Stephen W. Lagakos

A Controlled Trial Comparing Continued Zidovudine with Didanosine in Human Immunodeficiency Virus Infection

BACKGROUND Although zidovudine is effective in patients with human immunodeficiency virus (HIV) infection, its efficacy may decline with prolonged use. Didanosine is another inhibitor of HIV reverse transcriptase. We evaluated the effectiveness of changing anti-HIV treatment from zidovudine to didanosine. METHODS This multicenter, double-blind study involved 913 patients who had tolerated zidovudine for at least 16 weeks. The patients had the acquired immunodeficiency syndrome (AIDS), AIDS-related complex with less than or equal to 300 CD4 cells per cubic milliliter, or asymptomatic HIV infection with less than or equal to 200 CD4 cells per cubic milliliter. They were randomly assigned to receive 600 mg per day of zidovudine, 750 mg per day of didanosine, or 500 mg per day of didanosine. RESULTS There were significantly fewer new AIDS-defining events and deaths among the 298 subjects assigned to 500 mg per day of didanosine than among the subjects who continued to receive zidovudine (relative risk, 1.39; 95 percent confidence interval, 1.06 to 1.82; P = 0.015). With 750 mg of didanosine, there was no clear benefit over zidovudine (relative risk, 1.10; 95 percent confidence interval, 0.86 to 1.42). The efficacy of didanosine was unrelated to the duration of previous zidovudine treatment. In the two didanosine groups, there were improvements in the number of CD4 cells (P less than 0.001 for both groups) and in p24 antigen levels (P = 0.03 in the 500-mg group; P = 0.005 in the 750-mg group), as compared with the zidovudine group. CONCLUSIONS Changing treatment from zidovudine to 500 mg per day of didanosine appears to slow the progression of HIV disease.

CD4+ Lymphocytes Are an Incomplete Surrogate Marker for Clinical Progression in Persons with Asymptomatic HIV Infection Taking Zidovudine

Identifying a valid surrogate end point for serious clinical events associated with human immunodeficiency virus (HIV) infection, such as the development of acquired immunodeficiency syndrome (AIDS)-defining opportunistic diseases or death, would make it possible for the clinical research of new anti-HIV therapies to be conducted more quickly and possibly with fewer patients [1-3]. However, the use of an end point that is not a true surrogate could undermine research efforts and deprive patients of effective therapies by creating the false impression of the activity of new drugs. The recent clinical trial of antiarrhythmic therapy for asymptomatic or mildly symptomatic ventricular arrhythmia after myocardial infarction illustrates this point well [4]. To determine if a marker is a valid surrogate for progression to a particular clinical end point and whether it will be useful in studies investigating anti-HIV therapies, it is not sufficient to show that a pretreatment marker value is associated with such progression. Rather, we need to show that changes in the marker over time are related to that progression and that the effect of a particular drug on this progression can be explained by its effect on the marker [5]. Recent work by DeGruttola and colleagues [6] has indicated that the absolute number of CD4+ lymphocytes in the peripheral blood (the CD4+ cell count) is not a complete surrogate marker for death in persons with AIDS or advanced AIDS-related complex. Their analyses of data from the original phase II zidovudine (3-azido-3-deoxythymidine, AZT) trial [7] and of data from Protocol 002 of the AIDS Clinical Trials Group [8] showed that only a small portion of zidovudines effect on survival was statistically related to its effect on the CD4+ cell count. Despite the limitations of these findings, their implications, coupled with the perceived similarity between zidovudine and didanosine (2,3-dideoxyinosine, ddI), appear to have played an important role in the recent Food and Drug Administration (FDA) provisional approval of didanosine for use in persons who cannot tolerate zidovudine or who are not benefiting from zidovudine therapy. Data were available to show that didanosine delayed the decrease in CD4+ cell counts during the first 24 weeks of therapy in persons with symptomatic HIV infection, but the data did not show a direct clinical benefit. This use of a surrogate marker for drug approval marks a precedent in AIDS research and may well pave the way for other drug-approval requests based on the effects on surrogate markers. However, the usefulness of the CD4+ cell count as a surrogate marker for death in persons with AIDS may have little bearing on its merit as a surrogate marker for the development of AIDS in persons with early HIV infection. Surrogate markers are more valuable in early disease populations than in more advanced disease populations. Also, it is not clear whether measurements of CD4+ lymphocytes other than the absolute count correlate better with clinical progression. We assessed the extent to which zidovudines effect on the development of AIDS is statistically related to its effect on CD4+ lymphocyte levels in persons with asymptomatic HIV infection. Methods Patients We analyzed data from the stratum of Protocol 019 of the AIDS Clinical Trials Group (ACTG 019) that enrolled asymptomatic HIV-infected men and nonpregnant women (ages 18 years or older with 500 or fewer CD4+ cells/mm3) to receive placebo, a 500-mg total daily dose of zidovudine, or a 1500-mg total daily dose of zidovudine. The primary results of this stratum of ACTG 019 have been reported elsewhere [9]. For the purpose of this report, all analyses were based on data available through March 1989, before prophylaxis against Pneumocystis carinii pneumonia, a leading AIDS-defining event, was widely permitted. Furthermore, only patients in whom at least one post-baseline CD4+ cell count had been taken were included in this study. The data from the two zidovudine dose groups were pooled because they were similar with respect to pretreatment characteristics and rates of progression to AIDS [9] and because few such progressions occurred in either arm alone. Laboratory Studies Blood samples were collected at enrollment and at follow-up visits at weeks 8, 16, 32, 48, 64, and 80 by the institutions participating in the trial. The CD4+ cell count was calculated as the product of the leukocyte count, the percentage of lymphocytes in all leukocytes (percent lymphocytes), and the percentage of lymphocytes that were CD4+ cells (CD4+ percent). The leukocyte count and the differential count were measured by standard automated techniques. The CD4+ percent was obtained by flow cytometry. Interlaboratory results were monitored by ACTG quality-control procedures [10]. Statistical Analysis The analyses in this report were based on an intention-to-treat approach. Estimates of distributions of the time-to-progression to AIDS were obtained by using the Kaplan-Meier method [11]. For assessing statistical associations among zidovudine, CD4+ lymphocyte levels, and progression to AIDS, the Cox regression [12] model was fitted with the current CD4+ lymphocyte values, the treatment assignment, or both. The current CD4+ cell count was the most recently measured preceding value. The amount of the zidovudine effect on progression to AIDS that could be explained by its effect on CD4+ lymphocyte levels was assessed by the proportional reduction in the regression coefficient for the treatment assignment after controlling for changes in the CD4+ lymphocyte levels. Separate analyses and analyses stratified by treatment were also made when appropriate. Missing marker values were imputed from trajectories of the most recent values by using a first-order autoregressive model [13] with time-varying autocorrelation coefficients. All reported P values are two sided. Results Effect of Zidovudine on Progression to AIDS and on CD4+ Lymphocytes A total of 1075 patients were assessable: 350 in the placebo group and 725 in the zidovudine groups. After a maximum follow-up of 90 weeks (median, 55 weeks), 44 patients had progressed to AIDS: 24 in the placebo group and 20 in the zidovudine groups (log rank; P = 0.04; Figure 1). The overall progression rates were 6.4 (placebo) and 3.2 (zidovudine) per 100 person-years. Figure 1. AIDS-free probabilities for the placebo group and for the zidovudine groups over time. Lymphocyte values were not available for 3% of patients at week 8, 8% at week 16, 14% at week 32, and 23% to 25% thereafter. A summary of the effects of zidovudine on the CD4+ cell count is shown in Figure 2. The effect of zidovudine on this marker appears to be transient, with an increase in the count for approximately 8 weeks followed by a slow decrease at approximately the same rate as that in patients given placebo. An opposite, adverse effect of zidovudine on the leukocyte count occurred that attenuated the drugs overall effects on the CD4+ cell count. In patients given zidovudine, a decrease occurred in the leukocyte count during the first 16 weeks (average loss of 60 cells/mm3 per week for the first 8 weeks and 30 cells/mm3 per week for the next 8 weeks); the leukocyte count was stable thereafter. The leukocyte count in patients given placebo was relatively stable throughout the observation period. Zidovudines effect on percent lymphocytes and CD4+ percent was similar to its effect on the CD4+ cell count. Figure 2. Cross-sectional medians of the CD4+ cell counts and the component markers in the placebo group and in the zidovudine groups. Association between Markers and Progression to AIDS Stratified (by treatment) Cox regression showed that the baseline values of the CD4+ cell count, leukocyte count, and CD4+ percent among the component markers and the net CD4+ percent (percentage of CD4+ lymphocytes among all leukocytes) were significantly correlated with the risk for clinical progression (Table 1). For example, a smaller baseline CD4+ cell count (50 cells/mm3) corresponded to a 36% higher risk for progression. When a patients current markers were used in Cox regression with time-dependent covariates, the CD4+ cell count and all of its components were significantly correlated with the risk for progression (Table 1). Furthermore, after the current marker values had been accounted for, the baseline values were no longer significant. Table 1. Prognostic Value of CD4+ Lymphocyte Levels for Progression to AIDS CD8+ lymphocytes, either the absolute count or the percentage, had no significant value in predicting the progression to AIDS in this HIV-infected but asymptomatic patients (data not shown). Also, no significant effect of zidovudine on CD8+ lymphocyte levels was observed. Effect of Zidovudine on Progression to AIDS that Is Explainable by Changes in CD4+ Lymphocyte Levels If the CD4+ cell count were a complete surrogate marker for progression to AIDS, no residual association between treatment and progression would exist after we controlled for the current CD4+ cell count [5]. However, as seen in Table 2, zidovudine was still significantly correlated with progression after adjustment for the current CD4+ cell count. Additionally, the resulting zidovudine-placebo relative risk was virtually identical to the relative risk of 2.10 obtained if we did not account for the current CD4+ cell count. In contrast, the net CD4+ percent accounted for 37% of zidovudines effect on progression. In either case, patients given zidovudine had a lower risk for clinical progression than did those given placebo, after we controlled for the current CD4+ cell count. This implies that the relation between the current CD4+ cell count and the risk for progression differed in the two treatment groups. Table 2. Effect of Zidovudine in Delaying Progression to AIDS Adjusted for Its Effect on CD4+ Lymphocyte Levels To quantify this difference, we fitted a time-dependent Cox regression

An analysis of contaminated well water and health effects in Woburn, Massachusetts

Abstract In 1979, two of the eight municipal wells servicing Woburn, Massachusetts, were discovered to be contaminated with several chlorinated organics. Shortly afterwards, the town was found to have an elevated rate of childhood leukemia. Using recent information about the space—time distribution of water from the two contaminated wells, we find positive statistical associations between access to this water and the incidence rates of childhood leukemia, perinatal deaths (1970–1982), two of five categories of congenital anomalies, and two of nine categories of childhood disorders. We find no associations with spontaneous abortions, low birth weight, or the other categories of congenital anomalies and childhood disorders. This article discussed these results and other features of the data relevant to their interpretation.

Design considerations for AIDS trials

Statisticians and clinicians involved in the design and conduct of trials of new treatments for the acquired immunodeficiency syndrome (AIDS) have realized that some traditional approaches to the c...

Size and power of two-sample tests of repeated measures data.

One method of using repeated measures data to compare treatment groups in a clinical trial is to summarize each subjects outcomes with a single summary statistic, and then perform a distribution-free comparison based on the resulting statistics. We examine extensions of this approach and conditions under which they retain proper size in the presence of missing data. The asymptotic relative efficiencies of several summary statistic tests are calculated to show which perform best in a variety of situations. The techniques are illustrated using data from an AIDS clinical trial.

A Stochastic Model for Censored-Survival Data in the Presence of an Auxiliary Variable

In clinical trials and other investigations of survival time, information is often available on a time-dependent event other than survival. An example of such an auxiliary event in cancer studies is objective progression of disease. While some patients expire without experiencing objective disease progression, others die after progression is observed. This paper proposes a stochastic model which utilizes this type of information in the evaluation of survival time. Our intentions in presenting this model are to provide a means of relating survival and another time-dependent event to one another (each of which may be used in the evaluation of a patients condition), and to obtain more precise estimates of survival time by exploiting its relationship with this other event. The intrinsic aspects of the model are related to the semi-Markov model proposed by Weiss and Zelen [1965]. An important difference is that the present model incorporates incomplete (censored) observations as well as covariante variables. Analysis of the model via the method of maximum likelihood and its testability are discussed. The methods are applied to the results of a recent lung cancer study.

Zidovudine in Asymptomatic Human Immunodeficiency Virus Infection

Zidovudine (AZT) is a potent inhibitor of the replication of the human immunodeficiency virus (HIV), and it has been shown to improve survival in advanced HIV disease. We conducted a randomized, double-blind trial in adults with asymptomatic HIV infection who had CD4+ cell counts of fewer than 500 per cubic millimeter on entry into the study. The subjects (92 percent male) were randomly assigned to one of three treatment groups: placebo (428 subjects); zidovudine, 500 mg per day (453); or zidovudine, 1500 mg per day (457). After a mean follow-up of 55 weeks (range, 19 to 107), 33 of the subjects assigned to placebo had the acquired immunodeficiency syndrome (AIDS), as compared with 11 of those assigned to receive 500 mg of zidovudine (P = 0.002; relative risk, 2.8; 95 percent confidence interval, 1.4 to 5.6) and 14 of those assigned to receive 1500 mg of zidovudine (P = 0.05; relative risk, 1.9; 95 percent confidence interval, 1.0 to 3.5). In the three treatment groups, the rates of progression (per 100 person-years) to either AIDS or advanced AIDS-related complex were 7.6, 3.6, and 4.3, respectively. As compared with those assigned to placebo, the subjects in the zidovudine groups had significant increases in the number of CD4+ cells and significant declines in p24 antigen levels. In the 1500-mg zidovudine group, severe hematologic toxicity (anemia or neutropenia) was more frequent than in the other groups (P less than 0.0001). In the 500-mg zidovudine group, nausea was the only toxicity that was significantly more frequent (in 3.3 percent) than in the placebo group (P = 0.001). We conclude that zidovudine is safe and effective in persons with asymptomatic HIV infection and fewer than 500 CD4+ cells per cubic millimeter. Additional study will be required to determine whether such treatment will ultimately improve survival for persons infected with HIV.

Surrogate Markers in AIDS: Where Are We? Where Are We Going?

Excerpt During the last several years, extensive research has been done on surrogate markers in patients with the acquired immunodeficiency syndrome (AIDS) (1). However, many questions remain about...

Estimation of the infection time and latency distribution of AIDS with doubly censored data

We consider the nonparametric estimation of the time to infection with HIV and the latency period between infection and the onset of AIDS in data where both the events of infection and AIDS are not directly observed. The methods use self-consistency equations that are more easily and quickly solvable than the nonparametric estimators proposed by De Gruttola and Lagakos (1989, Biometrics 45, 1-11). The techniques are illustrated with data on hemophiliacs who became infected through contamination of the blood factor they were given to control their hemophilia.

Challenges to HIV Prevention — Seeking Effective Measures in the Absence of a Vaccine

In the 15 to 20 years it may take to develop and evaluate a highly efficacious vaccine, the world may be facing 20 to 60 million new HIV infections. Stephen Lagakos and Alicia Gable write that it is critical to learn how to optimize the use of multiple, partially effective biomedical and behavioral interventions in the settings and populations in which they are most effective.