British HIV Association treatment guidelines have once again broken with the treatment orthodoxy that has prevailed since 1996, this time by declaring that considerations of toxicity and adherence are more important in the choice of first-line regimen than the likely resistance pattern if that regimen fails.
Two years ago the British guidelines declared that treatment need not start until the CD4 cell count fell towards 200 cell/mm3, the level at which the risk of opportunistic infections rises sharply. US treatment guidelines still support a higher threshold for starting therapy (around 350 cells/mm3).
Previous guidelines developed in the US and Europe have emphasized the need for rational sequencing of drugs to preserve future treatment options. Now, acting on evidence that the majority of first-line regimens fail due to side-effects rather than lack of potency, a panel of UK experts have agreed to avoid prescribing one drug in first-line therapy altogether, and have explicitly recommended that it is best to use a non-nucleoside reverse transcriptase inhibitor rather than a protease inhibitor in first-line treatment based on their side-effect and dosing profiles.
Key statements from the 2003 guidelines
When to start treatment
“Treatment should be initiated when the CD4 count is between 200 and 350 cells/mm3, and the exact timing should depend on individual factors such as symptoms, patient preference, likely adherence and potential toxicity.”
Treatment in primary infection
“For patients with primary HIV infection, treatment is only recommended for the purpose of resolving severe symptoms. Otherwise the committee feels there is insufficient evidence to recommend treatment outside clinical controlled trials.”
Initial therapy
“In the present state of knowledge more weight should be given to ease of adherence and minimisation of toxicity, including development of lipodystrophy, than to the likely pattern of resistance mutations emerging following treatment failure.”
“Combinations including stavudine are not recommended for initial therapy due to possible risks of more rapid development of lipodystrophy.”
“There are no studies of sufficient size that directly compare NNRTIs with boosted PIs, which the committee recommend when a PI-containing regimen is used.”
“Hence at present the writing committee considers that NNRTIs are more suitable as the agents of first choice for initial regimens.”
As to the choice of the NNRTI, the committee are non-commital. However, the guidelines draw attention to higher rates of hepatotoxicity and rash in nevirapine-treated patients, compared to psychological problems and potential teratogenicity in efavirenz-treated patients.
“On current data abacavir/lamivudine/zidovudine should not be considered as a first line option for initial therapy.”
Regarding tenofovir, the committee says that the drug “is likely to become an attractive first-line option in the future”. This statement is likely to be seen as more encouraging than the one voiced by Dr Duncan Churchill at April’s British HIV Association Annual Meeting in Manchester, when he said that the writing committee would want to see more evidence on long-term safety before recommending its use in first-line therapy.
Changing therapy
Clinicians should consider changing a regimen when a patient has experienced two consecutive viral loads above 400 copies/ml, and resistance testing should be used afyer ruling out poor adherence and inadequate drug levels to select the new regimen.
In cases of failure due to adherence problems, a simpler regimen may be indicated. Switching due to toxicity, such as lipodystrophy, is discussed in detail.
In those with few options, “where it is unlikely that further treatment will produce complete inhibition of viral replication, continuation of current therapy is reasonable if the imminent risk of death is low, judged by the CD4 count. However, there is a rationale for switching – albeit to a less than optimally suppressive regimen - in those individuals in whom the imminent risk of death is high, in order to try to improve viral suppression with the aim of raising the CD4 count.”
Atazanavir
The committee also notes that atazanavir may prove “an attractive first protease inhibitor if early results are confirmed”. Since there is no requirement for the manufacturer to provide longer-term data, this may take some time.
T-20
T-20 “should be reserved for salvage use in combination with one or preferably two other new drugs that are expected to be active on the basis of resistance data, to give a realistic prospect of suppressing viral replication completely. This may mean keeping some patients on their current regimen while waiting for other new drugs to become available for use alongside T20. Only in individuals at imminent risk of clinical disease and death might it have a limited role as additional therapy in a failing regimen where there are no other active drugs available.”
Further information on this website
The full draft guidelines can be read by clicking the links below.