When talking about “failure,” one must be careful to distinguish patients who were antiretroviral-naïve before HAART from those who were pre-tested, and to distinguish “failure” for reasons of resistance and escape, from “failure” for reasons of side-effects. In my talk, I shall concentrate on ART-naïves before HAART, and use a broad definition of failure. When “failure” is defined as any change from an initial regimen of combination anti-retroviral treatment, it is the rule rather than the exception. In the Swiss HIV Cohort Study such change had occurred in 42 percent of previously antiretroviral-naïve
patients at one year after starting HAART, 65 percent at two years, and 70 percent at three years, as shown in the Figure, prepared by B. Ledergerber (Zurich). FIGURE CHART: Probability of stopping drugs from initial HAART-regimen of 2279 ART-naïve patients Most of these changes were due to toxicity, convenience and tolerance (32, 54, and 60 percent after 1, 2, and 3 years respectively). The rates of virologic failure, defined as a change in treatment with a concomitant viral load >400, were 7, 15, and 20 percent. Looking at virologic failure only, certain predictive parameters can be identified. Surprisingly, the pre-ART viral load is not predictive. However, the regimen used plays a role, favoring the NRTI+ efavirenz combinations as
opposed to PI-contaning combinations. This is in agreement with published prospective randomized studies, and with detailed retrospective analyses from the Swiss HIV Cohort Study. The apparent superiority of efavirenz will have to be reassessed against the second generation of protease inhibitors such as lopinavir and atazanavir. In patients with early virologic failure, a majority do not harbor resistance mutations, as shown in analyses from Trilege and ACTG 343, and confirmed by data from the Swiss HIV Cohort Study. So why does treatment fail? Some patients do not take their pill, others have low plasma levels despite good compliance, and in still others, variations in enzymes responsible for drug transport may play a role. Many factors
determine the absorption, transformation and excretion of drugs, and passage between intracellular and extracellular compartments; the relative contribution of these factors to the success of failure of therapy is not clear at the present time. However, the outlook for antiretroviral-naïve patients on HAART continues to improve. With multiple changes in therapy, 70 to 80 percent of patients have satisfactory control of viremia four to five years after starting therapy. The graph shows that the number of drugs to which the average patient is exposed, increases steadily with time. Continued development of new antirviral drugs will be necessary to keep pace with the evolution of HIV, and to have alternatives in cases of intolerable side
effects. GRAPH: Drug exposure by type of starting regimen
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