A modification to the 3D modified driven equilibrium Fourier transform
(MDEFT) imaging technique is proposed that reduces its sensitivity to RF
inhomogeneity. This is especially important at high field strengths where RF
focusing effects exacerbate B1 inhomogeneity,
causing significant signal nonuniformity in the images. The adiabatic inversion
pulse used during the preparation period of the MDEFT sequence is replaced by a
hard (nonadiabatic) pulse with a nominal flip angle of 130°. The spatial
inhomogeneity of the hard pulse preparation compensates for the inhomogeneity of
the excitation pulses. Uniform signal intensity is obtained for a wide range of
B1 amplitudes and the high CNR characteristic of
MDEFT is retained. The new approach was validated by numerical simulations and
successfully applied to human brain imaging at 4.7 T, resulting in highquality
T1-weighted images of the whole human brain at
high field strength with uniform signal intensity and contrast, despite the
presence of significant RF inhomogeneity.
high field MRI; T1-weighted imaging; RF inhomogeneity; human brain imaging; structural brain imaging
Background. Proinflammatory cytokines play a critical role in antiviral immune responses. Large-scale genome studies have found correlations between single-nucleotide polymorphisms (SNPs) in the interleukin (IL) 18 promoter and spontaneous control of hepatitis C virus (HCV), suggesting a role in clearance.
Methods. Plasma IL-18, IL-1β, IL-6, IL-8, IL-12, interferon-γ, tumor necrosis factor–α, alanine aminotransferase (ALT), and HCV RNA levels were assessed longitudinally in subjects with known dates of HCV acquisition and analyzed according to IL-18 SNPs and outcome, either spontaneous clearance (SC) (n = 13) or persistent infection (PI) (n = 25).
Results. No significant change in plasma proinflammatory cytokine expression was observed with the exception of IL-18, which increased in every subject with initial detection of HCV RNA. In every SC subject, IL-18 returned to the preinfection baseline concomitant with HCV control. In PI subjects, IL-18 declined following the acute phase of infection but remained above the preinfection baseline throughout chronic infection and did not correlate with HCV RNA or ALT levels.
Conclusions. Plasma IL-18 was an early and the most reliably detected host response to HCV infection measured in blood. Reduced IL-18 production with transition to chronic infection without correlation with HCV RNA or ALT levels suggests modulation of the innate response with persistent infection.
Single-nucleotide polymorphisms (SNPs) around IL28B are associated with spontaneous hepatitis C virus (HCV) clearance of genotypes 1 and 3 in white and African-American populations. This study investigated whether the IL28B SNP (rs12979860) is associated with spontaneous clearance of HCV, principally genotype 4, in 162 Egyptians (80 with clearance). The protective C allele was more common in those with spontaneous clearance (76.3% vs 57.9%; P = .0006). Individuals with clearance were 3.4 (95% confidence interval, 1.8–6.5) times more likely to have C/C genotype. Thus, IL28B plays a role in spontaneous clearance of HCV genotype 4 in North Africa.
To evaluate the prevalence and risk factors for low bone mineral density (BMD) in persons co-infected with HIV and Hepatitis C.
HIV/HCV co-infected study participants (n=179) were recruited into a prospective cohort and underwent dual-energy X-ray absorptiometry (DXA) within 1 year of a liver biopsy. Fibrosis staging was evaluated according to the METAVIR system. Osteoporosis was defined as a T-score ≤ −2.5. Z-scores at the total hip, femoral neck, and lumbar spine were used as the primary outcome variables to assess the association between degree of liver disease, HIV-related variables, and BMD.
The population was 65% male, 85% Black with mean age 50.3 years. The prevalence of osteoporosis at either at the total hip, femoral neck, or lumbar spine was 28%, with 5% having osteoporosis of the total hip, 6% at the femoral neck, 25% at the spine. The mean Z-scores (standard deviation) were −0.42 (1.01) at the total hip, −0.16 (1.05) at the femoral neck, and −0.82 (1.55) at the lumbar spine. In multivariable models, controlled HIV replication (HIV RNA < 400 copies/mL vs ≥400 copies/mL) was associated with lower Z-scores (mean ± standard error) at the total hip (−0.44±0.17, p=0.01), femoral neck (−0.59±0.18, p=0.001), and the spine (−0.98±0.27, p=0.0005). There was no association between degree of liver fibrosis and Z-score.
Osteoporosis was very common in this population of predominately African-American HIV/HCV co-infected patients, particularly at the spine. Lower BMD was associated with controlled HIV replication, but not liver disease severity.
hepatitis C; bone mineral density; hepatic fibrosis; HIV
CXCL9 (monokine induced by IFN γ [Mig]) and CXCL10 (interferon [IFN] γ−inducible protein 10 [IP-10]) have been associated with hepatic fibrosis in predominantly white hepatitis C virus (HCV)–infected patients. We investigated their potential as noninvasive markers of hepatic fibrosis and fibrosis progression in African-American patients. Peripheral chemokine levels were measured in 115 HCV-infected patients within 4 months of liver biopsy; patients underwent a second biopsy after 3–5 years. CXCL10 levels appeared to be higher in patients with advanced fibrosis on the contemporaneous biopsy and were significantly higher in patients with advanced fibrosis compared with those with minimal fibrosis on the later biopsy (P = .0045). Therefore, CXCL10 has potential as a marker of fibrosis progression in African-American HCV-infected patients.
Background & Aims
Hepatitis C virus (HCV) screening can provide opportunities to reduce disease progression through counseling against alcohol use, but empirical data on this issue are sparse. We determined the efficacy of a behavioral intervention in reducing alcohol use among young, HCV-infected injection drug users (IDUs) (n=355) and assessed whether changes in liver enzymes were associated with changes in alcohol consumption.
Both the intervention and attention-control groups were counseled to avoid alcohol use, but the intervention group received enhanced counseling. Logistic regression, ANOVA, and continuous time Markov models were used to identify factors associated with alcohol use, changes in mean ALT and AST levels and change in alcohol use post-intervention.
Six months post-intervention, alcohol abstinence increased 22.7% in both groups, with no difference by intervention arm. Transition from alcohol use to abstinence was associated with a decrease in liver enzymes, with a marginally greater decrease in the intervention group (p=0.05 for ALT; p=0.06 for AST). In multivariate Markov models, those who used marijuana transitioned from alcohol abstinence to consumption more rapidly than non-users (RR=3.11); those who were homeless transitioned more slowly to alcohol abstinence (RR=0.47); and those who had ever received a clinical diagnosis of liver disease transitioned more rapidly to abstinence (RR=1.88).
Although, behavioral counseling to reduce alcohol consumption among HCV-infected IDUs had a modest effect, reductions in alcohol consumption were associated with marked improvements in liver function. Interventions to reduce alcohol use among HCV-infected IDUs may benefit from being integrated into clinical care and monitoring of HCV infection.
(See the editorial commentary by Grebely and Dore, on pages 571–4.)
Background. Population-level hepatitis C virus (HCV) infection incidence is a surrogate for community drug-related risk.
Methods. We characterized trends in human immunodeficiency virus (HIV) and HCV infection incidence and HCV infection prevalence among injection drug users (IDUs) recruited over 4 periods: 1988–1989, 1994–1995, 1998, and 2005–2008. We calculated HIV and HCV infection incidence within the first year of follow-up among IDUs whose test results were negative for these viruses at baseline (n = 2061 and n = 373, respectively). We used Poisson regression to compare trends across groups.
Results. HIV infection incidence declined significantly from 5.5 cases/100 person-years (py) in the 1988–1989 group to 2.0 cases/100 py in the 1994–1995 group to 0 cases/100 py in the 1998 and 2005–2008 groups. Concurrently, HCV infection incidence declined but remained robust (22.0 cases/100 py in the 1988–1989 cohort to 17.2 cases/100 py in the 1994–1995 cohort, 17.9 cases/100 py in the 1998 cohort, and 7.8 cases/100 py in the 2005–2008 cohort; P = .07). Likewise, HCV infection prevalence declined, but chiefly in younger IDUs. For persons aged <39 years, relative to the 1988–1989 cohort, all groups exhibited significant declines (adjusted prevalence ratio [PR] for the 2005–08 cohort, .73; 95% confidence interval [CI], .65–.81). However, for persons aged ≥39 years, only the 2005–2008 cohort exhibited declining prevalence compared with the 1988–1989 cohort (adjusted PR, .87; 95% CI, .77–.99).
Conclusions. Although efforts to reduce blood-borne infection incidence have had impact, this work will need to be intensified for the most transmissible viruses, such as HCV.
Background and Aims
Hepatic steatosis is a common histological finding in patients that are co-infected with HIV and hepatitis C virus (HCV), although little is known about its natural history. We prospectively examined the natural history of steatosis in patients co-infected with HIV and HCV that attended an urban HIV clinic.
The study cohort consisted of 222 co-infected patients (87% African American, 94% with HCV genotype 1 infection) who had at least 2 liver biopsies performed between 1993 and 2008. Biopsies were scored by a single pathologist; samples were classified as having trivial (< 5% of hepatocytes affected) or significant (>5%) levels of fat (steatosis). We characterized progression to significant levels of fat among patients whose first biopsy samples had no or trivial levels of fat, and regression among those with significant fat, using logistic regression.
Initial biopsies from most patients (88%) had no or trivial amounts of fat. Among second biopsy samples, 74% had no or trivial fat and 13% had significant amounts of fat. The strongest risk factors for steatosis progression were alcohol abuse and overweight/obesity; cumulative exposure to anti-retroviral therapy between biopsies and high counts of CD4+ T cells were associated with reduced progression of steatosis. Among the 28 patients whose initial biopsy had significant fat levels, most (75%) regressed.
Antiretroviral therapy and high counts of CD4+ T cells are associated with reduced progression of steatosis in patients co-infected with HIV and HCV. Efforts to diagnose and prevent steatosis should focus on persons with high body mass index and excessive alcohol intake.
pathology; cirrhosis; AIDS; liver disease
We tested the hypothesis that a single nucleotide polymorphism (SNP) located near the interleukin-28B gene is associated with the control of hepatitis C virus and HIV-1 replication in elite controllers/suppressors. We show here that the protective genotype is not overrepresented in elite controllers/suppressors compared with HIV-1-seronegative patients and HIV-1-infected patients with viral loads more than 10 000 copies/ml. Thus, it appears that this SNP is not associated with the elite control of HIV-1 infection.
Alternatives to liver biopsy for staging liver disease caused by hepatitis C virus (HCV) have not appeared accurate enough for widespread clinical use. We characterized the magnitude of the impact of error in the “gold standard” on the observed diagnostic accuracy of surrogate markers.
We calculated the area under the receiver operating characteristic curve (AUROC) for a surrogate marker against the gold standard (biopsy) for a range of possible performances of each test (biopsy and marker) against truth and a gradient of clinically significant disease prevalence.
In the ‘best’ scenario where liver biopsy accuracy is highest (sensitivity and specificity of biopsy are 90%) and the prevalence of significant disease 40%, the calculated AUROC would be 0.90 for a perfect marker (99% actual accuracy) which is within the range of what has already been observed. With lower biopsy sensitivity and specificity, AUROC determinations > 0.90 could not be achieved even for a marker that perfectly measured disease.
We demonstrate that error in the liver biopsy result itself makes it impossible to distinguish a perfect surrogate from ones that are now judged by some as clinically unacceptable. An alternative gold standard is needed to assess the accuracy of tests used to stage HCV-related liver disease.
liver disease; biopsy; hepatitis C virus; validity; surrogate markers
Treatment-induced and spontaneous clearance of hepatitis C virus (HCV) infection are affected by various host factors. Polymorphisms in the region of the gene IL28B are associated with HCV clearance, implicating the gene product, interferon (IFN)-γ3, in the immune response to HCV. Although it is not clear how the IL28B haplotype affects HCV clearance, IFNγ3 upregulates interferon-stimulated genes (ISGs), similar to interferon-α and β, but via a different receptor. There is also evidence that IFNγ3 affects the adaptive immune response. The IL28B genotype can be considered, along with other factors, in predicting patient responses to therapy with pegylated interferon-α and ribavirin. We review the genetic studies that uncovered the association between IL28B and HCV clearance, the biology of IFNγ3, the clinical implications of the genetic association, and areas of future research.
IL28B; Hepatitis C Virus; Interferon Lambda; Interferon Sensitivity; HCV Treatment
Hepatitis C virus (HCV) infection is the most common blood borne infection in the U.S. with estimates of 4 million HCV-infected individuals in the U.S. and 170 million worldwide1. The majority (70%–80%) of HCV infections persist and about 30% of individuals with persistent infection develop chronic liver disease, including cirrhosis and hepatocellular carcinoma2. Epidemiological, viral, and host factors have been associated with the differences in HCV clearance or persistence and studies have demonstrated that a strong host immune response against HCV favors viral clearance3,4. Thus, variation in genes involved in the immune response may contribute to the ability to clear the virus. In a recent genome-wide association study, a single nucleotide polymorphism (rs12979860) 3kb upstream of the IL28B gene, which encodes the type III interferon IFN-λ3, was shown to associate strongly with more than a 2-fold difference in response to HCV drug treatment5. To determine the potential effect of rs12979860 variation on outcome to HCV infection in a natural history setting, we genotyped this variant in HCV cohorts comprised of individuals who spontaneously cleared the virus (N = 388) or had persistent infection (N = 620). We show that the C/C genotype strongly enhances resolution of HCV infection amongst individuals of both European and African ancestry (European: OR = 0.38, p = 10−7; African: OR = 0.32, p = 10−4; combined: OR = 0.33, p <10−12). To date, this is the strongest and most significant genetic effect associated with natural clearance of HCV, and these results implicate a primary role for IL28B in resolution of HCV infection.
Liver disease is a leading cause of mortality among HIV-infected persons in the US and Europe; however, data regarding effects of HIV and anti-retroviral therapy (ART) on liver disease in Africa remains sparse.
500 HIV-infected participants in an HIV care program in Rakai, Uganda were frequency-matched by age, gender and site to 500 HIV-uninfected participants in a population cohort. All participants underwent transient elastography (FibroScan®) to quantify liver stiffness measurements (LSM) and identify participants with significant liver fibrosis, defined as LSM ≥9.3 kPa (≈ Metavir F ≥2). 962 (96 %) of participants had valid LSM data. Risk factors for liver fibrosis were identified by estimating adjusted prevalence risk ratios (adjPRR) and 95% confidence intervals (CI) using modified Poisson multivariate regression.
The prevalence of significant fibrosis was 17% among HIV-infected and 11% in HIV-uninfected participants (p =0.008). In multivariate analysis, HIV infection was associated with a 50% increase in liver fibrosis (adjPRR 1.5, 95%CI 1.1–2.1; p=0.010). Fibrosis was also associated with male gender (adjPRR 1.4, 95% CI 1.0–1.9; p=0.045), herbal medicine use (adjPRR 2.0, 95%CI 1.2–3.3; p=0.005), heavy alcohol consumption (adjPRR 2.3, 95% CI 1.3–3.9; 0.005), occupational fishing (adjPRR 2.5, 1.2–5.3; p=0.019), and chronic HBV infection (adjPRR 1.7, 95% CI 1.0–3.1; p=0.058). Among HIV-infected participants, ART appeared to reduce fibrosis risk (adjPRR 0.6, 95% CI 0.4–1.0; p=0.030).
The burden of liver fibrosis among rural Ugandans is high, particularly among persons with HIV infection. These data suggest that liver disease may represent a significant cause of HIV-related morbidity and mortality in Africa; clarifying the etiology of liver disease in this population is a research priority.
HIV; fibrosis; hepatitis co-infection; liver; Uganda
Fibrosis stages from liver biopsies reflect liver damage from hepatitis C infection, but analysis is challenging due to their ordered but non-numeric nature, infrequent measurement, misclassification, and unknown infection times.
We used a non-Markov multistate model, accounting for misclassification, with multiple imputation of unknown infection times, applied to 1062 participants of whom 159 had multiple biopsies. Odds ratios (OR) quantified the estimated effects of covariates on progression risk at any given time.
Models estimated that progression risk decreased the more time participants had already spent in the current stage, African American race was protective (OR 0.75, 95% confidence interval 0.60 to 0.95, p = 0.018), and older current age increased risk (OR 1.33 per decade, 95% confidence interval 1.15 to 1.54, p = 0.0002). When controlled for current age, older age at infection did not appear to increase risk (OR 0.92 per decade, 95% confidence interval 0.47 to 1.79, p = 0.80). There was a suggestion that co-infection with human immunodeficiency virus increased risk of progression in the era of highly active antiretroviral treatment beginning in 1996 (OR 2.1, 95% confidence interval 0.97 to 4.4, p = 0.059). Other examined risk factors may influence progression risk, but evidence for or against this was weak due to wide confidence intervals. The main results were essentially unchanged using different assumed misclassification rates or imputation of age of infection.
The analysis avoided problems inherent in simpler methods, supported the previously suspected protective effect of African American race, and suggested that current age rather than age of infection increases risk. Decreasing risk of progression with longer time already spent in a stage was also previously found for post-transplant progression. This could reflect varying disease activity, with recent progression indicating active disease and high risk, while longer time already spent in a stage indicates quiescent disease and low risk.
For persons living with HIV, hepatitis C is a major public health problem that must be controlled and could be eliminated. The challenge arises because the hepatitis C virus (HCV) is prevalent among HIV-infected persons in most parts of the world, because HIV worsens all HCV outcomes, and because HCV may add additional individual economic and psychosocial complications to HIV disease. Despite the major benefits of antiretroviral therapy on HIV outcomes, antiretroviral therapy is not sufficient to halt the complications of HCV. Nonetheless, HCV can be controlled at all stages, including prevention of infection and cure. Thus, HCV is an eradicable disease. There are significant inequalities worldwide in HCV control that could markedly constrain the impact of these measures.
Heat shock protein 27 (HSP27) has a major role in mediating survival responses to a range of central nervous system insults, functioning as a protein chaperone, an antioxidant, and through inhibition of cell death pathways. We have used transgenic mice overexpressing HSP27 (HSP27tg) to examine the role of HSP27 in cerebral ischemia, using model of permanent middle cerebral artery occlusion (MCAO). Infarct size was evaluated using multislice T2-weighted anatomical magnetic resonance imaging (MRI) after 24 h. A significant reduction of 30% in infarct size was detected in HSP27tg animals compared with wild-type (WT) littermates. To gain some insight into the mechanisms contributing to cell death and its attenuation by HSP27, we monitored the effect of induction of c-jun and ATF3 on tissue survival in MCAO and their effects on the expression of endogenous mouse HSP25 and HSP70. It is important that, the c-jun induction seen at 4 h tended to be localized to regions that were salvageable in HSP27tg mice but became infarcted in WT animals. Our results provide support for the powerful neuroprotective effects of HSP27 in cerebral ischemia.
focal ischemia; heat shock protein 27; MRI; permanent middle cerebral artery occlusion
Background & Aims
We followed persons with ongoing hepatitis C virus (HCV) exposure following control of an initial HCV infection to determine whether primary control conferred protection against future persistent infections.
Twenty-two active injection drug users (IDU) who had cleared a primary hepatitis C viremia for at least 60 days were monitored monthly. Reinfection was defined as the detection of a new hepatitis C virus infection. Protection was assessed based on the magnitude and duration of viremia following reinfection and generation of T-cell and neutralizing antibody (nAb) responses
Reinfection occurred in 11 IDUs (50%) who previously spontaneously controlled primary HCV infection. Although viral clearance occurs in approximately 25% of patients with primary infections, spontaneous viral clearance was observed in 83% of reinfected patients. The duration and maximum level of viremia during subsequent episodes of reinfection were significantly decreased, compared with those of the primary infection in the same subjects. In contrast to chronic infection, reinfection was associated with a significant increase in the breadth of T-cell responses. During acute infection, nAbs against heterologous viral pseudoparticles were detected in 60% of reinfected subjects; cross-reactive nAbs are rarely detected in patients who progress to chronic infection.
HCV reinfection is associated with a reduction in the magnitude and duration of viremia (compared with the initial infection), broadened cellular immune responses, and the generation of cross-reactive humoral responses. These findings are consistent with the development of adaptive immunity that is not sterilizing but protects against chronic disease.
To determine if lower levels of hepatitis C virus (HCV)-specific neutralizing antibodies (nAb) are associated with an increased risk of mother-to-child transmission (MTCT) of HCV, anti-HCV nAb titers were assessed in 63 mothers co-infected with HCV and human immunodeficiency virus type 1 (HIV). Among the mothers, 16 transmitted HCV to their infant but no difference was detected between the ability of maternal plasma from transmitters and non-transmitters to neutralize heterologous HCV pseudoparticles (median nAb titer 1:125 vs. 1:100, P=0.23). In the setting of HIV/HCV co-infection, we found no evidence that anti-HCV nAbs are associated with prevention of MTCT of HCV.
HCV; HIV; mother-to-infant transmission; perinatal transmission; hepatitis C virus; neutralizing antibody; HCVpp; MTCT
Recovery from acute hepatitis B virus (HBV) infection occurs in 95% of adult-acquired infections. A 32-base pair deletion in CCR5 (CCR5Δ32), which encodes for a nonfunctional receptor, increases the likelihood of recovery. Using 181 subjects with persistent HBV infection and 316 who had recovered, we tested the hypothesis that an epistatic interaction between functional polymorphisms in RANTES (a CCR5 ligand) and CCR5 impacts recovery. Specific models designed to assess individual contributions of compound genotypes demonstrated that the only combination associated with recovery from an HBV infection was RANTES -403A with CCR5Δ32 (OR 0.36, P= 0.02). Since the phenotypic consequence of -403A is reported to be higher levels of RANTES, we propose a model where excess RANTES in combination with low CCR5 favor recovery from an HBV infection, which will require validation through functional testing. “This is an author-produced version of a manuscript accepted for publication in The Journal of Immunology (The JI). The American Association of Immunologists, Inc. (AAI), publisher of The JI, holds the copyright to this manuscript. This version of the manuscript has not yet been copyedited or subjected to editorial proofreading by The JI; hence, it may differ from the final version published in The JI (online and in print). AAI (The JI) is not liable for errors or omissions in this author-produced version of the manuscript or in any version derived from it by the U.S. National Institutes of Health or any other third party. The final, citable version of record can be found at www.jimmunol.org.”
Viral infection; chemokines; human
We comprehensively studied the cellular immune response during acute human hepatitis C virus (HCV) infection by monthly prospective sampling of persons with high risk of infection. In 19 of 23 subjects, interferon-gamma secreting T cells specific for one or more peptides spanning the entire HCV polyprotein were detected 1–3 months after infection. The median time to development of interferon gamma responses to HCV peptides was 33 days (range 29 to 50 days), and these responses peaked between 180 and 360 days. Nineteen subjects had sufficient follow-up to determine outcome, with 15 (79%) developing persistent viremia and 4 (21%) clearing viremia spontaneously. Of those with progression to chronic infection and detectable T cell responses, all lost recognition of one or more antigens recognized during acute infection and the median reduction in the magnitude of responses was 85%. Most significantly, despite ongoing viremia those who had persistent infection did not develop new epitope specificities after the first six months of infection. In conclusion, these results suggest that in the majority of individuals, the CD8+ T cell responses generated early in HCV infection decline in peripheral blood and are not replaced with new responses.
Viral; Immunology; HCV; CD8; ELISpot
In multi-echo imaging sequences like fast spin echo (FSE), the point spread function (PSF) in the phase encoding direction contains significant secondary peaks (sidebands). This is due to discontinuities in adjacent k-space data obtained at different echo times caused by T2 decay, and leads to ghosting and hence reduced image quality. Recently, utilising multiple coils for signal reception has become the standard configuration for MR systems due to the additional flexibility that parallel imaging (PI) methods can provide. PI methods generally obtain more data than is required to reconstruct an image. Here, this redundancy in information is exploited to reduce discontinuity-related ghosting in FSE imaging. Adjacent phase encoded k-space lines are acquired at different echo times alternately in the regions of discontinuity (called ‘feathering’). This moves the resulting ghost artefacts to the edges of the field of view. This property of the ghost then makes them amenable to removal using PI methods. With ‘feathered’ array coil data it is possible to reconstruct data over the region of the discontinuity from both echo times. By combining this data, a significant reduction in ghosting can be achieved. We show this approach to be effective through simulated and acquired MRI data.
Magnetic resonance imaging; Fast spin echo; Turbo spin echo; High field; Artefacts; Parallel imaging; Point spread function; Ghosting
Transient elastography is a novel, noninvasive method for staging liver fibrosis. We compared elastography with histologic methods among hepatitis C virus (HCV)–infected and human immunodeficiency virus (HIV)–HCV-coinfected participants in an urban, predominantly black study population.
Participants recruited from the AIDS Linked to the Intravenous Experience and the Johns Hopkins HIV Clinical Cohort studies underwent elastography to determine liver stiffness measurements. Liver biopsy specimens were staged F0–F4 in accordance with the Metavir score. Diagnostic accuracy and determination of liver stiffness cutoff values, compared with histologic methods, were determined by receiver operating characteristic analysis. Logistic regression methods identified parameters associated with discordant classification status.
Of 192 participants, 139 (72%) were coinfected with HIV and HCV, 121 (63%) had insignificant fibrosis, and 48 (25%) had cirrhosis. Overall, the area-under-the-curve receiver operating characteristic was 0.87 for detection of both significant fibrosis (95% confidence interval, 0.82–0.92) and cirrhosis (95% confidence interval, 0.81–0.93). With use of cutoff values of ≥9.3 kPa for fibrosis and ≥12.3 kPa for cirrhosis, 79%–83% of participants were correctly classified by liver stiffness measurement (compared with histologic methods); accuracy appeared to be higher among HIV-uninfected participants than among HIV-infected participants. Most discordance occurred when liver stiffness measurements indicated liver disease and histologic examination did not (in 16% of participants); the patients with these discordant results were more likely to have attributes that increased the odds of significant fibrosis, such as elevated serum fibrosis markers or HIV-related immunosuppression, compared with persons in whom low fibrosis was predicted by both examination of a biopsy specimen and elastography.
For most HCV-infected persons, fibrosis stage predicted by elastography is similar to that predicted by examination of a biopsy specimen. Elastography-based measurement of liver stiffness holds promise to expand liver disease screening and monitoring, particularly among injection drug users.
Background & Aims
HIV-1 infection has been associated with enhanced microbial translocation, and microbial translocation is a mechanism through which alcohol and some enteric conditions cause liver disease. We hypothesized that HIV promotes liver disease by enhancing microbial translocation.
We studied human cohorts in which hepatitis C virus (HCV) and HIV outcomes were carefully characterized.
HIV-related CD4+ lymphocyte depletion was strongly associated with microbial translocation as indicated by elevated levels of circulating lipopolysaccharide (LPS), LPS binding protein, soluble CD14, fucose-binding lectin (AAL) reactive to IgG specific for the alpha galactose epitope, and suppressed levels of endotoxin-core antibodies (EndoCAb IgM) in HIV-infected subjects compared with the same persons before they had HIV infection and compared with HIV-uninfected subjects. The same measures of microbial translocation were strongly associated with HCV-related liver disease progression (cirrhosis), e.g. LPS, odds ratio 19.0 (p = 0.002), AAL, odds ratio 27.8 (p<0.0001); in addition, levels of LPS were elevated prior to recognition of cirrhosis.
Microbial translocation may be a fundamental mechanism through which HIV accelerates progression of chronic liver disease.