Sixth International Congress Drug Therapy in HIV Infection 17-21 November, 2002 Glasgow, UK

When highly active antiretroviral therapy (HAART) first became available in 1996, it represented the last hope for many thousands of people with a fatal disease. Compared to the threat of AIDS, side effects, as far as they were known at the time, appeared insignificant. Given the lack of alternative treatment in case of resistance the quest for primary efficacy dominated: your first chance was your only chance.

Using data of the Swiss HIV Cohort Study, I will show that this is now an overly pessimistic view. Prospective randomised studies properly use the intention-to-treat principle where all use of non-protocol medication, and loss to follow-up, is counted as "failure", raising the spectre of AIDS and death. In real life, however, a patient who drops treatment A and starts treatment B, may actually do better on B, and would be surprised to know that his treatment "failed". The pattern shown by our patients combines frequent treatment changes - more often motivated by convenience, side effects, or intolerance rather than by viral resistance - with maintenance of low viral loads, high CD4 counts, and a low rate of HIV-related complications. An average patient who started with 1 protease inhibitor plus 2 nucleoside reverse transcriptase inhibitors in 1999, is likely to have tried 2 more drugs three years later. We can only hope that pharmacological innovation will keep pace with the need for new drugs.

So, what's the best HAART in 2002? In the Swiss cohort (and according to sales figures, elsewhere too) there has been an increase in the use of efavirenz and lopinavir/ritonavir (Kaletra) over the last two years. This reflects both increasing use in primary therapy, and switching from other types of HAART. Both lopinavir, and efavirenz, were superior to first generation protease inhibitors in prospective, randomised studies. Such studies do not exist for ritonavir-boosted indinavir or saquinavir, or for nevirapine. Whereas anxiety about loss of efficacy has been receding, the fear of side effects has increased. In a transversal study within the Swiss Cohort, the prevalence of clinical side effects was 47 percent. Among these, the lipodystrophy syndrome is the most important. Treatment regimens which avoid or reverse the lipodystrophy syndrome are being investigated. Replacing a protease inhibitor with abacavir leads to lower serum cholesterol. Reversal of lipo-atrophy, and of truncal fat accumulation, is more difficult to achieve, but replacing stavudine with abacavir or zidovudine may be worth a try. For 2003 and beyond, atazanavir holds the promise of convenience without ill effects on plasma cholesterol. However, in my view, it must still prove its mettle against state-ofthe- art HAART, i.e. combinations including efavirenz, or ritonavir-boosted protease inhibitors.

It is reasonable to believe that our successful patients now have essentially normal life expectancy, which in Western Europe means 40 to 50 years. 40 to 50 years of HAART? Many view this prospect with less than total enthusiasm, and are looking for ways to interrupt therapy. The hope that such interruptions would lead to improved anti-HIV immune responses, and to control of viremia without drugs, must be abandoned, at least for the majority of patients who start treatment during chronic infection. Treatment interruptions may still reach their more modest goals of lesser side effects and increased cost-effectiveness. Trials comparing the current standard of continuous therapy with various schemes of interruption, are underway and will yield results 3 to 4 years hence.

Presenting author: Bernard Hirschel

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1HUG Hospital Cantonal, Geneva, Switzerland

2002-11-17
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