Dataset Information

Clinical prognostic value of RNA viral load and CD4 cell counts during untreated HIV-1 infection--a quantitative review.

ABSTRACT:

Background

The prognostic value of CD4 counts and RNA viral load for identifying treatment need in HIV-infected individuals depends on (a) variation within and among individuals, and (b) relative risks of clinical progression per unit CD4 or RNA difference.

Methodology/principal findings

We reviewed these measurements across (a) 30 studies, and (b) 16 cohorts of untreated seropositive adults. Median within-population interquartile ranges were 74,000 copies/mL for RNA with no significant change during the course of infection; and 330 cells/microL for CD4, with a slight proportional increase over infection. Applying measurement and physiological fluctuations observed on chronically infected patients, we estimate that 45% of population-level variation in RNA, and 25% of variation in CD4, were due to within-patient fluctuations. Comparing a patient with RNA at upper 75(th) centile with a patient at median RNA, 5-year relative risks were 1.4 (95% CI 1.2-1.7) for AIDS and 1.5 (1.3-1.9) for death, without change over the course of infection. In contrast, for a patient with CD4 count at the lower 75(th) centile, relative risks increased from 1.0 at seroconversion to maxima of 6.3 (4.4-8.9) for AIDS and 5.5 (2.7-10.1) for death by year 6, when the population median had fallen to 300 cells/microL. Below 300 cells/microL, prognostic power did not increase, due to a narrower CD4 range.

Conclusions

Findings support the current WHO recommendation (used with clinical criteria) to start antiretroviral treatment in low-income settings at CD4 thresholds of 200-350 cells/microL, without pre-treatment RNA monitoring--while not precluding earlier treatment based on clinical, socio-demographic or public health criteria.

SUBMITTER: Korenromp EL

PROVIDER: S-EPMC2694276 | biostudies-literature | 2009 Jun

REPOSITORIES: biostudies-literature

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Publications

Clinical prognostic value of RNA viral load and CD4 cell counts during untreated HIV-1 infection--a quantitative review.

Korenromp Eline L EL Williams Brian G BG Schmid George P GP Dye Christopher C

PloS one 20090617 6

<h4>Background</h4>The prognostic value of CD4 counts and RNA viral load for identifying treatment need in HIV-infected individuals depends on (a) variation within and among individuals, and (b) relative risks of clinical progression per unit CD4 or RNA difference.<h4>Methodology/principal findings</h4>We reviewed these measurements across (a) 30 studies, and (b) 16 cohorts of untreated seropositive adults. Median within-population interquartile ranges were 74,000 copies/mL for RNA with no signi ...[more]

PMID: 19536329

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Project description:BACKGROUND: HCV RNA viral load is an important predictor of sustained virological response and, recently, a significant correlation with liver fibrosis was described. We investigated on possible influence of clinical and viro-immunological variables on HCV viral load in HIV-HCV co-infected patients over a study time of three years (2009-2012). METHODS: We retrospectively enrolled 98 adult patients with a diagnosis of chronic HIV infection in 2009, a diagnosis of chronic HCV infection with a detectable plasma HCV RNA in 2009 and 2012, HCV therapy-naïve or with failed and stopped antiviral treatment before June 2008. The following variables were recorded: age, gender, HCV genotype, IL28B rs12979860 CC genotype, HCV treatment status, advanced liver fibrosis diagnosis, antiretroviral therapy, CD4+ cell count, HCV viral load, HIV RNA (plasma HIV-1 RNA levels were measured from blood samples every three months at least). The correlation was established using linear regression analysis, analysis of variance and Fisher's exact test. Comparisons between groups were performed using Fisher's exact test, the independent samples t-test and the t-test for paired data, as appropriate, for continuous variables. A mixed mode (ME) maximum likelihood linear regression model was constructed to evaluate the dependence of HCV viral load. RESULTS: HCV RNA levels did not change significantly from 2009 to 2012 (from 3924650?±?5320177 IU/ml to 3085128?±?3372347 IU/ml, p?=?0.13); the CD4+ count increased significantly (from a mean of 576 to a mean of 654, p?=?0.003). Using linear regression, a positive correlation was observed for HCV load and genotype 1 (p?=?0.002), nonresponder status (p?=?0.04) and with interleukin 28B CC allele (p?=?0.05). Other studied covariates failed to reach a significant correlation. CONCLUSIONS: The HCV RNA load, a known pretreatment predictor of response to antiviral therapy, was independent of the two main parameters of HIV disease, plasma HIV RNA and CD4 cell count, over an observation time of 3 years in patients with recovered or spontaneously maintained immunocompetence.

Project description:Disease progression in the absence of therapy varies significantly in HIV-1 infected individuals. Both viral and host cellular molecules are implicated; however, the exact role of these factors and/or the mechanism involved remains elusive. To understand how microRNAs (miRNAs), which are regulators of transcription and translation, influence host cellular gene expression (mRNA) during HIV-1 infection, we performed a comparative miRNA and mRNA microarray analysis using PBMCs obtained from infected individuals with distinct viral load and CD4 counts.RNA isolated from PBMCs obtained from HIV-1 seronegative and HIV-1 positive individuals with distinct viral load and CD4 counts were assessed for miRNA and mRNA profile. Selected miRNA and mRNA transcripts were validated using in vivo and in vitro infection model.Our results indicate that HIV-1 positive individuals with high viral load (HVL) showed a dysregulation of 191 miRNAs and 309 mRNA transcripts compared to the uninfected age and sex matched controls. The miRNAs miR-19b, 146a, 615-3p, 382, 34a, 144 and 155, that are known to target innate and inflammatory factors, were significantly upregulated in PBMCs with high viral load, as were the inflammatory molecules CXCL5, CCL2, IL6 and IL8, whereas defensin, CD4, ALDH1, and Neurogranin (NRGN) were significantly downregulated. Using the transcriptome profile and predicted target genes, we constructed the regulatory networks of miRNA-mRNA pairs that were differentially expressed between control, LVL and HVL subjects. The regulatory network revealed an inverse correlation of several miRNA-mRNA pair expression patterns, suggesting HIV-1 mediated transcriptional regulation is in part likely through miRNA regulation.Results from our studies indicate that gene expression is significantly altered in PBMCs in response to virus replication. It is interesting to note that the infected individuals with low or undetectable viral load exhibit a gene expression profile very similar to control or uninfected subjects. Importantly, we identified several new mRNA targets (Defensin, Neurogranin, AIF) as well as the miRNAs that could be involved in regulating their expression through the miRNA-mRNA interaction.

Project description:BackgroundThe U.S. National HIV/AIDS Strategy targets for 2015 include "increasing access to care and improving health outcomes for persons living with HIV in the United States" (PLWH-US).ObjectiveTo demonstrate the utility of the NA-ACCORD (North American AIDS Cohort Collaboration on Research and Design) for monitoring trends in the HIV epidemic in the United States and to present trends in HIV treatment and related health outcomes.DesignTrends from annual cross-sectional analyses comparing patients from pooled, multicenter, prospective, clinical HIV cohort studies with PLWH-US, as reported to national surveillance systems in 40 states.SettingU.S. HIV outpatient clinics.PatientsHIV-infected adults with 1 or more HIV RNA plasma viral load (HIV VL) or CD4 T-lymphocyte (CD4) cell count measured in any calendar year from 1 January 2000 to 31 December 2008.MeasurementsAnnual rates of antiretroviral therapy use, HIV VL, and CD4 cell count at death.Results45 529 HIV-infected persons received care in an NA-ACCORD-participating U.S. clinical cohort from 2000 to 2008. In 2008, the 26 030 NA-ACCORD participants in care and the 655 966 PLWH-US had qualitatively similar demographic characteristics. From 2000 to 2008, the proportion of participants prescribed highly active antiretroviral therapy increased by 9 percentage points to 83% (P < 0.001), whereas the proportion with suppressed HIV VL (≤2.7 log10 copies/mL) increased by 26 percentage points to 72% (P < 0.001). Median CD4 cell count at death more than tripled to 0.209 × 109 cells/L (P < 0.001).LimitationThe usual limitations of observational data apply.ConclusionThe NA-ACCORD is the largest cohort of HIV-infected adults in clinical care in the United States that is demographically similar to PLWH-US in 2008. From 2000 to 2008, increases were observed in the percentage of prescribed HAART, the percentage who achieved a suppressed HIV VL, and the median CD4 cell count at death.Primary funding sourceNational Institutes of Health; Centers for Disease Control and Prevention; Canadian Institutes of Health Research; Canadian HIV Trials Network; and the government of British Columbia, Canada.

Dataset Information

Clinical prognostic value of RNA viral load and CD4 cell counts during untreated HIV-1 infection--a quantitative review.

Background

Methodology/principal findings

Conclusions

Publications

Clinical prognostic value of RNA viral load and CD4 cell counts during untreated HIV-1 infection--a quantitative review.

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