Guidelines for managing HIV infection

The goal is maximal suppression of HIV replication for as long as possible

The medical management of HIV infection and AIDS has finally been rewarded with some success, witnessed by falls in AIDS associated deaths in industrialised countries, fewer opportunistic infections, and fewer admissions for HIV infection.1 2 What constitutes optimal practice, however, remains a topic of debate. Two widely publicised sets of guidelines on antiretroviral treatment have appeared over the past year, one from the International AIDS Society in the United States,3 and the other from the British HIV Association.4 While their emphasis was different, the recommendations were broadly similar.

The guidelines agreed on the need for regular monitoring of HIV-1 plasma RNA (“viral load”) and for using antiretroviral treatment in people with low CD4 lymphocyte counts or symptomatic disease. The British guidelines were less prescriptive and placed less emphasis on introducing treatment for people with CD4 cell counts >300x10⁶/l and high viral load.4 Both guidelines endorsed combinations of nucleoside analogues such as zidovudine and didanosine (AZT/ddI), zidovudine and zalcitabine (AZT/ddC), or zidovudine and lamivudine (AZT/3TC) as first line treatments and discussed indications and options for switching treatments.3 4

Practice in many quarters, however, has moved beyond these guidelines.5 6 Many doctors now use triple therapy including a protease inhibitor as first line treatment for all HIV infected patients, and some start treatment earlier. Logic and current concepts of pathogenesis supporting such an approach are that virus replication is intense from initial infection,7 8 viral load is the most important prognostic marker of risk of progression,9 10 drug resistant strains emerge in the face of incomplete suppression of replication,11 treatment with two nucleoside analogues does not provide long term suppression in most cases,12 13 14 15 and favourable clinical outcome is most likely if virus replication is maximally suppressed before the immune system is irreversibly damaged.

Several arguments have been advanced in favour of delaying treatment or using only two nucleoside analogues initially. These are that clinical evidence for a more aggressive approach is lacking, long term side effects of these drugs are unknown, early use of the most potent combinations limits later therapeutic options, asymptomatic patients may be turned into pill-taking invalids, long term adherence to treatment by asymptomatic people is unlikely, and, inevitably, the greater cost of triple therapy.

This debate has now been joined by heavy hitters from the United States in the guise of two panels that have just published draft reports for public comment.16 17 A panel convened by the National Institutes of Health has defined the scientific principles that should guide treatment and its monitoring in clinical practice. The second panel, sponsored by the Department of Health and Human Services and the Henry J Kaiser Family Foundation, developed recommendations based on these principles for the clinical use of antiretroviral treatment. Together, the documents clearly state that triple therapy (generally consisting of two nucleoside analogues and a protease inhibitor) should be the standard treatment for any person with HIV infection, including as initial therapy. Treatment is recommended essentially for all people with CD4 cell counts <500x10⁶/l, as well as for asymptomatic people with counts >500x10⁶/l and active viral replication (>10 000 viral copies/ml). It is stated, however, that many experts would advise treatment for HIV infected people with CD4 cell counts >500x10⁶/l and any detectable level of virus.

The guidelines emphasise that the goal of treatment should be maximal suppression of HIV replication for as long as possible. For people undergoing treatment for primary HIV infection, the recommendation is for indefinite treatment with triple therapy. After a 30 day period for public comment, the documents will be published in their final form in the Morbidity and Mortality Weekly Report, and they will be updated when necessary.

The debate raises many issues. HIV infection illustrates the limits of the paradigm of practice based exclusively on controlled trials using clinical endpoints. Some guidelines usefully grade the quality of evidence on which recommendations are based and acknowledge that some depend on biological plausibility rather than clinical results.4 18 Even if evidence of more favourable clinical outcome with triple therapy compared with two nucleoside analogues is only just emerging,19 analogy with diseases such as tuberculosis or lymphoma, plus subjective assessments (“What would you take if…?”), will persuade many that triple therapy should now be the standard of care for HIV infection. It is likely that international prescribing practices will ultimately vary more over when to start treatment than what to start with. Nevertheless, practice based on data using surrogate markers (viral load and CD4 cell counts) requires careful follow up to ensure that clinical response and survival continue to correlate with changes in markers.20 The initial promise but ultimate failure of zidovudine monotherapy must not be forgotten.

We must ensure that care for HIV infected patients across the United Kingdom meets international standards. Anecdotal reports suggest antiretroviral therapy and monitoring of viral load are not equally available in all NHS trusts and that some patients use the open access policies of distant sexually transmitted disease clinics to obtain treatments not available locally. More extensive assessment is required of performance of viral load tests for non-B subtypes of HIV-1, which predominate in heterosexual subjects in Europe.21 22 Inevitably, spending on antiretroviral drugs and monitoring of viral load will increase as treatments are started earlier, triple therapy becomes more widely used, and reduced mortality from AIDS results in its increased prevalence.23

The promise of modern antiretroviral therapy is threatened by the emergence of drug resistance, the strongest risk factors for which are non-adherence to treatment and the use of suboptimal regimens. Surveillance for transmission of drug resistant strains and research into improving adherence of patients and their doctors to treatment should be priorities. Finally, although current discussions have concerned only industrialised countries, antiretroviral drugs are also in circulation in developing countries, where most of the world's HIV infected people live. Their use in settings with few resources will therefore increase. If thought is not given to the rational use of antiretroviral drugs everywhere their long term utility may be jeopardised by the spread of resistant viral strains.