Other HIV-related separate articles 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 and HIV Counselling.
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 HAART (= highly active antiretroviral therapy) which usually includes two nucleoside reverse transcriptase inhibitors (NRTIs) with either a non-nucleoside reverse transcriptase inhibitor (NNRTI) or one or two protease inhibitors (PIs).
Drugs used for human immunodeficiency virus infection
There are six antiretroviral classes:
- Non-nucleoside reverse transcriptase inhibitors (NNRTIs).
- Nucleoside reverse transcriptase inhibitors (NRTIs).
- Protease inhibitors (PIs).
- Fusion inhibitors.
- CCR5 antagonists.
- Integrase inhibitors.
Regimens usually consist of three or more antiretrovirals from at least two different classes.
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Non-nucleoside reverse transcriptase inhibitors
- These are efavirenz, etravirine and nevirapine.
- 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.
- NRTIs 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 gastro-intestinal disturbances, headaches and blood disorders (including anaemia, neutropenia, and thrombocytopenia).
- Abacavir is associated with increased cardiovascular risk and treatment should be avoided or changed in those with increased risk, eg presence of other cardiovascular risk factors.
- 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 PIs are metabolised by cytochrome P450 enzyme systems and so there is a significant potential for drug interactions.
- PIs are associated with gastro-intestinal disturbances, headaches, hyperglycaemia (caution in diabetes), increased risk of bleeding (especially in haemophilia), hepatic impairment, lipodystrophy and metabolic effects (see 'Lipodystrophy syndrome', below).
- PIs 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 HAART.
- Eviplera® is a new 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 ≤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, cardiovascular disease (CVD) risk with ECG and ECHO, renal function, etc.
- The British HIV Association (BHIVA) recommends that:
- Treatment in primary infectionshould only be routinely considered in those with:
- Neurological involvement.
- Any AIDS-defining illness.
- A CD4 cell count persistently less than 200 cells/mm3 for three months or more.
- Treatment should be started for established HIV infectionwhen:
- 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). A study suggested treatment begins when CD4 count is around 500 cells/mm3, but this is not currently recommended.
- 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 HAART.
- 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.
- Treatment in primary infectionshould only be routinely considered in those with:
BHIVA recommends that:
- Efavirenz should be considered first-line in all patients.
- The preferred regimens are efavirenz with either Truvada® (tenofovir/emtricitabine) or Kivexa® (abacavir/lamivudine).
- In primary NRTI and/or NNRTI resistance, boosted PIs should be considered (they may also be considered in women who wish to become pregnant and those with psychiatric problems). ("Boosted" refers to pharmacological enhancement of the PI by adding a second antiretroviral, usually ritonavir at a concentration lower than that associated with antiretroviral activity).
- Nevirapine - this is reserved for women planning a pregnancy and some patients with mental health problems.
Note: both nevirapine and Kivexa® have special precautions before use, e.g CD4 cell count and viral load criteria or HLA status.
- Metabolic effects associated with antiretroviral treatment (especially protease inhibitors (PIs)) 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 PIs and nucleoside reverse transcriptase inhibitors (NRTIs).
- Plasma lipids, blood glucose and the other risk factors for CVD should be taken into account before prescribing drug regimes containing a PI. Patients receiving PIs should be monitored for changes in plasma lipids and blood glucose.
- 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.
- Resistant strains have been identified in up to 15% of recently infected patients in the USA 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.
- 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 8-12 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.
Pregnancy and breast-feeding
See separate Management of HIV in Pregnancy article.
- 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, Combivir®) maximises the chance of preventing transmission and represents optimal therapy for the mother.
- 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.
- Immediate expert advice should be sought in such cases - in the UK this is usually by the local A&E departments.
- For healthcare workers there are national guidelines and the usual procedure involves contacting occupational health in hours and A&E out-of-hours (virology specialists on-call may in some trusts also be consulted out-of-hours).
- For post-exposure prophylaxis (PEP) following sexual exposure there is British Association for Sexual Health and HIV (BASHH) guidance which lists the conditions when PEP would and would not be recommended.
- The recommended drugs for PEP starter packs were previously: zidovudine, lamivudine and nelfinavir but have now been superseded by the following: tenofovir, emtricitabine, lopinavir and ritonavir. The combination of four antiretrovirals is thought to be more effective (although clinical trials are lacking). The combination should be taken for at least 28 days.
- Severe nausea and diarrhoea may occur, which may reduce adherence; prescribing anti-emetics and antimotility drugs may help.
The above treatment of HIV relates to infection with HIV-1. 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 RCTs are available. The main points are as follows:
- Non-nucleoside reverse transcriptase inhibitors (NNRTIs) 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 treatment earlier than in HIV-1 or 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 antagonists but these may be used in third-line therapy.
Further reading & references
- Consultation draft Addendum to BHIVA Treatment Guidelines, British HIV Association, 2009
- Guidelines for the treatment of HIV-infected adults with antiretroviral therapy, The British HIV Association (2008)
- UK Medicines Information; New Drugs Online Report for rilpivirine + emtricitabine + tenofovir; last updated 29th Nov 2011.
- 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 Nov;11(10):611-9. doi: 10.1111/j.1468-1293.2010.00889.x.
|Original Author: Dr Gurvinder Rull||Current Version: Dr Gurvinder Rull||Peer Reviewer: Dr Adrian Bonsall|
|Last Checked: 10/02/2012||Document ID: 230 Version: 6||© EMIS|
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