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Balancing immunological benefits and cardiovascular risks of antiretroviral therapy: when is immediate treatment optimal?

ABSTRACT: We developed a mathematical model to identify the timing of antiretroviral therapy (ART) initiation that optimizes patient outcomes as a function of patient CD4 count, age, cardiac mortality risk, sex, and personal preferences. Our goal was to find the conditions that maximize patient quality-adjusted life expectancy (QALE) in the context of our model. Under the assumption that ART confers disease progression and mortality benefits at any CD4 count, immediate treatment initiation yields the greatest remaining QALE for young patients under most circumstances. The timing of ART initiation depends on the magnitude of benefit from ART at high CD4 counts, the magnitude of increases in cardiac risk, and patients' preferences. If ART reduces HIV progression at high CD4 counts, immediate ART is preferable for most newly infected individuals <35 years even if ART doubles age- and sex-specific cardiac risk.

SUBMITTER: Negoescu DM

PROVIDER: S-EPMC3478144 | biostudies-literature | 2012 Nov

REPOSITORIES: biostudies-literature

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Balancing immunological benefits and cardiovascular risks of antiretroviral therapy: when is immediate treatment optimal?

Negoescu Diana M DM Owens Douglas K DK Brandeau Margaret L ML Bendavid Eran E

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 20120831 10

We developed a mathematical model to identify the timing of antiretroviral therapy (ART) initiation that optimizes patient outcomes as a function of patient CD4 count, age, cardiac mortality risk, sex, and personal preferences. Our goal was to find the conditions that maximize patient quality-adjusted life expectancy (QALE) in the context of our model. Under the assumption that ART confers disease progression and mortality benefits at any CD4 count, immediate treatment initiation yields the grea ...[more]

PMID: 22942203

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Project description:BACKGROUND:Randomized-trial data on the risks and benefits of antiretroviral therapy (ART) as compared with zidovudine and single-dose nevirapine to prevent transmission of the human immunodeficiency virus (HIV) in HIV-infected pregnant women with high CD4 counts are lacking. METHODS:We randomly assigned HIV-infected women at 14 or more weeks of gestation with CD4 counts of at least 350 cells per cubic millimeter to zidovudine and single-dose nevirapine plus a 1-to-2-week postpartum "tail" of tenofovir and emtricitabine (zidovudine alone); zidovudine, lamivudine, and lopinavir-ritonavir (zidovudine-based ART); or tenofovir, emtricitabine, and lopinavir-ritonavir (tenofovir-based ART). The primary outcomes were HIV transmission at 1 week of age in the infant and maternal and infant safety. RESULTS:The median CD4 count was 530 cells per cubic millimeter among 3490 primarily black African HIV-infected women enrolled at a median of 26 weeks of gestation (interquartile range, 21 to 30). The rate of transmission was significantly lower with ART than with zidovudine alone (0.5% in the combined ART groups vs. 1.8%; difference, -1.3 percentage points; repeated confidence interval, -2.1 to -0.4). However, the rate of maternal grade 2 to 4 adverse events was significantly higher with zidovudine-based ART than with zidovudine alone (21.1% vs. 17.3%, P=0.008), and the rate of grade 2 to 4 abnormal blood chemical values was higher with tenofovir-based ART than with zidovudine alone (2.9% vs. 0.8%, P=0.03). Adverse events did not differ significantly between the ART groups (P>0.99). A birth weight of less than 2500 g was more frequent with zidovudine-based ART than with zidovudine alone (23.0% vs. 12.0%, P<0.001) and was more frequent with tenofovir-based ART than with zidovudine alone (16.9% vs. 8.9%, P=0.004); preterm delivery before 37 weeks was more frequent with zidovudine-based ART than with zidovudine alone (20.5% vs. 13.1%, P<0.001). Tenofovir-based ART was associated with higher rates than zidovudine-based ART of very preterm delivery before 34 weeks (6.0% vs. 2.6%, P=0.04) and early infant death (4.4% vs. 0.6%, P=0.001), but there were no significant differences between tenofovir-based ART and zidovudine alone (P=0.10 and P=0.43). The rate of HIV-free survival was highest among infants whose mothers received zidovudine-based ART. CONCLUSIONS:Antenatal ART resulted in significantly lower rates of early HIV transmission than zidovudine alone but a higher risk of adverse maternal and neonatal outcomes. (Funded by the National Institutes of Health; PROMISE ClinicalTrials.gov numbers, NCT01061151 and NCT01253538 .).

Project description:HIV infection and certain antiretroviral therapy (ART) medications increase atherosclerotic cardiovascular disease risk, mediated, in part, through traditional cardiovascular disease risk factors. We studied cardiovascular disease risk factor changes in the START (Strategic Timing of Antiretroviral Treatment) trial, a randomized study of immediate versus deferred ART initiation among HIV-positive persons with CD4+ cell counts >500 cells/mm3. Mean change from baseline in risk factors and the incidence of comorbid conditions were compared between groups. The characteristics among 4685 HIV-positive START trial participants include a median age of 36 years, a CD4 cell count of 651 cells/mm3, an HIV viral load of 12 759 copies/mL, a current smoking status of 32%, a median systolic/diastolic blood pressure of 120/76 mm Hg, and median levels of total cholesterol of 168 mg/dL, low-density lipoprotein cholesterol of 102 mg/dL, and high-density lipoprotein cholesterol of 41 mg/dL. Mean follow-up was 3.0 years. The immediate and deferred ART groups spent 94% and 28% of follow-up time taking ART, respectively. Compared with patients in the deferral group, patients in the immediate ART group had increased total cholesterol and low-density lipoprotein cholesterol and higher use of lipid-lowering therapy (1.2%; 95% CI, 0.1-2.2). Concurrent increases in high-density lipoprotein cholesterol with immediate ART resulted in a 0.1 lower total cholesterol to high-density lipoprotein cholesterol ratio (95% CI, 0.1-0.2). Immediate ART resulted in 2.3% less BP-lowering therapy use (95% CI, 0.9-3.6), but there were no differences in new-onset hypertension or diabetes mellitus. Among HIV-positive persons with preserved immunity, immediate ART led to increases in total cholesterol and low-density lipoprotein cholesterol but also concurrent increases in high-density lipoprotein cholesterol and decreased use of blood pressure medications. These opposing effects suggest that, in the short term, the net effect of early ART on traditional cardiovascular disease risk factors may be clinically insignificant." URL: http://www.clinicaltrials.gov. Unique identifier: NCT00867048.

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Balancing immunological benefits and cardiovascular risks of antiretroviral therapy: when is immediate treatment optimal?

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Balancing immunological benefits and cardiovascular risks of antiretroviral therapy: when is immediate treatment optimal?

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