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Using Registries to Monitor HIV Pre-ExposureProphylaxis Safety in Clinical Settings

Hugh H. Tilson, MD, DrPH

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Background

Registries provide an essential element of an over-all strategy to understand the safety and safe useof new medications following marketing, and

heywill be part of the postmarketingmonitoring of dailyral antiretroviral pre-exposure prophylaxis (PrEP). The.S. national registry of spontaneous voluntary reports ofuspected adverse drug reactions and the Antiretroviralsn Pregnancy Registry will be among registry approacheso PrEP. More challenging will be voluntary registries ofrEP used to understand knowledge, attitudes and be-aviors, adherence, and eventual success of PrEP. Severalossible approaches are proposed, and their challengesnd limitations are explored.

IntroductionRegistries provide one vital tool to extend understandingof the effectiveness and safety of a drug, in original andsubsequent uses (indications). Based on observationalapproaches, the registry is a non-interventional, non-experimental way to study and learn from routine clin-ical practice.1 Registries of exposures to drug canrovide the observational cohorts that can permitollow-up of large populations over the short and longerm, to identify important outcomes associated withlinical practice. Registries of expected or hypotheticalbut important) outcomes (“cases” of one or more ofhe outcomes under scrutiny), together with retrospec-ive collection of data concerning possibly relevantrior exposures, provide a complementary approach,ften one that is less resource-intensive than the effortsequired to assemble a prospective registry/cohort.aken together, exposure and outcome registries canid early detection of untoward adverse outcomes andonitor efforts at risk management.The regulatory process for approval of a new drug, or aew indication for an existing drug or drug combinationas in the case of PrEP), generally requires two well-

From the Gillings School of Global Public Health, University of NorthCarolina at Chapel Hill, North Carolina

Address correspondence to: Hugh H. Tilson, MD, DrPH, UNCGillingsSchool of Global Public Health, 4106 McGavran-Greenberg, Campus Box7469, Chapel Hill NC 27599-7469. E-mail: htilson@email.unc.edu.

s0749-3797/$36.00http://dx.doi.org/10.1016/j.amepre.2012.09.042

© 2013 American Journal of Preventive Medicine • Published by Elsev

controlled, blinded RCTs. Such trials frequently are pow-ered very narrowly to demonstrate signifıcant separationof effıcacy end points, not, for example, rarer adverseevents or those emerging from longer-term care. Newdrug and new indication approvals are based on as few asone or two thousand patients, studied for a period of timelong enough to satisfy regulatory requirements.Thus, continuing studies of those drugs, particularly

the use of the registry approach in general clinical use, areneeded to provide the broader scientifıc database neededfor clinical guidance.2,3 The emergence of the new indi-ation for the use of a fıxed-dose combination of thentiretroviral medications tenofovir disoproxil fumaratend emtricitabine (Truvada®) for PrEP to prevent sexualHIV acquisition by uninfected people—medications al-ready shown to be safe and effective for treatment ofHIV-infected individuals—calls for such complementaryregistry approaches. This paper examines the currentexperiences with such registries and the application oflessons learned to PrEP.

Outcome RegistriesAdverse Event Reporting SystemThe largest and most widely accepted registry for post-approval monitoring of the safety of approved drugs is theU.S. Food and Drug Administration (FDA) Adverse EventReporting System (AERS).4 All sponsors (manufacturers/evelopers/marketers) of branded and generic drugs areequired, by FDA regulation, to monitor the adversexperience in association with the use of their pr-ducts. All adverse events coming to the attentionf sponsors from any source—provider, consumer,tudy, or literature—must be followed up, analyzed,nd reported to the FDA. To qualify for inclusion inhis national registry, a report must specify a reporter,n identifıable event, a patient, and drug exposure.Truvada and the component medications have beenonitored through this AERS system since initial ap-roval, with more than 10 million treatments over thentervening years. PrEP use will be subjected to similaronitoring, further extending this database. However,ERS has substantial limitations. The nature of the sys-em invites under-ascertainment, inaccurate attribution,nder-reporting, and unclear reporting biases for the

afety events of interest.

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Other Outcome RegistriesOther forms of outcome registries have proved very use-ful in understanding possible causal factors for adverseoutcomes in populations. Disease or condition registriesare powerful tools for understanding (retrospectively)underlying possible causal factors and (prospectively) thelongitudinal course of diseases and conditions, undervarying approaches for treatment/management. Cancer5

and birth defect registries,6 for example, have been im-ortant in suggesting important possible causal factorsor these important adverse outcomes of prior exposures.Vital for these registries is the collection of importantistorical data from patients suffering from an adverseondition/outcome. For registries to be used in theseays, they must collect information on potential riskactors or possible causal agents, as elementary as smokingistory or occupation, or short- and long-term drug expo-ures. Such collection often requires detailed person-o-person interviews and poses major methodologic andechnical challenges, especially for registry reporting gener-ted from busy clinical practice settings.For outcome registries to be useful with PrEP, it will beecessary tospecifywhatadverseoutcomesof interestmighte followed by such a registry. Described elsewhere7 in thissupplement to theAmerican Journal of PreventiveMedicineis a concern that under-dosing (through poor adherence,for example) might lead to infection with drug-resistantstrains of HIV. Thus, using the existing laboratory-basedmonitoring systems for tracking the emergence of drug-resistant strains (“registering” such cases and investigat-ing possible antecedent events, including use of PrEP)will be a useful component of national outcomes moni-toring response to this new medical intervention. Theaddition of questions about PrEP use to existing investi-gations of emerging drug resistance will doubtless be partof such monitoring and, if reported to a PrEP outcomesregistry, could be very useful.Limitations of retrospective/case registries include the

challenges of incomplete and inaccurate recall since aretrospective evaluation requires that people be asked torememberwhat theymay have done andwhen they did it,at a time in the near or remote past. Further, if exposureto/use of one of the agents/activities causing a problem isrelatively infrequent, then it will takemany cases to fınd acontributing exposure. For example, it may be diffıcult toconfırm a substantial increase in the use of PrEP by HIV-uninfected people (a few of whom may become in-fected) as one of the causal explanations for a relativelyfrequent fınding of HIV treatment failure due to anti-retroviral resistance among the large number of peoplewith HIV infection8,9 without following up on very

any “cases.”

Exposure (Prospective/Follow-Up) RegistriesTo address many of the limitations of retrospective ap-proaches, prospective registries have much to commendthem. In this approach,groups/populations/cohorts sharinga common experience, in this case, for example, healthypeople takingPrEP, are invited to contribute their follow-upexperiences to tracking the natural history of their healthexperience following such treatments.

Registries and Risk ManagementNon-adherence to the recommended daily dosing hasbeen identifıed as a risk for prevention failure and devel-opment of resistant strains among those with unrecog-nized HIV infection who inadvertently are prescribedPrEP. Prevention of this type will require organized riskmanagement activities following PrEP approval, particu-larly aggressive efforts at physician andpatient education.In addition, registries likely will be initiated.A carefully designed, simple, and easy-to-participate-in

PrEP registry could provide current informational up-dates for physicians and, with proper incentives, monitortheir evolving knowledge, attitudes, and practices. Like-wise, a registry involving patients could collect similarinformation over time. By inviting prescribers and pa-tients into a registry, those conducting it can encourageparticipants to report their evolving experiences withPrEP adherence and collect data on health outcomes.Such a registry can be designed to encourage and rein-force the importance of adherence for patients and clini-calmonitoring for prescribers, and thus, the registry itselfcan be a tool to increase the success of adherence and totest the outcome of specifıc messages.The limitations of such a PrEP registry should be rec-

ognized by anyone who undertakes them. Voluntary reg-istration involves self-selection by clinicians and/or pa-tients; thus, participants are unlikely to be entirelyrepresentative of the broader population. Dropouts fromthe registry cannot provide information about evolvingattitudes, long-term use, and safety experience, yet it maybe the case that the very peoplewhodiscontinue use of theregistry have done so because of side effects, toxicities, oradherence problems that are not being captured. Fullprotections of privacy will be needed that are commensu-rate with the sensitive nature of medical records andreported sexual behaviors that are primary indicationsfor PrEP use. Even then, concerns about confıdentialitymay discourage potential participants.Finding motivation for registering and continuing

data reporting on PrEP patients will be challenging.Among incentives worthy of consideration are access toinformation that might be valued (e.g., periodic data re-

ports from the registry) and possible fınancial or in-kind

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(e.g., coupon) incentives appropriate to the voluntaryreporting. Within such limitations, registering and fol-lowing an engaged cohort has the potential to provideimportant information about which messages and inter-ventions are at least successfully having an impact onthosewho remain in the registry; such registriesmay havethe added benefıt of encouraging adherence to treatmentand testing recommendations; therefore, registries willdoubtless be attempted under conditions of HIV preven-tion programs.

Pregnancy RegistriesThePartnersPrEPstudyconductedwithHIV-discordantcou-les in Kenya and Uganda10 included vigorous efforts toducate about the need for condom use and active con-raception. Nonetheless, more than 200 women in thetudy became pregnant, 80 while taking Truvada andnother 112 while taking Viread®, leading to fetal drugxposure in the fırst trimester. Medication was with-rawn as soon as pregnancy was detected. The rates ofetal loss and birth defects among those in the studyere similar, comparing those exposed to tenofovir/mtricitabine and those 96 whose mothers receivedlacebo; birth defects reported did not exceed the pop-lation expected background rate of three defects/100ive births.11 Nonetheless, the numbers are relativelysmall. To increase participation, one potentially help-ful PrEP registry approach will be to encourage allphysicians to register women who become pregnantwhile on PrEP in a registry, such as the existing Anti-retroviral Pregnancy Registry (APR), described below.The APR uses a standard voluntary exposure-registration

strategy. The registry makes its availability knownthrough all practical information sources for medicalpractitioners providing care towomenwhobecomepreg-nant, through publication, presentation, displays at an-nual meetings, and of course, personal communications.The APR is listed in approved labeling for all antiretrovi-ral drugs and was added to the PrEP indication labelingfor Truvada.12

Physicians are encouraged to register any patient withknown periconception exposure or at any time duringpregnancy. Anonymous patient information is providedby the physician through the use of a simple registrationform available online. A follow-up request for pregnancyoutcome information is sent at the time of expected de-livery, and information requests are pursued tomaximizereporting of follow-up data.Pregnancies in which an adverse outcome is already

known (e.g., through prenatal testing or that fırst comesto the attention of the registry after delivery) are classifıed

as “retrospective” reports and are not included in the

January 2013

primary analysis, although they are monitored as well.The APR currently reports13 404 outcomes with birthdefects identifıed among 14,035 live births with exposureat any time during pregnancy, a prevalence of 2.9 birthdefects per 100 live births, and a prevalence of birthdefects per 100 live births among women with a fırst-trimester exposure to any of the antiretroviral therapiesincluded in the registry of 2.9 (i.e., 177 outcomes withdefects among 6057 live births). The commensurate ratewithin the APR for Viread (tenofovir disoproxil fumar-ate) is 31 defects among 1370 exposed pregnancies (2.3%,95% CI�1.5%, 3.2%) and for Emtriva® (emtricitabine) is1/899 exposures (2.4%, 95% CI�1.4%, 3.5%; see APRonsensus Statement at end of text). PrEP involves these of these two products, which already are usedidely for HIV treatment and therefore already in-luded in the APR. No signal of possible teratogenicityas been detected.The APR already includes 53 reports with completed

ollow-up of live births after exposures to antiretroviralrugs among pregnant women without HIV infectionho have taken either PrEP or 28 days of post-exposurerophylaxis (PEP) following a potential exposure toHIV;nd an additional 203womenwithoutHIV infectionwhoave taken antiretrovirals for treatment of hepatitis Bnfection. As part of the registry approach to PrEP, clini-ians who care for pregnant women receiving PrEP needo be aware of the APR and their reporting facilitated.Of course, pregnancy registries also have real limita-

ions. Voluntary pregnancy registries are only as power-ul as the numbers/proportions of pregnancies registerednd only as good as the quality of the data provided. Eachear, the APR enrolls approximately 1500 women inhich an antiretroviral exposure during pregnancy hasccurred, approximately 15% of the estimated 8700HIV-ositive women giving birth each year in the U.S. Theotential biases introduced by this selective reporting arenknown. The prospective approach enrolls and moni-ors only those patients in whom there are no knowndverse outcomes at the time of registration. This mini-izes the potential for biased enrollment in general, andiases in reporting of known adverse outcomes. How-ver, such a registry cannot monitor, for example, earlyetal loss. Thus, a combination of strategies that alsoonitors retrospective reports for any sign of unexpectedarly fetal toxicity, a strategy also used by the APR, isritical.

Automated Records, Linked Systems, andOther Emerging TechnologiesAmong limitations to existing strategies for conduct of

registries, important is the extent to which they require

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hands-on efforts by those who actually must registerpatients, outcomes, and exposures. Recent develop-ments promise to harness technology to simplify andenhance accrual of such information. One emergingresource, with great promise to contribute to the con-duct of registries, including those monitoring the useof antiretroviral medicines, is the realm of the Internet,with hand-held device access including optical scan-ning technologies to monitor reports of medicationuse through websites, chat rooms and affınity groups,and personal communication technology. Althoughstill best left to the ranks of “promising” tools for theactual conduct of registries, clearly such mechanismscan and will be harnessed to increase awareness andrecruit into registries in the future. One such use re-cently has been demonstrated for epilepsy,14 in which aatient-based website coordinates and learns from pa-ient drug diaries. Particularly for relatively infrequentircumstances, such as PrEP, recruitment on the weberits exploration.A second powerful potential resource is the large,

utomated, multipurpose population-based systemsLAMPS), creating a database for registries from ad-inistrative or automated medical record systems.he landmark legislation, the FDA Amendments ActFDAAA) of 2007,15 which mandated risk manage-ment (discussed earlier) also included provisions todramatically increase the scope and use of such sys-tems that mine patient medical records for drug safety(and effectiveness) monitoring. Under the FDAAA,the FDA was mandated to support the development ofsystems to harness such data covering more than 100million people. In its “mini-sentinel network,”16,17 theFDA is well on the way to fulfılling this mandate.Linking data across time and space for enrolled popu-lations, such a system is capable of ascertaining all (ormost) drug exposures with all (or most) major medicalevents, particularly those requiring hospitalization.As these techniques mature, they will doubtless pro-

vide a powerful complement to many of the more tradi-tional and labor-intensive registry strategies. However,in the case of pregnancy monitoring, algorithms areneeded to consistently link maternal data with fetal/neonatal data to ensure that all peri-conception and preg-nancy drug exposures are captured.18 Similarly, for anyrEP registry that relies on automated population-basedata, algorithms will be needed to consistently link drug-xposure data for individual patients from multipleources which may provide components of PrEP serviceso important medical outcomes (e.g., clinical care visits,ounseling visits, laboratory results) that may occur in

ore than one healthcare setting.

The Way ForwardRegistries will be needed for monitoring of the safe andeffective use of antiretroviral drugs for PrEP. Creativeapproaches to such registries will be required to addressthe unique circumstances of PrEP. However, the verynature of the registry makes it well suited for such de-mands. With PrEP, the patient is, by defınition, not in-fected with HIV and enters the broader medical systemfor clinical HIV prevention services. For continuedmon-itoring of safety in such clinical use, the registration ofvoluntarily reported adverse events to the FDA and thepharmaceutical company in AERS is likely to captureinformation about PrEP use and adverse clinical out-comes, because it appeals to all reporters for all circum-stances to report all expected and unexpected importantadverse experiences.With all its limitations, the AERS will nevertheless be

no less robust for PrEP than for other uses and otherdrugs and should be a centerpiece of any registry strategy.For specifıc monitoring of the safety of PrEP in preg-nancy, the APR is, similarly, well suited. The APR alreadyreaches out to and enrolls the patients of healthcare pro-viders providing pregnancy and delivery services, tothose with and without HIV. It should be engaged in thePrEP registry strategy. Public health concerns for ex-panded use of PrEP pose new challenges for riskmanage-ment and monitoring strategies at the population level,including monitoring for non-adherence and for emerg-ing drug resistance. The coupling of the registry approachto more-structured studies, including LAMPS efforts,promises to be useful to the overall public health strategy.

Publication of this article was supported by the CDC throughthe Association for Prevention Teaching and Research (CDC-APTR) Cooperative Agreement number 11-NCHHSTP-01.HHT consults widely with the pharmaceutical sector includ-

ing regulators, academia, and the pharmaceutical industry onmatters of drug safety epidemiology. He is a paid senior epide-miology advisor to the Antiretrovirals in Pregnancy Registry(which in turn receives fınancial support from all manufactur-ers of antiretroviral drugs). He is a paid consultant to Gilead,manufacturer of Truvada®.

Consensus statement (required when citing data from theAntiretroviral Pregnancy Registry):“In reviewing all reported defects from the prospective reg-

istry, informed by clinical studies and retrospective reports ofantiretroviral exposure, the Registry fınds no apparent in-creases in frequency of specifıc defects with fırst trimester ex-posures and no pattern to suggest a common cause. The Regis-try notesmodest but statistically signifıcant elevations of overalldefect rates with didanosine and nelfınavir compared with its

population comparator, the MACDP (Metropolitan Atlanta

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Congenital Defects Program). While the Registry populationexposed and monitored to date is not suffıcient to detect anincrease in the risk of relatively rare defects, these fındingsshould provide some assurance when counseling patients.However, potential limitations of registries such as this shouldbe recognized. The Antiretroviral Pregnancy Registry is ongo-ing. Health care providers are encouraged to report eligiblepatients to the registry at www.APRegistry.com.”

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