Antiretroviral Drugs

Antiretrovirals are a group of drugs that are used in the treatment of HIV infected individuals to decrease the viral burden. They are potent inhibitors of viral replication. As of August 2010, 22 antiretroviral drugs are approved for use in HIV-infected adults and adolescents; 17 of these have an approved pediatric treatment indication and 15 are available as a pediatric formulation or capsule size. These drugs fall into 3 major classes – Nucleoside Reverse Transcriptase Inhibitors (NRTIs), Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs) and Protease Inhibitors (PIs).

Nucleoside Reverse Transcriptase Inhibitors (NRTIs)

The NRTIs were the first class of antiretroviral drugs that became available for treatment of HIV. They inhibit the reverse transcriptase enzyme (See the Chapter on Transmission and Pathogenesis). They have activity against both HIV-1 and HIV-2. The parent compounds need to undergo intracellular phosphorylation to become active against HIV. NRTIs act by competing with normal nucleoside triphosphates for incorporation into the growing proviral DNA chain. The abnormal nucleoside prevents the addition of further nucleosides to the chain, and viral replication ceases. Dual NRTI is the backbone of current combination of various antiretroviral therapies.
Drugs in this class include:

• Zidovudine (AZT/ZDV)
• Lamivudine (3TC)
• Stavudine (d4T)
• Didanosine (ddI)
• Abacavir (ABC)
• Zalcitabine (ddC) - It is not available in India.
• Emtricitabine (FTC)
• Tenofovir (TDF)

 – It is a nucleotide reverse transcriptase inhibitor (NtRTI). It affects the bone mineral density thus potentially limiting its use in pre-pubertal children. It also acts against Hepatitis B.

Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs)

NNRTIs  were the second class of anti-HIV agents to be developed. The parent compounds are the active moieties, and are therefore immediately active on entering the cell. They inhibit HIV-1 reverse transcriptase by binding to a hydrophobic pocket on the enzyme close to the active site, thereby locking the enzyme in an inactive conformation. The NNRTI class of drugs rapidly reduce viral load; however drug resistance develops quickly after initiation of monotherapy and cross-resistance between drugs in this class is common. There are currently 3 NNRTIs used for treatment of HIV infection.

• Nevirapine (NVP)
• Efavirenz (EFV)
• Etavirine:

It was approved in January 2008 in adults and is considered a ‘second generation’ NNRTI, in part because it retains activity against HIV-1 isolates which are resistant to other NNRTIs.Stavudine (d4T)

Protease Inhibitors (PIs)

The PIs inhibit the protease enzyme (See chapter on Transmission and Pathogenesis) by binding to the active site of the enzyme, thus preventing cleavage of precursor polyproteins at a late stage of viral replication. Virions are produced, but they are incomplete and non-infectious. PIs were the third class of ARVs to be developed. They are highly potent. They are active against both HIV-1 and HIV-2. PIs have a high genetic barrier to resistance, and PI resistance at regimen failure is uncommon.
The various PIs used for treatment of HIV infection are:

• Nelfinavir (NFV)
• Ritonavir (RTV)
• Lopinavir / Ritonavir (LPVr)
• Amprenavir
• Indinavir (IDV)
• Saquinavir (SQV)
• Atazanavir
• Darunavir
• Tipranavir

Low-dose ritonavir (RTV), itself a potent PI acts as a potent inhibitor of the cytochrome P450 3A4 (CYP3A4) isoenzyme, thereby inhibiting the metabolism of other PIs, and has been used in low doses combined with another PI as a “pharmacokinetic booster,” increasing drug exposure by prolonging the second drug’s half-life. Boosted PI-based regimens are commonly used in treatment of adults, but adequate pediatric data are only available for co-formulated lopinavir/ritonavir in children older than 6 weeks of age and for atazanavir, fosamprenavir, darunavir, and tipranavir with low-dose ritonavir in children age >6 years.

Protease Inhibitors (PIs)

The PIs inhibit the protease enzyme (See chapter on Transmission and Pathogenesis) by binding to the active site of the enzyme, thus preventing cleavage of precursor polyproteins at a late stage of viral replication. Virions are produced, but they are incomplete and non-infectious. PIs were the third class of ARVs to be developed. They are highly potent. They are active against both HIV-1 and HIV-2. PIs have a high genetic barrier to resistance, and PI resistance at regimen failure is uncommon.
The various PIs used for treatment of HIV infection are:

• Nelfinavir (NFV)
• Ritonavir (RTV)
• Lopinavir / Ritonavir (LPVr)
• Amprenavir
• Indinavir (IDV)
• Saquinavir (SQV)
• Atazanavir
• Darunavir

New Classes of Antiretroviral drugs
Entry Inhibitors
These agents inhibit viral binding or fusion to host target cells. T-20 (Enfurvirtide) is the drug currently used and has to be given subcutaneously twice daily and is to be used only in children > 6 years of age. It is a 36 amino acid peptide that binds to a region of the gp41 glycoprotein on the HIV cell surface and prevents virus-cell fusion. It is used as part of salvage regime in patients who have multi-antiretroviral therapy regime failures.

CCR5 co-receptor antagonist
Maraviroc blocks the chemokine CCR5 coreceptor on the CD4 cell surface thereby preventing HIVfrom entering the cell. This was the first antiretroviral drug to be developed that does not actually target the virus itself. Maraviroc is effective as part of Combination therapy in patients with multi-drug-resistant HIV-1. Before starting treatment with this drug, however, it is necessary to check for CCR5 or CXCR4 virus tropism. CCR5 antagonists will be inactive against CXCR4-tropic virus. Maraviroc is not yet routinely used in young children, but may be used in adolescents. There are considerable interactions with both PI and NNRTI classes, requiring alteration in maraviroc dosing depending on other drugs in the regimen.

Integrase Inhibitors
They block the integrase enzyme (See Chapter on Transmission and Pathogenesis) thereby preventing incorporation of viral DNA into human genome. Raltegravir and elvitegravir are integrase strand-transfer inhibitors (INSTIs). These drugs have been found to be useful in the treatment of patients with multi-drug-resistant HIV-1. Raltegravir is being evaluated in treatment-experienced children, but pharmacokinetic, safety, and efficacy data are not yet available and no pediatric formulation is commercially available.

Dosage recommendations of various ARVs
Dosing of various ARVs are based as per weight or surface area in children. The doses are depicted in Table 3.