The International AIDS Society (IAS) convened an expert panel at the end of 1995 to come up with recommendations on how to use anti-HIV drugs in the light of the rapid growth in the number of drugs available during 1995 and 1996. The guidelines were first published in July 1996 to coincide with the Vancouver International AIDS Conference.

The guidelines are revised via full-panel consensus on a regular basis to ensure they reflect the latest scientific knowledge and practice, with updates published in the Journal of the American Medical Association.

The most recent version published in January 2000, addresses HIV disease as a long-term chronic infection. The challenge to clinicians is to chart a strategic therapeutic course for individual patients such that drugs are used to maximize effectiveness over time, the guidelines state. These guidelines signal a subtle move away from early treatment, relative to earlier ISA guidelines, and a greater acknowledgement of the difficulties of adherence and long-term adverse events. Key points of the guidelines are summarised below. The full document is available free on the Internet at http://jama.ama-assn.org/issues/v283n3/full/jst90023.html.

Starting treatment

The new document outlines a more conservative approach to initiation of therapy than the 1998 version. There are two key reasons for this shift: the evidence of significant immune reconstitution following viral suppression, and the emergence of the long-term adverse effects of treatment - negative impact on quality of life, drug interactions, viral resistance and metabolic abnormalities.

The guidelines emphasise that initiation of therapy must be a decision of the doctor and patient, based on the individual's clinical, virologic and immunologic status, plus his/her commitment to taking a complex regimen of pills.

While an individualised approach is necessary, therapy is generally recommended for the following patients:

• patients with HIV RNA above 30,000 copies/ml, irrespective of CD4 count

• patients with CD4 counts below 350, regardless of viral load

• patients with HIV RNA between 5,000-30,000 copies/ml and CD4 counts between 350-500.

Treatment is also recommended for individuals with symptomatic, established HIV infection, although treatment of a specific opportunistic infection may take precedence over initiation of antiretroviral therapy.

The panel agreed that treatment should be considered for individuals with CD4 counts above 500 with viral loads between 5,000-30,000 copies based on the risk of disease progression although survival benefit of treatment in people with CD4 counts above 500 has not been demonstrated.

Initiation of therapy is not recommended for individuals with CD4 counts above 500 and viral loads below 5,000, although monitoring is recommended.

Treatment recommendations are the same for men and women.

Therapy during or immediately after seroconversion is discussed under Primary Infection below.

Initial therapy

The panel recommend that selection of a first-line therapy should be based on the following factors: strength of supporting data; potency of the regimen; tolerability; adverse events profile; likely drug interactions; convenience and adherence likelihood; potential alternative regimens if initial therapy fails, and possibly baseline resistance test results.

Generally, combinations of a protease inhibitor (PI) plus two nucleoside analogues (NRTIs) or a non-nucleoside (NNRTI) plus two NRTIs are recommended.

A triple NRTI combination is an alternative first-line option currently being evaluated. While such a regimen saves both protease inhibitors and NNRTIs for later, there is some evidence of reduced potency among individuals with high baseline viral loads. Limited long-term data is available.

For people with CD4 counts below 50 and/or viral loads above 100,000, more potent four-drug combinations may be considered as initial therapy, although the clinical superiority of four drugs versus three drugs has not yet been proven in people with advanced disease. Four drug regimens may include at least one drug from each key drug class or two PIs and two NRTIs.

Commentary on recently approved drugs indicates that abacavir is a potent drug when used as part of a triple drug combination. Amprenavir may be considered although data on its effectiveness as a first-line therapy is limited.

Full-dose ritonavir has been associated with adverse events that reduce long-term adherence. The panel comments that future use of ritonavir is likely to be at low doses in combination with other PIs. Dual PI combinations including low dose ritonavir offer advantages of increased potency, plus reduced pill burden, dosing frequency, cost and food restrictions. Long-term benefit and toxicity of this approach is unknown.

Adherence

The panel recommends that doctors question patients in detail regarding daily routines before selecting a treatment regimen. Patients should be given clear written instructions regarding dosing. Other devices such as alarms and pill organisers may be considered. Furthermore, adherence should be monitored by careful questioning at every follow-up visit. Questions regarding how well medications fit into daily activities, and which doses are the hardest to take, are recommended.

Monitoring

The 2000 guidelines recommend monthly monitoring of viral load and CD4 count after initiation or change in treatment until a viral load below detection is achieved, and every two or three months thereafter.

The 1998 guidelines endorsed the use of ultra-sensitive viral load tests (which measure down to 40-50 copies/mL) in monitoring. Nadir response and an undetectable viral load by 4-8 weeks are associated with greater durability of viral suppression.

Monitoring HIV viral load around the time of illness, non-adherence or vaccinations should be avoided because such episodes are associated with transient viral load increase. Any significant increase in viral load should be confirmed by a second assay.

CD4 increase may reflect, in part, immune restoration, and may continue despite viral rebound. Close CD4 monitoring is recommended in this situation.

The role of drug level monitoring in clinical practice is not yet established. Monitoring drug levels may allow more effective and individualised dosing in the future.

The panel are cautious about the clinical use of resistance testing due to poor quality assurance, high cost and a lack of information about how best to use the results. Accurate and correctly interpreted test information may improve treatment, the panel state, by identifying which drugs are likely to be less effective. Resistance testing may also reduce cost and toxicity. However, the limitations of current technology may mean that resistance testing may not accurately predict which drugs will be active against HIV.

Defining drug failure

The 2000 guidelines state that a viral load decrease of between 1.5 and 2.0 log₁₀ should occur within four weeks of starting initial treatment. By weeks 16 to 24, viral load should be below 50 copies/ml.

Failure to achieve this goal does not necessarily indicate the need to change treatment immediately. Detectable viral load at weeks 16-24 should prompt consideration of poor adherence, inadequate drug absorption or drug resistance.

Drug failure should not be defined by CD4 response alone because a poor CD4 response is a function of both viral suppression and immunologic reserve. The average CD4 increase during the first year of viral suppression is 150, although wide variability occurs.

A CD4 increase while failing to suppress viral replication may provide a breathing space which allows the highly treatment-experienced individual to await the availability of new medications. However, detectable viral load while on therapy will most likely lead to the emergence of drug resistance. The panel recommends that patients who have other treatment options should change their regimen before the emergence of high-level resistance.

Localised inflammations (such as CMV) are transient manifestations of immune recovery and do not constitute drug failure.

Changing treatment

Once the need for a new combination is established, selection of a new regimen should be driven by the reasons for treatment failure and available options.

If adverse events are the reason for switching in a patient with undetectable viral load, the offending drug alone may be changed. However, the panel state that changes to successful regimens should be conducted with caution. A temporary break from all drugs is an alternative approach before re-starting a modified regimen.

Patients who have low levels of detectable virus (50-500 copies) after 12-16 weeks of treatment may not have developed drug resistance. One drug may be added to intensify the regimen if resistance or non-adherence are not the reasons for virologic failure. However, this strategy may increase non-adherence and limit future treatment options.

Patients with high viral loads while on treatment are likely to have developed drug resistance. For these patients, the panel recommends changing all drugs in the regimen. The new combination should be selected on the basis of greatest likelihood of potency, tolerability and adherence, and least likelihood of cross-resistance with the failed regimen. Resistance testing may assist in determining likely sensitivity to drugs in this scenario. Awareness of possible pharmacological interactions is also recommended.

Primary infection

The aim of treatment during primary infection (the time from initial exposure to full seroconversion) is to maintain or restore HIV-specific immune responses and possibly to improve the course of the disease in the long-term. Clinical benefit of treatment during primary infection has not been established.

The panel recommends that all patients with primary infection should be referred to a clinical trial. If clinical trials are not available, potent antiretroviral therapy should be offered. Potential disadvantages and unknowns should be fully discussed with the patient.

Post-exposure prophylaxis

In the 1998 guidelines, the panel recommended post-exposure prophylaxis with at least two drugs never used in the source patient in occupational and accidental situations in which there is a definite high risk of transmission. The maximum benefit is likely to be obtained from post-exposure prophylaxis which begins as soon as possible after the potential exposure. The duration of prophylaxis necessary is uncertain; whilst 4 to 6 weeks has been proposed for AZT monotherapy, 2 weeks may be adequate to block or abort infection when using a potent triple combination, given current knowledge about viral pathogenesis.

Mother-to-baby transmission

The panel recommended that all pregnant women should be offered counselling and HIV testing, in the 1998 guidelines. Perinatal prophylaxis is recommended for all HIV-infected women, as is treatment for the newborn child regardless of whether the mother is treated.

The panel recommended that in most respects, pregnant women should be treated in the same way as non-pregnant women, and offered combination anti-retroviral treatment. Combination therapy reduces the chance of transmission while protecting the woman against resistance which is possible with AZT monotherapy. If HIV infection and pregnancy are identified at the same time, treatment may be deferred until the second trimester (that is, after the first three months).

Reference

Carpenter CCJ et al. "Consensus statement: antiretroviral therapy for HIV infection in 1996: recommendations of an international panel". Journal of the American Medical Association 276(2): 146-154, 1996.

Carpenter CCJ et al. Antiretroviral therapy for HIV infection in 1997. Updated recommendations of the International AIDS Society. Journal of the American Medical Association 277: 1962-1969, 1997.

Carpenter CCJ et al. Antiretroviral therapy for HIV infection in 1998. Updated recommendations of the International AIDS Society - USA panel. Journal of the American Medical Association 280(1): 78-86, 1998.

Carpenter CCJ et al. Antiretroviral therapy in adults. Updated recommendations of the International AIDS Society - USA panel. Journal of the American Medical Association 283(3): 381-390 2000.