Antiretroviral Agents

Other HIV related articles include Human Immunodeficiency Virus (HIV), Managing HIV Positive Individuals in Primary Care, Childhood AIDS, Complications of HIV Infection, Management of HIV In Pregnancy, AIDS Acquired Immune Deficiency Syndrome, HIV and Skin Disorders and HIV Counselling.

Antiretroviral agents have greatly improved the prognosis of patients infected with the human immunodeficiency virus. There has also been a dramatic decrease in the complications of HIV infection. The development of drug resistance is reduced by using a combination of drugs. In the UK, the standard treatment for HIV infection is called HAART (highly active antiretroviral therapy) which usually includes 2 nucleoside reverse transcriptase inhibitors with either a non-nucleoside reverse transcriptase inhibitor or 1 or 2 protease inhibitors.

• The choice of agents will depend on many factors including previous drug exposure, source of infection, development of resistance, tolerability, concomitant medication and compliance.
• The British HIV Association recommends that:¹
  • Treatment in primary infection should only be routinely considered in those with:
    • Neurological involvement.
    • Any AIDS-defining illness.
    • A CD4 cell count persistently less than 200 cells/mm³ for 3 months or more.
  • Treatment should be started for established HIV infection when:
    • The CD4 count falls below 500 cells/mm³.
  • The goal of treatment must always be to achieve a viral load of less than 50 copies/mL and to achieve this within 4–6 months of starting treatment.

• Deterioration of the condition (including clinical and virological changes) may require either switching therapy or adding another antiretroviral drug. If initial treatment fails to reduce viral load by 10 fold within eight to 12 weeks, modification of therapy should be considered.
• The choice of an alternative regimen depends on factors such as the response to previous treatment, tolerance and the possibility of cross-resistance.

See Managing HIV in pregnancy.

• The teratogenic potential of most antiretroviral drugs is unknown.
• Zidovudine monotherapy reduces transmission of infection to the neonate. However, combination antiretroviral therapy (zidovudine plus lamivudine is the combination of choice)¹ maximises the chance of preventing transmission and represents optimal therapy for the mother.

• Prophylaxis with antiretroviral drugs (unlicensed indication) may be appropriate following occupational exposure to HIV-contaminated material.
• Immediate expert advice should be sought in such cases.
• National guidelines on post-exposure prophylaxis for healthcare workers have been developed by the Chief Medical Officer's Expert Advisory Group on AIDS. The recommended drugs for post-exposure prophylaxis starter packs are now a combination of zidovudine, lamivudine and nelfinavir.²

The British HIV Association recommends that:¹

• Efavirenz should be considered first line in all patients.
• The preferred regimens are efavirenz plus either tenofovir or abacavir, plus either emtricitabine or lamivudine.

Nucleoside reverse transcriptase inhibitors

• Inhibit the RNA-dependent DNA polymerase (reverse transcriptase) which HIV uses to convert viral RNA into DNA before its incorporation into the cell genome.
• Include zidovudine, abacavir, didanosine, emtricitabine, lamivudine, stavudine and tenofovir.
• Nucleoside reverse transcriptase inhibitors should be used with caution in patients with chronic hepatitis B or C (greater risk of hepatic side-effects), in hepatic impairment, renal impairment and in pregnancy.
• Side-effects include gastro-intestinal disturbances, headaches and blood disorders (including anaemia, neutropenia, and thrombocytopenia).

Protease inhibitors

• Inhibit HIV enzyme required to produce mature infectious viral particles by cleaving structural proteins and enzymes from their precursors. They are potent inhibitors of HIV replication and work synergistically with nucleoside drugs.
• They reduce HIV viral load and increase CD4 counts more effectively than nucleoside analogues, especially when used in triple therapy.
• Include atazanavir, darunavir, fosamprenavir, indinavir, lopinavir, nelfinavir, ritonavir,saquinavir and tipranavir.
• Ritonavir in low doses boosts the activity of indinavir, lopinavir and saquinavir, increasing the persistence of plasma concentrations of these drugs. Ritonavir has no intrinsic antiretroviral activity in low dose.
• Fosamprenavir (actually a pro-drug with active derivative amprenavir) is licensed for use only in combination with low-dose ritonavir (it is a pharmacokinetic enhancer of amprenavir). A combination of lopinavir with low-dose ritonavir is available.
• The protease inhibitors are metabolised by cytochrome P450 enzyme systems and so there is a significant potential for drug interactions.
• Protease inhibitors are associated with hyperglycaemia and should be used with caution in diabetes. Caution is also needed in patients with haemophilia (increased risk of bleeding) and hepatic impairment.
• Atazanavir and fosamprenavir may be used at usual doses in patients with renal impairment, but other protease inhibitors should be used with caution in renal impairment. Protease inhibitors should also be used with caution during pregnancy.
• Protease inhibitors are associated with lipodystrophy and metabolic effects (see below for lipodystrophy syndrome). Other side-effects include gastro-intestinal disturbances and headaches.

• The non-nucleoside reverse transcriptase inhibitors are efavirenz, etravirine and nevirapine.
• Nevirapine is associated with a high incidence of rash (including Stevens-Johnson syndrome) and occasionally fatal hepatitis.
• Efavirenz treatment has also been associated with an increased plasma cholesterol concentration.
• Rash is also associated with efavirenz but it is usually milder than may occur with nevirapine.

Fusion inhibitors

• Enfuvirtide, which inhibits HIV from fusing to the host cell, is licensed for managing infection that has failed to respond to a regimen of other antiretroviral drugs. It is used with other antiretroviral drugs.
• Enfuvirtide is administered by subcutaneous injection twice daily.

Other antiretrovirals

• Maraviroc is the first CCR5 receptor antagonist licensed for the treatment of HIV infection.¹
• Maraviroc is indicated for CCR5-tropic HIV infection. It is not effective against CXCR4-tropic virus. The CCR5-tropic variant of the virus is common in earlier HIV infection, whereas viruses adapted to use the CXCR4 receptor gradually become dominant as HIV infection progresses.¹
• Raltegravir is indicated in combination with other antiretroviral drugs for HIV infection resistant to first line HAART.

• Metabolic effects associated with antiretroviral treatment (especially protease inhibitors) include fat redistribution, insulin resistance and dyslipidaemia (lipodystrophy syndrome).
• Fat redistribution (with loss of subcutaneous fat, increased abdominal fat, buffalo hump and breast enlargement) is associated with regimens containing protease inhibitors and nucleoside reverse transcriptase inhibitors.
• Plasma lipids, blood glucose and the other risk factors for cardiovascular disease should be taken into account before prescribing drug regimes containing a protease inhibitor. Patients receiving protease inhibitors should be monitored for changes in plasma lipids and blood glucose.

• Major factor in treatment failure is appearance of resistant viral mutants arising spontaneously.
• Occurs more commonly when viral load is high than when HIV replication is completely suppressed.
• Resistant strains have been identified in up to 15% of recently infected patients in US and transmitted drug resistance is becoming more common in Europe.
• Tests to identify codon mutations that relate to resistance are available, as are assays of the ability of HIV to replicate in increasing concentrations of drugs.