Limited reporting of major harms in studies of initial combination antiretroviral therapy: a systematic review Frederick J. Leea, Janaki Aminb and Andrew Carra Objectives: Risk–benefit assessment of combination antiretroviral therapy (cART) requires consideration of all potential serious harms. Studies of initial cART may permit identification of associations between particular regimens and uncommon harms, but only if comprehensively reported in the public domain. Design: Study-based, systematic review of published initial cART studies (in adult patients) for completeness of serious harms reporting. Methods: Electronic databases, abstracts, and regulatory/sponsor reports were searched (1 January 1996 – 31 December 2012). Reporting of pre-specified harms – deaths, new/recurrent AIDS events, serious non-AIDS events (2010 INSIGHT classification) and serious adverse events (SAEs) – were assessed as the proportion of studies providing data (reporting frequency). Pharmaceutical sponsors were approached for unreported data. Results: 103 studies (86% randomized, 54% industry-sponsored) were included. Deaths, AIDS events, serious non-AIDS events and SAEs were reported for 85 (83%), 55 (53%), 26 (25%) and 43 (42%) studies, respectively. Deaths were better reported for academic than industry-sponsored studies (91 vs. 75%; P ¼ 0.03); the converse applied for SAEs (26 vs. 55%; P ¼ 0.002). SAEs were better reported for randomized than cohort studies (46 vs. 14%; P ¼ 0.03), and for phase 3 than phase 2 or 4 studies (58 vs. 32 and 29%, respectively; P ¼ 0.02). SAE reporting increased over time [r ¼ 0.704, P ¼ 0.002 (Spearman)]. Unreported data acquired for 34 (61%) of 56 industry-sponsored studies improved ascertainment in these studies to between 82 and 100% (P < 0.001). Conclusion: Public domain reporting of serious harms for initial cART studies is limited. Insufficient data exist to determine if particular ART drugs/regimens are associated with Copyright ß 2015 Wolters Kluwer Health, Inc. All rights reserved. most serious harms.

AIDS 2015, 29:921–929 Keywords: antiretroviral, cohort, CONSORT statement, harms, HIV, randomized trial, safety reporting

Introduction Data from cohort studies indicate that non-AIDS clinical events now account for the majority of deaths in adults with HIV infection (Antiretroviral Therapy Cohort Collaboration: 51% of deaths 1999–2004; D:A:D study: 70% of deaths 1999–2008) [1,2]. The concept of ‘serious

non-AIDS events’ (SNAEs) as a distinct class of HIV clinical endpoint was originally introduced by the Strategies for Management of Antiretroviral Therapy (SMART) study [3]. The definitions for SNAEs have since been refined, with the International Network for Strategic Initiatives in Global HIV Trials (INSIGHT) classification scheme currently recognizing 12 distinct

a

Clinical Research Program, St Vincent’s Centre for Applied Medical Research, and bThe Kirby Institute, Faculty of Medicine, The University of New South Wales, Sydney, Australia. Correspondence to Frederick J. Lee, Clinical Research Program, St Vincent’s Centre for Applied Medical Research, Level 4, Xavier Building, St Vincent’s Hospital, 390 Victoria Street, Darlinghurst, NSW 2010, Australia. Tel: +61 2 9828 3000; fax: +61 2 8382 3869; e-mail: [email protected] Received: 7 January 2015; revised: 18 February 2015; accepted: 19 February 2015. DOI:10.1097/QAD.0000000000000633

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events: cardiovascular disease (acute myocardial infarction, coronary artery disease requiring drug treatment, congestive cardiac failure, coronary revascularization, deep venous thrombosis, peripheral arterial disease, pulmonary embolism, stroke); decompensated liver disease; diabetes mellitus; end-stage renal disease and non-AIDS-defining cancers [4]. Classification of non-AIDS morbidities, however, remains non-standardized [5,6]. Multiple lines of evidence indicate that combination antiretroviral therapy (cART) may actually increase the risk of certain serious/severe non-AIDS morbidities: myocardial infarction with indinavir, lopinavir/ritonavir, didanosine and abacavir [7,8]; diabetes with stavudine and zidovudine [9]; renal impairment and bone mineral density loss with tenofovir [10,11]; and myopathy with raltegravir [12]. Thus, cART regimen selection may represent a modifiable risk factor for non-AIDS morbidities, despite the pathogenic mechanisms being only partially understood [7,12]. Furthermore, these aforementioned associations were detected through postmarketing surveillance or meta-analysis, and not during pre-approval trials; there are minimal randomized trial data linking ART drugs with specific SNAEs. Thus, for drugs recently approved at the time of writing (e.g. dolutegravir, elvitegravir/cobicistat), such associations may not be evident, and the current SNAE list may yet grow. Therefore, reporting intention-to-treat plasma viral load suppression alone is insufficient to evaluate the true risk– benefit profile of cART. Rather, all adverse events (both expected and unexpected) occurring on cART also require examination. In this respect, studies of initial cART are well positioned to identify specific adverse event associations, because they employ fixed regimens, and the participants are unencumbered by complex treatment histories which may confound assessment. By pooling safety data across such studies, meta-analytical techniques may then identify clinically relevant associations with specific regimens and/or drugs. However, such an analysis is feasible only if morbidity data are comprehensively, rather than selectively, reported within the public domain. To determine if such an analysis was indeed possible, we undertook a systematic review of the reporting of major clinical adverse events for studies of initial cART in HIVinfected adults. The reporting of four major clinical adverse event categories – deaths, AIDS events, SNAEs and serious adverse events (SAEs) – were quantitatively assessed. Differences in reporting by study characteristics, and the effect of adding unreported adverse event data were also analysed. In keeping with the 2004 Consolidated Standards of Reporting Trials (CONSORT) Statement Extension, which defines ‘harms’ as the totality of possible adverse consequences of an intervention or therapy [13], the term ‘harms’ was used in lieu of ‘adverse events’ or ‘safety’ for this review.

Methods Prospective studies of initial cART, employing single, fixed regimens per arm or cohort, conducted in adults, and published in a journal through 31 December 2012, were reviewed. To capture data when all participants exposed to study drug were analysed, only studies reporting intention-to-treat outcomes were considered. Studies were excluded if they were non-prospective, or assessed regimens listed as not to be offered in key international guidelines (United States Department of Health and Human Services [14], International Antiviral Society USA [15], European AIDS Clinical Society [16], WHO [17]). In order to maximize the quality of included studies and the reporting of harms, unpublished studies (e.g. those reported only as conference abstracts) were excluded. This review was conducted in accordance with the 2009 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement [18]. The protocol and analysis plan are available from the authors upon request.

Data sources and search strategy All data sources were searched/reviewed for the period 1 January 1996 – 31 December 2012. Eligible published studies were identified using the same strategy as a recent meta-analysis of initial cART efficacy [19]. Electronic databases (MEDLINE, the United States National Institutes of Health clinical trials registry, the Cochrane Register of Controlled Trials, the International Standard Randomised Controlled Trial Numbers registry) were searched using the query: ‘(‘drug’) and (‘HIV’ or ‘antiretroviral’) and (‘cohort’ or ‘randomised trial’)’, where drug was the generic or pre-approval code name of each antiretroviral drug. No language restriction was applied. For eligible studies, additional public domain sources were reviewed manually for harms data: key scientific meeting abstracts (Conference on Retroviruses and Opportunistic Infections, International AIDS Society Conferences, Interscience Conference on Antimicrobial Agents and Chemotherapy, International Congress on Drug Therapy in HIV); product labels and medical reviews of antiretroviral drugs published by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA); and study synopses provided on the websites of Abbott/Abbvie, Boehringer-Ingelheim, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, and Roche (equivalent websites for other antiretroviral manufacturers did not exist at the time of data collection). Finally, study sponsors were directly approached to provide, for eligible studies, harms data not reported in public domain sources.

Data extraction For included studies, characteristics recorded were: year of commencement, study type/phase/sponsorship, ART drugs, use of placebo, participant numbers and maximum

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Harms in HIV trials: a systematic review Lee et al.

reported duration of follow-up. Explicit mention of SNAEs as an endpoint was noted. Study sponsorship was determined on author affiliations and disclosures listed in the published journal article, and the profile submitted to clinical trials registries. Studies initiated and funded by antiretroviral manufacturers were classified as ‘industrysponsored’; investigator-initiated studies were classified as ‘academic-sponsored’, even if they received material or financial support from antiretroviral manufacturers. For each study, public domain source data were examined for reports of treatment-emergent deaths, new or recurrent AIDS events, SNAEs and SAEs – regardless of suspected causality; however, incidence data for these harms were not collected. Serious non-AIDS events were the 12 events listed in the 2010 INSIGHT classification, divided into five categories (cardiovascular, diabetes, hepatic or renal failure, nonAIDS cancer) [4]. As SNAE definitions were not introduced until 2006, or were not a pre-planned endpoint, SNAEs were retrospectively identified from each study by manual examination of adverse events (performed in duplicate). It was assumed that AIDS events were those listed under Category C of the 1993 US Centers for Disease Control (CDC) classification [20], and that SAEs conformed to the International Conference on Harmonization (ICH) Good Clinical Practice guidelines definition [21]. Harms were deemed reported if the total number of treatment-emergent events in the intention-to-treat population was either provided or calculable for each arm/cohort, including ‘zero’ events. Omission of harms data for an endpoint was regarded as ‘missing’, with no imputation of ‘zero’. Harms reported solely as data pooled between multiple treatment groups were regarded as nonreporting. To account for any bias towards reporting particular harms, for each study, the reporting of all SNAE categories and of at least one SNAE category were recorded separately. Partial descriptions (e.g. reporting events in only one arm; reporting fatal but not non-fatal SNAEs) were also regarded as non-reporting.

Data synthesis The primary outcome measure was the reporting frequency, defined as the percentage of studies providing data (from all public domain sources) for each harms category. Harms incidence was not an outcome measure of this study. Reporting frequency was associated with the following characteristics: study design/phase/sponsorship, use of placebo, year of commencement and total study size (relative to the median number of participants per study). Effect of including unreported harms data was assessed in a subgroup of industry-sponsored studies. Spearman correlation was used to assess trends in reporting frequency over time (by year of commencement). Between-group comparisons were performed

using the chi-square test; P values were two-sided with a significance level of 0.05. In order to assess the effect of pivotal publications on reporting frequency, three pre-planned sensitivity analyses were conducted, comparing reporting frequencies of: death/AIDS event/SNAE/SAE data pre and post2004, accounting for the 2004 CONSORT Extension [13]; SNAE data pre and post-2006, accounting for the SMART study [3]; cardiovascular SNAE data pre and post-2008, accounting for the D:A:D study abacavir meta-analysis [22]. All sensitivity analyses were conducted using the year of commencement relative to the year of publication for the landmark in question; studies also commenced during the landmark year were included amongst the ‘pre’ category (e.g. for sensitivity analysis 1, studies commenced in 2004 were included as ‘pre-2004’). As individual studies were the unit of analysis, no adjustment was made for the number of participants per study. All analyses were performed using STATA, Version 11 (StataCorp LP, College Station, Texas, USA).

Results Of the 103 included studies (196 treatment arms, 35 975 participants), 56 (54%) were industry-sponsored and 89 (86%) were randomized controlled trials (Table 1). Details of the included studies and the 2009 PRISMA Statement flowchart are available as supplementary data (http:// links.lww.com/QAD/A667) (Supplementary Table 1, http://links.lww.com/QAD/A667; Supplementary Fig. 1, http://links.lww.com/QAD/A667). Table 1. Characteristics of included studies. Industry (n ¼ 56) Study design [n (%)] Randomized 54 (96) Cohort 2 (4) Placebo-controlled [n (%)] Yes 25 (45) No 31 (55) Study phase [n (%)] 2 14 (25) 3 34 (61) 4 8 (14) Year commenced [n (%)] Pre-1997 2 (4) 1997–1999 11 (19) 2000–2002 11 (19) 2003–2005 16 (29) 2006–2008 10 (18) 2009 onwards 6 (11) Maximum follow-up [n (%)] 48 weeks 35 (63) 96 weeks 18 (32) 144 weeks 3 (5) Treatment arms 108 Participant numbers Total (N) 24 142 median, n (SD) 340 (312)

Academic (n ¼ 47)

Total (N ¼ 103)

35 (74) 12 (26)

89 (86) 14 (14)

6 (13) 41 (87)

31 (30) 72 (70)

11 (24) 9 (19) 27 (57)

25 (24) 43 (42) 35 (34)

4 14 10 15 3 1

6 25 21 31 13 7

(9) (30) (21) (32) (6) (2)

(6) (24) (20) (30) (13) (7)

33 (70) 9 (19) 5 (11) 88

68 (66) 27 (26) 8 (8) 196

11 833 120 (334)

35 975 206 (333)

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Public domain reporting frequencies Deaths, AIDS events, at least one SNAE category and SAEs were reported for 85 (83%), 55 (53%), 26 (25%) and 43 (42%) of studies, respectively (Fig. 1); 18 studies (17%) reported all four endpoints. Only 13 studies (13%) reported all SNAE categories; non-AIDS cancer [21 studies (20%)] was the most frequently reported SNAE category. One study (1%), commenced in 2007, listed SNAEs as an endpoint.

studies (46 vs. 14%; P ¼ 0.03); phase 3 vs. phase 2 or 4 studies (58 vs. 32 and 29%, respectively; P ¼ 0.02); and for industry vs. academic-sponsored studies (55 vs. 26%; P ¼ 0.002). Reporting of AIDS events and of all SNAE categories did not differ significantly by study characteristics; nor did reporting frequency vary with total study size relative to the median (200 participants per study), or the maximum duration of study follow-up at the time of publication.

Reporting of death data was higher for academic than industry-sponsored studies (91 vs. 75%; P ¼ 0.03) (Table 2). Placebo-controlled studies more frequently reported data for at least one SNAE category (39 vs. 19%; P ¼ 0.04) and for SAE data (61 vs. 33%; P ¼ 0.008), than for non-placebo-controlled studies. SAE data were also more frequently reported for: randomized vs. cohort

Over time (Fig. 2), reporting frequency of SAE data increased significantly (r ¼ 0.704, P ¼ 0.002). Trends for death (r ¼ 0.082, P ¼ 0.75), AIDS event (r ¼ 0.360, P ¼ 0.16) and SNAE (r ¼ 0.241, P ¼ 0.35) reporting frequencies were non-significant. The increase in SAE reporting over time was reflected in the three sensitivity analyses (Table 2); reporting frequency of cardiovascular SNAEs was similar for pre and post-2008 studies [15 (16%) vs. 2 (29%); P ¼ 0.37].

(a) 100

Reporting frequency (%)

80

60

40

20 85 (83%)

55 (53%)

26 (25%)

13 (13%)

43 (42%)

18 (17%)

Deaths

AIDS events

SNAEs (≥ type)

SNAEs (all)

SAEs

All harms*

0

Addition of publically unreported harms data Publically unreported harms data were provided by four antiretroviral manufacturers, for 34 of the 56 (59%) industry-sponsored studied: Bristol–Myers Squibb (15 August 2012), Gilead Sciences (10 August 2012), Merck Sharp & Dohme (MSD) (31 July 2012) and ViiV Healthcare (29 November 2012). Requests for publically unreported harms data were also submitted to Abbott/ Abbvie, Boehringer Ingelheim and Janssen-Cilag, but no data were received. Attempts to contact academic sponsors for unreported data proved unsuccessful; requests either went without reply, or contact details for corresponding authors were not current.

Harms endpoint

Within this 34-study subgroup, adding unreported data resulted in highly significant (P < 0.001) absolute increases in the reporting frequencies of all harms data (Fig. 3).

(b) 100

80

Reporting frequency (%)

924

60

Discussion

40

20 18 (17%)

15 (15%)

18 (17%)

21 (20%)

16 (16%)

Cardiovascular

Diabetes

Hepatic

Non-AIDS cancer

Renal

0

Serious non-AIDS event category

Fig. 1. Overall reporting frequencies from public domain data. Reporting frequencies calculated from public domain data only, of: (a) pre-specified harms endpoints; and (b) individual SNAE categories. () Combined reporting of deaths, AIDS events, at least one SNAE category and SAEs. SAE, serious adverse event; SNAE, serious non-AIDS event.

Public domain reporting of major clinical harms for studies of initial cART is very incomplete. Of the four pre-specified harms, data for three – AIDS events, SNAEs and SAEs – were reported for no more than half the included studies. Therefore, the amount of unreported harms data means it is not currently possible to systematically review the overall risk-benefit of initial cART. Sensitivity analyses showed modest absolute increases in harms reporting following three major publications (CONSORT Statement extension [13], SMART study [3] and the 2008 D:A:D abacavir analysis [8]). Only SAE reporting improved over time, making it difficult to speculate on the role that the shift towards earlier cART initiation had on our results.

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Harms in HIV trials: a systematic review Lee et al. Table 2. Harms reporting frequencies, stratified by study characteristics. Harms category Deaths [n (%)]

AIDS events [n (%)]

1 SNAE [n (%)]

All SNAEs [n (%)]

Study design Randomized (n ¼ 89) 72 (81) 48 (54) 23 (26) 11 (12) Cohort (n ¼ 14) 13 (93) 7 (50) 3 (21) 2 (14) P 0.27 0.78 0.72 0.84 Phase 2 (n ¼ 25) 21 (84) 14 (56) 8 (32) 4 (16) 3 (n ¼ 43) 36 (84) 22 (51) 13 (30) 4 (9.3) 4 (n ¼ 35) 28 (80) 19 (54) 5 (14) 5 (14) P 0.89 0.92 0.18 0.68 Sponsorship Industry (n ¼ 56) 42 (75) 27 (48) 16 (29) 7 (13) Academic (n ¼ 47) 43 (91) 28 (60) 10 (21) 6 (13) P 0.03 0.25 0.40 0.97 Placebo-controlled Yes (n ¼ 31) 26 (84) 19 (61) 12 (39) 4 (13) No (n ¼ 72) 59 (82) 36 (50) 14 (19) 9 (13) P 0.81 0.29 0.04 0.96 Participant number

Limited reporting of major harms in studies of initial combination antiretroviral therapy: a systematic review.

Risk-benefit assessment of combination antiretroviral therapy (cART) requires consideration of all potential serious harms. Studies of initial cART ma...
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