Updated guidelines for the treatment of HIV in countries able to offer access to an unrestricted choice of anti-HIV drugs have been issued by the International AIDS Society-USA (IAS) and are published in the July 14th edition of the Journal of the American Medical Association.
The guidelines mirror those of the British HIV Association in many areas, not least in their advice about when to start HIV therapy. However, there are subtle differences. The IAS guidelines fall short of recommending the discontinuation of the use of d4T (if other agents are available) because of the risk of fat wasting.
The IAS guidelines also include recommendations about how to use new agents, including T-20, atazanavir, and fosamprenavir.
The guidelines were prepared by the IAS’s US panel and are concerned with four questions:
- When to start anti-HIV therapy
- What to start with
- When to change treatment
- What to change to
When to start HIV treatment
HIV treatment is recommended for all patients with symptomatic HIV disease. However, if a patients requires treatment for a potentially life-threatening opportunistic infection that requires drugs which are difficult to provide at the same time as HAART (such as tuberculosis or hepatitis C virus) then therapy for these infections such take precedence over HAART.
HIV treatment should be provided before an individual’s CD4 cell count falls below 200 cells/mm3. Decisions regarding the commencement of treatment in individuals with a CD4 cell count between 200-350 cells/mm3 should be individualised and take into account the speed of CD4 cell loss.
Treatment is not recommended in individuals with a CD4 cell count above 350 cells/mm3, but may be considered in circumstances when a patient has a high viral load and a rapidly falling CD4 cell count.
What to start with
A regimen containing a non-nucleoside analogue (NNRTI) is often the first initial choice. The advantages of NNRTI-containing regimens include ease of adherence, virological potency, a relatively benign side-effect profile, and a lack of interaction with other medication.
The IAS panel says that the weight of evidence favours efavirenz, however, nevirapine is a reasonable option. However, there are concerns about nevirapine’s possible toxic effects, particularly for individuals with hepatitis C virus and women with a CD4 cell count above 250 cells/mm3.
Efavirenz should not be used by pregnant women, recommend the panel. In addition, the liver enzymes of pregnant women taking nevirapine should be closely monitored.
If an initial regimen includes a protease inhibitor, then one boosted by ritonavir is recommended. There are more data on the use of lopinavr/ritonavir (Kaletra) than other ritonavir-boosted protease inhibitors.
Recommended nucleoside/nucleotide analogue backbones are AZT/3TC, AZT/FTC, tenofovir/3TC, tenofovir/FTC, or FTC/ddI. For once-daily dosing with efavirenz, FTC/ddI or 3TC/abacavir can be used.
Triple NRTI regimens are not recommended except in exceptional circumstances, nor are four drug combinations, or dual therapy (boosted protease inhibitor and NNRTI), or monotherapy with Kaletra.
When to change and what to change to
Changing because of toxicity
If side-effects associated with a particular drug do not resolve after a short period, or laboratory toxicity develops, then a single drug substitution should be considered.
If it is not possible to say which drug is causing a side-effect, then the entire regimen should be changed. Staggered discontinuation should be initiated if an individual is taking a drug with a long half-life (such as efavirenz).
Changing treatment because of metabolic abnormalities
If it is thought that continuing therapy with a protease inhibitor has benefits outweighing the risks, then increased blood lipids can be controlled, in many cases, with diet, exercise or lipid-lowering drugs. This may have to be considered in individuals with extensive treatment experience.
Switching to an NNRTI may be a more attractive option, however, when a patient is virologically susceptible to this class of drugs.
Individuals should be closely monitored for fat loss or fat gain, and treatment changed, if options exist, immediately if these symptoms develop.
Treatment should be stopped immediately if symptomatic lactic acidosis develops. Following recovery an NRTI-sparing regimen should be used (NNRTI and boosted protease inhibitor). However, it may be safe to use 3TC, abacavir, or tenofovir following full recovery if the benefits are thought to outweigh the risks.
Changing because of treatment failure
Treatment failure can be clinical, immunological, or virological.
Individuals who fail their first regimen despite having susceptible virus should have close attention given to their adherence. If their viral load is above 1000 copies/ml a resistance test should be performed and appropriate drugs selected.
The aim of the second regimen should be the suppression of viral load below 50 copies/ml.
Later treatment changes are more of a challenge. If viral suppression below 50 copies/ml is thought to be unrealistic, then the aim of treatment should be to preserve immune function and prevent HIV disease progression.
Ideally a regimen should include two or three active drugs and where possible changes should not compromise the future use of entire drug classes.
There are currently too little data to recommend the use of multiple boosted protease inhibitors.
Investigations for blood toxicities should be undertaken when a patient achieves a good virological response but fails to experience an increase in CD4 cell count. Changing or intensifying treatment has not been shown to increase CD4 cell count response in these circumstances, and the use of interlukin 2 is still being researched.
Structured treatment interruptions for the management of failing regimens are not recommended.
The role of new drugs
T-20 (enfuvirtude), which is unique amongst HIV drugs in being administered by injection, involves inconvenience to the patient, say the IAS panel. It is also very costly. It is therefore only used in individuals with limited treatment options. It is best considered from the second treatment change when there are still other viable drugs with which to construct a regimen.
Regarding other recently licensed drugs, data suggest that atazanavir should be boosted by ritonavir for use in treatment-experienced individuals. Similarly, fosamprenavir should be ritonavir-boosted and dosed twice-daily in treatment-experienced patients.
Clinical trials can provide important options for heavily experienced patients and doctors should be aware of the availability of new drugs through trials.
Monitoring HIV
Clinical monitoring, along with CD4 cell counts and viral load remain the basic tools for monitoring HIV-positive individuals. In addition, doctors should provide close attention to the level of an individual’s adherence to his or her anti-HIV drugs.
Resistance tests, in both treatment-naïve and treatment-experienced individuals should be used as needed.
The use of therapeutic drug monitoring remains controversial, and the utility of using tests to predict an individual’s risk of side-effects, such as human leukocyte antigen typing for abacavir hypersensitivity, requires further validation.
Yeni PG et al. Treatment for adult HIV infection: 2004 recommendations of the International AIDS Society-USA panel. JAMA 292: 251-265, 2004.