to date, in vitro resistance requires only a single point mutation (eg, at codons 148 or 155). The low genetic barrier to resistance emphasizes the importance of combination therapies and of adherence. Integrase mutations are not expected to affect sensitivity to other classes of antiretroviral agents. 

Enfuvirtide (formerly called T-20) is a newly approved antiretroviral agent of a novel class, ie, a fusion inhibitor that blocks entry into the cell. Enfuvirtide, a synthetic 36-amino-acid peptide, binds to the gp41 subunit of the viral envelope glycoprotein, preventing the conformational changes required for the fusion of the viral and cellular membranes. 

In a decade of extensive research, we have made great progress in the identification of novel anti-HIV drugs, which has led to the discovery of bevirimat, a compound representing a completely new class of antiretroviral agents that block HIV-1 replication by disrupting virus maturation. Bevirimat is currently in Phase lib clinical development and has a great potential to offer a valuable new option for the treatment of HIV/AIDS. 

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