Virological efficacy of abacavir: systematic review and meta-analysis
Mario Cruciani1*, Carlo Mengoli2, Marina Malena1, Giovanni Serpelloni1, Saverio G. Parisi2, Graeme Moyle3 and Oliviero Bosco1
1Centre of Community Medicine & HIV Outpatient Clinic, Verona, Italy; 2Department of Histology, Microbiology and Medical Biotechnology, University of Padua, Padua, Italy; 3Department of HIV and Genitourinary Medicine, Chelsea and Westminster Hospital, London, UK
*Corresponding author. E-mail: [email protected]
Received 9 May 2014; returned 28 May 2014; revised 19 June 2014; accepted 23 June 2014
Objectives: The efficacy of abacavir/lamivudine has been reported to be inferior to tenofovir/emtricitabine. Several randomized clinical trials (RCTs) investigated the effectiveness and safety of abacavir/lamivudine and tenofovir/emtricitabine combined antiretroviral treatment (cART) and we have reviewed the available evidence.
Design: Systematic review and meta-analysis of RCTs using standard Cochrane Collaboration methodologies.
Methods: We calculated risk ratios (RRs) with 95% CIs. The primary outcome was the rate of patients with viral load (VL) below the pre-defined cut-off at 48 weeks and/or at 96 weeks. Where available, results were analysed according to VL screening levels (,100000 or .100000 copies/mL) with conventional meta-analytical pooling by subgroups and meta-regression.
Results: Meta-analytical pooling of RCTs with a direct comparison of abacavir/lamivudine and tenofovir/emtricitabine according to baseline VL at 48 weeks (six trials, 4118 patients) showed that the proportions of subjects with VL
,50 copies/mL were similar in the overall comparison (RR 0.98; 95% CI 0.94– 1.03), in the low baseline VL strata (RR 1.01; 95% CI 0.99 – 1.03) and in the high baseline VL strata (RR 0.96; 95% CI 0.90 – 1.03). Meta-regression analysis at 48 weeks confirms the results of subgroup analysis. Similar virological results were found at 96 weeks (four trials, 2003 patients). Differences in the occurrence of adverse events requiring discontinuation of treatment favoured tenofovir recipients (RR 1.26; 95% CI 0.99 – 1.61), but this difference, mostly related to suspected abacavir hypersensitivity reaction, was not statistically significant.
Conclusions: Our cumulative, cross-sectional data suggest a similar virological efficacy of abacavir/lamivudine and tenofovir/emtricitabine regardless of the baseline VL.
Keywords: meta-regression, tenofovir, antiviral
Introduction
The current standard of care for HIV treatment is a three-drug regimen containing either a non-nucleoside reverse transcriptase inhibitor (NNRTI), a protease inhibitor (PI) or an integrase strand transfer inhibitor plus two nucleoside/tide reverse transcriptase inhibitors (NRTIs).1,2 The most widely used NRTI backbones are available as fixed-dose coformulations that combine two drugs, tenofovir/emtricitabine or abacavir/lamivudine, in a single tablet taken once daily. Factors such as efficacy, lack of severe adverse events and patient convenience have led to tenofovir/emtricita- bine and abacavir/lamivudine becoming the most widely pre- scribed initial backbones in industrialized countries. However, some divergences between European and US guidelines exist. While the European AIDS Clinical Society guidelines recommend tenofovir/emtricitabine or abacavir/lamivudine as the nucleoside backbone component of initial combination regimens, US
guidelines recommend tenofovir/lamivudine as the first line and abacavir/lamivudine as an alternative regimen. However, in the 2014 updated US guidelines, in patients who are HLA-B*5701 negative abacavir/lamivudine dolutegravir and, only for patients with baseline viral load (VL) value ,100000 copies/mL, abacavir/ lamivudine efavirenz, are among the preferred regimens.1
Current guidelines assume lamivudine and emtricitabine to be equivalent.1 Compared with lamivudine, emtricitabine shows a longer plasma and intracellular triphosphate half-life. The results of a recent meta-analysis of clinical trials comparing emtricitabine with lamivudine as part of a combination regimen have demon- strated that the two compounds are clinically equivalent.3 Thus, in clinical practice the choice of emtricitabine versus lamivudine will most likely be made in the context of their coformulation partner.
Differences between abacavir and tenofovir are of more interest. While tenofovir has few initial treatment-limiting initial side effects,
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older studies with abacavir are difficult to interpret due to the excess of abacavir hypersensitivity reactions, which lead to early discontinuation and hence an excess of ‘failure’ in intention-to- treat analysis. The establishment of HLA-B*5701 testing has largely led to the abolition of this adverse effect from clinical practice. Recent data have offered conflicting evidence concerning the rela- tive efficacy of NRTI backbone combinations. A randomized con- trolled trial (ACTG 5202) showed that among patients with a high VL at study entry (screening) (HIV RNA .100000 copies/mL), those taking abacavir/lamivudine with either boosted atazanavir or efa- virenz were more likely to experience virological failure than those taking tenofovir/emtricitabine.4 By contrast, a randomized clinical trial (RCT) with a head-to-head comparison of abacavir/lamivudine with tenofovir/emtricitabine, in combination with lopinavir/ritona- vir, and a retrospective analysis of six previous abacavir trials found that the backbones had similar efficacy.5,6 Of note, all these studies did not employ routine HLA-B*5701 screening and the ACTG 5202 study used endpoints and analyses that differed from the other studies.
Numerous RCTs have been conducted to assess the effective- ness and safety of abacavir- and tenofovir-containing combined antiretroviral treatment (cART). Recently, two meta-analyses on the safety of abacavir have been published.7,8 However, these reviews were mostly focused on cardiovascular complications of cART. The current review is therefore aimed to shed more light on the effectiveness of abacavir-containing cART.
Methods
Criteria for considering studies for this review
We included in the analysis any RCTs in HIV-infected adults (starting a first antiretroviral regimen as well as antiretroviral-experienced participants) with ≥24 weeks of abacavir exposure compared with other cARTregimens. cART taken while in the studies was categorized as abacavir-containing or non-abacavir-containing. Exposure to any possible formulation of abacavir was considered, including double (abacavir +lamivudine) and triple (abacavir+lamivudine+zidovudine) fixed-dose coformulation as well as both once- and twice-daily dosing.
Outcomes
Primary outcomes were rates of patients with VL below the pre-defined cut-off (,50 copies/mL and/or 200 – 500 copies/mL) at 48 weeks and/or
at 96 weeks.
Where available, we reported the results for this endpoint according to VL screening levels (,100000 or .100000 copies/mL) and according to the missing¼failure approach (assigning anyone who has to stop the drug of interest as having failed), the ‘time to loss of virological response’ (TLOVR) algorithm (a composite of all available safety and antiviral activity data from all subjects enrolled in a trial through 48 weeks of treatment) or the ‘snapshot’ approach, not affected by transitional changes in HIV levels. A high concordance between the TLOVR algorithm and snapshot results was observed.9
Secondary outcomes were rates of patients with adverse events requir- ing treatment interruption and/or switching.
Search methods for identification of studies
We updated (June 2014) the search conducted for a previous meta- analysis.7 The search included the following relevant MeSH terms, in vari- ous combinations: highly active antiretroviral therapy; antiretroviral
agents; abacavir; abacavir/lamivudine combination; Trizivir; Kivexa; Epzicom; tenofovir; randomized controlled trial, controlled trial; adverse effects, resistance, treatment outcome, treatment failure.
The following electronic databases were searched for relevant trials: the Cochrane Central Register of Controlled Trials (CENTRAL) published in the Cochrane Library (issue 6 of 12 June 2014), PUBMED (1980 to June 2014) and EMBASE (1988 to June 2014). In addition, we searched trials registries via the World Health Organization International Clinical Trials Registry Platform Search Portal (http://apps.who.int/trialsearch/Default. aspx). We also searched the following electronic database: AIDSInfow (http://www.aidsinfo.nih.gov/); the International AIDS Society Conference on HIV Pathogenesis and Treatment (2001, 2003, 2005, 2007, 2009, 2011,
2013); International AIDS Conference (2002, 2004, 2006, 2008, 2010, 2012); Conference on Retroviruses and Opportunistic Infections, Interscience Conference on Antimicrobial Agents and Chemotherapy; the European AIDS Clinical Society (2001 to 2013).
Hand searches of the reference lists of all the relevant reviews and studies found was undertaken. Information about trials not registered in MEDLINE, including unpublished ones, was attempted by contacting drug manufacturers for repository data and scanning reference lists of articles.
Data collection and extraction
Two authors (M. C. and C. M.) independently screened for potential rele- vance the titles and abstracts of references identified by the search. Disagreement or doubt was resolved by discussion. We obtained in full any study that potentially met the inclusion criteria based on the title, abstract or both and assessed these studies against the inclusion criteria. The following data were extracted independently by two reviewers (M. C. and C. M.): administrative details (authors and year of publication); details of participants (number, setting and baseline characteristics by group); details of the study (study design, type and duration of follow-up); details of the ART regimen used; primary and secondary outcome descrip- tions and outcome measures; and number of withdrawals in each group
with reasons.
The data abstracted for dichotomous variables were the number of affected participants and the total number of participants in the experi- mental and the comparison groups. When additional data were needed, we contacted the corresponding author of each study by e-mail in order to access further information.
Assessment of risk of bias in included studies
Two authors (M. C. and M. M.) independently assessed studies fulfilling the review inclusion criteria for methodological quality given in the Cochrane Handbook for Systematic Reviews of Interventions.10 The risk of bias was assessed in individual studies across six domains: random sequence gen- eration; allocation concealment; blinding of participants and personnel ( performance bias); blinding of outcome assessors (detection bias); incomplete outcome data; and selective outcome reporting. We categor- ized these judgements as ‘low risk’, ‘high risk’ or ‘unclear risk’ of bias.
Assessment of heterogeneity
We assessed statistical heterogeneity using t2, Cochran’s Q and I2 statis- tics. The I2 statistic describes the percentage of total variation across trials that is due to heterogeneity rather than sampling error.11,12
Data synthesis
Dichotomous outcomes (e.g. rate of patients with virological suppression) are presented as risk ratios (RRs) with 95% CIs. The software used was RevMan5. In the case of no heterogeneity (I2 0), studies were pooled using a fixed-effects model. Where values of I2 were .0, a random-effects
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analysis was undertaken.10,13 Where I2 values of .75% indicated a very high level of heterogeneity, we refrained to pool data from different stud- ies and we undertook a narrative overview.
Subgroup and sensitivity analyses
Since fixed-dose coformulations of abacavir/lamivudine and tenofovir/ emtricitabine are currently the most widely prescribed NRTI backbone, we performed subgroup analysis of studies with a head-to-head com- parison of abacavir/lamivudine and tenofovir/emtricitabine and a separ- ate analysis of studies comparing abacavir-containing regimens with other cART regimens (i.e. those not containing tenofovir). We also per- formed subgroup analyses according to relevant study-level variables: studies dealing with naive patients; studies dealing with experienced patients; studies with baseline VL ,100 000 copies/mL; and studies with baseline VL .100000 copies/mL. Finally, we performed a subgroup analysis after exclusion of data available from repository data only.
A sensitivity analysis was performed systemically excluding each study in turn, in both the standard meta-analytical pooling and meta-regression.
Meta-regression
A comparison between studies with baseline plasma HIV viraemia
,100000 copies/mL and studies with baseline VL .100000 copies/mL was performed on a subset of studies comparing an experimental treat- ment (abacavir) with a control treatment (tenofovir). For this purpose, we used meta-regression, which allows a direct comparison between the two subgroups. The null hypothesis is that the baseline VL in the experimental treatment does not alter the treatment effect. The effect size under com- parison was the rate ratio for events (VL,cut-off) between the experimen- tal arm and the control arm. The method was the residual maximum likelihood estimate of between-study variance. The dependent variable was the RR obtained from conventional meta-analytical pooling and the explanatory variable was the baseline VL. Meta-regression was performed using Stata 12.
Results
Electronic searches yielded 1471 potentially relevant studies (Figure 1). Some 1430 articles were excluded after preliminary screen and 41 were deemed eligible and the full-text assessed. Eleven studies were then excluded because they were not rando- mized or did not report outcomes of interest; 13 additional records were available through the HIV Clinical Trial data reposi- tory of the manufacturer of abacavir. Therefore, we included in the analysis data from 43 reports, including 30 published articles (29 full-length papers and 1 abstract) related to RCTs conducted from 1996 to 2013, comparing cART containing abacavir with cART containing other NRTIs.4,5,14 – 41 When outcome data were available both from published and non-published reports, we extracted data from the published material only; likewise, for these studies we counted the total number of patients from the published papers only. Two trials were not randomized for abaca- vir/lamivudine and tenofovir/emtricitabine assignment, though randomization for the third drug was stratified based on the NRTI backbone, and there were no systematic differences between the baseline characteristics of the two NRTI groups com- pared.34,35,38 The main features of the included studies are sum- marized in Table 1.
Table 2 summarizes the pooled outcome data and heterogen- eity assessment (I2) for the outcomes in overall analyses and sub- group analyses. Figure 2 shows forest plots of the RR and 95% CI
Figure 1. Flow chart of study inclusion.
for individual studies and pooled estimates of the meta-analysis for the outcomes ‘rates of patients with VL ,50 copies/mL at 48 and 96 weeks’. Rates were similar among abacavir recipients and controls in all possible comparisons.
Rates of patients requiring discontinuation of treatment due to adverse events related to study treatment are shown in Table 2 and Figure 3. In the comparison of abacavir- versus non- tenofovir-containing regimens, the rate of discontinuation was lower in the abacavir group compared with controls (P 0.0001); however, in the subgroup of studies comparing abacavir- versus tenofovir-containing regimens the RR of discontinuation favoured tenofovir, though this difference did not reach statistical signifi- cance (RR 1.26; 95% CI 0.99 – 1.61; P ¼ 0.06).
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Table 1. Main characteristics of selected RCTs
Follow-up No. of patients,
Study identifier (ref.) (weeks) ABC regimen Controls ABC/controls Median age (years), ABC/controls Type of patients
CNA3002440 48 ABC+ 3TC+EFV ZDV+ 3TC+ EFV 324/325
35/36 (mean) naive
CNAB300140 52 ABC+background ther. ABC placebo+background ther. 46/48
41/40 exp.
CNAB300240 48 ABC+background ther. ABC placebo+background ther. 91/91
36/36 exp.
CNAAB300340 48 ABC+ZDV+ 3TC ABC placebo+ZDV+ 3TC 83/80
35/35 naive
CNAAB300540 96 ABC+Combivir IDV+Combivir 262/264
37/37 (mean) naive
NZTA400240 48 ABC+Combivir NFV+Combivir 150/151
NA naive
Clumeck 2001/CNA30017a14,40 48 ABC+ 2 NRTIs PI+ 2 NRTIs 104/103
38/38 exp.
Staszewski 200115 48 ABC+Combivir IDV+Combivir 262/265
36/36 naive
Opravil 200216 84 Trizivir 2 NRTIs+PI 84/79
38/41 exp.
Katlama 200317 48 Trizivir 2 NRTIs+ PI 106/103
40/37 exp.
Maggiolo 200318 104 ABC+ 2 NRTIs PI or EFV+ 2 NRTIs 69/140
36/36 exp.
Mart´ınez 200319 48 ABC+ 2 NRTIs NVP or PI+ 2 NRTIs 149/311
40/38-43 exp.
Matheron 2003/CNAF3007a20,40 48 ABC+Combivir NFV+Combivir 95/91
34/34 naive
Vibhagool 2004/CNB3014a21,40 48 ABC+Combivir IDV+Combivir 169/173
33/33 naive
Bonjoch 200522 48 Trizivir Combivir+NVP 68/66
43/43 exp.
Keiser 2005/ESS40003a23,40 28 ABC+ 2 NRTIs PI+ 2 NRTIs 52/52
43/42 exp.
Orkin 200524 48 Trizivir+EFV Combivir+EFV 26/27
NA naive
Kumar 2006/ESS40002a25,40 96 Trizivir d4T+ 3TC+NFV or Combivir+NFV 87/174
38/36 naive
Moyle 200626 48 ABC+background ther. TDF+background ther 53/52
34/34 exp.
Mart´ınez 200727 48 ABC+ 2 NRTIs 2 NRTIs+ EFV or NVP 149/311
NA exp.
Kumar 2009/ESS10032728,40 48 Trizivir 3TC+ZDV+ATV 138/140
38/36 naive
Martin 200929 96 ABC/3TC+NNRTI or PI TDF/FTC+ NNRTI or PI 179/178
43/43 exp.
Mart´ınez 200930 48 ABC/3TC+NNRTI or PI TDF/FTC+ NNRTI or PI 167/166
43/43 exp.
Smith 20095 96 ABC/3TC+LPV/r TDF/FTC+ LPV/r 343/345
38/38 naive
Sax 2008, 2009, 2011b4,39,41 48 and 96 ABC/3TC+ATV/r or EFV TDF/FTC+ATV/r or EFV 438/439
38/40 naive
Amin 2010c31 96 ABC/3TC+NNRTI or PI TDF/FTC+ NNRTI or PI 167/166
c c
Daar 2011b32 96 ABC/3TC+ATV/r or EFV TDF/FTC+ATV/r or EFV 928/929
38 naive
Post 2010/CNA109586a/Moyle 2013a33,37,40 48 and 96 ABC/3TC+EFV TDF/FTC+ EFV 192/193
38/36 naive
Raffi 2013a34,35 48 and 96 ABC/3TC+dolutegravir or raltegravird TDF/FTC+dolutegravir or raltegravird 333/489
NAe naive
Nishijima 201336 48 and 96 ABC/3TC+ATV/r TDF/FTC+ATV/r 54/55
39/35 naive
Clotet 2014a38 48 ABC/3TC+dolutegravir or DRV/rd TDF/FTC+dolutegravir or DRV/rd 159/325
NAe naive
ABC, abacavir; ZDV, zidovudine; 3TC, lamivudine; TDF, tenofovir; FTC, emtricitabine; d4T, stavudine; ATV, atazanavir; NFV, nelfinavir; IDV, indinavir; LPV, lopinavir; /r, /ritonavir; EFV, efavirenz; NVP, nevirapine; DRV, darunavir; ther., therapy; NA, not available; exp., experienced.
aPart of the outcomes data also available from repository data or correspondence with authors.
bResults of the ACTG 5202 study available from several reports.4,32,39,41
cThe study by Amin et al.31 is a meta-analysis of BICOMBO and STEAL studies (Mart´ınez et al.30 and Martin et al.29) with an updating of BICOMBO data.
dSPRING 2 and FLAMINGO34,35,38 were not randomized for ABC and TDF assignment, though randomization for the third drug was stratified based on baseline VL and NRTI backbone.
eMedian age is 37 years for the dolutegravir recipients and 35 years for the raltegravir recipients.
Table 2. Abacavir versus controls; summary of the pooled outcome data
Outcome or subgroup Studies Participants Effect estimate, RR (95% CI) P Heterogeneity (I2), % Rates of patients with HIV RNA below the cut-off
,50 copies/mL, 48 weeks
,
,
,
ABC versus TDF according to baseline VL 48 weeks
overall 6 4118 0.98 (0.94 – 1.03) 0.50 54
,100000 copies/mL 5 2202 1.01 (0.99 – 1.03) 0.19 0
.100000 copies/mL 5 1916 0.96 (0.90 – 1.03) 0.22 36
96 weeks
overall
4
2003
0.98 (0.93 – 1.03)
0.73
0
,100000 copies/mL 4 1272 0.99 (0.93 – 1.04) 0.62 1
.100000 copies/mL 3 731 0.97 (0.87 – 1.08) 0.54 0
Discontinuation for adverse events
ABC versus TDF 7 3051 1.26 (0.99 – 1.61) 0.06 0
ABC versus other 16 4778 0.68 (0.56 – 0.83) 0.0001 27
ABC, abacavir; TDF, tenofovir.
Results are provided for all possible comparisons and separately for subgroups of studies comparing ABC with TDF or with other cART regimens.
aNot performed due to the high heterogeneity (I2.75%).
There was a very high level of heterogeneity (I2.75%) for the outcome ‘rates of patients with HIV ,200 – 500 copies/mL at 48 weeks’, and for the subgroup of studies abacavir versus other, for the outcome ‘rates of patients with HIV ,50 copies/mL at 96 weeks’; for these outcomes we did not perform a quantitative analysis of data. Rates of patients with HIV ,200– 500 copies/mL at 96 weeks are shown in Table S1 and Figure S1 (both available as Supplementary data at JAC Online).
Subgroup analyses in Table 2, Figures 2 and 4 show the out- come data for the subgroup of studies (11 studies and 15 reports) from where a direct comparison between abacavir/lamivudine and tenofovir/emtricitabine was available.4,5,26,29 – 39,41 Overall, the virological outcomes did not differ between the two groups. There were a higher number of adverse events requiring discon- tinuation of treatment among abacavir recipients compared with tenofovir recipients, but the difference was not statistically significant.
Subgroup analysis of studies conducted in naive patients and in experienced patients did not significantly affect the pooled esti- mates of the meta-analysis (data not shown). Likewise, the results were much the same in subgroup analysis of studies after the exclusion of repository data (data not shown).
Subgroup analysis of studies comparing abacavir and tenofovir according to baseline viraemia
Data from the nine reports (eight trials) with a head-to-head com- parison of abacavir and tenofovir and subgroup analysis according to baseline VL values (,100000 or .100000 copies/mL) were pooled.4,5,33–39 The proportions of subjects with VL ,50 copies/mL at 48 and 96 weeks are shown in Figure 4. At week 48, rates were similar among abacavir and tenofovir in the overall compari- son (RR 0.98; 95% CI 0.94 – 1.03), in the high baseline VL strata (RR 0.96; 95% CI 0.90 – 1.03) and in the low VL strata (RR 1.01; 95% CI
0.99 – 1.04). Likewise, at week 96, rates of patients with undetect- able VL were comparable in the abacavir and tenofovir groups, regardless of the baseline VL (RR 0.98, 95% CI 0.93 – 1.03 in the overall comparison; RR 0.97, 95% CI 0.87 – 1.08 in the high baseline VL strata; and RR 0.99, 95% CI 0.93 – 1.04 in the low VL strata).
Meta-regression
By meta-regression, the null hypothesis of the same virological effect exerted by abacavir/lamivudine and tenofovir/emtricitabine
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48 weeks
Abacavir Control Risk ratio Risk ratio
Study or subgroup
1.1.1 ABC vs TDF Clotet 2014 Nishijima 2013 Post 2010
Raffi 2013
Smith 2009
Subtotal (95% CI)
Total events
Events
139
44
114
716
231
1244
Total
159
54
192
747
343
1495
Events
278
44
137
859
232
1550
Total
325
55
193
908
345
1826
Weight
24.4%
7.6%
10.7%
40.2%
17.2%
100.0%
M–H, Random, 95% CI
1.02 (0.95, 1.10)
1.02 (0.85, 1.22)
0.84 (0.72, 0.97)
1.01 (0.99, 1.04)
1.00 (0.90, 1.11)
0.99 (0.94, 1.05)
M–H, Random, 95% CI
Heterogeneity: t2 = 0.00; c2 = 8.62, df = 4 (P = 0.07); I2 = 54% Test for overall effect: Z = 0.24 (P = 0.81)
1.1.2 ABC vs others
Bonjoch 2005 44 68 42 66 7.0% 1.02 (0.79, 1.31)
Clumeck 2001 94 104 88 103 11.6% 1.06 (0.96, 1.17)
CNA30024 226 324 224 325 11.6% 1.01 (0.91, 1.12)
CNAAB3003 38 83 3 81 0.7% 12.36 (3.97, 38.45)
CNAAB3005 104 262 121 265 8.5% 0.87 (0.71, 1.06)
CNAB3002 12 92 0 93 0.1% 25.27 (1.52, 420.61)
ESS100327 54 95 53 91 7.1% 0.98 (0.76, 1.25)
Katlama 2003 85 138 83 140 8.8% 1.04 (0.86, 1.26)
Keiser 2005 79 106 71 103 9.4% 1.08 (0.91, 1.28)
Kumar 2006 32 52 39 52 6.6% 0.82 (0.63, 1.07)
Martínez 2003 85 138 83 140 8.8% 1.04 (0.86, 1.26)
NZTA4002 54 95 53 91 7.1% 0.98 (0.76, 1.25)
Staszewski 2001 30 150 48 152 4.1% 0.63 (0.43, 0.94)
Vibhagool 2004 104 262 121 265 8.5% 0.87 (0.71, 1.06)
Subtotal (95% CI) 1969 1967 100.0% 0.99 (0.89, 1.09)
Total events 1041 1029
Heterogeneity: t2 = 0.02; c2 = 37.48, df = 13 (P = 0.0003); I2 = 65% Test for overall effect: Z = 0.30 (P = 0.76)
96 weeks
0.5 0.7 1 1.5 2
Favours controls Favours ABC
Abacavir Control Risk ratio Risk ratio
95% CI
Heterogeneity: t2 = 0.00; c2 = 1.10, df = 3 (P = 0.78); I2 = 0% Test for overall effect: Z = 0.23 (P = 0.82)
0.5 0.7 1 1.5 2
Favours controls Favours ABC
Figure 2. Forest plot of comparison: abacavir (ABC) versus controls; outcome: percentage of patients with HIV RNA ,50 copies/mL at 48 weeks and 96 weeks. Subgroup analysis of studies comparing ABC with tenofovir (TDF) (1.1.1 and 1.2.1) and ABC with other cART regimens (i.e. not containing TDF) at 48 weeks (1.1.2). Subgroup analysis of ABC versus other cART regimens at 96 weeks not performed due to the high heterogeneity (I2.83%).
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Abacavir Control Risk ratio Risk ratio
Study or subgroup
Events Total Events Total Weight
M–H, Random, 95% CI
M–H, Random, 95% CI
1.3.1 ABC vs TDF
Martin 2009 12 179 8 178 7.9% 1.49 (0.62, 3.56)
Martínez 2009 18 167 11 166 11.7% 1.63 (0.79, 3.34)
Moyle 2013 28 192 26 193 24.6% 1.08 (0.66, 1.78)
Nishijima 2013 6 54 6 55 5.3% 1.02 (0.35, 2.96)
Post 2010 25 192 20 193 19.7% 1.26 (0.72, 2.18)
Sax 2009 24 397 13 397 13.8% 1.85 (0.95, 3.57)
Smith 2009 20 343 21 345 17.1% 0.96 (0.53, 1.73)
Subtotal (95% CI) 1524 1527 100.0% 1.26 (0.99, 1.61)
Total events 133 105
Bonjoch 2005 13 68 14 66 6.2% 0.90 (0.46, 1.77)
Clumeck 2001 8 104 14 103 4.5% 0.57 (0.25, 1.29)
CNA 30024 46 324 58 325 13.8% 0.80 (0.56, 1.13)
CNAAB3003 6 83 8 81 3.1% 0.73 (0.27, 2.02)
CNAAB3005 46 262 64 264 14.4% 0.72 (0.52, 1.02)
ESS100327 12 138 13 140 5.2% 0.94 (0.44, 1.98)
Katlama 2003 16 106 16 103 6.7% 0.97 (0.51, 1.84)
Keiser 2005 7 52 1 52 0.8% 7.00 (0.89, 54.91)
Kumar 2006 2 87 11 174 1.6% 0.36 (0.08, 1.60)
Martínez 2003 6 138 11 140 3.4% 0.55 (0.21, 1.45)
Martínez 2007 9 149 53 311 6.1% 0.35 (0.18, 0.70)
Matheron 2003 13 149 68 311 8.1% 0.40 (0.23, 0.70)
NZTA4002 17 95 25 91 8.4% 0.65 (0.38, 1.12)
Opravil 2002 2 84 1 88 0.6% 2.10 (0.19, 22.68)
Staszewski 2001 6 84 16 79 4.0% 0.35 (0.15, 0.86)
Vibhagool 2004 41 262 50 265 13.0% 0.83 (0.57, 1.21)
Subtotal (95% CI) Total events
250 2185
423 2593 100.0% 0.68 (0.56, 0.83)
0.1 0.2 0.5 1 2 5 10
Favours ABC Favours controls
Figure 3. Forest plot of studies reporting rate of discontinuation due to adverse events to the administered treatment. Subgroup analysis of studies comparing abacavir (ABC) with tenofovir (TDF) (1.3.1) and ABC with other cART regimens (i.e. not containing TDF) (1.3.2).
at 48 weeks was never rejected (Figure 5). The meta-regression analysis reported an RR of abacavir producing a different success rate with respect to tenofovir with a VL .100000 copies/mL not significantly different from the null hypothesis of 1 (RR 0.95; 95% CI 0.89 – 1.02; P 0.165) (Table S1). Due to the small number of studies at 96 weeks, the meta-regression was limited at 48 weeks.
Sensitivity analysis
After exclusion of an individual study in turn, the summary esti- mates were not affected in the overall comparison and in sub- group analysis of studies with baseline VL ,100000 copies/mL (Table S2, Table S3 and Table S4, all available as Supplementary data at JAC Online). However, in the subgroup of studies with VL
.100000 copies/mL, the overall estimates, in both standard
meta-analytical pooling and meta-regression, changed after exclusion of the study by Raffi et al.:34 RR favouring tenofovir, 0.92 (95% CI 0.86 – 0.98) and 0.91 (95% CI 0.84 – 0.98), respect-
ively (Table S3 and Table S4).
Bias assessment and heterogeneity
Summary graphs of methodological quality items are presented in Figure S2 and Figure S3 (both available as Supplementary data at JAC Online) for 41 reports, corresponding to 29 primary trials, but not for the meta-analysis of BICOMBO and STEAL data.31 The generation of the randomization process was clearly described in 62% (18/29) of trials and was unclear in the other trials. Allocation concealment was adequately described in 37% of trials. There were 10 placebo-controlled trials and 19 open- label trials. The remaining items were graded as free of bias in
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all trials but one: a repository study (NZTA4002) from which it was not possible to have clear information on some quality items.
Heterogeneity data (t2, x2 and I2) are reported in the footnotes
to the forest plots. Substantial heterogeneity (e.g. I2 .50%) was found for some of the virological outcomes.
Discussion
Controversy about the relative performance of abacavir/lamivudine and tenofovir/emtricitabine in combination antiretroviral therapy exists and recent clinical trials and reviews have raised concerns about each combination’s relative risks and benefits. In a compara- tive safety study of abacavir/lamivudine and tenofovir/emtricitabine, differences in tubular protein loss, bone turnover markers and declines in bone density were observed favouring abacavir/lamivu- dine.37 A number of reports have linked renal tubular dysfunction and acute renal failure with tenofovir; moreover, modest decreases in bone density and hypophosphataemia have been observed among tenofovir recipients.1 An association between cART and
the risk of myocardial infarction has been observed in some cohort studies,42–45 but not in other observational studies.46– 48 Moreover, no excess risk of myocardial infarction with abacavir therapy has been observed in the aggregated clinical trials database maintained by the manufacturer of abacavir and in two independent meta-analyses comparing abacavir-containing cART with other regimens not containing abacavir.7,8,49 The majority of studies con- ducted in the absence of confounding factors have not demon- strated an increased abacavir-attributable cardiovascular risk. To date, many hypotheses and in vitro data investigating biological mechanisms to explain a potential increase in the risk of cardiovas- cular diseases in abacavir recipients have been produced, but the topic remains controversial and none of the hypotheses has been established or clinically proven.50 Treatment with cART improves endothelial dysfunction, but data on abacavir use and endothelial function are limited to small cohort studies.51,52 Results from other studies failed to demonstrate specific abnormalities in coagulation or inflammation markers that might explain the increased risk of myocardial infarction in abacavir recipients.5,33,53– 55 On the basis
48 weeks
Experimental Control Risk ratio Risk ratio
Study or subgroup
Events
Total
Events
Total
Weight
M–H, Random, 95% CI
M–H, Random, 95% CI
2.1.1 baseline <100 000 copies/mL
Clotet 2014 119 134 198 228 14.2% 1.02 (0.95, 1.11)
Nishijima 2013 44 54 44 55 4.7% 1.02 (0.85, 1.22)
Post 2010 61 95 62 83 4.3% 0.86 (0.71, 1.05)
Raffi 2013 527 537 604 623 24.5% 1.01 (0.99, 1.03)
Smith 2009 133 188 141 205 8.0% 1.03 (0.90, 1.17)
Subtotal (95% CI) 1008 1194 55.7% 1.01 (0.99, 1.03)
Total events 884 1049
Heterogeneity: t2 = 0.00; c2 = 3.26, df = 4 (P = 0.52); I2 = 0% Test for overall effect: Z = 1.32 (P = 0.19)
2.1.2 baseline >100 000 copies/mL
Clotet 2014 20 25 80 97 3.6% 0.97 (0.78, 1.20)
Post 2010 53 97 75 110 3.4% 0.80 (0.64, 1.00)
Raffi 2013 189 210 254 285 17.3% 1.01 (0.95, 1.07)
Sax 2008 298 398 319 399 14.7% 0.94 (0.87, 1.01)
Smith 2009 98 155 91 140 5.3% 0.97 (0.82, 1.15)
Subtotal (95% CI) 885 1031 44.3% 0.96 (0.90, 1.03)
Total events 658 819
Heterogeneity: t2 = 0.00; c2 = 6.28, df = 4 (P = 0.18); I2 = 36% Test for overall effect: Z = 1.21 (P = 0.22)
Total (95% CI) Total events
1542
1893
1868
2225
100.0%
0.98 (0.94, 1.03)
Heterogeneity: t2 = 0.00; c2 = 19.69, df = 9 (P = 0.02); I2 = 54%
Test for overall effect: Z = 0.68 (P = 0.50)
Test for subgroup differences: c2 = 2.29, df = 1 (P = 0.13), I2 = 56.3%
0.5 0.7 1 1.5 2
Favours TDF Favours ABC
Figure 4. Forest plot of comparison: rates of patients with VL ,50 copies/mL at 48 weeks and 96 weeks in studies comparing abacavir (ABC) and tenofovir (TDF) according to baseline VL values. Cumulative results and subgroup analyses based on screening values: ,100000 copies/mL (analyses
2.1.1 and 2.2.1) or .100000 copies/mL (analyses 2.1.2 and 2.2.2).
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96 weeks
ABC TDF Risk ratio Risk ratio
Study or subgroup
Events
Total
Events
Total
Weight
M–H, Fixed, 95% CI
M–H, Fixed, 95% CI
2.2.1 baseline <100 000 copies/mL
Moyle 2013 47 96 49 83 7.3% 0.83 (0.63, 1.09)
Nishijima 2013 39 53 43 55 5.9% 0.94 (0.76, 1.17)
Raffi 2013a 243 257 322 335 39.0% 0.98 (0.95, 1.02)
Smith 2009 118 188 119 205 15.9% 1.08 (0.92, 1.27)
Subtotal (95% CI) 594 678 68.0% 0.99 (0.93, 1.04)
Total events 447 533
Heterogeneity: c2 = 3.03, df = 3 (P = 0.39); I2 = 1% Test for overall effect: Z = 0.50 (P = 0.62)
2.2.2 baseline >100 000 copies/mL
Moyle 2013 51 96 64 110 8.3% 0.91 (0.71, 1.17)
Raffi 2013a 64 76 128 154 11.8% 1.01 (0.90, 1.14)
Smith 2009 87 155 81 140 11.9% 0.97 (0.80, 1.18)
Subtotal (95% CI) 327 404 32.0% 0.97 (0.87, 1.08)
Total events 202 273
Heterogeneity: c2 = 0.72, df = 2 (P = 0.70); I2 = 0% Test for overall effect: Z = 0.54 (P = 0.59)
Total (95% CI) 921 1082 100.0% 0.98 (0.93, 1.03)
Total events 649 806
Heterogeneity: c2 = 3.66, df = 6 (P = 0.72); I2 = 0% Test for overall effect: Z = 0.73 (P = 0.46)
Test for subgroup differences: c2 = 0.06, df = 1 (P = 0.80), I2 = 0%
0.5 0.7 1 1.5 2
Favours TDF Favours ABC
Figure 4. Continued
of these findings, abacavir/lamivudine has been repositioned as an ‘alternative’ dual fixed-dose NRTI option for the treatment of naive HIV-infected patients in the US Department of Health and Human Services HIV treatment guidelines and in the International AIDS Society—USA HIV treatment guidelines.1,56 Nonetheless, abaca- vir/lamivudine continues to be a ‘preferred’ option in international and European guidelines.2,57
At present, perhaps more relevant are issues related to the com- parative efficacy of abacavir and tenofovir fixed-dose combinations. The efficacy of abacavir in viral suppression has been reported to be inferior to tenofovir among patients with baseline HIV VL
.100000 copies/mL: results of the ACTG 5202 study showed that among patients with baseline HIV RNA 100000 copies/mL, time to virological failure was significantly shorter and the rate of viro- logical failure higher for the abacavir/lamivudine recipients.4,39 Subsequently, guidelines have started to recommend caution in the use of abacavir in patients with high pre-treatment HIV RNA levels.1,2
Given that a variety of RCTs have been conducted to assess the effectiveness and safety of abacavir-containing cART, we have performed a systematic review and meta-analysis of RCTs to assess the virological efficacy of cART containing abacavir relative to abacavir-sparing cART. Moreover, a subgroup comparison has been performed in studies comparing cART containing abacavir relative to cART containing tenofovir.
Bias assessment using Cochrane methodology showed that the studies analysed had few methodological limitations. Although the generation of randomization process and allocation concealment were often not adequately described, there were no systematic differences between the baseline characteristics of the groups that were compared in individual studies. Only one-third of included studies were blind. However, the primary outcome of the analysis and its measurement (VL) are not likely to be influenced by lack of blinding; on the other hand, blinding could have been important for assessment of subjective outcomes such as inter- ruption of treatment for adverse events, namely hypersensitivity reactions.
Our quantitative findings suggest that virological outcomes did not differ between abacavir-containing and -non-containing cART, both in the overall comparison and in the comparison with tenofovir-containing cART. Differences in the occurrence of adverse events requiring discontinuation of treatment favoured tenofovir recipients, but not in a statistically significant manner. In some of the included studies, this difference was driven by aba- cavir discontinuation due to suspected hypersensitivity reaction and HLA-B*5701 screening for hypersensitivity reaction was required in only two trials,30,37 while in the ACTG 5202 study the test was permitted but not required. In the remaining studies, HLA-B*5701 screening was not performed and in some of these trials (e.g. the BICOMBO and HEAT studies) the difference in
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Predictive margins with 95% CIs
.05
Nishijima 2013
0
–.05
–.1
–.15
–.2
0 1
HIV load
Figure 5. Meta-regression of virological efficacy at 48 weeks in studies comparing abacavir-containing cART with tenofovir-containing cARTaccording to baseline VL. On the y-axis the natural logarithm (ln) of the risk ratio (RR) is given. The baseline viraemia is given on the x-axis: VL¼ 0 (,100 000 copies/mL) and VL¼ 1 (.100 000 copies/mL). The circles indicate the studies and the line of the mean represents the VL effect on ln(RR). There was a large overlap between the 95% CIs at VL¼ 0 and VL¼ 1.
treatment efficacy was mostly related to abacavir discontinuation due to suspected hypersensitivity reaction. In a study from Japan, screening was permitted but not required due to the low prevalence of the HLA-B*5701 allele in the Japanese population.36,58–60 At pre- sent, when HLA-B*5701 screening is not readily available, it remains reasonable to initiate abacavir with appropriate clinical counselling and monitoring for any signs of hypersensitivity reaction.1
Meta-analytical pooling of studies with a head-to-head com- parison of abacavir and tenofovir and subgroup analysis according to baseline VL values (,100000 or .100000 copies/mL) showed that the proportions of subjects with VL below the cut-off of detectability at 48 and 96 weeks were similar among abacavir and tenofovir in the overall comparison, in the high baseline VL strata and the low VL strata. In addition, meta-regression analysis at 48 weeks confirms the results of meta-analytical pooling by subgroups, not supporting a rejection of the null hypothesis of abacavir producing a different success rate with respect to teno- fovir with a VL .100000 copies/mL. In other words, the baseline VL does not appear to affect the virological efficacy of abacavir. In sensitivity analysis, exclusion of any one study had a small effect
failure higher for the abacavir/lamivudine recipients. The discord- ance with our findings and those seen in the ACTG 5202 study can be partially related to the specific endpoints (week 16 definitions of viral failure, plus later ones) used in this study but not in other studies. Furthermore, once subjects were suppressed in the ACTG 5202 on abacavir-based therapy they maintained suppression, and in ‘as treated’ analysis rates of suppression were similar in the two arms. This suggests an anomaly arising from the early endpoint definitions in ACTG 5202 over classifying abacavir recipi- ents as failures. Our analysis shows that the rate of virological fail- ure is not higher in abacavir recipients compared with tenofovir recipients, regardless of baseline VL. However, our estimates are based on cross-sectional data and it was not possible, from the available evidence, to perform a time-to-event meta-analysis. Nevertheless, no differences in time to virological failure were observed in a large Canadian cohort of HIV-infected individuals.61 The time to regimen failure was similar for abacavir/lamivudine and tenofovir/emtricitabine even when stratified by baseline VL (,100000 or .100000 copies/mL). These results support the use of abacavir/lamivudine as one of the ‘preferred’ NRTI options.
on the pooled RR estimate, but exclusion of the study by Raffi
et al.34 from the subgroup analysis of high baseline viraemia stud- ies had influence on the cumulative results, leading to an RR favouring tenofovir. This is not surprising considering that this study has a large sample size (495 patients) and, based on the inverse of variance, the highest meta-analytical weight (38%) in the subgroup of studies with high baseline viraemia.
Our findings of similar virological efficacy according to NRTI backbone regardless of the baseline VL contrast with those of the ACTG 5202 trial. In the ACTG 5202 study, the time to viro- logical failure was significantly shorter and the rate of virological
Acknowledgements
Part of this study was presented at the Fourteenth European AIDS Conference, Brussels, 2013 (Abstract PE7/2).
We thank Paolo Rizzini and Martin Gardland of ViiV Healthcare for providing additional repository data from ASSERT and FLAMINGO studies.
Funding
This study was carried out with internal funding.
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Transparency declarations
M. C. has been an advisor/consultant for Bayer, Cephalon and ViiV Healthcare, and has received honoraria for educational lectures from Abbott, Gilead, Novartis and ViiV Healthcare. These activities were not related to his work with this review. G. M. has received research grants from Abbott, Ardea Biosciences, Bionor, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Merck, Pfizer, Theratechnologies and Tibotec. He has received honoraria as a speaker and/or advisor from Boehringer-Ingelheim, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Merck, Pfizer, Theratechnologies, Tibotec and ViiV Healthcare. All other authors: none to declare.
Author contributions
M. C. designed the study and contributed to the systematic review, selec- tion of studies, data extraction, data analysis and writing of the report. C. M. performed the statistical analyses and contributed to the writ- ing of the report. G. M. contributed to the design of the study, selection of studies, data interpretation and writing and revision of the report. S. G. P.,
M. M., G. S. and O. B. contributed to the study selection, data extraction and interpretation and writing of the report. All authors have seen and approved the final version.
Supplementary data
Tables S1 to S4 and Figures S1 to S3 are available as Supplementary data at JAC Online (http://jac.oxfordjournals.org/).
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