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When to initiate combined antiretroviral therapy to reduce mortality and AIDS-defining illness in HIV-infected persons in developed countries: an observational study.

ABSTRACT: Most clinical guidelines recommend that AIDS-free, HIV-infected persons with CD4 cell counts below 0.350 × 10(9) cells/L initiate combined antiretroviral therapy (cART), but the optimal CD4 cell count at which cART should be initiated remains a matter of debate.To identify the optimal CD4 cell count at which cART should be initiated.Prospective observational data from the HIV-CAUSAL Collaboration and dynamic marginal structural models were used to compare cART initiation strategies for CD4 thresholds between 0.200 and 0.500 × 10(9) cells/L.HIV clinics in Europe and the Veterans Health Administration system in the United States.20, 971 HIV-infected, therapy-naive persons with baseline CD4 cell counts at or above 0.500 × 10(9) cells/L and no previous AIDS-defining illnesses, of whom 8392 had a CD4 cell count that decreased into the range of 0.200 to 0.499 × 10(9) cells/L and were included in the analysis.Hazard ratios and survival proportions for all-cause mortality and a combined end point of AIDS-defining illness or death.Compared with initiating cART at the CD4 cell count threshold of 0.500 × 10(9) cells/L, the mortality hazard ratio was 1.01 (95% CI, 0.84 to 1.22) for the 0.350 threshold and 1.20 (CI, 0.97 to 1.48) for the 0.200 threshold. The corresponding hazard ratios were 1.38 (CI, 1.23 to 1.56) and 1.90 (CI, 1.67 to 2.15), respectively, for the combined end point of AIDS-defining illness or death.CD4 cell count at cART initiation was not randomized. Residual confounding may exist.Initiation of cART at a threshold CD4 count of 0.500 × 10(9) cells/L increases AIDS-free survival. However, mortality did not vary substantially with the use of CD4 thresholds between 0.300 and 0.500 × 10(9) cells/L.

SUBMITTER: HIV-CAUSAL Collaboration

PROVIDER: S-EPMC3610527 | biostudies-other | 2011 Apr

REPOSITORIES: biostudies-other

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When to initiate combined antiretroviral therapy to reduce mortality and AIDS-defining illness in HIV-infected persons in developed countries: an observational study.

Cain Lauren E LE Logan Roger R Robins James M JM Sterne Jonathan A C JA Sabin Caroline C Bansi Loveleen L Justice Amy A Goulet Joseph J van Sighem Ard A de Wolf Frank F Bucher Heiner C HC von Wyl Viktor V Esteve Anna A Casabona Jordi J del Amo Julia J Moreno Santiago S Seng Remonie R Meyer Laurence L Perez-Hoyos Santiago S Muga Roberto R Lodi Sara S Lanoy Emilie E Costagliola Dominique D Hernan Miguel A MA

Annals of internal medicine 20110401 8

<h4>Background</h4>Most clinical guidelines recommend that AIDS-free, HIV-infected persons with CD4 cell counts below 0.350 × 10(9) cells/L initiate combined antiretroviral therapy (cART), but the optimal CD4 cell count at which cART should be initiated remains a matter of debate.<h4>Objective</h4>To identify the optimal CD4 cell count at which cART should be initiated.<h4>Design</h4>Prospective observational data from the HIV-CAUSAL Collaboration and dynamic marginal structural models were used ...[more]

PMID: 21502648

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Project description:HIV-1 infection leads to chronic inflammation and to an increased risk of non-AIDS mortality. Our objective was to determine whether AIDS-defining events (ADEs) were associated with increased overall and cause-specific non-AIDS related mortality after antiretroviral therapy (ART) initiation. We included HIV treatment-naïve adults from the Antiretroviral Therapy Cohort Collaboration (ART-CC) who initiated ART from 1996 to 2014. Causes of death were assigned using the Coding Causes of Death in HIV (CoDe) protocol. The adjusted hazard ratio (aHR) for overall and cause-specific non-AIDS mortality among those with an ADE (all ADEs, tuberculosis (TB), Pneumocystis jiroveci pneumonia (PJP), and non-Hodgkin's lymphoma (NHL)) compared to those without an ADE was estimated using a marginal structural model. The adjusted hazard of overall non-AIDS mortality was higher among those with any ADE compared to those without any ADE (aHR 2.21, 95% confidence interval (CI) 2.00 to 2.43). The adjusted hazard of each of the cause-specific non-AIDS related deaths were higher among those with any ADE compared to those without, except metabolic deaths (malignancy aHR 2.59 (95% CI 2.13 to 3.14), accident/suicide/overdose aHR 1.37 (95% CI 1.05 to 1.79), cardiovascular aHR 1.95 (95% CI 1.54 to 2.48), infection aHR (95% CI 1.68 to 2.81), hepatic aHR 2.09 (95% CI 1.61 to 2.72), respiratory aHR 4.28 (95% CI 2.67 to 6.88), renal aHR 5.81 (95% CI 2.69 to 12.56) and central nervous aHR 1.53 (95% CI 1.18 to 5.44)). The risk of overall and cause-specific non-AIDS mortality differed depending on the specific ADE of interest (TB, PJP, NHL). In this large multi-centre cohort collaboration with standardized assignment of causes of death, non-AIDS mortality was twice as high among patients with an ADE compared to without an ADE. However, non-AIDS related mortality after an ADE depended on the ADE of interest. Although there may be unmeasured confounders, these findings suggest that a common pathway may be independently driving both ADEs and NADE mortality. While prevention of ADEs may reduce subsequent death due to NADEs following ART initiation, modification of risk factors for NADE mortality remains important after ADE survival.

Project description:BACKGROUND:The differential effects of commonly prescribed combined antiretroviral therapy (cART) regimens on AIDS-defining neurological conditions (neuroAIDS) remain unknown. SETTING:Prospective cohort studies of HIV-positive individuals from Europe and the Americas included in the HIV-CAUSAL Collaboration. METHODS:Individuals who initiated a first-line cART regimen in 2004 or later containing a nucleoside reverse transcriptase inhibitor backbone and either atazanavir, lopinavir, darunavir, or efavirenz were followed from cART initiation until death, lost to follow-up, pregnancy, the cohort-specific administrative end of follow-up, or the event of interest, whichever occurred earliest. We evaluated 4 neuroAIDS conditions: HIV dementia and the opportunistic infections toxoplasmosis, cryptococcal meningitis, and progressive multifocal leukoencephalopathy. For each outcome, we estimated hazard ratios for atazanavir, lopinavir, and darunavir compared with efavirenz via a pooled logistic model. Our models were adjusted for baseline demographic and clinical characteristics. RESULTS:Twenty six thousand one hundred seventy-two individuals initiated efavirenz, 5858 initiated atazanavir, 8479 initiated lopinavir, and 4799 initiated darunavir. Compared with efavirenz, the adjusted HIV dementia hazard ratios (95% confidence intervals) were 1.72 (1.00 to 2.96) for atazanavir, 2.21 (1.38 to 3.54) for lopinavir, and 1.41 (0.61 to 3.24) for darunavir. The respective hazard ratios (95% confidence intervals) for the combined end point were 1.18 (0.74 to 1.88) for atazanavir, 1.61 (1.14 to 2.27) for lopinavir, and 1.36 (0.74 to 2.48) for darunavir. The results varied in subsets defined by calendar year, nucleoside reverse transcriptase inhibitor backbone, and age. CONCLUSION:Our results are consistent with an increased risk of neuroAIDS after initiating lopinavir compared with efavirenz, but temporal changes in prescribing trends and confounding by indication could explain our findings.

Project description:BackgroundHigh-throughput approaches are increasingly being used to identify genetic associations across multiple phenotypes simultaneously. Here, we describe a pilot analysis that considered multiple on-treatment laboratory phenotypes from antiretroviral therapy-naive patients who were randomized to initiate antiretroviral regimens in a prospective clinical trial, AIDS Clinical Trials Group protocol A5202.Participants and methodsFrom among 5 9545 294 polymorphisms imputed genome-wide, we analyzed 2544, including 2124 annotated in the PharmGKB, and 420 previously associated with traits in the GWAS Catalog. We derived 774 phenotypes on the basis of context from six variables: plasma atazanavir (ATV) pharmacokinetics, plasma efavirenz (EFV) pharmacokinetics, change in the CD4+ T-cell count, HIV-1 RNA suppression, fasting low-density lipoprotein-cholesterol, and fasting triglycerides. Permutation testing assessed the likelihood of associations being by chance alone. Pleiotropy was assessed for polymorphisms with the lowest P-values.ResultsThis analysis included 1181 patients. At P less than 1.5×10, most associations were not by chance alone. Polymorphisms with the lowest P-values for EFV pharmacokinetics (CYPB26 rs3745274), low-density lipoprotein -cholesterol (APOE rs7412), and triglyceride (APOA5 rs651821) phenotypes had been associated previously with those traits in previous studies. The association between triglycerides and rs651821 was present with ATV-containing regimens, but not with EFV-containing regimens. Polymorphisms with the lowest P-values for ATV pharmacokinetics, CD4 T-cell count, and HIV-1 RNA phenotypes had not been reported previously to be associated with that trait.ConclusionUsing data from a prospective HIV clinical trial, we identified expected genetic associations, potentially novel associations, and at least one context-dependent association. This study supports high-throughput strategies that simultaneously explore multiple phenotypes from clinical trials' datasets for genetic associations.

Project description:Developing countries can generate effective solutions for today's global health challenges. This paper reviews relevant literature to construct the case for international cooperation, and in particular, developed-developing country partnerships. Standard database and web-based searches were conducted for publications in English between 1990 and 2010. Studies containing full or partial data relating to international cooperation between developed and developing countries were retained for further analysis. Of 227 articles retained through initial screening, 65 were included in the final analysis. The results were two-fold: some articles pointed to intangible benefits accrued by developed country partners, but the majority of information pointed to developing country innovations that can potentially inform health systems in developed countries. This information spanned all six WHO health system components. Ten key health areas where developed countries have the most to learn from the developing world were identified and include, rural health service delivery; skills substitution; decentralisation of management; creative problem-solving; education in communicable disease control; innovation in mobile phone use; low technology simulation training; local product manufacture; health financing; and social entrepreneurship. While there are no guarantees that innovations from developing country experiences can effectively transfer to developed countries, combined developed-developing country learning processes can potentially generate effective solutions for global health systems. However, the global pool of knowledge in this area is virgin and further work needs to be undertaken to advance understanding of health innovation diffusion. Even more urgently, a standardized method for reporting partnership benefits is needed--this is perhaps the single most immediate need in planning for, and realizing, the full potential of international cooperation between developed and developing countries.

Dataset Information

When to initiate combined antiretroviral therapy to reduce mortality and AIDS-defining illness in HIV-infected persons in developed countries: an observational study.

Publications

When to initiate combined antiretroviral therapy to reduce mortality and AIDS-defining illness in HIV-infected persons in developed countries: an observational study.

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