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Other separate articles related to human immunodeficiency virus (HIV) include Human Immunodeficiency Virus (HIV), Managing HIV-positive Individuals in Primary Care, Congenital HIV and Childhood AIDS, Complications of HIV Infection, Management of HIV In Pregnancy, Acquired Immune Deficiency Syndrome (AIDS), HIV and Skin Disorders, HIV Counselling and Primary HIV Infection.
Antiretroviral agents have greatly improved the prognosis of patients infected with HIV. 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 antiretroviral therapy (ART) which usually includes two nucleoside reverse transcriptase inhibitors with either a non-nucleoside reverse transcriptase inhibitor or one or two protease inhibitors. The term ART has largely replaced HAART (= highly active antiretroviral therapy) in the literature, as all approved agents are now highly active. The reader may also see the term cART (combined antiretroviral therapy) when the author wishes to emphasise the difference between the use of combinations of agents versus monotherapy.
Drugs used for human immunodeficiency virus infection
There are six antiretroviral classes:
- Non-nucleoside reverse transcriptase inhibitors.
- Nucleoside reverse transcriptase inhibitors.
- Protease inhibitors.
- Fusion inhibitors.
- CCR5 receptor antagonists.
- Integrase inhibitors.
Regimens usually consist of three or more antiretrovirals from at least two different classes.
Non-nucleoside reverse transcriptase inhibitors
- These are efavirenz, etravirine, nevirapine and rilpivirine.
- They can be associated with rashes including Stevens-Johnson syndrome (especially with nevirapine and efavirenz), increased plasma cholesterol concentrations (efavirenz) and occasionally with fatal hepatitis (nevirapine).
Nucleoside reverse transcriptase inhibitors
- These inhibit the RNA-dependent DNA polymerase (reverse transcriptase) which HIV uses to convert viral RNA into DNA before its incorporation into the cell genome.
- They 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 hepatitis C (there is greater risk of hepatic side-effects), in hepatic impairment, renal impairment and in pregnancy.
- Side-effects include gastrointestinal disturbances, headaches and blood disorders (including anaemia, neutropenia and thrombocytopenia).
- Abacavir is associated with increased cardiovascular risk and the British National Formulary recommends caution in patients at high risk of cardiovascular disease (CVD) - 10-year risk greater than 20%.
- These 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.
- They 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 prodrug 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 gastrointestinal disturbances, headaches, hyperglycaemia (caution in diabetes), increased risk of bleeding (especially in haemophilia), hepatic impairment, lipodystrophy and metabolic effects (see 'Lipodystrophy syndrome', below).
- Protease inhibitors should be used with care in pregnancy and dose reduction may be required in renal impairment (except atazanavir and fosamprenavir).
- 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 and is administered by subcutaneous injection twice daily.
- Maraviroc is the first CCR5 receptor antagonist licensed for the treatment of HIV infection.
- 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.
- Raltegravir is an integrase inhibitor and is indicated in combination with other antiretroviral drugs for HIV infection resistant to first-line ART.
- Eviplera® is a one-tablet formulation, consisting of emtricitabine/rilpivirine/tenofovir disoproxil. It has recently been licensed for use in the UK and is likely to be used in antiretroviral-naïve patients with HIV-1 with a viral load of ≤100,000 HIV-1 RNA copies/mL.
Initiation of treatment
- The choice of agents will depend on many factors, including previous drug exposure, source of infection, development of resistance, tolerability, concomitant medication and compliance.
- Treatment has to be individualised and thus a thorough baseline assessment has to be undertaken including a full psychiatric history, concomitant infection with hepatitis B and/or hepatitis C, CVD risk with ECG and echocardiography (ECHO), renal function, etc.
- Treatment guidelines in primary infection has recently changed. BHIVA (UK) 2015 guidelines recommend the following indications:
- Immediately after HIV diagnosis.
- Any acquired immune deficiency syndrome (AIDS)-defining illness or major bacterial infection, where the CD4 count is <200 cells per μL.
- Treatment should be started for established HIV infection when:
- The CD4 count is around 350 cells/mm3 (confirmed on at least one consecutive sample and where there was no other reason for depletion of the CD4 count). The WHO recommendation is to commence treatment when CD4 count is around 500 cells/mm3, but this has not been adopted in the UK.
- Treatment may be started at CD4 counts above 350 cells/mm3 when concomitant illnesses are present - eg, AIDS diagnosis, hepatitis B or hepatitis C in some cases and established CVD.
- If patients present with opportunistic disease then treatment should begin early (a median of 12 days after starting therapy for the opportunistic disease). Along similar lines, patients who have lymphoma and are to start chemotherapy should be started immediately on ART.
- 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.
BHIVA recommends that:
- The preferred regimen for therapy-naïve patients is a nucleoside reverse transcriptase inhibitor 'backbone', plus one of a protease inhibitor, a non-nucleoside reverse transcriptase inhibitor or an integrase inhibitor.
- Convenient once-daily combination preparations are available - eg, Atripla® (efavirenz/emtricitabine/tenofovir disoproxil), Eviplera® (see above).
- Metabolic effects associated with ART (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 CVD 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.
- Deep dermal injection of non-absorbable gel polymer for HIV-related lipoatrophy is available but infection, granuloma formation and migration are common side effects. The National Institute for Health and Care Excellence (NICE) recommends that the procedure should only be used with special arrangements for clinical governance, consent and audit or research.
- A major factor in treatment failure is the appearance of resistant viral mutants arising spontaneously.
- It occurs more commonly when viral load is high than when HIV replication is completely suppressed.
- Prevalence of transmitted HIV drug resistance (evidence of one or more mutations from the WHO 2009 list of mutations) in the UK remained stable at 8% between 2008 and 2010 and declined slightly to 6.8% in 2012.
- 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.
- Deterioration of the condition (including clinical and virological changes) may require either switching therapy or adding another antiretroviral drug.
- Other reasons for changing may be adverse effects, poor compliance and cost.
- The choice of an alternative regimen depends on factors such as the response to previous treatment, tolerance and the possibility of cross-resistance.
Pregnancy and breast-feeding
See separate article Management of HIV in Pregnancy.
- The teratogenic potential of most antiretroviral drugs is unknown.
- Choice of antiretroviral drug depends on several factors, including CD4 count, viral load and method of delivery.
- Zidovudine monotherapy reduces transmission of infection to the neonate. Combination ART (zidovudine plus lamivudine is the combination of choice (Combivir®)) maximises the chance of preventing transmission and represents optimal therapy for the mother, although it may be associated with a greater risk of preterm delivery.
- Alternative combinations are tenofovir plus emtricitabine or abacavir plus lamivudine in combination with a protease inhibitor.
Prophylaxis with antiretroviral drugs (unlicensed indication) is recommended as soon as possible (within hours ideally but up to 72 hours following sexual exposure) to anyone who has had a significant exposure to HIV-contaminated material or material at high risk of HIV. This includes patients, healthcare workers, assault victims and through unprotected intercourse.
See separate article HIV Post-exposure Prophylaxis.
Human immunodeficiency virus type 2 infection
The above treatment of HIV relates to infection with HIV-1. Human immunodeficiency virus type 2 (HIV-2) is structurally different and thus treatment differs. The two viruses do not protect from each other and both mono-infection with HIV-2 and dual infection with both HIV-1 and HIV-2 have been described (but are rare in the UK). Testing for HIV-2 is not universal and viral load assays and drug resistance testing are only present at selected sites in the UK.
Patients with HIV-2 need to be referred to HIV-2 experienced treatment centres and, at present, much of the advice is based on case studies, as no randomised controlled trials (RCTs) are available. The main points are as follows:
- Non-nucleoside reverse transcriptase inhibitors should not be used, as HIV-2 has innate resistance.
- Other drugs with reduced efficacy in the treatment of HIV-2 include nelfinavir, amprenavir, atazanavir and enfuvirtide and these are therefore not recommended.
- Therapy should be initiated earlier than in HIV-1 at viral load of HIV-2 above 1,000 copies/mL.
- In dually infected patients, HIV-1 guidance should be used, as it is considered the dominant virus. However, care needs to be taken to ensure all potential drug resistances to HIV-1 and HIV-2 are take into consideration.
- First-line preferred therapy includes lopinavir/ritonavir with tenofovir and emtricitabine.
- Alternatives include darunavir/ritonavir with zidovudine.
- There is no evidence for the use of CCR5 receptor antagonists but these may be used in third-line therapy.
Further reading and references
Cote J, Godin G, Ramirez-Garcia P, et al; Virtual intervention to support self-management of antiretroviral therapy among people living with HIV. J Med Internet Res. 2015 Jan 617(1):e6. doi: 10.2196/jmir.3264.
Prendergast AJ, Essajee S, Penazzato M; HIV and the Millennium Development Goals. Arch Dis Child. 2015 Feb100 Suppl 1:S48-52. doi: 10.1136/archdischild-2013-305548.
Guidelines for the treatment of HIV-1-positive adults with antiretroviral therapy; British HIV Association (2015)
British National Formulary; NICE Evidence Services (UK access only)
New Drugs Online Report for rilpivirine + emtricitabine + tenofovir; UK Medicines Information
Deep dermal injection of non-absorbable gel polymer for HIV-related facial lipoatrophy; NICE Interventional Procedure Guidance, Jan 2013
HIV in the United Kingdom: 2014 Report; Public Health England
Ammaranond P, Sanguansittianant S, Raju PA, et al; Development of a cost-effective assay for genotyping of HIV-1 non-B subtype for drug resistance. J Virol Methods. 2014 Apr199:102-7. doi: 10.1016/j.jviromet.2014.01.007. Epub 2014 Jan 22.
Guidelines for the management of HIV infection in pregnant women (2014 interim review); British HIV Association
HIV post-exposure prophylaxis; Guidance from the UK Chief Medical Officers' Expert Advisory Group on AIDS, Dept of Health, 2008
Guideline for the use of post-exposure prophylaxis for HIV following sexual exposure; British Association for Sexual Health and HIV (2011)
Gilleece Y, Chadwick DR, Breuer J, et al; British HIV Association guidelines for antiretroviral treatment of HIV-2-positive HIV Med. 2010 Nov11(10):611-9. doi: 10.1111/j.1468-1293.2010.00889.x.
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