A guide to drug therapy in HIV

Since its first identification, treatment of HIV has been revolutionised, write Dr Lance Turtle and Dr Raj Thakkar.

Since the advent of highly active antiretroviral therapy (HAART) for the treatment of HIV infection this area of medicine has been revolutionised.

What was once a terminal diagnosis has become a chronic manageable illness.

However, along with this improvement have come problems associated with the antiretroviral drugs themselves.

The aim of HAART is to reduce the morbidity and mortality associated with progressive HIV disease. To achieve this, it is necessary to suppress viral replication until the plasma viral load is below the limit of detection with modern assays - usually <50 genomes/ml plasma. With effective viral suppression resistance is unlikely to emerge. If resistance does emerge it usually manifests as a rising viral load on treatment.

Antiretroviral therapies
There are four classes of antiretroviral drugs: nucleoside analogue reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors and fusion inhibitors. There are two further classes in development: viral integrase inhibitors and chemokine receptor blockers.

NRTIs are usually used in combination and are the backbone of most HAART regimens.

NNRTIs are often used in combination with two NRTIs as first-line therapy.

There are many protease inhibitors available and they are an alternative to NNRTIs in the choice of an effective treatment combination with two NRTIs. Some protease inhibitors are particularly useful in drug-resistant HIV.

There is one fusion inhibitor, enfuvirtide. It is given parenterally and is expensive so is used only in salvage therapy - for drug-resistant virus where earlier treatment is failing.

Several fixed-dose combinations are available to make antiretroviral drugs easier to take.

There are many drug interactions with antiretroviral drugs, particularly with protease inhibitors. Those described here are only those that you are most likely to encounter in primary care and this discussion is by no means comprehensive.

Metabolism of atazanavir is enhanced by tenofovir so it must be boosted with ritonavir. Absorption is inhibited by acid-suppressing drugs like proton pump inhibitors.

Metabolism of statins is inhibited by protease inhibitors, which can lead to rhabdomyolysis or hepatitis. The safest is probably atorvastatin at a dose of 10-20mg per day.

In addition to the important interaction with statins, protease inhibitors inhibit the metabolism of many drugs. Examples include inhaled steroids which can accumulate sufficiently to cause Cushing's syndrome if used combined with ritonavir, and warfarin, the dose of which needs to be reduced.

Starting therapy is nearly always based on two NRTIs and a third drug.

Analogues of two different nucleotides should be chosen, hence lamivudine and emtricitabine are not used together (cytosine analogues), nor are stavudine and zidovudine (thymidine analogues).

Usually a fixed-dose combination such as Truvada or Kivexa is chosen along with an NNRTI or a protease inhibitor, provided no resistance is detected. The choice depends on the views of the patient and the perceived importance of different side-effects. For example, a woman with a CD4 count greater than 250 would normally be offered efavirenz or a protease inhibitor (especially if pregnancy is a possibility) rather than nevirapine.

Atripla now contains a well-established first-line regimen in one pill, once a day. If resistance is detected the choice becomes more complex.

Concordance
The key to effective viral suppression is continually taking the medication.

It is estimated that 95 per cent of doses per month must be taken correctly to achieve viral suppression.

If viral suppression is not achieved then resistance may emerge which, once present, is always present. It is therefore sometimes better to delay therapy if the patient is not ready to take it to avoid limiting future treatment options.

Patients who are not adhering to treatment and those in whom resistance has developed show a rising viral load. Only an open and honest relationship will allow the difference to be known.

Dr Turtle is specialist registrar in infectious diseases and tropical medicine at Royal Liverpool University Hospital, and Dr Thakkar is a GP in Wooburn Green, Buckinghamshire

Characteristics of antiretroviral drugs

NRTIs

  • Abacavir (ABC)

Commonly used first-line NRTI. Causes a potentially life-threatening hypersensitivity reaction in a small proportion of patients.

  • Didanosine (ddI)

No longer used as first-line treatment because of toxicity. Causes pancreatitis, neuropathy and lactic acidosis.

Needs to be taken in fasting state, avoid in combination with tenofovir.

  • Emtricitabine (FTC)

Well-tolerated and common first-line drug, often with tenofovir. Can cause reversible skin pigmentation.

  • Lamivudine (3TC)

Very similar to emtricitabine. Safe and effective. Very commonly used drug.

  • Stavudine (d4T)

Not used as first-line treatment because of toxicity. Causes neuropathy, lactic acidosis and lipodystrophy.

  • Tenofovir (TDF)

Commonly used first-line NRTI. Has been associated with nephrotoxicity in some patients and with Fanconi's syndrome.

  • Zidovudine (ZDV, AZT)

No longer used as first-line treatment. Causes bone marrow suppression and lipodystrophy. Other previously described toxicities very uncommon at lower doses used today.

  • NNRTIs

Efavirenz (EFV)

Commonly used first-line drug. Causes neuropsychiatric side-effects, a rash and is teratogenic; avoid in pregnancy.

  • Nevirapine (NVP)

Less commonly used than efavirenz. Causes a rash - can cause Stevens-Johnson syndrome - and is hepatotoxic. Fatal hepatitis has been reported.

  • Protease inhibitors

Atazanavir (ATZ)

Once-daily dosing. Better lipid profile than most other protease inhibitors.

Causes hyperbilirubinaemia which usually does not require stopping the drug.

  • Darunavir (DRV)

Highly effective against drug-resistant virus. Must be administered with ritonavir. Not first-line therapy.

  • Fosamprenavir (FOS)

Causes a rash and GI symptoms.

  • Indinavir (IND)

Seldom used now because it causes renal stones.

  • Lopinavir (LPV)

Commonly used effective drug, often as first-line therapy. Causes diarrhoea.

Comes co-formulated with ritonavir.

  • Nelfinavir (NLF)

Not commonly used any more because other options are more effective.

Still used in some post-exposure prophylaxis regimens. Causes diarrhoea.

  • Ritonavir (RTV)

First protease inhibitor, no longer used at therapeutic dose because of GI side-effects. Potent liver cytochrome P450 enzyme inhibitor so used to boost the efficacy of other protease inhibitors. Must be refrigerated.

  • Saquinavir (SAQ)

Commonly used first-line protease inhibitor. Current formulation must be boosted with ritonavir.

  • Tipranavir (TPV)

Effective for drug-resistant HIV but carries a risk of severe hepatotoxicity.

Used only in salvage therapy.

  • Fusion inhibitors

Enfuvirtide (T-20)

Must be given parenterally so is only used in salvage therapy.

FIXED-DOSE COMBINATION DRUGS
Combivir Lamivudine + zidovudine
Kivexa Lamivudine + abacavir
Trizivir Lamivudine + zidovudine + abacavir
Truvada Emtricitabine + tenofovir
Kaletra Lopinavir + ritonavir
Atripla Emtricitabine + tenofovir + efavirenz

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