Prescribing Notes of HIV Infection

Although an optimum time to start antiretroviral therapy has not been established, the decision to treat is generally based on clinical symptoms and/or biological markers such as CD4 counts. The British HIV Association recommends that treatment should be initiated in patients before irreversible damage has been done to the immune system, i.e. CD4 counts above 350 cells/ml. Treatment should also be started in those with CD4 counts below 300 cells/mlwith or without viral loads greater than 10,000 to 50,000 HIV RNA copies/ml. Treatment should be considered for patients with viral loads below 10,000 copies/ml but with falling CD4 counts.

Combination therapy has proven superior to monotherapy and typical initial treatment regimens combine a thymidine nucleoside analogue (zidovudine or stavudine) with a non-thymidine nucleoside analogue ^ (didanosine, lamivudine or zalcitabine), except that stavudine and zalcitabine should not be used together because of the increased risk of peripheral neuropathy. The addition of a non-nucleoside reverse transcriptase inhibitor may significantly increase antiviral effect, while the addition of a protease inhibitor in the later stages of disease may also improve outcome. Alternatively, two protease inhibitors may be used for initial therapy for those intolerant of nucleoside analogues. The choice of agents will depend on many factors including previous drug exposure, source of infection, development of resistance, tolerability, concomitant medication and compliance. If initial treatment fails to reduce viral load by 10 fold within 8 to 12 weeks, modification of therapy should be considered.

Nucleoside Reverse

Transcriptase Inhibitors (NRTIs)

Abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, zalcitabine, zidovudine become active once phosphorylated by intracellular kinases to their triphosphate form. The triphosphates act as substrates for and competitive inhibitors of HIV reverse transcriptase. Also, as the monophosphate, they are then incorporated into viral DNA, but because formation of the phosphodiesterbridge_is inhibited, DNA chain termination occurs.

Non-Nucleoside Reverse

Transcriptase Inhibitors (NNRTIs)

Efavirenz and nevirapine bind directly to reverse transcriptase, causing structural alteration of the catalytic site, and blocking both RNA-dependent and DNA-dependent DNA polymerase activities, preventing HIV from replicating. Unlike earlier reverse transcriptase inhibitors they are not nucleoside analogues and are not incorporated into viral DNA.

Protease Inhibitors

Amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, ritonavir and saquinavir block the action of HIV protease rendering the enzyme incapable of processing the polyprotein required for production of mature HIV particles. As a result, the spread of HIV from cell to cell is slowed and disease progression is delayed. Their use may be associated with a syndrome of lipodystrophy, hyperlipidaemia and insulin resistance. At low doses, ritonavir is used to enhance the action of other protease inhibitors by inhibiting their metabolism by blocking CYP3A.

Fusion Inhibitors

Enfuvirtide binds to extracellular viral surface proteins blocking the fusion of the viral cell with human CD4 cells, thereby preventing viral RNA from entering the host's cell. Unlike existing, therapies that act on already infected cells, fusion inhibitors act on non-infected cells and are therefore active against HIV strains that have become resistant to these therapies.

CMV Retinitis in Aids

Dna Polymerase Inhibitors

Cidofovir, foscarnet, ganciclovir, valganciclovir exert their antiviral action in two stages, initially they become phosphorylated via viral thymidine kinase. The triphosphate form of the drug then acts as an inhibitory substrate for viral DNA polymerase enzymes preventing viral replication and causing chain termination without affecting normal cellular processes.

Cidofovir, in combination with probenecid, is indicated for the second line treatment of CMV retinitis in AIDS. Ganciclovir is indicated for CMV infections in immunocompromised conditions including AIDS, organ transplantation or chemotherapy. It may cause blood dyscrasias. Valganciclovir is an orally active prodrug of ganciclovir indicated for the treatment of CMV retinitis in AIDS patients. Following oral administration, it achieves equivalent plasma levels of the active antiviral agent as ganciclovir given via the intravenous route. Foscarnet is indicated for CMV infections where ganciclovir is contraindicated. It does not induce neutropenia but can cause nephrotoxicity, therefore adequate hydration should be ensured.

Oligonucleotides

Fomivirsen sodium inhibits CMV through an antisense mechanism. It binds to mRNA of CMV and prevents it from encoding the proteins which control viral gene expression and viral replication. It is indicated as second line treatment of CMV retinitis in AIDS.

P. Carinii Pneumonia

Pneumocystis carinii pneumonia can be treated with antiprotozoal agents such as co-trimoxazole-pentamidme or trimetrexate. They interfere with tolate transformation, inhibiting DNA. RNA and protein synthesis. Atovaquone exerts its antiprotozola effect by blocking mitochondrial electron transport leading to inhibition of uncleic acid and ATP synthesis.

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