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PROCEEDINGS HOW TO DEFINE TREATMENT SUCCESS AND FAILURE* — Jens Lundgren, MD ABSTRACT Highly active antiretroviral therapy (HAART) has dramatically improved the prognosis for HIVinfected patients in the last 5 years, as demonstrated by several studies, including the EuroSIDA study—in which patients’ CD4 cell counts of <20 cells/mL improved to 20 to 49 cells/mL and the projected 25% mortality rate over the following year was reduced to <10, and a collaborative effort among 8 European cohorts, in which researchers concluded that treatment with HAART had increased and maintained patients’ CD4 cell counts and conferred clinical protection despite the discontinuation of a secondary prophylaxis. To date, virologic failure has been managed in several ways, including switch therapy, continued therapy, interruption of HAART, and using interleukin-2 to boost CD4 counts. Trials examining the possibility of drug recycling are currently underway, as are trials examining the rate at which failing regimens increase plasma viral load, accumulation of resistant mutations, and immunologic failure. Success or failure of treatment can be measured and defined in several ways; each method of definition should be explored and compared. Controlled trials must offer critical analyses of the efficacy and treatment-limiting toxicities of all treatments they examine. (Advanced Studies in Medicine 2001;1(12):483-485) *This article is based in part on a presentation given by Dr Lundgren at the 1st International AIDS Society Conference on HIV Pathogenesis and Treatment. Correspondence to Jens Lundgren, MD, Coordinating Centre, EuroSIDA/Copenhagen HIV Programme (CHIP), Department of Infectious Diseases, Hvidovre Hospital, University of Copenhagen, 2650 Hvidovre, Denmark. Advanced Studies in Medicine ■ ighly active antiretroviral therapy (HAART) strives to suppress viral replication, prevents resistance, preserves and improves immune function, and prevents the development of clinical disease. It has dramatically improved the prognosis of HIV-infected patients in the last 5 years: in 1994 and 1995, before these drugs became available in Europe, approximately 22% of patients were expected to die within the next year, and more than 30% were expected to develop a new AIDS-defining event. With the introduction of triple combination therapy, the incidence of death and new AIDS-defining events has dropped and continues to decline (Figure 1). Clearly, HAART is successful where it is available, as demonstrated by several studies. As illustrated by the EuroSIDA study, among patients with a CD4 cell count of <20 cells/mL before initiating HAART, as many as 25% of patients will die within the following year.1 However, even with small HAART-induced increments in the CD4 count, there are dramatic decreases in the death rate, ie, an increase in the CD4 count to between 20 and 49 cells/mL reduces the risk of death within the following year to <10% (Figure 2). In a collaborative effort among 8 European cohorts, we studied more than 300 patients who had previously been diagnosed with Pneumocystis carinii pneumonia. Patients initially had clinical signs and symptoms of severe immune deficiency that permitted the development of opportunistic infections. Patients with a history of P carinii pneumonia usually require secondary prophylaxis to prevent relapse. Between October 1996 and January 2000, the patients in this cohort study discontinued secondary prophylaxis while being treated with at least 3 anti-HIV drugs after having at least 1 peripheral-blood CD4 cell count of H 483 PROCEEDINGS MANAGING VIROLOGIC FAILURE To date, virologic failure has been managed in several ways, including switch therapy, continued therapy, interruption of HAART, and using interleukin-2 to boost CD4 counts. Each method has its strengths and weaknesses. Switch therapy offers renewed control, but may result in the defeat of a newly introduced class of drugs. Continued therapy may prevent toxicity and preserve the activity of new drugs, but bears the risk of additional resistance mutations and class resistance. Interruption therapy, on the other hand, is not costly, nor will it increase toxicity, but can cause the CD4 count to plummet and can increase the risk of clinical disease. Interleukin-2 can be effective regardless of the plasma viral load, but the clinical protection of this method is yet unproved. Further controlled trials should increase our understanding of the effects and safety of treatment interruptions. Trials examining the possibility of drug recycling are currently under way, as are trials examining the rate at which failing regimens increase a patient’s plasma viral load, accumulation of resistant mutations, and immunologic failure. We do know, however, that HAART has been successful: it keeps patients alive and increases CD4 cell counts. Even in patients who lack complete control of viral replication and are therefore at 484 Figure 1. Clinical Effect of HAART: Incidence of AIDS and Death 1994-2000 Incidence (per 100 PYFU) >200 cells/mL. CD4 cell count levels were subsequently maintained at >200 cells/mL for a median of 11 months. After a median follow-up period of 13 months, CD4 cell counts remained at levels ≥ 200 cells/mL. Researchers concluded that treatment with HAART had increased patients’ CD4 cell counts and clearly conferred clinical protection, despite elimination of disease-specific prophylaxis.2 9/ 94 9 >9 3/ 3/ 9 3/ 3 9/ 3/ 98 9/98 99 97 /97 /9 95 /96 /96 95 9 -9 3/ 9/ 9/ 3/ -3 9/ 3/ 9/ 3/ 9 9 9 9 9 9 9 / 9 /9 8 95 8 9 7 7 9 6 6 5 Calendar period EuroSIDA Reprinted with permission from The EuroSIDA study group, 2001, Coordinating Centre, Copenhagen, Denmark. Figure 2. Death Rate According to Latest CD4 Count in People Treated with HAART, with Initial CD4 Count <20 Cells/mL Reprinted with permission from The EuroSIDA study group, 2001, Coordinating Centre, Copenhagen, Denmark. Vol. 1, No. 12 ■ December 2001 PROCEEDINGS increased risk of drug resistance, the plasma viral load still diminishes. Plasma viral load, however, remains a weak predictor of the risk of clinical disease progression; another strong predictor may be the current level of hemoglobin. Most controlled trials analyze a regimen’s ability to suppress plasma viral load and the tolerability of the regimen, since discontinuations are counted as virologic failures. Despite the important data often provided by trials that assess the efficacy and toxicity of drugs, trial design, small patient cohorts, and short duration of some studies may severely limit these data. An efficacy-only endpoint requires continued followup in patients who discontinue treatment. Treatmentlimiting toxicity should be evaluated separately. Extended follow-up until the completion of the trial, regardless of whether the patient discontinues the study medication, should be encouraged to better determine the presence of late-onset adverse events and resistance. Moreover, studies that focus solely on effect, such as suppression of plasma viral load that is Advanced Studies in Medicine ■ independent of discontinuations, may prove useful. The risk of virologic failure associated with numbers needed to treat vs the numbers needed to treat to harm should also be examined. Several definitions of treatment success and failure exist; however, each should be explored and compared. Controlled trials must offer critical analyses of the efficacy and treatment-limiting toxicities of all treatments they examine. REFERENCES 1. Miller V, Mocroft A, Reiss P, et al. Relations among CD4 lymphocyte count nadir, antiretroviral therapy, and HIV-1 disease progression: results from the EuroSIDA study. Ann Intern Med. 1999;130:570-577. 2. Ledergerber B, Mocroft A, Reiss P, et al. Discontinuation of secondary prophylaxis against Pneumocystic carinii pneumonia in patients with HIV infection who have a response to antiretroviral therapy. Eight European Study Groups. N Engl J Med. 2001;344:168-174. 485