Klein, Marina B.

Ledergerber, Bruno

Young, Jim

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Noncirrhotic PortalHypertension andDidanosine: A Re-AnalysisTo the Editor—In 2020, Kovari et al[1] reported a strong association betweenexposure to didanosine (DDI) and non-cirrhotic portal hypertension (NCPH),a rare condition likely to be of multifacto-rial etiology. However, the authors werenot able to control confounding throughmultivariate modeling because of thesmall number of case patients. This limi-tation is typical of a rare condition,making it more difficult to evaluate theassociation of antiretroviral use with suchevents because of the number of factorsthat influence the prescription of thesedrugs. With only 15 cases, adding evena single confounder to a model may in-troduce more bias than it removes becauseof small sample bias away from the nullvalue (an odds ratio of 1) [2]. Their studywas, however, nested within the SwissHIV Cohort Study; thus, other methods ofconfounder control are available. Thesemethods require additional modeling ofDDI use in the wider cohort.Using logistic regression, we modeledthe probability of first use of DDI overtime for each patient in the cohort,starting from the month when eitherinfection was first known or DDI wasfirst marketed in Switzerland until themonth of either first use of DDI or theend of follow-up. Our model for first useof DDI had a time-dependent interceptbased on a cubic spline and covariates ofsex, ethnicity, education, likely trans-mission group, age, the number of failedregimens (time dependent), and time-dependent indicators for hepatitis(chronic B or C), lipoatrophy, diabetes,nervous system toxicity, Centers forDisease Control and Prevention groupsB and C, use of zalcitabine, use of sta-vudine, use of tenofovir, gastrointestinaltoxicity, and pregnancy and further in-teraction terms between these last 4 in-dicators and the time of related warningsissued either by the US Food and Drug154 d CID 2011:52 (1 January) d CORRESPONDENCEAdministration or the drug company.From this model, we then calculateda propensity score for each patient ateach point in time: the probability ofexposure to DDI, given the patient’scovariate and treatment history up tothat point. This probability is related toan inverse probability of treatmentweight (IPTW) (see Appendix 1 in [3])and can therefore be calculated ina similar way (see Appendix in [4]).We then re-analysed the original 15case patients and 75 matched controlsubjects, adjusting for a single covariate:the propensity score at the date of di-agnosis in the case patient. This meansthat case and control exposures werecompared at a common value of thepropensity to be exposed to DDI. Wemade this comparison at a commonvalue of the log-transformed propensityscore; with a log transformation, bothexposed and unexposed patients hadpropensity scores with a similar vari-ance, as is necessary for this method ofadjustment [5]. Finally, we added priorinformation to our re-analysis. Withonly a few matched sets, small samplebias can be severe even when exposure isthe only variable in the model [6].Adding prior information can limit thisbias by assigning essentially zero priorprobability to clinically implausible val-ues of an estimate. One of us (MBK),a clinician with expertise in liver diseaseand HIV infection, having read othercase reports and series (see Table 1 in[1]) and before reading about this study,asserted her opinion that the odds ofNCPH in exposed patients, compared tothose unexposed, was a ratio of 1.2 peryear of exposure to DDI, with a 95%confidence interval (CI) of .5–2.5. Wegenerated a set of matched case-controlpairs to represent this prior opinion andthen reran the analysis using both priorand real data [7,8].The published unadjusted odds ratiofor a year of exposure to DDI is 3.4(95% CI, 1.5–8.1) [1]. After adjustmentusing the log propensity score, ourestimate was 4.0 (95% CI, 1.2–13); aweighted analysis using IPTWs gave anestimate of 4.7 (95% CI, 1.4–16). In theBayesian analysis of prior and real data,the adjusted estimate was 2.2 (95% CI,1.5–3.3).Propensity scores and IPTWs are idealmethods of confounder control if theoutcome is rare but treatment is common[9]. The 2 methods use very differentstatistical logic; that both lead to a similarestimate is reassuring. Propensity scoreshave a Bayesian interpretation [5]; thus,we used this method for our Bayesiananalysis. Our re-analysis showed howeven a large number of factors that po-tentially influence treatment allocationcan be accounted for in the analysis ofa rare outcome. The strong associationbetween DDI and NCPH reported byKovari et al [1] does not appear to be anartifact of inadequate confounder con-trol. However, the published estimate isprobably an over-estimate to some de-gree, because of small sample bias. Thatsaid, there is sufficient evidence in thesedata to convince a knowledgeable clini-cian that the association may be of anorder of magnitude (of >2) to justify theFood and Drug Administration warningin January 2010 of an increased riskof NCPH among patients exposed toDDI [10].AcknowledgmentsWe thank the Swiss HIV Cohort Study andHelen Kovari for the use of cohort and case-control data.Funding. None reported.Potential conflicts of interest. M.B.K. hasbeen a consultant for GlaxoSmithKline/Viiv;has received grants from Merck, CanadianInstitutes of Health Research, National In-stitutes of Health Research, and Fonds de re-cherches en sante du Quebec; has served on thespeakers’ bureau for Bristol-Myers Squibb,and GlaxoSmithKline/Viiv; has developed pre-sentations for Gilead, GlaxoSmithKliine/Viiv; and has had meeting expenses paid byGlaxoSmithKline/Viiv. B.L. has served on theboard for Tibotec and the speakers’ bureau forTibotec, Roche, and Gilead (paid to in-stitution); and has had meeting expenses paidby Bristol-Myers Squibb (paid to institution).J.Y.: no conflicts.Jim Young,1 and Marina B. Klein,3Bruno Ledergerber21Basel Institute for Clinical Epidemiology andBiostatistics, University Hospital Basel, Basel,2Division of Infectious Diseases and HospitalEpidemiology, University of Zurich, Zurich,Switzerland, and 3Division of Infectious Diseases andImmunodeficiency Service, McGill University HealthCentre, Montreal, CanadaReferences1. Kovari H, Ledergerber B, Peter U, et al. As-sociation of noncirrhotic portal hypertensionin HIV-infected persons and antiretroviraltherapy with didanosine: a nested case-con-trol study. Clin Infect Dis 2009; 49:626–635.2. Greenland S, Schwartzbaum JA, Finkle WD.Problems due to small samples sparse data inconditional logistic regression analysis. Am JEpidemiol 2000; 151:531–539.3. Robins JM, Hernan MA, Brumback B. Mar-ginal structural models causal inference inepidemiology. Epidemiology 2000; 11:550–560.4. Hernan MA, Brumback B, Robins JM. Mar-ginal structural models to estimate the causaleffect of zidovudine on the survival of HIV-positive men. Epidemiology 2000; 11:561–570.5. Rosenbaum PR, Rubin DB. The central roleof the propensity score in observationalstudies for causal effects. Biometrika 1983;70:41–55.6. Greenland S. Small-sample bias correctionsfor conditional maximum-likelihood odds-ratio estimators. Biostatistics 2000; 1:113–122.7. Greenland S, Christensen R. Data augmenta-tion priors for Bayesian semi-Bayes analyses ofconditional-logistic and proportional-hazardsregression. Stat Med 2001; 20:2421–2428.8. Greenland S. Prior data for non-normal pri-ors. Stat Med 2007; 26:3578–3590.9. Braitman LE, Rosenbaum PR. Rare out-comes, common treatments: analytic strate-gies using propensity scores. Ann Intern Med2002; 137:693–695.10. US Food and Drug Administration. FDA drugsafety communication: serious liver disorderassociated with the use of Videx/Videx EC(didanosine) Available at: http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm199169.htm. Accessed 31 August 2010.Correspondence: Dr Jim Young, Basel Institute for ClinicalEpidemiology and Biostatistics, Hebelstrasse 10, UniversityHospital Basel, CH-4031 Basel, Switzerland (jyoung@uhbs.ch).Clinical Infectious Diseases 2011;52(1):152–155 The Author 2011. Published by Oxford University Press. Allrights reserved.1058-4838/2011/521-0001$37.00DOI: 10.1093/cid/ciq079CORRESPONDENCE d CID 2011:52 (1 January) d 155

Noncirrhotic Portal Hypertension and Didanosine: A Re-Analysis

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