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The challenges related to conducting and reporting subgroup analyses are discussed.

Researchers working on the Adenomatous Polyp Prevention on Vioxx (APPROVe) trial collected data on adverse cardiovascular events, the assessment of which raises important issues about the analysis and interpretation of a time-to-event end point. These issues include the appropriate period of follow-up for safety outcomes after the discontinuation of treatment and the implications of the results of a trial examining long-term use about the safety of a drug if it were given for shorter periods.

Zidovudine treatment of HIV-infected adults in the early stages of infection may not extend survival with or without AIDS. HIV-infected individuals without symptoms and with a CD4 cell count of at least 500 cells/cubic milliliter were divided into three groups: 547 who initially received a placebo, 549 who received 500 milligrams/day of zidovudine, and 541 who received 1500 mg/day of zidovudine. After two years all participants were given the option of receiving 500 mg/day of zidovudine. Patients were followed for a median of 5 years. There were no significant differences between the groups in survival without AIDS. The death rate in each group was approximately 2 years/100 person-years of follow-up. However, the median amount of time for CD4 counts to drop below 500 cells/cubic ml was 1.0 in the delayed treatment group and 1.5 in the immediate treatment groups. Thus, early treatment did delay CD4 depletion. The overall frequency of side effects was low, but most significant in the 1500 mg/day group.

Zidovudine appears to retard the development of AIDS in those infected with HIV, but its effectiveness seemingly lasts no longer than approximately two years. A total of 1,565 HIV-positive patients who were asymptomatic for AIDS but had CD4 lymphocyte counts below 500 per microliter were given either zidovudine or a placebo and were followed for up to 4.5 years. A dose of 500 milligrams of zidovudine was found to significantly slow the progression to AIDS. However, its effectiveness was less pronounced on those whose initial CD4 cell counts were less than 300 per microliter, and the relative risk of AIDS progression between those receiving zidovudine and those receiving a placebo was the same after roughly 2 years. Other drug treatment and prevention measures should be developed to overcome the long-term ineffectiveness of zidovudine., Objective.--To determine the durability of zidovudine-induced delay in clinical progression of asymptomatic human immunodeficiency virus (HIV) disease and to assess the relationship between this effect and the entry [CD4.sup.+] cell count. Design and Interventions.--Extended follow-up data from subjects participating in protocol 01 9 of the AIDS [acquired immunodeficiency syndrome] Clinical Trials Group were examined. Subjects were offered a total daily dose of 500 mg of open-label zidovudine after the unblinding of the original randomized trial in 1989. Original treatment groups included placebo, 500 mg of zidovudine, or 1500 mg of zidovudine daily in divided doses. Three distinct analyses were conducted to assess the duration of zidovudine's effect on progression to AIDS or death: (1) analysis of all follow-up information from all subjects, (2) analysis of all subjects but with follow-up of original placebo-assigned subjects censored at the time open-label zidovudine was initiated, and (3) analysis of the effect of initiating zidovudine in subjects initially assigned to receive placebo. Setting.--University-based and university-affiliated AIDS research clinics participating in AIDS Clinical Trials Group protocol 019. Patients.--A total of 1565 asymptomatic HIV-infected subjects with entry [CD4.sup.+] cell counts less than 0.50x[10.sup.9]/L (500/[mu]L). Main Outcome Measure.--Time to progression to AIDS or death. Results.--During follow-up of up to 4.5 years (mean, 2.6 years), 232 subjects progressed to AIDS or died. In each of the three analyses described herein, zidovudine was associated with a significant (P=.008,.004,.007) decrease in the risk of such progression. However, each of these analyses also indicated a decreasing placebo:zidovudine relative risk with duration of use (P=.002,.08,.04), suggesting a nonpermanent effect. The duration of benefit appeared to be related to entry [CD4.sup.+] cell count, with greater benefit in those with higher counts at entry. No significant differences in survival were found between those originally randomized to zidovudine or placebo. Conclusions.--Zidovudine at 500 mg/d caused a significant delay in progression to AIDS or death, but its earlier use in asymptomatic disease was not associated with an additional prolongation of survival compared with delayed initiation. The delay in progression diminished over time especially in subjects with entry [CD4.sup.+] cell counts less than 0.30x[10.sup.9]/L (300/[mu]L). Treatment strategies that alter drug regimens before the loss of zidovudine benefit should be explored. (JAMA. 1994;272:437-442)

Patients receiving 500 mg. didanosine had a slower progression of HIV disease and fewer deaths within a study period than did those receiving zidovudine (AZT) or 750 mg. of didanosine. These results may occur from the change in medication or from other unknown factors and suggest that didanosine may have wider use than only for patients who cannot tolerate AZT. The effectiveness of didanosine was not related to the length of time patients had previously taken AZT. The lower rate of pneumonia and HIV related problems occurred in patients with AIDS-related complex and those with no symptoms. There were different rates of various side effects for each drug. Both the number of CD4 cells and p24 antigen levels were higher in both groups taking didanosine. Patients who voluntarily withdrew from the study had lower initial CD4 counts and pretreatment AIDS diagnosis. They discontinued the medication to receive other antiviral agents. Mortality rates did not differ among the groups.

The AIDS (acquired immunodeficiency disease syndrome) epidemic has yet to be felt in its full intensity. Blood testing has shown that millions of individuals are already infected by the presumed causative agent, human immunodeficiency virus (HIV). It is supposed that approximately half of all individuals now infected with HIV will, during the course of a 10-year period, develop AIDS. Of the remaining individuals, most if not all will eventually develop serious complications or will die from the infection. It is therefore extremely important to determine the ideal time to begin treating the infection. Zidovudine, also called AZT, is an antiviral medication that has been shown to delay the advance of AIDS and to give some protection to infected individuals against the other opportunistic infections that accompany HIV infection. HIV infection causes a chronic depression in a group of white blood cells that have a particular biologic marker, in the form of a protein, on their cell surfaces. These cells are called CD4+ cells, and they are intimately connected with the body's immune response. The decline in the level of CD4+ cells is an important measure of the progression of the HIV infection to symptomatic disease. The current study examines the value of treating individuals known to be infected with HIV with zidovudine at an earlier time (when the CD4+ population dropped below 500 per cubic millimeter) than is currently recommended (200 per cubic millimeter). Subjects were divided into three treatment groups by random chance: zidovudine at 500 mg per day (453 subjects); 1500 mg zidovudine per day (457 subjects); or placebo (428 subjects). The average follow-up period was 55 weeks, at which time 33 of the placebo treated group had developed AIDS, as compared with 11 out of the 500 mg group and 14 of the 1500 mg group. Zidovudine at both dose levels was statistically significant in reducing the number of individuals who progressed to full-blown AIDS during the period studied. Those individuals in the zidovudine groups also had significantly higher CD4+ cells, and lower levels of HIV (as determined by p24 antigen tests). It is important to note that the lower dose of zidovudine, which has fewer side effects, was equally as effective as the higher dose level. The authors believe that zidovudine is both safe and effective for treatment of asymptomatic HIV infection. (Consumer Summary produced by Reliance Medical Information, Inc.)