This paper reviews recent statistical advances in HIV/AIDS therapy trials. Our emphasis is on three emerging areas that address key challenges in AIDS research: the determination of optimal treatment sequences, estimating efficacy of intended treatment, and inference for repeated measures with dependent censoring. A common theme of these topics is the use of observational data within clinical trials to answer questions not addressed by the conventional intent-to-treat analysis. We also give a brief overview of some recent contributions to other topics relevant to AIDS clinical trials, including modelling of treatment compliance data, modelling of repeated measures, and group sequential testing.
Get full access to this article
View all access options for this article.
References
1.
Albert JM , Ioannidis JPA , Reichelderfer Pet al.Statistical issues for HIV surrogate endpoints: point/counterpoint . Statistics in Medicine1998; 17: 2435-2462 .
2.
Ellenberg SS , Finkelstein DM , Schoenfeld DA.Statistical issues arising in AIDS clinical trials . Journal of American Statistical Association1992; 87: 562-569 .
3.
Stanley K , Lagakos SW.Biostatistical considerations in the design and analysis of AIDS clinical trials. In: Merigan TC , Bartlett JG , Bolognesi D , eds. Textbook of AIDS medicine. Baltimore, MD: Williams & Wilkins , 1994.
4.
Ellenberg SS , Dixon DO.Statistical issues in designing clinical trials of AIDS treatments and vaccines . Journal of Statistical Planning and Inference1994; 42: 123-135 .
5.
Dixon DO , Albert JM.Issues in the design and analysis of AIDS clinical trials. In: Thall PF , ed. Recent advances in clinical trial design and analysis. Norwell, MA: Kluwer Academic Publishers , 1995.
6.
Foulkes MA.Advances in HIV/AIDS statistical methodology over the past decade . Statistics in Medicine1998; 17: 1-25 .
7.
Carpenter CC , Fischl MA , Hammer SMet al.Antiretroviral therapy for HIV infection in 1998 . Journal of the American Medical Association1998; 280: 78-86 .
8.
Miles SA.Long-term therapeutic strategies in HIV . Journal of Acquired Immunodeficiency Syndromes and Human Retrovirology1997; 16: S36-S41 .
9.
Steinbrook R.Battling HIV on many fronts . New England Journal of Medicine1997; 337: 779-781 .
10.
Elashoff M , Lagakos S.HIV treatment strategies utilizing virologic and immunologic markers as criteria for changing treatments . Statistics in Medicine1996; 15: 2425-2443 .
11.
Hogg RS , Rhone SA , Yip Bet al.Antiviral effect of double and triple drug combinations amongst HIV-infected adults: lessons from the implementation of viral load-driven antiretroviral therapy . AIDS1998; 12: 279-284 .
12.
O’Brien WA , Hartigan PM , Martin Det al.Changes in plasma HIV-1 RNA and CD4+ lymphocyte counts and the risk of progression to AIDS . New England Journal of Medicine1996; 334: 426-431 .
13.
Cox DR.Regression models and life-tables (with discussion) . Journal of the Royal Statistical Society1972; B34: 187-220 .
14.
Wei LJ , Lin DY , Weissfeld L.Regression analysis of multivariate incomplete failure time data by modeling marginal distributions . Journal of American Statistical Association1989; 84: 1065-1073 .
15.
Prentice RL , Williams BJ , Peterson AV.On the regression analysis of multivariate failure time data . Biometrika1981; 68: 373-379 .
16.
Lin DY.Cox regression analysis of multivariate failuretimedata:themarginalapproach . Statistics in Medicine1994; 13: 2233-2247 .
17.
Li QH , Lagakos SW.Use of the Wei-Lin-Weissfeld method for the analysis of a recurring and terminating event . Statistics in Medicine1997; 16: 925-940 .
18.
Lee YJ , Ellenberg JH , Hirtz DG , Nelson KB.Analysis of clinical trials by treatment actually received: is it really an option?Statistics in Medicine1991; 10: 1595-1605 .
19.
Sheiner LB , Rubin DB.Intention-to-treat analysis and the goals of clinical trials . Clinical Pharmacology and Therapeutics1995; 57: 6-15 .
20.
Fischl MA , Parker CB , Pettinelli Cet al.A randomized controlled trial of a reduced daily dose of zidovudine in patients with acquired immunodeficiency syndrome . New England Journal of Medicine1990; 323: 1009-1014 .
21.
Robins JM , Greenland S.Adjusting for different rates of prophylaxis therapy for PCP in high-dose versus low-dose AZT treatment arms in an AIDS randomized trial . Journal of the American Statistical Association1994; 89: 737-749 .
22.
Robins JM.The analysis of randomized and nonrandomized AIDS treatment trials using a new approach to causal inference in longitudinal studies. In: Sechrest L , Freeman H , Mulley A eds. Health service research methodology: a focus on AIDS. NCHSR, US Public Health Service , 1992.
23.
Concorde Coordinating Committee . Concorde: MRC/ANRS randomised double-blind controlled trial of immediate and deferred zidovudine in symptom-free HIV infection . Lancet1994; 343: 871-881 .
24.
White IR , Babikar AG , Walker S , Darbyshire JH.Randomization-based methods for correcting for treatment changes: examples from the Concorde trial . Statistics in Medicine1999; 18: 2617-2634 .
25.
Cox DR , Oakes D.Analysis of survival data. New York: Chapman & Hall , 1984.
26.
Mittlböck M , Whitehead J.The interpretation of clinical trials of immediate versus delayed therapy . Lifetime Data Analysis1998; 4: 253-263 .
27.
Hardy DWet al.A controlled trial of trimethoprim-sufamethoxazole or aerosolized pentamidine for secondary prophylaxis of pneumocystis carinii pneumonia in patients with the acquired immunodeficiency syndrome: ACTG 021 . New England Journal of Medicine1992; 327: 1842-1848 .
28.
Robins JM , Finkelstein DM.Correcting for non-compliance and dependent censoring in an AIDS clinical trial with inverse probability of censoring weighted (IPCW) log-rank tests . Biometrics2000; 56: 779-788 .
29.
Robins JM.Addendum to ‘A new approach to causal inference in mortality studies with sustained exposure periods - application to control of the healthy worker survivor effect.’Computers and Mathematics with Applications1987; 14: 923-945 .
30.
Albert JM.A threshold causal model for clinical trials with departures from intended treatment . Statistics in Medicine1999; 18: 1615-1626 .
31.
Robins JM.Correcting for noncompliance in randomized trials using structural nexted mean models . Communications in Statistics1994; 2379-2412 .
32.
Robins JM , Rotnitsky A , Zhao LP.Analysis of semiparametric regression models for repeated outcomes in the presence of missing data . Journal of the American Statistical Association1995; 90: 106-121 .
33.
Dawson JD , Lagakos SW.Analyzing laboratory marker changes in AIDS clinical trials . Journal of Acquired Immune Deficiency Syndromes1991; 4: 667-676 .
34.
Dawson JD.Sample size calculations based on slopes and other summary statistics . Biometrics1998; 54: 323-330
35.
Hogan JW , Laird NM.Increasing efficiency from censored survival data by using random effects to model longitudinal covariates . Statistical Methods in Medical Research1998; 7: 28-48 .
36.
Rotnisky A , Robins JM , Scharfstein DO.Semiparametric regression for repeated outcomes with non-ignorable non-response . Journal of the American Statistical Association1998; 93: 1321-1339 .
37.
Scharfstein DO , Rotnitzky A , Robins JM.Adjusting for nonignorable drop-out using semiparametric nonresponse models . Journal of the American Statistical Association1999; 94: 1096-1120 .
38.
Finkelstein DM , Schoenfeld DA.Combining mortality and longitudinal measures in clinical trials . Statistics in Medicine1999; 18: 1341-1354 .
39.
Englund JA , Baker C , Raskino Cet al.Clinical and laboratory characteristics of a large cohort of symptomatic, human immunodeficiency virus-infected infants and children. AIDS clinical trials group protocol 152 study team . Paediatric Infectious Disease Journal1996; 15: 1025-1036 .
40.
Bozzette S , Finkelstein D , Feinberg Jet al.A randomized trial comparing fluconazole with clotrimazole troches for the prevention of fungal infections in patients with advanced HIV infection . New England Journal of Medicine1995; 332: 700-705 .
41.
Wei LJ , Johnson WE.Combining dependent tests with incomplete repeated measurements . Biometrika1985; 72: 359-364 .
42.
Brady MT , McGrath N , Browers Pet al.Randomized study of the tolerance and efficacy of high-versus low-dose zidovudine in HIV-infected children with mild-to-moderate symptoms (ACTG 128) . Journal of Infectious Diseases1996; 173: 1097-1106 .
43.
Yao Q , Wei LJ , Hogan JW.Analysis of incomplete repeated measurements with dependent censoring times . Biometrics1998; 85: 139-149 .
44.
Parzen MI , Wei LJ , Ying Z.Are sampling method based on pivotal estimating functions . Biometrika1994; 81: 341-350 .
45.
Glidden DV , Wei LJ.Rank estimation of treatment differences based on repeated measurements subject to dependent censoring . Journal of the American Statistical Association1999; 94: 888-895 .
46.
Girard P , Blaschke TF , Kastrissios H , Sheiner LB.A Markov mixed effect regression model for drug compliance . Statistics in Medicine1998; 17: 2313-2333 .
47.
Gray SM , Brookmeyer R.Multidimensional longitudinal data: estimating treatment effect from continuous, discrete or time-to-event response variables . Journal of the American Statistical Association2000; 95: 369-406 .
48.
Gray SM , Brookmeyer R.Estimating treatment effect from multidimensional longitudinal data . Biometrics1998; 54: 976-988 .
49.
Betensky RA.Local estimation of smooth curves for longitudinal data . Statistics in Medicine1997; 16: 2429-2445 .
50.
Tibshirani R , Hastie TJ.Local full likelihood estimation for the proportional hazards model . Biometrics1987; 82: 559-567 .
51.
Bass HJ , Hardy WD , Mitsuyasu RTet al.The effect of zidovudine treatment on serum neopterin and β2-microglobulin levels in mildly symptomatic, HIV type 1 seropositive individuals . Journal of Acquired Immune Deficiency Syndromes1992; 5: 215-221 .
52.
Hu XJ , Lagakos SW.Group sequential analyses for the mean function of a repeated measure process . Statistics in Medicine1999; 18(17-18): 2287-2299 .
53.
Jennison C , Turnbull BW.Interim analyses: the repeated confidence interval approach (with discussion) . Journal of the Royal Statistical Society1989; B51: 305-361 .
54.
Scharfstein DO , Tsiatis AA.The use of simulation and bootstrap in information-based group sequential studies . Statistics in Medicine1998; 17: 75-87 .
55.
Scharfstein DO , Tsiatis AA , Robins JM.Semiparametric efficiency: implications for the design and analysis of group sequential studies . Journal of the American Statistical Association1997; 92: 1342-1350 .
56.
Betensky RA.Conditional power calculations for early acceptance of H0 embedded in sequential tests . Statistics in Medicine1997; 16: 465-477 .
57.
Rida WN , Lawrence DN.Some statistical issues in HIV vaccine trials . Statistics in Medicine1994; 13: 2155-2178 .
58.
Gilbert P , DeGruttola V , Hammer S.Efficient trial designs for studying combination antiretroviral treatments in patients with various resistance profiles . Journal of Infectious Diseases1998; 178: 340-348 .
59.
Kim S , De Gruttola V.Strategies for cohort sampling under the Cox proportional hazards model, application to an AIDS clinical trial . Lifetime Data Analysis1999; 5(2): 149-172 .
60.
Friedman LM , Furberg CD , DeMets DL.Fundamentals of clinical trials. New York: Springer-Verlag , 1998.
