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The ALLRT ACTG Cohort, The French Cohort and the DAD Study all reported at CROI on MIs with regards to abacavir. Both DAD and the French group reported orals finding an association of abacavir and risk for developing an MI and the ALLRT ACTG group did not find an association. There were various additional studies reporting on inflammation markers and related outcomes. Below are abstracts from these studies. The full slidesets from the French and DAD ora presentations will be emailed along with this report and the ALLRT poster is forthcoming. Also Peter Reiss is presenting an oral talk at CROI reviewing the issue of MI and abacavir. Additional reporting on this issue is forthoming from NATAP. This question remains a controversial and unresolved question. Both DAD and the French groups are cohorts subject to the same limitations of a cohort study, which are subject to potential confounding although they attempt to adjust for the confounders. NATAP has a faculty of 16 writers at CROI who are thought leaders in HIV and HCV/HIV coinfection in their specialties and so opinion and review of this question will be provided in the faculty reporting forthcoming. All HIV ART drugs have potential toxicities and adverse events. I have spoken with a number of researchers/doctors at this meeting regarding this question and there are mixed opinions with some saying the risk for MI reported to be associated with abacavir is very low, others not convinced of an MI-ABC risk from these studies, some whose their patient population is such that they have risks for kidney disease and cardiovascular disease, some who say patients with several cardiovascular risk factors who have another nuke option are switched, and some who buy the DAD/French results. Another criticism offered is that the French and DAD studies should divide their data into before 2004 and after 2004 to see if there is a difference. In the earlier days patients were sicker and had fewer prescription options; abacavir was on the market for several years before tenofovir, which I think was launched in 2001, and so perhaps abacavir use prior to 2001 provides the risk observed in DAD and the French studies. Jules Levin
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No Association of Abacavir Use with Risk of Myocardial Infarction or Severe Cardiovascular Disease Events: Results from ACTG A5001
Constance Benson*1, H Ribaudo2, E Zheng2, S Koletar3, M Smurzynski2, R Bosch2, B Bastow4, A Collier5, J Schouten5, and the ACTG A5001/ALLRT Protocol Team
1Univ of California, San Diego Sch of Med, US; 2Harvard Sch of Publ Hlth, Boston, MA, US; 3Ohio State Univ Coll of Med, Columbus, US; 4Social & Sci Systems Inc, Silver Spring, MD, US; and 5Univ of Washington Sch of Med, Seattle, US
Background: The D:A:D study reported that the recent use of abacavir (ABC) was associated with increased risk of myocardial infarction (MI); the SMART study noted a similar association with severe cardiovascular disease (CVD). We evaluated the association between ABC use and the risk of MI and severe CVD after starting ART in ART-nave HIV-infected patients.
Methods: Data were analyzed from 3205 patients randomized to their first ART regimen in one of 5 ACTG studies; extended follow-up was available for 2164 patients through the ALLRT long-term protocol. Follow-up was censored at the first of off-study, death, initiation of non-randomized ABC or 6 months after the last visit or discontinuation of randomized ART (not including within class substitutions not involving ABC). Relative risk (RR) for randomized ABC exposure (crude and adjusted) for gender, race/ethnicity, and baseline age, HIV RNA, and CD4, didanosine (ddI) use, and classic risk factors for CVD, e.g., smoking, hypertension, dyslipidemia, CVD, and family history of CVD, were estimated with Poisson regression. With follow-up censored as described randomization to ABC is interpreted as recent exposure. MI were included if assessed as definite or probable by 2 independent reviewers.
Results: For 3205 patients, median CD4 was 205 cells/L, HIV RNA 5 log10, age 37, 40% white non-Hispanic, 37% black non-Hispanic, 20% Hispanic; 18% women; 781 patients were randomized to ABC. We identified 63 severe CVD events, including 27 MI. Significant associations between either MI or severe CVD and recent ABC exposure were not detected in unadjusted (RR = 1.02, 95%CI 0.4 to 2.5, p = 0.96, RR = 0.8, 95%CI 0.5 to 1.6, p = 0.58, respectively) and adjusted analyses (table). Significant increases in the risk of events were detected for some classic CVD risk factors, i.e. older age and hypertension.
Conclusions: In contrast to D:A:D and SMART, we did not find a significant association between recent ABC use and MI or severe CVD risk for ART-nave patients randomized to an initial ABC regimen. Our results suggest the association with recent ABC use in other studies may be a marker for other factors not discerned in their analyses.
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Abacavir and Cardiovascular Risk
Peter Reiss
Academic Med Ctr, Univ of Amsterdam, The Netherlands
Background: The current or recent (within the last 6 months) use of abacavir (ABC) has been associated with an increased risk of cardiovascular disease (CVD) within the setting of an observational cohort study (D:A:D) and a randomized trial (SMART). The risk was removed upon drug discontinuation. Of note, other than what has been the case for HIV PI, no association was found with the cumulative use of ABC. CVD events in both these studies were captured and validated prospectively according to predefined procedures. In contrast, an analysis of an aggregated clinical trials database maintained by the manufacturer of ABC, which includes data on CVD, but only captured as part of general reporting of adverse events, did not confirm the earlier mentioned association. The latter was also the case for an analysis performed in patients randomized to their first ART regimen in 1 of 5 ACTG studies for whom extended follow-up was available through the ALLRT long-term protocol. Interestingly, an intermediate size randomized trial which compared treatment simplification with fixed-dose combination (FDC) of tenofovir (TDF)/emtricitabine (FTC) or ABC/lamivudine (3TC) in patients with prior HIV suppression to <50 copies/mL (STEAL) did find a higher rate of CVD events (predefined as secondary endpoints) in those randomized to FDC-ABC/3TC.
Conclusions: Although differences in study design, statistical power, endpoint definitions, and procedures to capture and validate endpoints may each contribute to these discrepant findings, additional possible explanations also need to be considered. Reviewing the characteristics of the various patient populations which were studied, one could for instance speculate whether the likelihood of identifying the CVD risk associated with ABC may be greater in those who are first exposed after their HIV infection is already suppressed. Data suggest a pathogenic mechanism (possibly of a proinflammatory nature) involving acute processes, such as plaque rupture or subesquent thrombosis, rather than a chronic one affecting atheroma formation. For now, it seems prudent to withold ABC from patients with high underlying CVD risk if suitable alternative regimens are available. If not, patients absolute CVD risk in the presence of ABC should be minimized by aggressive management of traditional CVD risk factors.
44LB
Risk of Myocardial Infarction with Exposure to Specific ARV from the PI, NNRTI, and NRTI Drug Classes: The D:A:D Study
Jens Lundgren*1, P Reiss2, S Worm1, R Weber3, W El-Sadr4, S De Wit5, M Law6, A dArminio Monforte7, C Pradier8, C Sabin9, and Aquataine, AHOD, ATHENA, INSIGHT, EuroSIDA, ICONA, Nice, SHCS, St Pierre Cohorts & D:A:D Study Group
1Rigshospitalet, Univ of Copenhagen, Denmark; 2Academic Med Ctr, Amsterdam, The Netherlands; 3Univ Hosp Zurich, Switzerland; 4Columbia Univ, New York, NY, US; 5St Pierre Hosp, Brussels, Belgium; 6Univ of New South Wales, Sydney, Australia; 7Univ of Milan, Italy; 8L`Archet Hosp, Nice, France; and 9Royal Free and Univ Coll Med Sch, London, UK
Background: Prior analyses from the D:A:D study showed an increased risk of MI with cumulative use of PI, but not NNRTI. In addition, current/recent use of abacavir (ABC) and didanosine (ddI), but not stavudine (d4T), zidovudine (ZDV), or lamivudine (3TC) were also associated with MI risk. Sufficient follow-up has now accrued to allow us to explore additional associations between specific drugs and MI risk.
Methods: The D:A:D collaboration includes data on 33,308 patients from 11 cohorts followed prospectively; 580 developed an MI over 178,835 person-years. Poisson regression, adjusted for demographics, cardiovascular risks, and use of other ARV, assessed the impact of cumulative (/year) or recent (current/in last 6 months) use of ARV with >30,000 person-years of exposure (table). Further analyses included adjustment for latest measures of lipids, metabolic parameters, CD4 and HIV-RNA to identify possible mechanisms for any associations. In the main analyses, exposure to indinavir (IDV) and saquinavir (SAQ) was calculated regardless of concomitant use of ritonavir, but sensitivity analyses also explored separate associations with IDV/r and SAQ/r.
Results: There were no statistically significant associations between recent or cumulative use of tenofovir (TDF), dideoxycytidine (ddC), ZDV, d4T, or 3TC and MI risk. As before, recent exposure to ABC or ddI was associated with an increased risk of MI. No association was seen with cumulative exposure to nevirapine (NVP), efavirenz (EFV), nelfinavir (NFV), or SAQ. Cumulative (but not recent) exposure to IDV or lopinavir/ritonavir (LPV/r) was associated with an increased risk of MI (relative rate [RR]: 1.12.and 1.13/year, respectively). These increased risks were attenuated slightly (1.08 [1.02 to 1.14] and 1.09 [1.01 to 1.18], respectively) after adjustment for lipids but were not altered further after adjustment for other metabolic parameters; neither association was affected by adjustment for CD4 or HIV RNA. In sensitivity analyses, RR/year for IDV/r (22,185 person-years) and SAQ/r (24,727 person-years) were 1.14 (1.02 to 1.28), and 1.06 (0.97 to 1.14), respectively.
Conclusions: Of the ARV considered, only IDV, LPV/r, ddI and ABC were associated with a significantly increased risk of MI. Additional follow-up will allow us to more definitively establish which of the specific (ritonavir-boosted) PI are most associated with MI risk. As with any observational study, our findings must be interpreted with caution given the potential for confounding.
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Simplification with Fixed-dose Tenofovir/Emtricitabine or Abacavir/Lamivudine in Adults with Suppressed HIV Replication: The STEAL Study, a Randomized, Open-label, 96-Week, Non-inferiority Trial
D Cooper1, M Bloch2, A Humphries1, J Amin1, D Baker3, S Emery1, Andrew Carr*4, and for the STEAL Study Investigators
1Natl Ctr in HIV Epi and Clinical Res, Univ of New South Wales, Sydney, Australia; 2Holdsworth House Gen Practice, Sydney, Australia; 3East Sydney Doctors, Australia; and 4St Vincent`s Hosp, Sydney, Australia
Background: There are 2 once-daily, dual-nucleoside, fixed-dose-combination (FDC) tablets that are used for adult HIV-1 infection: tenofovir (TDF; 300 mg) + emtricitabine (FTC; 200 mg); and abacavir (ABC; 600 mg) + lamivudine (3TC; 300 mg). Which FDC is more effective and safe is uncertain.
Methods: We compared TDF+FTC- and ABC+3TC-based therapy over 96 weeks when either FDC was substituted for current NRTI in HLA-B*5701 adults with plasma HIV viral load <50 copies/mL. The primary endpoint was virological failure, defined by repeat viral load >400 copies/mL plasma by intention-to-treat, missing=failure (ITTM=F) analysis. Secondary endpoints (ITT) included death, AIDS, serious non-AIDS events (see table), metabolic parameters and body composition (bone/soft-tissue; ITT-LOCF). We used exact statistics for differences in proportions, t tests to compare means, and Cox regression for hazard ratios for ABC+3TC/TDF+FTC (HR 95%CI).
Results: From January to August 2006, we randomized 360 patients. Key baseline characteristics of the 357 treated participants were: male 98%, mean age 45.1 years, prior NRTI therapy 5.8 years, current TDF 30%, current ABC 20%, current PI 24%, mean CD4 count 612 cells/mm3, eGFR 98 mL/min/1.73 m2, limb fat 5.5 kg, and hip t score 0.49. Groups were well balanced, except smoking was more prevalent with ABC+3TC (40%) than with TDF+FTC (29%); 1.7% were lost to follow-up with no between-group difference. No patient developed AIDS or renal failure. TDF+FTC was associated with more bone loss. There was no significant between-group, week-96 difference for limb fat, eGFR, CD4 count, insulin sensitivity, total:HDL cholesterol ratio, or lactate.
* 3 myocardial infarctions; 2 leg arterial disease; 1 stroke, 1 coronary artery by-pass
Conclusions: In this population, TDF+FTC and ABC+3TC had similar virological efficacy and protection against AIDS. ABC+3TC was associated with more serious non-AIDS events.
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Impact of Specific NRTI and PI Exposure on the Risk of Myocardial Infarction: A Case-Control Study Nested within FHDH ANRS CO4
S Lang1, M Mary-Krause1, L Cotte2, J Gilquin3, M Partisani4, A Simon5, F Boccara6, Dominique Costagliola*1, and the Clinical Epi Group of the French Hosp Database on HIV
1INSERM U943, Univ of Pierre and Marie Curie, Paris, France; 2Hosp Hotel Dieu, Lyon, France; 3Hosp St-Joseph, Paris, France; 4CHRU Strasbourg, France; 5Hosp Pitie-Salpetriere, Paris, France; and 6Hosp St Antoine, Paris, France
Background: Cumulative exposure to PI has been shown to increase the risk of myocardial infarction (MI) and more recently specific NRTI, such as abacavir, have also been incriminated. Our objectives were to analyze the effect of exposure to specific NRTI and PI on the risk of MI in the French Hospital Database on HIV using a nested case-control study.
Methods: Cases were patients enrolled in the database who, between January 2000 and December 2006, had a first MI prospectively reported, definite or probable after validation using the European Society of Cardiology definition. As many as 5 controls were selected at random with replacement among patients with no history of MI, followed at the time of MI diagnosis, matched with the case for age (3 years), sex, and clinical center of follow-up. Data on cardiovascular risk factors and cardiovascular treatments were collected from the medical records. Conditional logistic regression models were used to assess the association of cumulative and/or recent (current or within last 6 months) and past (>6 months ago) use of each NRTI (AZT, DDI, DDC, D4T, 3TC, ABC, TNF, FTC) and cumulative use of each PI (IDV, SQV, NFV, LPV, APV/fPV), after adjustment for known cardiovascular risk factors, plasma HIV-1 RNA, CD4/CD8 ratio and use of other antiretrovirals.
Results: Overall 286 cases and 865 controls were included in the analysis, 76% enrolled in the FHDH while ARV naive. Cases were mainly male (89%) with a median age of 47 years. For abacavir (ABC), there was evidence of an interaction between recent and cumulative exposure and, after exploration, we found an increased risk of MI in those with <1 year of exposure and recent use (OR=2.19, 95%CI: 1.19-4.02) but not in others. No interaction was found between exposure to abacavir and the number of cardiovascular risk factors. No other NRTI was associated with the risk of MI. Cumulative exposure to PI were associated with an increased risk of MI for all (indinavir [IDV] OR = 1.11 per year, 95%CI 0.98 to 1.25 and nelfinavir [NFV] OR = 1.13/year, 95%CI 0.99 to 1.30) except saquinavir (SQV) (OR = 0.96/year, 95%CI 0.80 to 1.15), reaching significance for lopinavir (LPV) (OR = 1.38/year, 95%CI 1.10 to 1.74), and amprenavir (APV)/fos-amprenavir (fPV) (OR = 1.55/year, 95%CI 1.20 to 1.99).
Conclusions: In our study, we found that the risk of MI was increased by cumulative exposure to LPV and to APV or fPV. Initiating ABC was also associated with an increased risk of MI while longer exposure to ABC was not.
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Platelet Hyper-Reactivity in HIV-1-infected Patients on Abacavir-containing ART
Claudette Satchell*1, E O'Connor2, A Peace3, A Cotter2, G Sheehan2, T Tedesco3, P Doran2, W Powderly1, D Kenny3, and P Mallon1,2
1Univ Coll Dublin, Ireland; 2Mater Misercordiae Univ Hosp, Dublin, Ireland; and 3Royal Coll of Surgeons in Ireland, Dublin
Background: Increased rates of cardiovascular disease (CVD) have been described in HIV-infected patients on antiretroviral therapy (ART) with a reversible increased risk of myocardial infarction (MI) observed in patients on abacavir (ABC) -containing ART. We hypothesized that patients on ABC would have increased platelet reactivity.
Methods: We completed a prospective study to assess platelet function in 58 ART-treated, HIV-infected patients attending the Mater Misericordiae University Hospital, Dublin, 30 of whom were on ABC-containing ART (ABC group) and 28 who were on non-ABC-containing ART (no ABC group). Platelet reactivity was assessed on fasting blood by measuring time-dependent platelet aggregation (by light absorbance) upon exposure to increasing concentrations of platelet agonists; ADP, collagen, epinephrine and thrombin receptor activating peptide (TRAP). We used parametric analysis to determine between-group differences in platelet aggregation and linear regression to control for potential confounders with data presented as mean [SD] unless otherwise stated.
Results: Groups were well matched for age (ABC group 38 [10] years versus 35 [10] in non-ABC group), gender (67% male versus 64% male respectively) and ethnicity (63% versus 54% respectively being Caucasian); 22 (79%) versus 20 (71%) had HIV RNA <50 copies/ml. Platelet reactivity was increased in the ABC group with ADP, collagen, and epinephrine inducing more platelet aggregation at sub-maximal agonist concentrations (ADP 30 [25]% versus 18 [18]% aggregation at 1.25 M, p = 0.032; collagen 13 [23]% versus 1 [4]% at 35.6 g/mL, p = 0.009: epinephrine 31 [20]% versus 21 [17]% at 1.25 M, p = 0.043). Although aggregation was increased with exposure to TRAP (12 [19]% versus 5 [2]% at 1.25M), this did not reach statistical significance (P=0.06). These differences remained significant when controlled for gender, age, ethnicity, mode of HIV acquisition, smoking history, diabetes, family history of CVD, systolic blood pressure, use of other classes of ART, use of aspirin and methadone and CD3+, CD4+, and CD8+ T cell count.
Conclusions: This study demonstrates consistently hyper reactive platelets in patients on ABC-containing ART and may help explain the increased rates of MI in ABC-treated patients. Further research is required to determine if this effect is reversible.
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Inflammatory Markers among Abacavir and non-Abacavir Recipients in the Womens Interagency HIV Study and the Multicenter AIDS Cohort Study
Frank Palella*1, S Gange2, R Elion3, L Benning2, R Kaplan4, C WIllliams5, A Landay6, L Jacobson2, and R Tracy7
1Feinberg Sch of Med, Northwestern Univ, Chicago, IL, US; 2Johns Hopkins Univ, Baltimore, MD, US; 3Whitman Walker Clinic, Washington, DC, US; 4Albert Einstein Coll of Med, New York, NY, US; 5NIAID, NIH, Bethesda, MD, US; 6Rush Univ, Chicago, IL, US; and 7Univ of Vermont, Burlington, US
Background: Use of abacavir (ABC) has been associated with increases in cardiovascular disease and markers of inflammation. Further evaluation of ABC use and inflammation is needed.
Methods: We identified Multicenter AIDS Cohort Study (MACS) men and Womens Interagency HIV Study (WIHS) women who initiated ABC either at or after first HAART initiation while under follow-up. Propensity score methods were used to identify ABC-unexposed person-visits matched by race/ethnicity, age, calendar time, smoking, body mass index, HDL, HCV serostatus, pre-HAART ART use, duration and consistency of HAART use, CD4, and HIV RNA levels. High-sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6), and D-dimer levels were measured at the pre-HAART visit (baseline) and at the on-HAART index visit defined as the first visit at which ABC use was reported (exposed) or a matched visit without ABC use (unexposed). Since visits were semi-annual, onset of ABC use could be <1 to 6 months before the study visit. Random-effects models were used to compare log-transformed markers and changes from pre-HAART levels in ABC and non-ABC initiators.
Results: We measured hsCRP and D-dimer levels in 326 matched pairs (197 women; 129 men) and IL-6 levels in 290 matched pairs (194 women; 96 men). In unadjusted models, ABC users at the index visit had 7% lower mean D-dimer levels (0.26 vs 0.28 mg/mL, p = 0.40), 8% higher hsCRP (1.69 vs 1.56 mg/mL, p = 0.41), and 1% higher IL-6 (2.20 vs 2.17 pg/mL, p = 0.90) than non-ABC users. In multivariate models, differences at index visit between ABC exposed and unexposed were: 3% for D-dimer (p = 0.66), +2% for hsCRP (p = 0.80), and 5% for IL-6 (p = 0.58). In this model women had lower mean D-dimer levels (5% difference, p = 0.70), significantly lower hsCRP levels (33%, p = 0.01), and significantly lower IL-6 levels (38%, p = 0.001) than men. Comparisons of baseline and index visits (mean 4.2 years apart) revealed decreases in D-dimer (p <0.001) and IL-6 (p = 0.08) and increases in hsCRP levels (p <0.001). However, the changes in markers between visits were not significantly different when comparing ABC exposed and unexposed persons (D-dimer p = 0.82, hsCRP p = 0.64, and IL-6 p = 0.47).
Conclusions: ABC use was not independently associated with elevated plasma levels of hsCRP, IL-6, and D-dimer. While changes in the levels of these markers were seen between the baseline and index visits (D-dimer and IL-6 decreases, hsCRP increases), they were comparable among persons who initiated ABC versus non-ABC containing HAART. Women had higher D-dimer and lower CRP levels than men.
744
Assessment of Renal Findings of Abacavir/Lamivudine Compared with Tenofovir/Emtricitabine in Combination with Once-daily Lopinavir/Ritonavir over 96 Weeks in the HEAT Study
Derek Fine*1, K Smith2, P Patel3, N Bellos4, L Sloan5, P Lackey6, P Kumar7, D Sutherland-Phillips3, L Yau3, and M Shaefer3
1Johns Hopkins Univ Sch of Med, Baltimore, MD, US; 2Rush Univ Med Ctr, Chicago, IL, US; 3GlaxoSmithKline, Research Triangle Park, NC, US; 4Southwest Infectious Disease Assoc, Dallas, TX, US; 5North Texas Infectious Disease Consultants, Dallas, US; 6ID Consultants, Charlotte, NC, US; and 7Georgetown Univ Sch of Med, Washington, DC, US
Background: HEAT is the first large, prospective, long-term, head-to-head trial to evaluate the efficacy and safety of these dual NRTI backbones with a boosted PI. Detailed comparison of the renal effects of these regimens has not been performed.
Methods: ART-nave subjects with plasma HIV-1 RNA (viral load) 1000 copies/mL, and any CD4+ count were randomized to receive abacavir/lamivudine (ABC/3TC) or tenofovir/emtricitibine (TDF/FTC) with open-label lopinavir/ritonavir (LPV/r) once daily in this double-blind, placebo-matched, multi-center, 96-week study. The primary objective at 96 weeks was to evaluate safety and tolerability. Detailed assessment of renal parameters was carried out as part of safety assessment. Renal data were collected through 96 weeks or the last sample date while subjects were still on randomized treatment.
Results: We randomized 688 subjects who were: median age 38 years, 18% female, 15% hypertensive, 3% diabetic, and 2% with renal or urinary disorders at baseline; 5 subjects developed proximal tubule renal dysfunction in the TDF/FTC arm according to predefined criteria. At the last study visit on randomized treatment, small increases in the estimated glomerular filtration rate (eGFR) and creatinine clearance (eCrCl) were observed in both treatment arms. Progression to a more advanced CKD stage occurred in 31 (10%) subjects in the ABC/3TC arm and 49 (15%) subjects in the TDF/FTC arm at the last visit on study drug; 4 in the ABC/3TC arm and 11 in the TDF/FTC arm progressed to stage 3 CKD (eGFR <60 mL/min/1.73m2).
* Excluded subjects: known diabetes, fasting glucose >126, any glucose >140 at any time-point
Conclusions: These results show that improvement in kidney function, as measured by eGFR and eCrCl, was slightly greater, though small in absolute terms, with ABC/3TC compared to TDF/FTC when combined with once-daily LPV/r through 96 weeks. In addition, fewer subjects in ABC/3TC group progressed to stage 3 CKD. Proximal tubule renal dysfunction, though not common, was seen only in those on TDF/FTC.
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96-Week Effects of Suppressive Efavirenz-containing ART, Abacavir, and Sex on High-sensitivity C-reactive Protein: ACTG A5095
Cecilia Shikuma*1, E Zheng2, H Ribaudo2, J Andersen2, M Glesby3, W Meyer III4, K Tashima5, B Bastow6, D Kuritzkes7, R Gulick3, and AIDS Clinical Trials Group A5095
1Univ of Hawaii, Honolulu, US; 2Harvard Sch of Publ Hlth, Boston, MA, US; 3Weill Med Coll of Cornell Univ, New York, NY, US; 4Quest Diagnostics, Baltimore, MD, US; 5Brown Univ, Providence, RI, US; 6Social & Sci Systems Inc, Silver Spring, MD, US; and 7Brigham and Women`s Hosp, Boston, MA, US
Background: High-sensitivity C-reactive protein (hs-CRP) levels predict cardiovascular risk and are associated with mortality in HIV-infected women. Indinavir-based therapy has been reported to result in stable or decreased hs-CRP levels. No information is available on hs-CRP changes with NNRTI-based therapy. We assessed the 96-week effects of efavirenz (EFV) -based therapy with or without abacavir (ABC) on hs-CRP levels among ARV-nave patients within the AIDS Clinical Trials Group A5095 trial.
Methods: hs-CRP was assayed in banked baseline and week-96 sera from 100 participants with HIV RNA <50 copies/mL at study weeks 24 and 96 who were randomized to and remained (through week 96 of study) on 1 of the 2 EFV-containing regimens of A5095: zidovudine (ZDV)/lamivudine (3TC)+EFV or ZDV/3TC/ABC+EFV. Analyses utilized all women enrolled in A5095 who satisfied these criteria with sufficient sample volume available (n = 39) and 61 randomly selected men from n = 346. hs-CRP levels at baseline and changes from week 0 to 96 were compared by sex and randomization arm by Wilcoxon rank sum test. Shifts in hs-CRP distribution were estimated by the Hodges-Lehmann method. Associations between week 0 to 96 changes in hs-CRP and week 0 to 96 changes in CD4 counts and fasting metabolic parameters were examined by Spearman correlation coefficients.
Results: The median hs-CRP level in the entire cohort was 2.3 mg/L (Q1 0.9, Q3 4.9) at baseline and not different for men and women (median 1.6 mg/L vs 2.6 mg/L, p = 0.36). Overall, there was an increase in hs-CRP from week 0 to 96 (median 1.3, p <0.001, [95%CI 0.7 to 2.7]). A larger increase in hs-CRP was seen for women compared to men (median 3.7 [95%CI 1.7 to 7.2] mg/L vs 0.5 [0.3 to 1.3] mg/L, p = 0.001, shift in center of distribution 3.3 mg/L [95%CI 1.3 to 5.8]). This change was significant in women (p <0.001) but not in men (p = 0.15). No significant difference in hs-CRP levels was noted between the arms with (n = 39) and without ABC (n = 61), at baseline (median 3.2 mg/L vs 2.0 mg/L, p = 0.25) or change to week 96 (median 1.7 mg/L vs 1.1 mg/L, p = 0.50). Significant correlations were not detected between changes in hs-CRP and changes in CD4 count or fasting metabolic measures (p >0.30).
Conclusions: Durably suppressive therapy with EFV-based regimens did not improve hs-CRP levels over a 96-week period. Overall, an increase was seen which was greater for women than men. Inclusion of ABC had no significant effect on changes in hs-CRP levels.
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Association of Abacavir and HIV Disease Factors with Endothelial Function in Patients on Long-term Suppressive ART
P Hsue, Y Wu, A Schnell, P Ganz, P Hunt, H Hatano, J Martin, and Steven Deeks*
San Francisco Gen Hosp, Univ of California, San Francisco, US
Background: HIV-infected individuals have accelerated atherosclerosis. This may be due to both HIV disease-associated factors (including inflammation) and treatment-associated factors. Recently, exposure to abacavir (ABC) has been associated with increased risk of cardiovascular events, for reasons that remain to be elucidated. As endothelial dysfunction is central to the pathogenesis of atherosclerosis and predicts adverse cardiovascular outcomes including myocardial infarction, we investigated the association between treatment- and disease-associated factors on endothelial function, focusing on patients responding to HAART.
Methods: We studied a cohort of 61 HAART-treated patients who had undetectable plasma HIV RNA levels in whom ABC was currently part of the treatment in half of the patients (n = 30, 49%). Endothelial function was assessed as flow-mediated vasodilation of the brachial artery and was measured using a validated approach in our laboratory; all studies were performed by a single technician blinded to treatment status. We adjusted for traditional risk factors and HIV characteristics (CD4 count, nadir CD4 count, and HAART duration).
Results: The median age was 50 years (IQR 45 to 57), and 95% were male. The median duration of HIV infection was 18 years (IQR 14 to 21), the median CD4 cell count was 369 cells/mm3 (IQR 189 to 673), and the median duration of HAART was 8.6 years. Overall, the median flow-mediated vasodilation in the HIV patients was impaired (3.5%; IQR 2.3 to 5.6%). The flow-mediated vasodilation was more impaired in the ABC-treated patients than those not on ABC (2.8% vs 4.9%, p = 0.01). After adjustment for age, gender, traditional risk factors, HIV-specific factors, and baseline brachial artery diameter, current ABC use was independently associated with lower flow-mediated vasodilation (p = 0.017). Duration of HAART and protease inhibitors, CD4 nadir, and proximal CD4 count were not associated with reduced flow-mediated vasodilation.
Conclusions: Endothelial function, a central mechanism in atherosclerosis and a marker of cardiovascular risk, is impaired among long-term HAART-treated patients with undetectable viral loads. Current use of ABC was independently associated with impaired endothelial function; this effect was not readily explained by measured confounders, including traditional risk factors. Further studies will need to determine whether ABC-associated changes in endothelial function contribute to the clinically observed relationship between ABC use and myocardial infarction.
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Similar Reductions in Markers of Inflammation and Endothelial Activation after Initiation of Abacavir/Lamivudine or Tenofovir/Emtricitabine: The HEAT Study
Grace McComsey*1, K Smith2, P Patel3, N Bellos4, L Sloan5, P Lackey6, P Kumar7, D Sutherland-Phillips3, L Yau3, and M Shaefer3
1Case Western Reserve Univ Sch of Med, Cleveland, OH, US; 2Rush Univ Med Ctr, Chicago, IL, US; 3GlaxoSmithKline, Research Triangle Park, NC, US; 4Southwest Infectious Disease Assoc, Dallas, TX, US; 5North Texas Infectious Disease Consultants, Dallas, US; 6ID Consultants, Charlotte, NC, US; and 7Georgetown Univ Sch of Med, Washington, DC, US
Background: Endothelial dysfunction and chronic inflammation have been reported in HIV-1-infected subjects. In STACCATO, elevations in the endothelial marker vascular cell adhesion molecule-1 (sVCAM-1) were observed during treatment interruption. In SMART, baseline elevations in interleukin-6 (IL-6) and high-sensitivity C-reactive protein (hs-CRP) were proposed as a mechanism for possible increased cardiovascular events in subjects taking abacavir (ABC). This analysis compared the effects of ABC/lamivudine (3TC) and tenofovir/embricitabine (TDF/FTC) on these biomarkers in a prospective, randomized study of ART-nave subjects to investigate causality.
Methods: Available samples from subjects randomized to ABC/3TC or TDF/FTC each with lopinavir/ritonavir were analyzed at baseline and weeks 48 and 96 for sVCAM-1, IL-6, and hsCRP. Biomarker concentrations were measured by Quest Diagnostics using ELISA (sVCAM-1, IL-6) and fixed rate nephelometry (hsCRP).
Results: This analysis included 476 subjects: mean age 39 years, 15% female, 45% non-white, with baseline median HIV-1 RNA and CD4+ of 4.88 log10 copies/mL and 211 cells/mm3, respectively. Mean percentage changes from baseline in sVCAM-1 and IL-6 were statistically significant at weeks 48 and 96 in both treatment arms. Reduction in hs-CRP from baseline was statistically significant in the TDF/FTC arm only. However, the reductions were not significantly different between arms for any of the 3 biomarkers (p >0.05). The low number of cardiovascular-related events (none related to study drug), ABC/3TC:1; TDF/FTC: 2, prevented correlation with any of the biomarkers.
Conclusions: Similar decreases in markers of inflammation and endothelial activation were observed over 96 weeks of treatment with ABC/3TC or TDF/FTC. These data do not suggest that ABC/3TC or TDF/FTC contribute to an increase in cardiovascular risk mediated by inflammation or worsening endothelial activation. The findings from this randomized, prospective data do not support the hypothesis of increased inflammation attributed to ABC from recent observational, cohort studies.
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Viral Dynamics and Pharmacokinetics in vivo of Tenofovir Disoproxil Fumarate and Abacavir: Evidence of a Non-additive Antiviral Effect
Miguel Goicoechea*1, S Jain1, C Kemper2, E Daar3, J Tilles4, B Ha5, J Flaherty6, D Richman1, S Louie7, R Haubrich1, and California Collaborative Treatment Group
1Univ of California, San Diego, US; 2Santa Clara Valley Med Ctr, San Jose, CA, US; 3Harbor-Univ of California, Los Angeles Med Ctr, Torrance, US; 4Univ of California, Irvine, US; 5GlaxoSmithKline, Research Triangle Park, NC, US; 6Gilead Sci, Foster City, CA, US; and 7Univ of Southern California, Los Angeles, US
Background: High rates of early viral failure were observed when tenofovir (TDF) + abacavir (ABC) + lamivudine (3TC) regimens were used in treatment-nave patients. We hypothesized that co-administration of TDF would decrease the intracellular exposure of combivir triphosphates (CBV-TP), the active metabolite of ABC, and reduce phase I viral decay.
Methods: This is a prospective, open-label, randomized trial that compared 7 days of TDF (300 mg once daily) or ABC (600 mg once daily) mono-therapy with 7 days of TDF+ABC dual-therapy in treatment-nave subjects. Each 7 day course was separated by a 35-day washout, followed by 46 weeks of combination therapy with efavirenz (EFV) +ABC+3TC (data not presented). Viral decay rates and steady-state intracellular concentrations of CBV-TP and TFV-diphosphates (DP) were measured during each course. With a sample size of 10 subjects per arm, this study had 80% power to detect a 30% difference in phase I viral decay rates and a 30% difference in intracellular concentrations between mono- and dual-therapy. Linear mixed effects models and Wilcoxon tests were used to assess differences in viral decay rates and intracellular concentrations, respectively, between mono- and dual-therapy.
Results: We randomized a total of 21 subjects (71% male) to initial mono-therapy with ABC (n = 11) or TDF (n = 10). Baseline characteristics were similar (median CD4 324 cells/mm3, HIV RNA 4.99 log10 copies/mL), except ABC subjects were younger (32 years vs 48 years; p = 0.014). No new HIV drug-resistance mutations were observed in resistance testing obtained at baseline and after dual therapy. Samples for deoxyribonucleoside triphosphate (dNTP) intracellular concentrations for one subject randomized to ABC were insufficient and not included in this analysis. Viral decay was faster for ABC (0.16 log10/day) vs TDF (0.11 log10/day) mono-therapy, but this difference was not statistically significant (p = 0.13). Viral decay during ABC+TDF dual-therapy was 0.04 log10/day faster than TDF mono-therapy (p = 0.005), but was similar to Viral decay during ABC mono-therapy (0.16 log10/day vs 0.15 log10/day). Neither intracellular concentrations of CBV-TP nor TFV-DP was correlated with viral decay during mono- or dual-therapy. Addition of second NRTI did not affect the intracellular concentration of CBV-TP or TFV-DP. Intracellular concentration CBV-TP was similar during both mono- and dual-therapy (median AUCt [fmol/106 cells]: 1895 vs 1694), however, intracellular concentration of TFV-DP was 2-fold higher after re-exposure in the TDF arm (median AUCt [fmol/106 cells]: 2700 vs 1209; p = 0.08).
Conclusions: TDF+ABC did not demonstrate additive antiviral potency compared to ABC alone. This lack of additive antiviral potency was not explained by differences in intracellular concentration of dNTP between mono- and dual-therapy.
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