The aim of antiretroviral therapy in HIV infection is to reduce the amount of replicating virus to as low a level as possible, thereby preventing infection of new cells and further damage to the immune system. There are now 14 different drugs from three distinct classes (see Panel). The first antiretroviral agent to become commercially available was zidovudine in 1987, followed by didanosine and zalcitabine in 1993. These drugs belong to the class of drugs known as nucleoside analogue reverse transcriptase inhibitors (NRTIs), which act on the reverse transcriptase enzyme involved in HIV RNA replication. A dramatic decline in clinical progression of HIV disease and HIV-related deaths followed the introduction of protease inhibitors (PIs) in 1996. These compounds act on the HIV protease enzyme, preventing the manufacture of essential proteins. The non-nucleoside reverse transcriptase inhib-itors (NNRTIs) are the third class of drugs currently available to treat HIV infection. These also act on the reverse transcriptase enzyme, but differ in structure from the NRTIs.
The current standard of care is to treat HIV-infected individuals using a combination of at least three drugs – this is commonly referred to as highly active antiretroviral therapy or HAART.
Classification of antiretroviral drugs
Nucleoside analogue reverse transcriptase inhibitors (NRTIs)
Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
Protease inhibitors (PIs)
*Not currently licensed in the UK – only available as part of an expanded access (named patient) programme
The British HIV Association (BHIVA) guidelines for the treatment of HIV-infected adults with antiretroviral therapy were first published in April, 1997. They have recently been revised and are now available on the NAM/BHIVA Internet website (http://www.aidsmap.com), prior to being published in HIV Medicine, the new official journal of BHIVA. The guidelines have been written by a team of leading physicians involved in the care of HIV-positive patients in the UK, in collaboration with patient representative groups, and attempt to provide consensus across a wide range of health care workers and people living with HIV disease.
The guidelines are intended to fulfil a number of important roles, including:
- Promoting a high standard of care in all treatment centres
- Assisting in discussions between purchasers and providers of HIV care
- Acting as a basis for clinical audit within clinical governance
- Clarifying research findings
- Acting as a reference source on treatments for physicians caring for patients infected with HIV
The guidelines represent the current state of knowledge, but it is inevitable that, as HIV is a rapidly evolving medical field, new data will change therapeutic choices. Consequently, the guidelines will require modifications as important new data emerge and the website will be amended at regular intervals to reflect these data. Complete updates are planned at least annually.
The guidelines cover issues such as when to start treatment, what drugs to start with, resistance testing, significance of clinical trials and comparisons between the BHIVA guidelines and the International AIDS Society (IAS) recommendations. Issues around pregnancy and post-exposure prophylaxis to HIV infection for health care workers are not covered.
When to start treatment? The guidelines recommend starting treatment when the CD4 count drops to around 350 cells/mm3, although thought should also be given to those patients with a rapidly declining CD4 count, those with a rapidly increasing viral load or those with a high viral load; these individuals are at greater risk of clinical progression. All patients with clinical symptoms of underlying immunosuppression or with a diagnosis of AIDS (according to the Centers for Disease Control case definition), should be offered therapy, regardless of their CD4 count or viral load.
What drugs to start with? Treatment combinations should comprise two NRTIs (see Panel), usually referred to as the backbone of the regimen, plus a third (and sometimes fourth) agent. The drug regimen needs to be individualised in order to maximise adherence (poor adherence can result in the development of resistance) and thought should be given to potential toxicities, drug interactions, potency and tolerability. The currently available options when choosing initial therapy are:
- 2NRTIs + PI
- 2NRTIs + 2PIs
- 2NRTIs + NNRTI
The guidelines list advantages and disadvantages of each option. Currently, any of the first three regimes listed above are recommended as choices for first-line therapy. There is concern that starting treatment with three NRTIs does not offer the same potency as the other combinations, and therefore may not be as effective in individuals with high viral loads.
Many clinicians and patients are now opting for a triple combination using an NNRTI, such as efavirenz or nevirapine, rather than a PI, because of the smaller pill burden, easier adherence and perceived reduced toxicity (see below).
What to do following virological failure of the first regimen? Viral load assays are currently able to detect the presence of HIV RNA to a limit of 50 copies per ml. A viral load result below this is described as being “below the level of detection”. The aim of therapy is to drive the viral load down as low as possible, ideally to this level.
Therapy change should be considered in those patients who have been on a HAART regimen, whose viral load was initially suppressed below the level of detection (<50 copies/ml), but has now become consistently detectable. Choosing which drugs to change the patient to will depend on those used in the initial regimen. It is recommended that all the drugs are changed, with the patient starting on an entirely new regime. Both PIs and NNRTIs have cross resistance with other drugs from within the same class. Therefore, if the initial regime consisted of a PI, then most physicians would switch to an NNRTI and use two new NRTIs as the backbone to the regime. If the patient has failed a regime containing an NNRTI, then switching to a PI-containing regime would be appropriate. Resistance testing may be particularly important at this stage in a patient’s treatment.
Salvage therapy is the term given to drug therapy after more than one previous failure, ie, third-line treatment. Patients by this stage have usually had multiple exposure to all three classes of antiretroviral drugs. Resistance testing is strongly recommended when attempting to construct a salvage regimen. The studies on salvage therapy to date have been of short duration with little follow up data. It is likely that therapy will be more successful in those patients who have a lower viral load. Improved outcome is more likely with use of drugs to which the patient has not been exposed or to which resistance is unlikely. In each case, it is important to construct a fully suppressive regimen from the remaining available drugs. Sometimes it may be more beneficial for the patient to wait for new therapies to become available, if being off therapy does not pose an immediate risk.
Protease inhibitors (PIs) One of the main drawbacks to PI therapy is the risk of lipodystrophy. The lipodystrophy syndrome is now well described with PIs and encompasses a range of manifestations such as body fat redistribution, hyperlipidaemia and insulin resistance. It is thought that this syndrome is caused by PIs somehow interfering with the process of fat metabolism through its effect on the cytochrome P450 enzyme system in the liver, although the exact mechanism is unknown.
Many patients are reluctant to take PIs because of the changes that they can produce in body shape, which sometimes make it obvious that an individual is taking therapy. The hyperlipidaemia caused by PIs means that these patients could be placed at increased risk of cardiovascular disease, which is a real problem now that HIV infected patients can potentially live much longer, since the introduction of HAART.
Studies have demonstrated that patients established on PIs who have an undetectable viral load can achieve some resolution of their lipodystrophy symptoms from switching to an NNRTI-based regime, without losing viral control. All the PIs are metabolised by and inhibit the cytochrome P450 enzyme system. This makes treatment of hyperlipidaemia more problematic because of possible drug interactions between the PIs and many of the statins, which could lead to increased toxicity.
Nucleoside analogue reverse transcriptase inhibitors (NRTIs) NRTIs have been associated with numerous toxicities, including lactic acidosis and hepatic steatosis, both of which have been linked to inhibition of mitochondrial DNA synthesis. It has also been suggested that inhibition of mitochondrial DNA synthesis may play some role in the development of lipodystrophy following case reports of lipodystrophy in patients not taking PIs. The Committee on Safety of Medicines issued a summary earlier this year of eight cases of mitochondrial dysfunction in infants following intrauterine and perinatal exposure to zidovudine, with or without lamivudine, for the prevention of vertical transmission of HIV infection. However, after consideration of all the available evidence, the CSM advised that there are insufficient data to establish a causal relationship between NRTI exposure and mitochondrial dysfunction, and that the benefits of treating HIV-infected pregnant women with antiretroviral therapy outweigh the possible risks. None of the eight infants became infected with HIV.
New treatment strategies
Pharmacokinetic studies have demonstrated interesting results when using dual PI therapy. For example, indinavir is licensed to be taken as a three times daily dose on an empty stomach (as fat inhibits its absorption). When given in combination with ritonavir, indinavir may be given twice daily with no food restrictions as there is a significant increase in the area under the curve (AUC), due to metabolic inhibition by ritonavir. This makes the regime much simpler to take.
Hydroxyurea, traditionally an anticancer drug, is now being used more widely in combination therapy. It has no anti-HIV activity itself, but it increases the potency of some NRTIs by raising the intracellular drug concentration. It is usually used in combination with didanosine, and may help to increase the potency of salvage regimens.
Subcutaneous interleukin-2 (IL2) is being studied in the UK in clinical trials. It stimulates the production of CD4 cells, and therefore boosts the immune system. There is a possible role for IL2 in patients who have achieved an undetectable viral load with HAART, but whose CD4 count is still low, putting them at risk of opportunistic infections. IL2 has recently been incorporated in the French treatment guidelines; however, its use has not been included in the revised BHIVA guidelines.
Therapeutic drug monitoring (TDM) is likely to play an important part in treatment in the future, particularly in protease inhibitor therapy. PIs are substrates for cytochrome P450 and P-glycoprotein, which results in a potential for marked inter-patient variability of drug levels. At present, TDM is only being performed on a small scale, but it is likely that it will start to be used more widely. This is an area in which the pharmacist may take on an extended role in the future.
BT378/r is a new PI currently in clinical trials. It will soon be available for some patients as part of an open label study. The drug is manufactured as a dual capsule containing a small dose (100mg) of ritonavir. The rationale for this is that much higher levels of ABT378 are obtained in the body as a result of metabolic inhibition by ritonavir, a potent inhibitor of the cytochrome P450 enzyme CYP3A4. The toxicity profile of this new PI appears to be very favourable and it is thought that it may be useful in patients who have previously failed on a PI-containing regimen.
Adefovir dipivoxil belongs to a new class of drugs called nucleotide analogues. It acts on the reverse transcriptase enzyme, but differs in structure from the NRTIs as it possesses an extra phosphate group. It therefore does not require triphosphorylation to its active form, as is the case with the NRTIs. Adefovir has activity against a range of viral infections, including HIV, hepatitis B and cytomegalovirus (CMV). It was expected to be made available in the UK as part of an expanded access programme but it has not yet been granted its licence by the US Food and Drug Administration, and so its availability in the UK may be delayed. The major drawback of adefovir is the potential for renal toxicity. Adefovir needs to be administered with L-carnitine, a nutritional supplement, because it has been found to reduce L-carnitine levels in the blood.
Other novel compounds are in various stages of development, including integrase inhibitors and fusion inhibitors, eg, T20. These target different sites in the HIV viral life cycle.