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Life Expectancy in HIV / Reyataz Reduced CVD Risk vs PIs/NNRTIs/Integrase
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from Jules: A few important points regarding this study finding Reyataz cardio-protective. Heart disease (CVD) is arguably the most worrisome individual comorbidity supported by data showing 50% higher risk in HIV+ for CVD & that in the general population heart disease is perhaps the most serious disease. The study authors say "Of concern, there is evidence of therapeutic inertia in this domain, with many HIV-infected patients not receiving optimal management of cardiovascular risk factors during routine clinical care". ART selection has an impact on life expectancy, quality of life and onset for comorbidities.
1. morbidity and mortality from cardiovascular disease are more than 50% greater in HIV-infected individuals than in uninfected individuals. In most studies, this difference persists even after adjustment for differences in traditional risk factors such as smoking, hypertension, dyslipidemia, and diabetes mellitus
2. Life Expectancy - Among patients with HIV infection, estimated life expectancy at age 20 has increased from 36.1 additional years during 1996-1999 [1] to 53.1 during 2008-2011 [2] because of progressive improvements in antiretroviral therapy (ART) regimens and earlier diagnosis and treatment [3,4]. Despite these improvements, a significant gap remains compared with the uninfected population for whom life expectancy at 20 years in 2011 was estimated at an additional 59.5 years [5]. This gap is likely due to a corresponding increase in chronic comorbidities, for which the increasingly aging HIV-infected population is at greater risk [6,7].." from Jules: First I want to mention the Samji study from 2013 that reported a 20 year lower life expectancy for HIV+ who started HAART with CD4 less than 350 study. Overall LE was 71 years, 67 years if started ART with <350 CD4 and 88 years if started ART with over 350 CD4 and this 88 year lifespan may be hard to believe. Although many life expectancy studies show perhaps several years reduction in life expectancy as this study referenced above, none of these studies are truly able to evaluate life expectancy because they are merely estimates based on projections and NEVER include estimates of comorbidities which is impossible to predict anyway. In particular frailty & disability are also cognitive impairment are pretty much beyond predicting estimates. In addition, quality of life cannot is never evaluated & is very difficult to evaluate and in HIV+ with multiple comorbidities & polypharmacy and even more in aging HIV+ quality of life is very often very burdensome. HERE is an interesting study that looks at life expectancy & quality of life and finds a BIG difference in life expectancy & quality of life between HIV+ & HIV-uninfected. The caveat here is the study is in British Columbia where IDU among HIV+ is high but the study does reflect how comorbidities affects lifespan & quality of life. Comorbidities & Life Expectancy: the affect of comorbidities on Life Expectancy - (03/15/17). Even in the Swiss Cohort reported at IAS 2016 life expectancy study the best estimates are a lifespan of 74 years in a 74% male population which still falls apparently 10 years short in HIV-uninfected and 5 years short for those with a higher education http://www.natap.org/2016/IAC/IAC_93.htm - In a Spanish cohort reported at Glasgow 2016 excess mortality rates in HIV+ were MUCH higher compared to the general population and for HIV+ over 50 the excess mortality rate was apparently 5 fold higher compared to general population http://www.natap.org/2016/GLASGOW/GLASGOW_45.htm - In a Kaiser study at CROI 2016, which also was an estimate based on data from 1996-2011, the life expectancy gap found was 12 years shorter for HIV+ compared with HIV-uninfected (73 years of age lifespan in HIV+ vs 85 in HIV-uninfected) and there still was an 8.5 year gap for those that initiated ART at CD4 over 500 with a life expectancy of 74 years, but Blacks (4 year gap among HIV+ for Blacks vs Whites) & IDUs and women (2 year gap for HIV+ women vs men) had lower life expectancies. In this study however if an HIV+ person initiated ART at over 500 CD4 the life expectancy gap was 7.9 years and for those with had NO history of HCV/HBV, smoking, no alcohol/drug abuse and initiated ART at over 500 CD4 life expectancy gap fell to 5.7 years.
3. After IPTW, adjusted hazard ratios (95% CIs) indicated a significantly reduced risk of both MI and stroke with ATV-containing regimens versus regimens containing other PIs (0.47 [0.25-0.88] and 0.51 [0.33-0.78], respectively), NNRTIs (0.63 [0.41-0.96] and 0.70 [0.53-0.91]), or INSTIs (0.47 [0.22-0.97] and 0.53 [0.31-0.90]) (Fig. 3).
In this population of primarily older males, ATV-containing regimens were associated with an adjusted 54% reduced risk of MI and 36% reduced risk of stroke compared with non-ATV-containing regimens. This significant reduction in MI and stroke risk in the primary analysis was consistently observed across all comparisons between regimens containing ATV and other PIs, NNRTIs, or INSTIs.
4. this population had a high prevalence of cardiovascular risk factors (i.e., 93% male, 56% black racial origin, 36% receiving antihypertensive therapy, 28% smokers, 25% dyslipidemia treatment, 22% alcohol abuse, 13% diabetes, and 10% history of cardiovascular disease).
5. The doubly-robust and guideline era adjusted analyses showed significant reductions in risk of stroke for ATV versus non-ATV, ATV versus other PI and ATV versus NNRTI comparisons, and significant reductions in risk of MI for the ATV versus non-ATV comparison (doubly-robust analysis) and ATV versus other PI comparison (both doubly-robust and guideline era adjusted analyses).
6. Sensitivity analyses largely supported the results of the primary analysis with some differences. The majority of analyses found a significant difference between ATV vs. other PIs for MI and stroke and vs. NNRTIs for stroke (Supplemental Table S5,
http://links.lww.com/QAD/B137).
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Reyataz Reduced CVD Risk Compared with other ART Regimens
from Jules: the discussion that Reyataz reduced CVD risk because Reyataz increases billirubin has been going on for years. At many conference including several over the past year at CROI and at the Comorbidities & Adverse Events Workshop there were presentations supporting this but this study provides the clearest support and evidence.
"In this population of primarily older males, ATV-containing regimens were associated with an adjusted 54% reduced risk of MI and 36% reduced risk of stroke compared with non-ATV-containing regimens. This significant reduction in MI and stroke risk in the primary analysis was consistently observed across all comparisons between regimens containing ATV and other PIs, NNRTIs, or INSTIs.".....Crude incidence rates for MI, stroke, and all-cause mortality with ATV-containing regimens (5.2, 10.4, and 16.0 per 1000 PYs, respectively) were lower than with regimens containing other PIs (10.2, 21.9, and 23.3 per 1000 PYs), NNRTIs (7.5, 15.9, and 17.5 per 1000 PYs), or INSTIs (13.0, 33.1, and 21.5 per 1000 PYs) (Fig. 3).......In addition to careful selection of antiretroviral agents, multifactorial interventions aimed at reducing cardiovascular risk (e.g., smoking cessation and treatment of hypertension and dyslipidemia) are essential components of cardiovascular risk management in patients with HIV infection. Of concern, there is evidence of therapeutic inertia in this domain, with many HIV-infected patients not receiving optimal management of cardiovascular risk factors during routine clinical care [55-57].
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Cardiovascular outcomes among HIV-infected veterans receiving atazanavir: a US national historical cohort study.
"In this population of primarily older males, ATV-containing regimens were associated with an adjusted 54% reduced risk of MI and 36% reduced risk of stroke compared with non-ATV-containing regimens. This significant reduction in MI and stroke risk in the primary analysis was consistently observed across all comparisons between regimens containing ATV and other PIs, NNRTIs, or INSTIs. No between-regimen differences in all-cause mortality were observed. Of note, the non-ATV comparison arm contained mostly contemporary antiretroviral agents, with 75% of the third agents used being either recommended or alternative agents for treatment-naïve individuals from the 2016 guidelines of the Department of Health and Human Services [3]. In addition, this population had a high prevalence of cardiovascular risk factors (i.e., 93% male, 56% black racial origin, 36% receiving antihypertensive therapy, 28% smokers, 25% dyslipidemia treatment, 22% alcohol abuse, 13% diabetes, and 10% history of cardiovascular disease).
Of the final cohort of 9500 patients, 1529 (16.1%) were receiving an ATV-containing regimen (82.6% boosted and 17.4% unboosted) and 7971 (83.9%) a non-ATV-containing regimen. Of these latter patients, 2053 (21.6%) were receiving PI containing regimens with a PI other than ATV (mostly lopinavir), 5307 (55.9%) an NNTRI-containing regimen (mostly efavirenz), and 611 (6.4%) an INSTI-containing regimen. Of the 9500 patients, the distribution receiving NRTIs was 6784 (71.4%) for tenofovir disoproxil fumarate, 5930 (62.4%) for emtricitabine, 3454 (36.4%) for lamivudine, 2029 (21.4%) for zidovudine, 1299 (13.7%) for abacavir, 394 (4.2%) for stavudine, and 351 (3.7%) for didanosine, with most patients being on 2 of these NRTIs.
Cardiovascular outcomes
Crude incidence rates for MI, stroke, and all-cause mortality with ATV-containing regimens (5.2, 10.4, and 16.0 per 1000 PYs, respectively) were lower than with regimens containing other PIs (10.2, 21.9, and 23.3 per 1000 PYs), NNRTIs (7.5, 15.9, and 17.5 per 1000 PYs), or INSTIs (13.0, 33.1, and 21.5 per 1000 PYs) (Fig. 3).
After IPTW, adjusted hazard ratios (95% CIs) indicated a significantly reduced risk of both MI and stroke with ATV-containing regimens versus regimens containing other PIs (0.47 [0.25-0.88] and 0.51 [0.33-0.78], respectively), NNRTIs (0.63 [0.41-0.96] and 0.70 [0.53-0.91]), or INSTIs (0.47 [0.22-0.97] and 0.53 [0.31-0.90]) (Fig. 3).
Hemorrhagic strokes were very uncommon (14 overall, and none in the ATV group); thus, results for stroke largely reflect risk for ischemic stroke and transient ischemic attack. The risk of all-cause mortality was not significantly reduced with ATV-containing regimens versus other comparator regimens.
To the best of our knowledge, the current study is the first to demonstrate a reduced risk of cardiovascular disease events with ATV-containing regimens versus non-ATV containing regimens. The D:A:D study did not find a significantly increased risk of cardiovascular events with ATV [29,41], and the CFAR Network of Integrated Clinical Systems (CNICS) cohort found a non-significant trend towards a reduced risk of atherosclerotic events with ATV compared to other PIs (hazard ratio 0.78; 95% CI: 0.42-1.45) [52].
The data from the current study provide further support to the hypothesis that hyperbilirubinemia-associated delayed cIMT progression [34-36] and reduction in biomarkers [38,40], and indeed hyperbilirubinemia itself [32,53], may be
cardioprotective in HIV-infected patients. Three studies that compared atherosclerotic progression as measured by changes in cIMT between ATV/r and various other antiretroviral agents found a slower progression with ATV/r [34-36]. Recent analyses from one of these studies, AIDS Clinical Trials Group (ACTG) A5260s, suggested that the slower progression of cIMT with ATV/r versus ritonavir-boosted darunavir (DRV/r) and raltegravir is mediated by the effect of bilirubin on reduction in lipid and glucose biomarkers, including oxidized lipoproteins, and potentially via its effect on markers of inflammation [40]. Significantly greater reductions in hs-CRP versus DRV/r and in D-dimer versus raltegravir were observed in a separate A5260s analysis [39]. Similar findings were observed in ACTG 5202, in which ATV-induced hyperbilirubinemia was inversely correlated with soluble receptor of tumor necrosis factor-α receptor type II and soluble vascular cellular adhesion molecule-1 [54], and in a prospective observational study demonstrating reduction in oxidized lipoproteins with ATV/r versus efavirenz, which was correlated with ATV-induced changes in serum bilirubin [38].
Finally, this analysis could not differentiate between type 1 (atherosclerotic) and type 2 (supply/demand mismatch) MI. Because ATV is hypothesized to specifically impact only type 1 MI, inclusion of both type 1 and type 2 MI within the MI outcome of interest may potentially mask larger treatment differences in type 1 MI. Further longitudinal research using adjudicated type 1 MI events [59] is warranted to address this question. To conclude, in the US national VHA database, regimens containing ATV were associated with a significantly lower risk for both MI and stroke compared with those containing other PIs, NNRTIs, or INSTIs in our primary analysis. Sensitivity analyses were largely consistent with the primary analysis, although some of them suggested that reduction in risk for MI may only be evident for the ATV versus other PI comparison and that the risk of stroke may only be reduced for ATV versus NNRTIs and other PIs and not INSTIs . Further research is warranted to elucidate the mechanism for the slower progression of atherosclerosis and potential reduced risk of cardiovascular disease events with ATV."
Fig. 3. Unadjusted incidence rates and IPTW adjusted hazard ratios of cardiovascular disease events. ATV, atazanavir; CI, confidence interval; INSTI, integrase strand transfer inhibitor; IPTW, inverse probability of treatment weighting; MI, myocardial infarction; NNRTI, non-nucleoside reverse transcriptase inhibitor; PI, protease inhibitor; PY, person-years.
Objective: Patients with HIV infection have an increased risk of cardiovascular disease compared with uninfected individuals. Antiretroviral therapy with atazanavir delays progression of atherosclerosis markers; whether this reduces cardiovascular disease event risk compared with other antiretroviral regimens is currently unknown.
Design: Population-based, non-interventional, historical cohort study conducted from July 1, 2003, through December 31, 2015.
Setting: Veterans Health Administration (VHA) hospitals and clinics throughout the United States.
Participants: Treatment-naive patients with HIV infection (N = 9500).
Antiretroviral exposures: Initiating antiretroviral regimens containing atazanavir, other protease inhibitors (PIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), or integrase strand transfer inhibitors (INSTIs).
Main outcome/effect size measures: Incidence rates of myocardial infarction (MI), stroke, and all-cause mortality within each regimen. Atazanavir versus other PI, NNRTI, or INSTI covariate-adjusted hazard ratios using Cox proportional hazards models and inverse probability of treatment weighting (IPTW).
Results: Incidence rates for MI, stroke, and all-cause mortality with atazanavir-containing regimens (5.2, 10.4, and 16.0 per 1000 patient-years, respectively) were lower than with regimens containing other PIs (10.2, 21.9, and 23.3 per 1000 patient-years), NNRTIs (7.5, 15.9, and 17.5 per 1000 patient-years), or INSTIs (13.0, 33.1, and 21.5 per 1000 patient-years). After IPTW, adjusted hazard ratios (95% confidence intervals) for MI, stroke, and all-cause mortality with atazanavir-containing regimens versus all non-atazanavir-containing regimens were 0.59 (0.41-0.84), 0.64 (0.50-0.81), and 0.90 (0.73-1.11), respectively.
Conclusions: Among treatment-naive HIV-infected patients in the VHA initiating atazanavir-containing regimens, risk of both MI and stroke were significantly lower than in those initiating regimens containing other PIs, NNRTIs, or INSTIs.
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