The British HIV Association (BHIVA) guidelines on the use of antiretroviral therapy were developed by a panel of doctors and community advocates and were first published in The Lancet in April 1997. The guidelines were revised in 2001, 2003 and 2005.

Guidelines are also available on the treatment of HIV-positive patients coinfected with hepatitis B or C or tuberculosis, as well as pregnant women.

The National Association of Providers of AIDS Care and Treatment (PACT) Framework for Antiretroviral Therapy was produced in 1997 through consultation between health-care providers and the health authority purchasers who fund medical services. It aims to define the principles that should inform treatment choices. However, the document is now somewhat out-of-date and should not be used as an accurate guide to anti-HIV treatments.

Like the PACT Framework, the BHIVA guidelines offer broad principles to guide therapy, but also review recent trial results and weigh the evidence for or against specific drug combinations. BHIVA argues that although randomised trials with clinical endpoints provide the best quality of evidence, the expanding range of HIV treatments means that this evidence is often not available. The guidelines therefore draw conclusions also based on what is logical and biologically plausible from surrogate markers, laboratory studies, mathematical models and other forms of indirect evidence about HIV disease.

When to start treatment

The aim of antiretroviral therapy is to prolong life and improve quality of life by maintaining suppression of viral replication for as long as possible.

For people with chronic or established HIV infection, BHIVA recommends treatment in the following circumstances:

• Symptomatic disease (illness or a condition associated with damage to the immune system).

• CD4 cell count below 200 cells/mm³ (advanced disease).

• No symptoms of HIV/AIDS and a CD4 cell count between 200 and 350 cells/mm³. Within this range, people may consider early treatment if they have a high viral load or a rapidly falling CD4 count or coinfection with hepatitis C. Patient preference, likely adherence, potential toxicity or a desire to use intermittent therapy may influence when treatment is started within the 200-350 range.

BHIVA recommends that treatment should be deferred for people with CD4 cell counts over 350 cells/mm³, regardless of viral load.

Treatment during primary infection

BHIVA recommends antiretroviral treatment for people with severe or prolonged symptoms of primary HIV infection.

The BHIVA guidelines note that treatment within six months of contracting HIV may provide a unique window of opportunity for treating the virus when it is most vulnerable and the immune system is strongest. However, due to the lack of data demonstrating the effectiveness of treatment during primary infection, treated individuals should be enrolled in a clinical trial. Possible benefits must be balanced against the known risks of lipodystrophy and the potential for developing drug resistance at an early stage. Many patients choose not to treat during primary infection and doctors should respect and support this decision.

What drugs to start with

The 2005 guidelines recommend the following combinations for first-line therapy:

• Efavirenz (Sustiva) plus two nucleoside or nucleotide reverse transcriptase inhibitors (NRTIs / NtRTIs). Nevirapine (Viramune) is a preferred non-nucleoside reverse transcriptase inhibitor (NNRTI) in women who want to become pregnant who have a CD4 cell count below 250 cells/mm³.

• Ritonavir-boosted lopinavir (Kaletra) plus two NRTIs / NtRTIs. Ritonavir (Norvir)-boosted saquinavir (Invirase / Fortovase) or ritonavir-boosted fosamprenavir (Telzir) are possible alternative protease inhibitors (PIs).

NNRTI)based combinations using efavirenz or nevirapine are the preferred option at this point in time, due to equivalent efficacy to PI-based regimens and their superior toxicity profile to the PIs, although nevirapine is linked to serious liver toxicity and efavirenz to depression and sleep disruption.

Given the greater potency of boosted PI regimens in comparison to single PI regimens, the current guidelines recommend the boosted PI strategy when PIs are used.

There are no published studies which directly compare NNRTI-based and boosted-PI-based regimens. In the absence of reliable data, the guidelines suggest that other factors should influence the decision to use an NNRTI or a PI. The advantages of NNRTIs "include suitability for use in once daily regimens, lower pill burdens, fewer clinically important lipid abnormalities, and a lower frequency of central fat accumulation".

The combination of three NRTIs AZT, 3TC and abacavir (Trizivir) is no longer recommended as a standard highly active antiretroviral regimen, due to trial data suggesting it is less potent that PI-based and NNRTI-based regimens. It may be used in special situations, for example, where poor adherence is likely or other medications for conditions such as TB make drug interactions likely.

The guidelines recommend that d4T (stavudine, Zerit) not be used due to the risk of lipodystrophy and abnormal lipid profiles. Recommended once-daily NRTI / NtRTI backbones include abacavir plus 3TC (Kivexa) and tenofovir plus FTC (Truvada). As AZT may be linked to lipdystrophy, the combination of AZT plus 3TC (Combivir), which must be taken twice a day, may fall from favour - although the ending of AZT's patent may make this a more cost-effective regimen.

Changing or stopping therapy

The BHIVA guidelines consider in detail the many reasons people change or stop therapy in the contemporary setting.

In many instances, people stop or change therapy in the absence of virological failure. The guidelines contain a chapter addressing these issues, including advice for people taking regimens which are no longer recommended, people experiencing specific side-effects, and people wanting to take intermittent therapy.

For people who have sustained viral rebound (e.g. over 400 or 1000 copies/ml) or who fail to achieve undetectable virus on their current regimen, change of therapy will be considered. The availability of a regimen likely to achieve a viral load below 50 copies/ml will inform the decision to change therapy, as will the availability of a regimen which the patient can adhere to and tolerate.

The new regimen should generally contain at least three active drugs, chosen on the basis of current and previous resistance test results and the patient's treatment history. The regimen should include at least one drug from a new drug class.

In patients starting salvage therapy, the aim of treatment should shift to maintaining or preserving immune function by maintaining the CD4 cell count. This may involve remaining on the current regimen until new treatment options are available, using T-20 (enfuvirtide, Fuzeon) plus another fully active drug in the background regimen, or by attempting to use investigational drugs, depending on the patient's circumstances.

Aiming for viral suppression below 50 copies/ml

The BHIVA guidelines state that the aim of first-line therapy should be suppression of viral load below the limit of detection within 24 weeks of commencing therapy, and that treatment should aim to suppress viral load below 50 copies/ml.

Viral load should be measured after one month on treatment, and again at 12 and 24 weeks, and every 12 weeks thereafter, using an ultra-sensitive assay. Failure to achieve at least a 1 log₁₀ reduction in viral load at week 4 should trigger investigation of adherence and possibly therapeutic drug monitoring and resistance testing.

Resistance testing

The BHIVA guidelines discuss research into the use of resistance testing in some detail, arguing that data indicate that resistance testing is associated with short-term virological benefit.

BHIVA recommends:

• Due to transmission of drug-resistant virus, all patients presenting with HIV infection should undergo resistance testing.

• Resistance testing should be conducted prior to starting therapy.

• Resistance testing should be conducted each time viral rebound occurs in people on therapy or following suboptimal response to first-line therapy.

• Phenotypic and genotypic tests are roughly equivalent although phenotypic tests cost more.

• In drug-experienced patients, resistance testing should be done while the person is still taking therapy. This can be of immense benefit in selecting an effective treatment regimen.

BHIVA also provides guidance to doctors on the interpretation of resistance test results.

Therapeutic drug monitoring

There is currently a lack of data to confirm the benefits of therapeutic drug monitoring (TDM). Nevertheless, evidence suggests that concentrations of drug in blood plasma and cells vary enormously among individuals, and that about 20% of people may have sub-therapeutic levels of drug in their blood.

BHIVA recommends use of TDM where drug concentrations are difficult to predict. Examples include:

• In the management of drug interactions.

• During pregnancy.

• In treating children.

• In highly treatment-experienced patients.

• In patients with liver or kidney problems.

• In patients who have had transplants.

• In patients in whom drug toxicity may be occurring.

• In patients taking dosing regimens that have not been assessed for safety and efficacy.

The guidelines state that inhibitory quotients may be more reliable than drug concentrations or resistance testing in heavily pre-treated patients starting salvage regimens. However, data supporting the use of inhibitory quotients are limited.

Adherence

The guidelines highlight the importance of adherence in successful treatment of HIV infection. However, they state that current evidence does not support any interventions that include intensive, frequent or prolonged contact with staff or structured group in improving patient adherence. However, brief individualised support may improve adherence in some patients.

Metabolic complications

The guidelines include a chapter on metabolic complications as a side-effect of HIV therapy, including altered blood fat levels, body fat redistribution and insulin resistance, as well as an increased risk of cardiovascular disease.

They state that the risks of lipodystrophy seem to be greater with PIs than NNRTIs and greater with d4T than with AZT. They state that a slow reversal of lipostrophy can occur after replacement of d4T or AZT with other drugs, but recommend avoiding d4T, and possibly AZT, if other options are available. They also state that while PIs are linked as a class to altered blood fat levels and insulin resistance, current evidence suggests that this does not apply to atazanavir (Reyataz), even when boosted with ritonavir.

New therapies and issues

The guidelines discuss new drugs and new formulations of existing drug which have become available recently through the National Health Service or through expanded access schemes in the United Kingdom:

• Tipranavir (Aptivus).

• TMC114.

• TMC125.

The guidelines also deal for the first time with:

• HIV testing and diagnosis, pressing for access to HIV testing in routine primary care through general practitioners and other general medical services.

• The costs of antiretroviral drugs, and their role in the choice of treatment.

• Issues surrounding structured treatment interruptions: these are only recommended by the writing committee for patients who are enrolled in a controlled clinical trial and who started antiretroviral therapy with CD4 cell counts above 400 cells/mm³.

HIV and hepatitis B guidelines

BHIVA has made the following recommendations about monitoring, testing and advice concerning hepatitis B and HIV:

• All HIV-positive patients should have tests for antibodies to hepatitis B core antigen (anti-HBc) and hepatitis B surface antigen (anti-HBs) within a month of diagnosis.

• All those negative for hepatitis B markers should be immunised against hepatitis B.

• All patients who are anti-HBc positive but negative for surface antigen (HBsAg) can relapse. Liver function should be monitored; if they become abnormal, check HBsAg.

• All infected persons should be assessed for hepatitis B virus (HBV) status before starting antiretroviral therapy.

• All persons not immune to hepatitis A should receive 2 doses of hepatitis A vaccine 6 to 18 months apart.

• Patients with HBV should be counselled about the dangers of alcohol consumption.

• Patients with HBV should be counselled regarding prevention of transmission of HBV.

Sexual and household contacts should be tested for HBV markers and receive HBV immunisation if susceptible.

• Newborns of co-infected mothers should receive HBIG and HBV vaccine at delivery, in addition to post-natal HIV prophylaxis, and complete the recommended vaccination programme.

• Patients with established cirrhosis should be screened for liver cancer every six months.

BHIVA makes the following recommendations about treatment:

• The optimal time for initiating anti-HBV therapy in co-infected patients has not been established.

• HBV-specific treatment should be considered in patients with active viral replication (usually HBeAg-positive) and raised liver function test results.

• Treatment with antiretroviral activity (eg 3TC/tenofovir) must only be given as part of, or in addition to, an effective antiretroviral regime and ideally as part of a clinical trial. Interferon (and adefovir when available) should be considered for patients not on antiretroviral therapy.

HIV and hepatitis C guidelines

BHIVA has made the following recommendations regarding HIV and hepatitis C coinfection:

• All HIV-positive patients should be screened for hepatitis C virus (HCV) infection by antibody test and confirm chronic infection with an HCV PCR test for virus.

• Patients with an unexplained liver disease should undergo a PCR test even if HCV-antibody negative.

• Testing for hepatitis B is recommended and vaccination should occur in patients who are not immune to hepatitis B and hepatitis A.

• Clinician should outline how to reduce the risk of transmission and recommend abstinence from alcohol.

• HCV genotype should be checked because it is a predictor of treatment response.

• Liver biopsy is recommended (if no contra-indications) to assess disease severity and exclude other causes of chronic liver disease.

• Early treatment should be considered, ideally with pegylated interferon + ribavirin or through a clinical trial.

• Liver function should be monitored carefully if combination antiretroviral therapy is initiated. Serum lactate should be monitored for nucleoside analogue toxicity, especially in those on ribavirin.

• ddI, and the combination of ddI and tenofovir, should be used with extreme caution in patients receiving ribavirin.

• All HCV-positive patients without evidence of cirrhosis in liver tissue should be screened annually. Patients with endstage liver disease should be scanned every six months.

• Patients diagnosed with acute hepatitis C should be treated with interferon and consideration given for using peginterferon +/- ribavirin.