Pediatric HIV Infection Medication

Antiretroviral drugs (ARDs) are used for the treatment of human immunodeficiency virus (HIV) infection and for postexposure prophylaxis (PEP). ARD monotherapy does not produce sustained clinical benefits, such as improved survival. This failure is partly due to the development of drug-resistant variants of HIV. Resistance develops rapidly during monotherapy, and cross-resistance among related drugs is common.

Combination therapy with ARDs (a strategy analogous to the treatment of TB and other infectious diseases) has improved efficacy, minimized toxicity, and delayed drug resistance.

Six classes of ARDs currently exist, as follows:

• Nucleoside or nucleotide reverse transcriptase inhibitors (NRTIs)
• Nonnucleoside reverse transcriptase inhibitors (NNRTIs)
• Protease inhibitors (PIs)
• Integrase inhibitors (IIs)
• Fusion inhibitors (FIs)
• Chemokine receptor antagonists (CRAs)

Initial therapy should be started with a combination of 3 ARDs, including a backbone of 2 NRTIs plus an NNRTI or a protease inhibitor.

As of 2010, 17 ARDs have been approved for pediatric usage and 15 are available as a pediatric formulation or capsule size. The generally preferred recommendation for children includes a combination antiretroviral regimen in previously untreated children with 1 non-NRTI (NNRTI) or 1 PI combined with a 2-drug NRTI combination. It recommends using a 3-drug NRTI regimen only when an NNRTI or a PI cannot be used as first-line treatment.^[29]

PI-based regimens have a few advantages over others, namely excellent virologic potency, a high genetic barrier for the development of resistance, and sparing of the NNRTI class of medications.

One study evaluated the use of lopinavir/ritonavir combination therapy in children younger than 6 years with HIV type 1 infection who have not undergone highly active antiretroviral therapy (HAART). Seventy percent of the 43 children in the study realized a virologic success at month 12. Overall, 20 children experienced virologic failure; risk factors for virologic failure were determined to be young age and low socioeconomic status.^[33]

If abacavir is to be used, genetic testing must be undertaken to determine if the patient carries the HLA B5701 genotype. This genotype carries with it a potentially life-threatening drug-associated hypersensitivity reaction to abacavir.

The following antiretroviral regimens are generally not recommended and should be considered only in unique exceptions:

• Monotherapy
• Two NRTIs alone
• Tenofovir plus abacavir plus lamivudine or emtricitabine as a triple-NRTI regimen
• Tenofovir plus didanosine plus lamivudine or emtricitabine as a triple-NRTI regimen

The goal of therapy in treatment-naive children is to reduce the level of HIV RNA levels to below detectable levels. Additionally, infants who have been receiving zidovudine chemoprophylaxis during the first 6 weeks of life and who are diagnosed as HIV-infected during this period should have zidovudine monotherapy discontinued. Antiretroviral resistance testing is recommended for all treatment-naive children prior to the initiation of treatment.

In addition to ARDs, other types of medication are required as appropriate for specific infections or malignancies. For example, Pneumocystis jiroveci pneumonia prophylaxis is recommended in patients who are HIV positive and younger than 1 year and in older children based on CD4⁺ counts.

Class Summary

NRTIs are nucleoside or nucleotide reverse transcriptase inhibitor analogs with antiretroviral activity. They are indicated for the treatment of HIV infection, and they delay the progression of the disease.

Abacavir (ABC, Ziagen)

Patients and parents must be cautioned about the risk of serious hypersensitivity reaction. Provide a medication guide and warning card.

Didanosine (ddI, dideoxyinosine, Videx, Videx EC)

This agent is a purine nucleoside analog with antiviral activity.

Lamivudine (3TC, Epivir, Epivir HBV)

Lamivudine is a dideoxynucleoside analog with antiretroviral activity. In combination with oral zidovudine, it produces substantial and sustained increases in CD4+ counts and decreases in viral load in HIV-infected patients. It is also approved by the US Food and Drug Administration (FDA) to treat hepatitis B.

Stavudine (d4T, Zerit)

Stavudine is a synthetic thymidine nucleoside analog active against HIV-1.

Zidovudine (ZDV, AZT, Retrovir)

This agent is a thymidine analog that inhibits viral replication. It inhibits activity of HIV reverse transcriptase by competing with natural substrate for use by and incorporation into viral DNA.

Emtricitabine (FTC, Emtriva)

A synthetic nucleoside cytosine analog, emtricitabine competes with deoxycytidine-5'-triphosphate and incorporates into viral DNA, causing chain termination.

Tenofovir disoproxil fumarate (TDF, Viread)

This antiretroviral agent used in treatment of AIDS inhibits activity of HIV reverse transcriptase by competing with natural substrate deoxyadenosine 5'-triphosphate and, after incorporation into DNA, by causing DNA chain termination. It is administered as prodrug bis-isopropoxycarbonyloxymethyl ester derivative of tenofovir, which is converted, in various enzymatic processes, to tenofovir, an acyclic nucleoside phosphonate (nucleotide) analog of adenosine 5'-monophosphate.

Administration with a high-fat meal enhances bioavailability. Prolonged intracellular levels allows for once-daily dosing.

Etravirine (Intelence)

Indicated in combination with other antiretroviral agents (ART) for treatment of HIV-1 infection in ART-experienced patients with evidence of viral replication and HIV-1 strains resistant to a NNRTIs and other antiretroviral agents.

Class Summary

NNRTIs inhibit both DNA-directed and RNA-directed polymerase functions of HIV-1 reverse transcriptase. The different sites of action of nonnucleoside and nucleoside inhibitors suggest potential synergistic effects of these agents and their potential activity against nucleoside-resistant HIV strains.

Delavirdine (DLV, Rescriptor)

Delavirdine is a potent NNRTI used primarily in combination regimens.

Efavirenz (DMP-266, EFV, Sustiva)

Efavirenz is used only in combination regimens.

Nevirapine (NVP, Viramune, Viramune XR)

Nevirapine is indicated for use in combination with other ARDs for treatment of HIV-1 infection.

Class Summary

Protease inhibitors inhibit HIV protease, which is required for HIV replication and the formation of mature, infectious viral particles.

Indinavir (Crixivan, IDV)

This agent prevents formation of protein precursors necessary for HIV infection of uninfected cells and viral replication.

Nelfinavir (Viracept, NPV)

Nelfinavir inhibits HIV-1 protease, resulting in the production of an immature and noninfectious virus.

Ritonavir (Norvir, RTV)

Ritonavir is an HIV protease inhibitor used as part of double or triple therapy with nucleosides and other protease inhibitors.

Saquinavir (SQV, Invirase)

Saquinavir is an HIV protease inhibitor used as part of double or triple therapy with nucleosides and other protease inhibitors. It is available as a 200-mg hard gel cap or 500-mg film-coated tablet.

Lopinavir and ritonavir (Kaletra, LVP/r)

Lopinavir inhibits HIV protease and renders enzyme incapable of processing polyprotein precursors, leading to production of noninfectious, immature HIV particles. Ritonavir inhibits CYP3A metabolism of lopinavir, increasing plasma levels. This product is available in tablets (200 mg/50 mg LPV/r), pediatric tablets (100 mg/25 mg LPV/r), and PO solution (80 mg/20 mg LPV/r; 42.4% alcohol by volume).

Atazanavir (ATV, Reyataz)

Atazanavir is an azapeptide HIV-1 protease inhibitor. It prevents virion maturation by selectively inhibiting Gag and Gag-Pol polyproteins in HIV-1 infected cells.

Darunavir (DRV, TMC-114, Prezista)

An HIV-1 protease inhibitor, darunavir selectively inhibits HIV-encoded Gag-Pol polyprotein cleavage in infected cells, preventing formation of mature virus particles. It is indicated to treat HIV disease not responding to other ARDs. Coadminister with low-dose ritonavir (ritonavir-boosted therapy decreases elimination and increases darunavir serum concentration).

Darunavir is typically coadministered with other anti-HIV agents (eg, NRTIs). Food increases maximum concentration (Cmax) and area under the concentration-time curve (AUC). It is indicated to treat HIV infection in ART–experienced adults (eg, those with HIV-1 strains resistant to >1 protease inhibitor).

Fosamprenavir (f-APV, Lexiva)

A prodrug of amprenavir (inhibitor of HIV protease), fosamprenavir is rapidly converted to amprenavir by cellular phosphatases in vivo. Amprenavir inhibits HIV-1 protease and binds its active site, preventing the processing of viral Gag and Gag-Pol polyprotein precursors and resulting in immature, noninfectious viral particles.

Tipranavir (TPV, Aptivus)

A nonpeptidic protease inhibitor, tipranavir inhibits HIV replication. It is indicated for combination ART of HIV-1 infection in adults with evidence of viral replication and who are highly treatment experienced or who have strains resistant to several protease inhibitors. This agent must be coadministered with ritonavir 200 mg to attain therapeutic levels. It is ineffective if used alone without ritonavir-boosted levels. Results of genotypic or phenotypic testing and/or treatment history should guide use. It is available as 250 mg caps or as PO solution of 100 mg/mL.

Class Summary

These agents disrupt HIV binding and, ultimately, fusion with host cells. Entry inhibitors bind to CCR5 chemokines coreceptors. Fusion inhibitors bind to the HR1 region of gp41.

Enfuvirtide (T-20, Fuzeon)

Enfuvirtide is the sole available fusion inhibitor. It blocks entry of HIV into human immune cells by inhibiting gp41 protein, disrupting viral structural rearrangement to fuse with healthy immune cells and preventing HIV replication. In clinical trials, selected patients with multidrug resistance were twice as likely to achieve undetectable HIV-1 plasma levels (< 40 copies/mL) when enfuvirtide was added to optimized antiretroviral regimens.

Maraviroc (MVC, Selzentry)

Maraviroc blocks viral entry via CCR5 co-receptor into host cells, reduces viral load, and increases T-cell counts in CCR5-tropic HIV-1 (ie, R5 virus). This agent is indicated for combination treatment with optimized background therapy in treatment-experienced adults infected with only R5 virus who have evidence of viral replication and have HIV-1 strains resistant to multiple antiretroviral agents.

Class Summary

HIV integrase is responsible for the transport and attachment of proviral DNA to host-cell chromosomes, allowing transcription of viral proteins.

Raltegravir (RAL, Isentress)

Raltegravir is an HIV-1integrase strand transfer inhibitor (INSTI). It is indicated for use in combination therapy regimens for the treatment of HIV infection.