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Fast Fibrosis Progression Between Repeated Liver Biopsies in Patients Coinfected with Human Immunodeficiency Virus/Hepatitis C Virus
Abstract
Unlabelled:
A few studies have assessed the observed fibrosis progression between serial liver biopsies (LB) in human immunodeficiency virus (HIV) / hepatitis C virus (HCV)-coinfected patients. Approximately half of the patients progressed at least one fibrosis stage over a short period of time. The risk factors for this fast progression need clarification. Because of this, we evaluated the observed fibrosis progression rates of HIV/HCV-coinfected patients and the risk factors for accelerated progression. Overall, 135 HIV-infected patients with positive serum HCV RNA, without other possible causes of liver disease, who underwent two LB, separated at least by 1 year, were included in this retrospective cohort study. The median (Q1-Q3) time between both LBs was 3.3 (2.0-5.2) years. Patients showed the following changes in fibrosis stage: regression >or =1 stage: 23 (17%), no change: 52 (39%), progression 1 stage: 38 (28%), and progression > or =2 stages: 22 (16%). Seventeen (13%) patients had cirrhosis in the second biopsy. Factors independently associated with progression > or =1 stage were undetectable plasma HIV RNA during the follow-up (relative risk [RR] [95% confidence interval, 95% CI] 0.61 [0.39-0.93], P = 0.03), moderate-to-severe lobular necroinflammation (1.77 [1.16-2.7], P = 0.009), time between biopsies (1.11 [1.08-1.2], P = 0.01), and end of treatment response to anti-HCV therapy (0.41 [0.19-0.88], P = 0.02).
Conclusion:
Fibrosis progresses with high frequency in HIV/HCV-coinfected patients over a period of time of 3 years. Absent-to-mild lobular necroinflammation at baseline, achievement of response with anti-HCV treatment, and effective antiretroviral therapy are associated with slower fibrosis progression.
... Data from cohorts including HIV/HCV-coinfected adults indicate that their progression to hepatic fibrosis is faster than that in HCV-monoinfected patients [3]. Some authors have suggested that both viruses could have a synergistic effect in terms of inflammation [4], and controversy exists regarding the effects of HCV coinfection on immune reconstitution after ART initiation in both children and adults [3,5]. ...
... Data from cohorts including HIV/HCV-coinfected adults indicate that their progression to hepatic fibrosis is faster than that in HCV-monoinfected patients [3]. Some authors have suggested that both viruses could have a synergistic effect in terms of inflammation [4], and controversy exists regarding the effects of HCV coinfection on immune reconstitution after ART initiation in both children and adults [3,5]. ...
... Despite the well-known risk of liver disease progression in HIV/HCV-coinfected adults [3], the evolution of vertically acquired HIV/HCV coinfection in children has scarcely been described. According to some studies, mild liver fibrosis progression in HIV/HCV-coinfected children [6,7] starts to worsen in adolescence [6][7][8]. ...
Data for a total of 57 patients vertically coinfected with human immunodeficiency virus (HIV)/hepatitis C virus (HCV) and 365 HIV-monoinfected patients were compared until their transition to adult care. No differences regarding the dynamics of CD4 and/or CD8 T-cell counts during childhood were found. The coexistence of HCV does not increase the risk of disease progression in vertically HIV-infected patients.
... Liver fibrosis progression rates are accelerated in patients coinfected with HIV and either HCV or HBV, compared to those who are monoinfected [8,9]. Consistent with this, levels of HIV RNA are directly associated with liver damage [10]. ...
... Liver injury is a typical feature of HIV infection and liver cells are prominently involved in HIV-mediated injury [9,42,43]. Studies have shown that the severity of liver damage is directly related to the levels of HIV RNA in patients [44]. Although the mechanisms behind liver injury are not yet fully understood, it is believed that immune mediators and direct viral effects on hepatic cells may be involved. ...
Liver fibrosis is the excessive accumulation of extracellular matrix proteins, primarily collagen, in response to liver injury caused by chronic liver diseases. HIV infection accelerates the progression of liver fibrosis in patients co-infected with HCV or HBV compared to those who are only mono-infected. The early event in the progression of liver fibrosis involves the activation of hepatic stellate cells (HSCs), which entails the loss of lipid droplets (LD) to fuel the production of extracellular matrix components crucial for liver tissue healing. Thus, we are examining the mechanism by which HIV stimulates the progression of liver fibrosis. HIV-R5 tropic infection was unable to induce the expression of TGF-β, collagen deposition, α-smooth muscle actin (α-SMA), and cellular proliferation. However, this infection induced the secretion of the profibrogenic cytokine IL-6 and the loss of LD. This process involved the participation of peroxisome proliferator-activated receptor (PPAR)-α and an increase in lysosomal acid lipase (LAL), along with the involvement of Microtubule-associated protein 1 A/1B-light chain 3 (LC3), strongly suggesting that LD loss could occur through acid lipolysis. These phenomena were mimicked by the gp120 protein from the R5 tropic strain of HIV. Preincubation of HSCs with the CCR5 receptor antagonist, TAK-779, blocked gp120 activity. Additionally, experiments performed with pseudotyped-HIV revealed that HIV replication could also contribute to LD loss. These results demonstrate that the cross-talk between HSCs and HIV involves a series of interactions that help explain some of the mechanisms involved in the exacerbation of liver damage observed in co-infected individuals.
... This is more pronounced in those with CD4 count less than 200cells/mm 3 (5). This accelerated progression can be delayed with the use of antiretroviral therapy such that co-infected patients with negligible HIV viral load take longer to develop cirrhosis than those with high HIV viral load (6). ...
Background: Worldwide, an estimated 58 million people have chronic hepatitis C virus (HCV) infection, with about 1.5 million new infections occurring per year. About 2.3 million people living with HIV globally have serological evidence of past or present HCV infection. The aim of this study was to determine the prevalence of active HCV infection and associated risk factors among HIV positive patients attending the HIV clinic, Lagos University Teaching Hospital (LUTH), Idi-Araba, Lagos, Nigeria. Methodology: A cross sectional study was conducted to determine the prevalence of and risk factors for HCV infection among randomly selected HIV positive patients at the LUTH HIV clinic. Socio-demographic, clinical and laboratory data were collected from the participants using a structured questionnaire. Blood samples were collected and tested for HCV antibodies with an enzyme linked immunosorbent assay (CTK Biotech USA) and HCV RNA was detected using reverse transcriptase polymerase chain reaction assay. Results: One hundred and ninety-five HIV infected participants were recruited into the study of which 134 (68.7%) were females and 61 (31.3%) were males. The mean age of participants was 40.1±7.8 years. Of the 195 participants, 5 tested positive for antibody to HCV, giving a seroprevalence rate of 2.6% (95% CI = 0.8-5.9%). Of the 5 seropositive participants, HCV RNA was detected in 1 (20.0%), giving a prevalence of 0.5% (1/195) for active HCV infection. The seroprevalence of HCV in males of 4.9% (3/61) and females of 1.5% (2/134) was not significantly different (OR=3.41, 95% CI=0.56-20.98%, p=0.18). The mean log10 HIV viral load was significantly higher among participants seropositive for HCV (5.1±0.9 log copies/ml) than those seronegative (2.7±1.2 log copies/ml) (p < 0.001). The mean duration of antiretroviral therapy was significantly lower among participants seropositive for HCV (2.6±1.3 years) than those seronegative (5.6±3.1 years) (p=0.004). The seroprevalence of HCV was significantly higher in those with CD4 count <350 cells/mm3 (8.5%) than those with CD4 count >350cells/mm3 (p=0.02). The seroprevalence of HCV in the HIV-positive participants was significantly associated with sexual partners (p=0.0473), with highest seroprevalence in those with ≥ 3 sexual partners (OR=11.625, 95% CI=1.049-128.83). Other risk factors were not significantly associated with seroprevalence of HCV (p>0.05), while risk factors associated with active HCV infection could not be evaluated with the only one HCV RNA positive participant Conclusion: Although the prevalence of active HCV infection in HIV infected individuals in this study was apparently low (0.5%), screening with HCV antibody test and confirmation with HCV RNA PCR assay are recommended.
... Even though there is no vaccine against HCV, since 2011 as direct-acting antivirals (DAA) were developed, there has been very-well-tolerated and effective treatment with HCV cure rates of over 95% [14,15]. As PLWH have an increased risk of developing endstage liver disease, all patients from this group should be vaccinated against HBV and HAV and treated for HBV and HCV [16][17][18]. The key to receive the necessary care and treatment to prevent or delay progression of liver disease and to decrease the further spread of HIV and viral hepatitis co-infection is the comprehensive screening of the population followed by preventive measures [19]. ...
(1) Background: Viral hepatitis C (HCV) and viral hepatitis B (HBV) are common co-infections in people living with HIV (PLWH). All PLWH should be vaccinated against HBV and hepatitis A (HAV) and treated for HBV and HCV. We aimed to compare testing, prophylaxis and treatment of viral hepatitis in PLWH in Central and Eastern Europe (CEE) in 2019 and 2022. (2) Methods: Data was collected through two on-line surveys conducted in 2019 and 2022 among 18 countries of the Euroguidelines in CEE (ECEE) Network Group. (3) Results: In all 18 countries the standard of care was to screen all PLWH for HBV and HCV both years; screening of HAV was routine in 2019 in 54.5% and in 2022 47.4% of clinics. Vaccination of PLWH against HAV was available in 2019 in 16.7%, in 2022 in 22.2% countries. Vaccination against HBV was available routinely and free of charge in 50% of clinics both in 2019 and 2022. In HIV/HBV co-infected the choice of NRTI was tenofovir-based in 94.4% of countries in both years. All clinics that responded had access to direct-acting antivirals (DAAs) but 50% still had limitations for treatment. (4) Conclusions: Although testing for HBV and HCV was good, testing for HAV is insufficient. Vaccination against HBV and especially against HAV has room for improvement; furthermore, HCV treatment access needs to overcome restrictions.
... 8 Due to the high prevalence of liver disease in PLWH and the accelerated progression of liver fibrosis, it is imperative to improve the early identification of those at the highest risk of mortality and liver-related complications and initiate appropriate surveillance and preventative interventions. [9][10][11] Liver stiffness measurement (LSM) by vibration-controlled transient elastography (TE) is a non-invasive tool that can diagnose advanced liver fibrosis and predict the occurrence of hepatic decompensation and all-cause mortality. 12,13 According to the Baveno VII consensus, LSM ≥ 10 kPa is highly suggestive of compensated advanced chronic liver disease (cACLD), while LSM < 15 kPa and normal platelet count rules-out clinically significant PH and presents with a negligible risk of decompensation. ...
Background and aims:
People living with HIV (PLWH) are at high risk for advanced chronic liver disease and related adverse outcomes. We aimed to validate the prognostic value of non-invasive scores based on liver stiffness measurement (LSM) and on markers of portal hypertension (PH), namely platelets and spleen diameter, in PLWH.
Methods:
We combined data from eight international cohorts of PLWH with available non-invasive scores, including LSM and the composite biomarkers liver stiffness-spleen size-to-platelet ratio score (LSPS), LSM-to-Platelet ratio (LPR) and PH risk score. Incidence and predictors of all-cause mortality, any liver-related event and classical hepatic decompensation were determined by survival analysis, controlling for competing risks for the latter two. Non-invasive scores were assessed and compared using area under the receiver operating curve (AUROC).
Results:
We included 1695 PLWH (66.8% coinfected with hepatitis C virus). During a median follow-up of 4.7 (interquartile range 2.8-7.7) years, the incidence rates of any liver-related event, all-cause mortality and hepatic decompensation were 13.7 per 1000 persons-year (PY) (95% confidence interval [CI], 11.4-16.3), 13.8 per 1000 PY (95% CI, 11.6-16.4) and 9.9 per 1000 PY (95% CI, 8.1-12.2), respectively. The AUROC of LSM was similar to that of the composite biomarkers, ranging between 0.83 and 0.86 for any liver-related event, 0.79-0.85 for all-cause mortality and 0.87-0.88 for classical hepatic decompensation. All individual non-invasive scores remained independent predictors of clinical outcomes in multivariable analysis.
Conclusions:
Non-invasive scores based on LSM, spleen diameter and platelets predict clinical outcomes in PLWH. Composite biomarkers do not achieve higher prognostic performance compared to LSM alone.
... Globally, an estimated 4 million to 5 million people are chronically coinfected with Hepatitis C Virus (HCV) and Human Immunodeficiency Virus (HIV). 1 HCV/HIV coinfected patients have higher risk of liver cirrhosis, hepatocellular carcinoma, hepatic decompensation and all-cause mortality than patients monoinfected with HCV. [2][3][4][5] Since the introduction of combination antiretroviral therapy (ART), HIV-related morbidity and mortality have decreased while liver related complications have become a leading cause of non-HIV-related morbidities and death in coinfected patients. 6,7 The introduction of direct-acting antiviral agents (DAAs) has revolutionized the treatment of HCV. ...
Background:
The direct-acting antiviral agents (DAAs) have revolutionized the treatment of Hepatitis C Virus (HCV) infection. However, a simple and feasible treatment strategy with high efficacy and safety for HCV in patients coinfected with Human Immunodeficiency Virus (HIV) remains an unmet medical need, especially in areas with limited health resource. This study aims to assess the efficacy and safety of 12 weeks of treatment with sofosbuvir and velpatasvir in patients with chronic HCV/HIV-1 coinfection.
Methods:
We conducted a multicenter, single-arm, open-label study in China, which involved chronic HCV/HIV-1 coinfected patients who are receiving an antiretroviral regimen of a combination tablet consisting of elvitegravir, cobicistat, emtricitabine, tenofovir alafenamide, (EVG/c/FTC/TAF) once daily. Patients with liver cirrhosis or experienced to DAAs treatment were excluded. All patients received combined sofosbuvir (400 mg) and velpatasvir (100 mg) tablet once daily for 12 weeks regardless of HCV genotype. The primary efficacy endpoint was sustained virologic response, defined as HCV RNA <15 IU/mL at 12 weeks after completion of treatment (SVR12). The primary safety endpoint was the proportion of patients who prematurely discontinued treatment because of adverse events. Safety and efficacy data were analyzed with an intention-to-treat (ITT) population (last observation carried forward) and per-protocol (PP) population. This trial is registered on ChiCTR.org.cn with number being ChiCTR1800020246.
Findings:
Of the 243 patients enrolled, 78% were male, 9% had been previously treated for HCV with interferon, and none had pre-defined cirrhosis, although 8% had Fibrosis 4 score (FIB-4) >3.25. A total of 233 patients completed 12-week post-treatment follow-up. Overall, 227/233 patients (97%) achieved SVR12: 100% (63/63) in those with HCV genotype 1, 67% (2/3) in those with genotype 2, 95% (84/88) in those with genotype 3, 99% (78/79) in those with genotype 6. Rates of SVR12 were lower among those with baseline FIB-4 >3.25 than those without (78% [14/18] vs. 99% [211/212], P < 0.001). HIV-1 suppression was not compromised. The most common adverse events were upper respiratory tract infection (5%), cough (3%), abnormal renal function (2%), abnormal liver function (2%), constipation (2%), urinary tract infection (2%) and sleep disorders (2%). No participant discontinued treatment because of adverse events or death.
Interpretation:
Twelve weeks of treatment with sofosbuvir/velpatasvir provide high rates of SVR and is well-tolerated in patients coinfected with HIV-1 and HCV regardless of HCV genotypes. Non-invasive liver fibrosis score may help to further distinguish patients at greater likelihood of a suboptimal response.
Funding:
The 13th Five Year Plan of the Ministry of Science and Technology of China for the prevention and treatment of major infectious diseases such as AIDS and viral hepatitis, the National Key Research and Development Program of China, Medical Key Discipline Program of Guangzhou-Viral Infectious Diseases (2021-2023), Basic research program on people's Livelihood Science and technology of Guangzhou, and National Natural Science Foundation of China.
... End-stage liver disease (ESLD) is a major cause of morbidity and mortality in HIV-infected patients [1,2].The prognosis and management of chronic hepatitis depends on the progression of liver fibrosis and the development of cirrhosis, both of which are accelerated in HIV/HCV co-infected patients [3]. ...
... [19] It has been similarly demonstrated that coinfected patients diagnosed with hepatocellular carcinoma tend to have a more advanced and aggressive liver disease at younger ages, associated with significantly higher mortality rates. [20] Although antiretroviral therapy (ART) appears to slow the rate of HCV disease progression in HCV-HIV coinfected patients, by preserving or restoring immune function and by reducing HIV-related immune activation and inflammation, [21][22][23] but several studies have demonstrated that the progression rate still continues to exceed that observed in patients without HIV infection. [24,25] The major contributor to mortality among HIV-HCV coinfected subjects during the highly active antiretroviral therapy (HAART) era is still a liver disease, [26][27][28] as the drug-induced liver injury following the initiation of ART is more common in HCV-HIV coinfected patients than in those with HIV mono-infection. ...
Background:
People who inject drugs are vastly over-represented, often accounting for 50% of prison inmates, so, the transmission of human immunodeficiency virus (HIV), hepatitis C virus (HCV) and tuberculosis (TB) is a serious problem in many prison systems. The prevalence of HCV infection is so disproportionately high in the correctional population that one in four detainees worldwide is living with HCV and the story is similar for HIV.
Objective:
The objective of the study is to find the prevalence of HIV, HCV and dual HIV-HCV infection in the prison inmates.
Materials and methods:
A sample of 1569 jail inmates was assessed, after obtaining formal approval from the ethical committee for assessment of the medical record of subjects, to know sero-positivity for HIV and HCV. The data generated is then analysed.
Results:
The results show a very high point prevalence of HIV (10.0%) and HCV (31.6%) in the jail inmates, which is 40 and 30 times higher, respectively, as compared to the national average. A staggering 8.5% of the inmates were found to be positive for both viruses. The sero-prevalence for mono-infection for HCV (23.1%) is found to be significantly higher compared to HIV (1.5%). The infection rate of HCV was found to be three times higher compared to HIV.
Conclusions:
Substantially high prevalence of HIV, HCV and dual HIV-HCV infection exists in the prison inmates. Data suggests high virulence for HCV compared to HIV, as both viruses have common routes of transmission. There is an urgent need to keep a constant check on the intravenous drug usage (IDU) in the prisons that is linked to the common transmission of both these blood-borne viruses.
... En pacientes coinfectados VIH/VHB, se ha demostrado que el control virológico e inmunológico de la infección de VIH se asocia a una menor velocidad de progresión de fibrosis y a una mejor evolución clínica, aún en casos de cirrosis descompensado 87 . El lamivudina (3TC), Tenofovir/emtricitabina (TDF/ FTC) son inhibidores nucleósidos de la transcriptasa reversa (INTR) con actividad tanto en el VIH como el VHB 88,89 , por lo que en los pacientes coinfectados VIH/VHB ambas infecciones se tratan concomitantemente. ...
... Hepatitis C virus (HCV) infection is one of the leading causes of chronic liver disease, cirrhosis, and hepatocellular carcinoma [1]. Furthermore, HCV infection is present in approximately 10-30% of HIV-infected patients, who have faster progression of cirrhosis, decompensation, or even death [2,3]. ...
Background
A better understanding of the evolution of cirrhosis after hepatitis C virus (HCV) clearance is essential since the reversal of liver injury may not happen. We aimed to assess the evolution of plasma metabolites after direct-acting antivirals (DAAs) therapy and their association with liver disease scores in HIV/HCV-coinfected patients with advanced HCV-related cirrhosis.
Methods
We performed a prospective study in 49 cirrhotic patients who started DAAs therapy. Data and samples were collected at baseline and 36 weeks after SVR. Metabolomics analysis was carried out using gas chromatography-mass spectrometry and liquid chromatography-mass spectrometry. Inflammation-related biomarkers were analyzed using ProcartaPlex Immunoassays.
Results
At 36 weeks after SVR, patients experienced significant decrease in taurocholic acid, 2,3-butanediol, and LPC(18:0); while several phosphatidylcholines (LPC(16:1), LPC(18:1), LPC(20:4), and PC(16:0/9:0(CHO))/PC(16:0/9:0(COH)), 2-keto-n-caproic acid/2-keto-isocaproic acid and N-methyl alanine increased, compared to baseline. The plasma decrease in taurocholic acid was associated with a reduction in Child-Turcotte-Pugh (CTP) (AMR=3.39; q-value=0.006) and liver stiffness measurement (LSM) (AMR=1.06; q-value<0.001), the plasma increase in LPC(20:4) was related to a reduction in LSM (AMR=0.98; q-value=0.027), and the rise of plasma 2-keto-n-caproic acid/2-keto-isocaproic acid was associated with a reduction in CTP (AMR=0.35; q-value=0.004). Finally, plasma changes in taurocholic acid were directly associated with inflammation-related biomarkers, while changes in LPC(20:4) were inversely associated.
Conclusions
Plasma metabolomic profile changed after HCV clearance with all oral-DAAs in HIV/HCV-coinfected with advanced HCV-related cirrhosis. Changes in plasma levels of LPC (20: 4), 2-keto-n-caproic acid/2-keto-isocaproic acid, and taurocholic acid were related to improvements in cirrhosis scores and inflammatory status of patients.
... One of the most prominent benefits of hepatitis C treatment in HIV patients is a delay in the fibrosis progression. [11][12][13] At the same time, some studies show that after hepatitis is cured, patients enhance virologic or/and immunologic response to ART. 14 All these studies refer to the era of interferon-containing therapy which was restricted in HIV patients. 15 Interferon-free therapy facilitates treatment of HIV/HCV co-infected patients though there are some drug interactions between ART and medications against hepatitis C. The most significant interactions occur when combining direct-acting anti-HCV antivirals with non-nucleoside transcriptase inhibitors (NNRTI: efavirenz, nevirapine, and etravirine) as they can decrease concentrations of DAAs (resulting in a loss of efficacy and potential virological failure) by inducing cytochrome P450 enzyme system and P-glycoprotein. ...
Patients with HIV-infection diagnosed at late stages usually have significant immunosuppression and demand simultaneous antiretroviral therapy and treatment of opportunistic infections. The presence of HCV coinfection makes treatment even more challenging because of possible adverse effects and drug-drug interactions. HCV cure in such clinical situations not only prevents fibrosis progression, but can also enhance virologic and/or immunologic response to antiretrovirals and thus effective treatment of opportunistic infections. Thorough consideration of all existing diseases and drug interactions of the combined therapy makes simultaneous treatment of HIV, chronic hepatitis C, and opportunistic infections not only possible but the best way to improve outcomes in a complex clinical situation.
... These individuals develop liver cirrhosis over decades that progress faster than in HCV-monoinfected patients (3). Likewise, HIV/ HCV-coinfected individuals have higher rates of liver-related events (LRE) that included liver decompensation, chronic liver failure, hepatocellular carcinoma (HCC), liver transplantation, and liver-related deaths (4)(5)(6)(7). Immunosuppression can explain this negative impact of HIV on chronic hepatitis C, but also because HIV can contribute to liver inflammation and fibrosis by the direct action of the virus itself on the hepatic stellate cells (8,9), as well as factors related to lifestyle, such as alcohol consumption. Additionally, different extrahepatic manifestations associated with HCV, such as autoimmune, lymphoproliferative, metabolic, renal, cardiovascular, and central nervous system disorders, may also contribute to the morbimortality of HIV/HCV-coinfected patients (10). ...
Hepatitis C virus (HCV) cure after all-oral direct-acting antiviral (DAA) therapy greatly improves the liver and immune system. We aimed to assess the impact of this HCV clearance on immune system-related markers in plasma and the gene expression profile in human immunodeficiency virus (HIV)/HCV-coinfected patients with advanced cirrhosis. We performed a prospective study on 33 HIV/HCV-coinfected patients at baseline and 36 weeks after the sustained virological response. Gene expression was evaluated by RNA-seq analysis on peripheral blood mononuclear cells (PBMCs) and plasma biomarkers by multiplex immunoassays. We found a decrease in plasma biomarkers (PD1, PDL1, CXCL10, CXCL8, IL12p70, IL10, and TGFβ) and liver disease markers (stiffness measurement (LSM), hepatic venous pressure gradient (HVPG), and transaminases, among others). Furthermore, decreased plasma levels of CXCL8, CXCL10, IL10, and PD1 were associated with reduced LSM values. We also found two upregulated (HAS1 and IRG1) and 15 downregulated (CXCL11, CCL8, CCL7, CCL2, ADARB2, RRAD, MX1, SIGLEC1, IFI44L, IFI44, IFI27, IFI6, IFIT3, IFIT1B, and IFIT1) genes at the end of follow-up, all interferon-stimulated genes (ISGs) grouped into four pathways (“cytokine-cytokine receptor interaction”, “viral protein interaction with cytokine and cytokine receptor”, “chemokine signaling pathway”, and “hepatitis C”). Additionally, the decrease in most of these ISGs was significantly related to reduced LSM and HVPG values. In conclusion, HIV/HCV-coinfected patients with advanced-HCV-related cirrhosis who eradicated HCV following DAA therapy exhibited an improvement in liver disease markers and a significant decrease in plasma biomarkers and gene expression related to antiviral/inflammatory response, particularly in levels of several chemokines and ISGs.
... Chronic infection by hepatitis C virus (HCV) is the most common co-infection of HIV positive patients especially in those who report intravenous drug use (IVDU) [1][2][3]. HIV/HCV co-infection plays an important role in the prognosis of HCV infection considering that co-infected patients develop end-stage liver disease with cirrhosis and hepatocellular carcinoma at a younger age than HCV mono-infected patients [4][5][6]. HIV/HCV co-infection may increase the risk of neurocognitive impairment [7], and increase the risk of cardiovascular disease [8]. To decrease the progression of liver disease, and to improve the treatment outcome, HCV should be treated in all patients. ...
Background
Estonia has a typical Eastern European HIV epidemic where the most frequent co-infection is chronic hepatitis C (HCV). We aimed to describe the changes in HCV prevalence, the distribution of HCV genotypes (GT), and HCV treatment in Estonian people living with HIV over 15 years.
Methods
We used data of subjects included to the Estonian HIV Cohort Study (E-HIV) before 31st of December 2015. We compared two time periods—first, 1st of January 2000 to 31st of December 2008 when the HIV epidemic was mostly spreading among people who inject drugs (PWID) and second, 1st of January 2009 to 31st of December 2015 when HIV started to emerge to the general population.
Results
Of 4422 HIV positives 3708 (84%) had information about their HCV serostatus; 2706 (61%) were HCV seropositive, of latter 1625 (60%) were HCV RNA positive, 239 (9%) had their HCV GT determined, and 141 (5%) received treatment for HCV. The dominating subtypes were 1b (42%) and 3a (37%) followed by 1a (16%), and the few cases of 2 (1.5%). HCV prevalence was 1.5 times (95% CI 1.4–1.6) higher in subjects diagnosed with HIV in first as compared to those diagnosed in second period (84% vs 56%, respectively). There were more men and the median age at HIV diagnosis was lower in HIV/HCV co-infected than in HIV mono-infected patients (70% vs 47% and 24 years vs. 30 years, respectively; both p < 0.001).
Conclusion
There is a decrease in HCV prevalence but it remains high among HIV positive PWID, suggesting that there is need for improvement of harm reduction programs among PWID.
... Some studies have found that TE improvements could be overstated when compared with histologic staging 27,33 , and that this decline might be correlated with inflammation or necrosis improvement 26,[34][35][36][37] . Our data support this hypothesis: if changes in LS were attributed only to fibrosis modifications, a direct correlation could have been detected with fibrosis marker changes; however, this correlation between changes in serum levels of CXCL4 or TGF-β1 and LS decline was not observed. ...
The objective of this work was to identify predictive factors of fibrosis regression after direct antiviral agents (DAAs) in HCV-monoinfected and HIV/HCV-coinfected patients. This was a prospective study of HCV-monoinfected (n = 20), HIV/HCV-co-infected (n = 66) patients and healthy controls (n = 15). Patients had started DAAs and achieved sustained virological response. Liver stiffness (LS) and serum concentrations of profibrotic transforming growth factor (TGF)-β1 and CXC chemokine ligand 4 (CXCL4) and antifibrotic HGF hepatocyte growth factor (HGF) were analyzed at baseline (M0) and 12 months after starting DAAs (M12). A M12 LS achievement of ≤ 9.5 kPa was considered the cutoff point to discharge from a liver clinic. The LS decrease from M0 to M12 was 34%. No significant differences were observed in LS decline between HCV- and HIV/HCV-infected individuals. Changes of serum CXCL4, TGF-β1 and HGF levels did not correlate with LS improvement. 16 out from 56 patients (28%) with a baseline LS > 9.5 achieved a M12 LS ≤ 9.5. HCV-monoinfected and HIV/HCV coinfected patients experienced a significant reduction of LS after sustained virological response. This improvement did not correlate with changes in serum profibrotic or antifibrotic markers. A 29% of those with a baseline LS > 9.5 achieved a LS under this cutoff point.
... sresino@isciii.es † Amanda Fernández-Rodríguez and Salvador Resino contributed equally to this work 1 Unidad de Infección Viral E Inmunidad, Centro Nacional de Microbiología, Instituto de Salud Carlos III (Campus Majadahonda), Carretera Majadahonda-Pozuelo, Km 2.2, 28220 MajadahondaMadrid, Spain Full list of author information is available at the end of the article progression is faster than in HCV-monoinfected patients [3], leading to higher rates of liver-related events (LREs) such as liver decompensation, end-stage liver disease, hepatocellular carcinoma (HCC), and liver-related death [4][5][6][7]. Chronic HCV infection promotes inflammation, immune activation, and dysregulation of immune function [8,9], which boosts the development of LRE and other comorbidities in infected people [7][8][9]. HIV infection also aggravates the dysregulation of the immune system [7,8], since many disturbances remain in patients infected with HIV after suppressive antiretroviral therapy (ART), such as deficits in T-cell functions [10][11][12][13][14][15], immune activation [13], inflammation [16], and dysbiosis [17][18][19]. ...
Objective
To evaluate the impact of hepatitis C virus (HCV) elimination via interferon (IFN)-based therapy on gene expression profiles related to the immune system in HIV/HCV-coinfected patients.
Methods
We conducted a prospective study in 28 HIV/HCV-coinfected patients receiving IFN-based therapy at baseline (HIV/HCV-b) and week 24 after sustained virological response (HIV/HCV-f). Twenty-seven HIV-monoinfected patients (HIV-mono) were included as a control. RNA-seq analysis was performed on peripheral blood mononuclear cells (PBMCs). Genes with a fold-change (FC) ≥ 1.5 (in either direction) and false discovery rate (FDR) ≤ 0.05 were identified as significantly differentially expressed (SDE).
Results
HIV/HCV-b showed six SDE genes compared to HIV-mono group, but no significantly enriched pathways were observed. For HIV/HCV-f vs. HIV/HCV-b, we found 58 SDE genes, 34 upregulated and 24 downregulated in the HIV/HCV-f group. Of these, the most overexpressed were CXCL2 , PDCD6IP, ATP5B, IGSF9, RAB26, and CSRNP1 , and the most downregulated were IFI44 and IFI44L . These 58 SDE genes revealed two significantly enriched pathways (FDR < 0.05), one linked to Epstein-Barr virus infection and another related to p53 signaling. For HIV/HCV-f vs. HIV-mono group, we found 44 SDE genes that revealed 31 enriched pathways (FDR < 0.05) related to inflammation, cancer/cell cycle alteration, viral and bacterial infection, and comorbidities associated with HIV/HCV-coinfection. Five genes were overrepresented in most pathways ( JUN, NFKBIA, PIK3R2, CDC42, and STAT3 ).
Conclusion
HIV/HCV-coinfected patients who eradicated hepatitis C with IFN-based therapy showed profound gene expression changes after achieving sustained virological response. The altered pathways were related to inflammation and liver-related complications, such as non-alcoholic fatty liver disease and hepatocellular carcinoma, underscoring the need for active surveillance for these patients.
... HIV/HCV coinfection is associated with higher risk of fibrosis progression, leading to cirrhosis of the liver and hepatocellular carcinoma if left untreated [10,11]. HCV disease has become a major cause of death among HIVpositive patients [12]. ...
IntroductionWhile coformulated ledipasvir (90 mg)/sofosbuvir (400 mg) (LDV/SOF) is approved for the treatment of hepatitis C virus (HCV) genotype 2 (GT2) infection in Taiwan, Japan, and New Zealand, data regarding its use for HIV (Human Immunodeficiency Virus)-positive patients infected with HCV GT2 are sparse. We aimed to assess the effectiveness and tolerability of LDV/SOF for HIV-positive patients with HCV GT2 coinfection.Methods
From January 2019 to July 2020, consecutive HIV-positive Taiwanese patients infected with HCV GT2 who received LDV/SOF were retrospectively included for analysis. The effectiveness was determined by sustained virologic response 12 weeks off-therapy (SVR12).ResultsOf the 114 patients (mean age, 38.6 years) initiating LDV/SOF during the study period, 0.9% had liver cirrhosis and 4.4% were HCV treatment-experienced. All patients had estimated glomerular filtration rate (eGFR) > 30 ml/min/1.73 m2 and were receiving antiretroviral therapy with 98.2% having CD4 counts ≥ 200 cells/mm3 and 93.9% plasma HIV RNA load < 50 copies/ml. Antiretrovirals prescribed included tenofovir alafenamide/emtricitabine in 42.1%, tenofovir disoproxil fumarate (TDF)/emtricitabine 18.4%, other nucleoside reverse transcriptase inhibitors (NRTIs) 39.5%, non-NRTIs 12.3%, protease inhibitors 13.2%, and integrase inhibitors 74.6%. All patients had undetectable plasma HCV RNA load at the end of treatment, and 96.5% achieved SVR12 in intention-to-treat analysis. The on-treatment eGFR decline was more pronounced in those receiving TDF-containing antiretroviral therapy (mean change, − 8.33 ml/min/1.73 m2), which was reversible after discontinuation of LDV/SOF. None of the patients interrupted LDV/SOF during the 12-week treatment course.Conclusion
Similar to the response observed among HIV-negative patients, LDV/SOF is effective for HIV-positive patients coinfected with HCV GT2.
... The impact of HIV coinfection on active HCV infection is well established. Immunosuppression due to HIV infection leads to a faster progression of HCV-related liver disease through a greater fibrogenesis [1], which is not completely reverted by antiretroviral therapy (ART) [2,3]. Consequently, HIV-coinfected individuals with active HCV infection show a greater risk of developing hepatic decompensation [3] and increased mortality rates [4]. ...
Background:
The aim of this study was to assess the impact of HIV infection on the risk of developing hepatocellular carcinoma (HCC) in HCV-infected patients who achieve sustained virological response (SVR) with direct-acting antiviral (DAA).
Methods:
Multisite prospective cohort study, where HCV-monoinfected patients and HIV/HCV-coinfected individuals were included if they met: 1) SVR with DAA-based combination; 2) Liver stiffness (LS) ≥9.5 kPa previous to treatment; 3) LS measurement at the SVR time-point. The main endpoint was the occurrence of HCC. Propensity score (PS) was calculated to address potential confounders due to unbalanced distribution of baseline characteristics of HIV/HCV-coinfected and HCV-monoinfected patients.
Results:
1035 HCV-infected patients were included, 667 (64%) coinfected with HIV. After a median (Q1-Q3) follow-up time of 43 (31-49) months, 19 (1.8%) patients developed HCC [11 (3.0%) HCV-monoinfected, 8(1.2%) HIV/HCV-coinfected individuals; p=0.013]. In the multivariable analysis, HIV co-infection was associated with a lower adjusted risk of developing HCC [sHR=0.27, 95% IC (0.08-0.90); p=0.034]. Predictors of HCC emergence were: HCV genotype 3 [sHR=7.9 (2.5-24.9); p<0.001], MELD score at SVR>10 [sHR=1.37 (1.01-1.86); p=0.043] and LS value at SVR [sHR=1.03 (1.01-1.06) for 1 kPa increase; p=0.011]. Using inverse probability weighting method on the PS, HIV-infected patients had a lower risk of HCC [powered HR=0.33 (0.11-0.85)].
Conclusions:
Among HCV-infected patients with advanced fibrosis, who achieve SVR with DAA, HIV-coinfection seems to be associated with a lower risk of HCC occurrence. The underlying causes for this finding need to be investigated.
... Most data, therefore, regarding fibrosis progression rates is derived from those with coinfection. These patients have a higher relative risk (RR) of cirrhosis, increased development of decompensated cirrhosis and accelerated fibrosis progression rates compared with those who are only infected with HCV or HBV (10,11). Furthermore, rapid fibrosis correlates with reduced CD4+ T cell counts and detectable plasma HIV levels. ...
While the interactions between HIV and various liver cell populations have been explored, the relevance of these interactions when patients are well-controlled on ART is less clear. Therefore, we focus this perspective on HIV-related alterations that may drive hepatic inflammation and fibrosis in aviremic patients, with a focus on Kupffer cells and Hepatic Stellate Cells. Persistent CD4+ T cell depletion in the gut resulting in increased gut permeability has been postulated to play a role in systemic immune activation in HIV patients. The liver, with its unique location, remains the gatekeeper between the gut and the systemic circulation. The resident liver macrophage, Kupffer cell, is responsible for clearing and responding to these products. We propose that changes in Kupffer cell biology, in the context of HIV infection, creates a mileu that drives hepatic inflammation and fibrosis in response to microbial translocation. Targeting these pathways may be helpful in improving liver-related outcomes in HIV patients.
... This may be because we have data regarding diabetes in a small number of patients and, fasting serum insulin levels and glucose tolerance test was not available. Several studies have shown that fibrosis and necroinflammation correlate with steatosis in CHC and it may play a role in disease progression [26,27]. In our study, there was a linear ascending correlation of steatosis with necroinflammatory score and stages of fibrosis but Sharma, et al., did not find a correlation between steatosis and fibrosis, though there was a correlation between steatosis and necroinflammation in chronic hepatitis C [20] (Figures 1 and 2). ...
... Chronic infection by hepatitis C virus (HCV) is the most common co-infection of HIV positive patients especially in those who report intravenous drug use (IVDU) (1)(2)(3). HIV/HCV coinfection plays an important role in the prognosis of HCV infection considering that co-infected patients develop endstage liver disease with cirrhosis and hepatocellular carcinoma at a younger age than HCV monoinfected patients (4)(5)(6). HIV/HCV co-infection may increase the risk of neurocognitive impairment (7), and increase the risk of cardiovascular disease (8). ...
Background
Estonia has a typical Eastern European HIV epidemic where the most frequent co-infection is chronic hepatitis C (HCV). We aimed to describe the changes in HCV prevalence, the distribution of HCV genotypes (GT), and HCV treatment in Estonian people living with HIV over 15 years.
Methods
We used data of subjects included to the Estonian HIV Cohort Study (E-HIV) before 31 st of December 2015. We compared two time periods – first, 1 st of January 2000 - 31 st of December 2008 when HIV epidemic was mostly spreading among people who inject drugs (PWID) and second, 1 st of January 2009 to 31 st of December 2015 when HIV started to emerge to general population.
Results
Of 4422 HIV positives 3708 (84%) had information about their HCV serostatus; 2706 (61%) were HCV seropositive, of latter 1625 (60%) were HCV RNA positive, 239 (9%) had their HCV GT determined, and 141 (5%) received treatment for HCV. HCV prevalence was 1.5 times (95% CI 1.4-1.6) higher in subjects diagnosed with HIV in first as compared to those diagnosed in second period (84% vs 56%, respectively). There were more men and the median age at HIV diagnosis was lower in HIV/HCV co-infected than in HIV mono-infected patients (70% vs 47% and 24 years vs. 30 years, respectively; both p<0.001).
Conclusion
There is a decrease in HCV prevalence but it remains high among HIV positive PWID, suggesting that there is need for improvement of harm reduction programs among PWID.
... Chronic hepatitis C virus infection (HCV) is a major cause of cirrhosis, liver transplantation and liver-related deaths worldwide [1]. Since HCV and HIV share routes of transmission, it is common to find that HIV-infected patients are also infected with HCV [2], which carries the worst prognosis in these patients due to its faster progression and comorbidities [3,4]. Hence, treatment uptake in this population is mandatory. ...
Several European countries have established criteria for prioritising initiation of treatment in patients infected with the hepatitis C virus (HCV) by grouping patients according to clinical characteristics. Based on neural network techniques, our objective was to identify those factors for HIV/HCV co-infected patients (to which clinicians have given careful consideration before treatment uptake) that have not being included among the prioritisation criteria. This study was based on the Spanish HERACLES cohort (NCT02511496) (April-September 2015, 2940 patients) and involved application of different neural network models with different basis functions (product-unit, sigmoid unit and radial basis function neural networks) for automatic classification of patients for treatment. An evolutionary algorithm was used to determine the architecture and estimate the coefficients of the model. This machine learning methodology found that radial basis neural networks provided a very simple model in terms of the number of patient characteristics to be considered by the classifier (in this case, six), returning a good overall classification accuracy of 0.767 and a minimum sensitivity (for the classification of the minority class, untreated patients) of 0.550. Finally, the area under the ROC curve was 0.802, which proved to be exceptional. The parsimony of the model makes it especially attractive, using just eight connections. The independent variable “recent PWID” is compulsory due to its importance. The simplicity of the model means that it is possible to analyse the relationship between patient characteristics and the probability of belonging to the treated group.
... In these patients, the progression of liver fibrosis is faster than for HCV-monoinfected patients, 15 with higher rates of cirrhosis, decompensation, hepatocellular carcinoma, and death. [16][17][18] During CHC, HCV infection promotes an immune response to control the viral infection, 19 but it also promotes chronic inflammation, non-specific immune activation, immune function dysregulation, and immune senescence, which accelerate liver fibrosis and the development of other comorbidities. [19][20][21] This dysregulation of the immune system can be aggravated by HIV infection. ...
Objective:
There are a lack of consistency among articles in regards to the evolution of peripheral immune biomarkers after HCV therapy. We aimed to detect the most relevant changes in peripheral immune biomarkers among HIV/HCV-coinfected patients who achieved sustained virologic response (SVR) following peg-IFN-α/ribavirin therapy and to evaluate its normalization with respect to an HIV-monoinfected control group.
Methods:
We performed a prospective cohort study in 99 HIV/HCV-coinfected patients with samples at baseline (HIV/HCV-b-group) and at week 24 after SVR (HIV/HCV-f-group). We also used a control group of 39 HIV-monoinfected patients (HIV-group) negative for HCV and HBV infections, and who had undetectable HIV viral load and CD4+ >500 cells/mm3. Peripheral T cell subsets were assessed by flow cytometry and plasma biomarkers by immunoassays.
Results:
HIV/HCV-coinfected patients had higher values of in IL-10, IL-4, IP-10, IL-8, IL-1β, IL-18, IL-6, IFN-γ, IL-12p70, TNF-α, sVCAM-1, sICAM-1, and sTNFR-1 than HIV control subjects, both at the beginning and at the end of follow-up. Moreover, three biomarkers (CD4+CD38+, telomere length, and IL-1RA) were normalized in relation to the control group at the end of follow-up (the HIV/HCV-b group had higher values and the HIV/HCV-f group had similar values as the HIV-group). Additionally, LPS, IL-2, and IL-17A levels were higher in the HIV/HCV-f group than the HIV-group (24 weeks after SVR). During the follow-up, HIV/HCV-coinfected patients had a significant decrease by the end of follow-up in CD8+CD45RA-CD28+, CD4+CD38+, CD4+CD25+CD127-/low, CD4+CD25+CD127-/low CD45RA-, FABP2, LBP, IP-10, sVCAM1. Only CD4+CD38+ was normalized.
Conclusion:
HIV/HCV-patients showed a slight improvement in the overall profile of immune biomarkers after achieving SVR.
... In patients with HIV/HCV coinfection, pre-treatment assessments prior to HCV treatment including the HCV genotype, liver fibrosis, stage of liver disease should be performed. HAART should be considered for HIV/HCV co-infected patients regardless of CD4+ T cell count [67][68][69]. If the CD4+ T cell count is low at <200/mm 3 , antiretroviral therapy should be initiated immediately, and HCV treatment can be delayed until HIV treatment stabilizes. ...
Since the establishment of the Committee for Clinical Guidelines for the Diagnosis and Treatment of human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) by the Korean Society for AIDS in 2010, clinical guidelines have been prepared in 2011, 2013, and 2015. As new research findings on the epidemiology, diagnosis, and treatment of AIDS have been published in and outside of Korea along with the development and introduction of new antiretroviral medications, a need has arisen to revise the clinical guidelines by analyzing such new data. The clinical guidelines address the initial evaluation of patients diagnosed with HIV/AIDS, follow-up tests, appropriate timing of medication, appropriate antiretroviral medications, treatment strategies for patients who have concurrent infections with hepatitis B or C virus, and treatment in pregnant women. Through these clinical guidelines, the Korean Society for AIDS and the Committee for Clinical Guidelines for the Diagnosis and Treatment of HIV/AIDS would like to contribute to overcoming AIDS by delivering the latest data and treatment strategies to healthcare professionals who treat AIDS in the clinic. Copyright © 2019 by The Korean Society of Infectious Diseases and Korean Society for Antimicrobial Therapy.
... Thus, HCV is sexually transmitted but the mechanisms remain unclear. Individuals living with HIV-1 are less likely to spontaneously clear HCV infection during acute infection, have higher HCV viral loads, and experience more rapid liver fibrosis progression than those without HIV-1 infection [9][10][11]. Moreover, mucosal tissue damage as well as sexual practices leading to rectal bleeding are factors that can enhance HCV susceptibility after sexual contact [12]. ...
Introduction
The significant rise in incidence of Hepatitis C virus (HCV) infection among men‐who‐have‐sex‐with‐men (MSM) living with HIV‐1 suggests that HCV under specific circumstances is transmitted via sexual contact. During sexual transmission HCV has to cross the epithelial barrier to either directly enter the blood stream or indirectly via mucosal immune cells. However, the mechanisms of sexual transmission of HCV remain unclear. We investigated the role of Langerhans cells (LCs) in HCV susceptibility during sexual contact as LCs are among the first cells in mucosal tissues to encounter invading viruses.
Methods
We investigated the phenotype of primary LCs in anal biopsies from MSM living with HIV‐1. To investigate the role of primary LCs in HCV infection and transmission, we have used both isolated primary skin LCs and the ex vivo tissue transmission model.
Results
Our data identified an important role for mucosal LCs in facilitating HCV transmission after HIV‐1 exposure or immune activation. LCs were detected within mucosal anal tissues obtained from HIV‐1 positive MSM biopsies. In order to perform functional studies, we used primary LCs from skin, which have a similar phenotype as mucosal LCs. Immature LCs were neither infected nor transmitted HCV to hepatocytes. Notably, exposure to HIV‐1 significantly increased HCV transmission by LCs in the ex vivo transmission model. HIV‐1 replication was crucial for the increased HCV transmission as HIV‐1 inhibitors significantly reduced HIV‐1‐induced HCV transmission. Moreover, tissue immune activation of LCs also increased HCV transmission to target cells.
Conclusions
Thus, our data strongly indicate that HIV‐1 or immune activation in MSM leads to capture of HCV by mucosal LCs, which might facilitate transmission to other cells or allow entry of HCV into the blood. This novel transmission mechanism by LCs also implicates that the activation state of LCs is an important cellular determinant for HCV susceptibility after sexual contact.
... Hepatitis C Virus (HCV) infection is frequent in people living with Human Immunodeficiency Virus (HIV), ranging from 6.2% to 82.4% in injection drug users [1]. HIV/HCV coinfection leads to an increased mortality compared to HIV mono-infected patients [2,3], and a more rapid liver disease progression [4,5]. Liver-related mortality has been ranked first [6,7] with a decline in more recent calendar years [8,9]. ...
Background:
The association between liver stiffness measurements (LSM) and mortality has not been fully described. In particular the effect of LSM on all-cause mortality taking sustained virological response (SVR) into account needs further study.
Methods:
HIV/HCV participants in the French nation-wide, prospective, multicenter ANRS CO13 HEPAVIH cohort, with ≥1 LSM by FibroScan (FS) and a detectable HCV RNA when the first valid FS was performed were included. Cox proportional hazards models with delayed entry were performed to determine factors associated with all-cause mortality. LSM and SVR were considered as time dependent covariates.
Results:
1,062 patients were included from 2005 to 2015 (69.8% men, median age 45.7 years (IQR 42.4-49.1)). 21.7% had baseline LSM >12.5 kPa. Median follow-up was 4.9 years (IQR 3.2-6.1). 727 (68.5%) were ever treated for HCV: 189 of them (26.0%) achieved SVR. 76 deaths were observed (26 liver-related, 10 HIV-related, 29 non-liver-non-HIV-related, 11 of unknown cause). At the age of 50, the mortality rate was 4.5% for patients with LSM ≤12.5 kPa and 10.8% for patients with LSM >12.5 kPa. LSM >12.5 kPa (adjusted Hazard Ratio [aHR] = 3.35 [2.06; 5.45], p<0.0001), history of HCV treatment (aHR = 0.53 [0.32; 0.90], p = 0.01) and smoking (past (aHR = 5.69 [1.56; 20.78]) and current (3.22 [0.93; 11.09]) versus never, p = 0.01) were associated with all-cause mortality independently of SVR, age, sex, alcohol use and metabolic disorders.
Conclusion:
Any LSM >12.5 kPa was strongly associated with all-cause mortality independently of SVR and other important covariates. Our results suggest that close follow-up of these patients should remain a priority even after achieving SVR.
... There is considerable evidence that HIV infection adversely affects the course of a hepatitis C infection. When HIV/HCV coinfection is compared with HCV monoinfection, a more rapid fibrosis [15,16] and liver cirrhosis [16,17] are observed. Coinfected subjects also have an increased risk of hepatocellular carcinoma, which occurs at an earlier age and in a shorter time interval after HCV infection [18][19][20]. ...
... It is now recognized that HIV/HCV co-infected patients are a special population who need special attention in monitoring and follow-up of liver disease: while approximately 20% of HCV untreated patients have a natural progression of liver disease in about 20-30 years, HIV/HCV co-infected patients have a seven times faster progression of the disease [18,19]. Furthermore, steatosis seems more frequent and severe among co-infected patients compared with HCV mono-infected patients, and it is associated with significant liver fibrosis, which may contribute to a more rapid progression of liver disease [20,21]. ...
Purpose
We aimed to assess the diagnostic reliability of two indirect biomarkers, APRI and FIB-4, for the staging of liver fibrosis using transient elastography (TE) as reference standard, among HIV/HCV co-infected and HCV mono-infected patients.
Methods
This is an observational, retrospective study on subjects who had access to the RESIST HCV from October 2013 to December 2016, a regional network encompassing 22 hospitals and academic centers throughout Sicily. Sensitivity, specificity and diagnostic accuracy of indirect biomarkers for liver stiffness measurement (LSM) < 9.5 kPa (significant fibrosis) and LSM ≥ 12.5 kPa (cirrhosis) were determined by receiver operator characteristics (ROC) curves.
Results
238 HIV/HCV co-infected and 1937 HCV mono-infected patients were included. Performances of FIB-4 and APRI for the detection of significant fibrosis and cirrhosis proved to be unsatisfactory, with very high false negative and false positive rates among both cohorts. No significant differences were found after stratification of HIV/HCV co-infected patients for BMI < or ≥ 25, ALT < or ≥ 40 IU/L, ALT < or ≥ 80 IU/L, and presence/absence of a bright liver echo pattern on ultrasonography.
Conclusions
Differently from other studies, we detected the unreliability of APRI and FIB-4 for the assessment of liver fibrosis in both HCV mono-infected and HIV/HCV co-infected patients.
... Consequently, a small but significant population of co-infected patients with HIV and chronic viral hepatitis exists [4,5]. It has long been known that patients with HBV or HCV and HIV coinfection have a more rapidly progressing course of liver disease [6][7][8][9][10][11][12] and increased risk of chronic kidney disease [13]. In addition, early initiation of highly active anti-retroviral therapy (HAART) is essential to avoid serious AIDS-related events among HIV infected individuals [14]. ...
Background
Early identification of patients with chronic viral hepatitis co-infected with HIV is essential for optimal care. The objectives of this study were to estimate the prevalence of HIV co-infection among patients newly diagnosed with chronic viral hepatitis, HIV testing prevalence and identify factors associated with co-infection.
Methods
Patients with chronic viral hepatitis newly enrolled in The Danish Database for Hepatitis B and C between 2002 and 2015 were identified. The HIV co-infection prevalence was calculated and risk factors associated with HIV co-infection estimated by logistic regression.
Results
In total, 8,490 patients were included, of whom 3,091 had chronic hepatitis B (CHB), 5,305 had chronic hepatitis C (CHC) and 94 had CHB and CHC. The prevalence of HIV co-infection was 4.4% [95% confidence interval (CI95%) 4.0; 4.9] and was higher among CHC and CHB-CHC patients than CHB patients with a prevalence of 5.3% [CI95% 4.7; 5.9], 6.4% [CI95% 2.4; 13.4], and 2.9 [CI95% 2.3; 3.5], respectively, p < 0.0001. The HIV testing prevalence increased from 65% to 88% between 2002 and 2014 concurrently with a decrease in the HIV co-infection prevalence from 7.8% [CI95% 5.5; 10.7] to 1.6% [95% 0.7; 3.2]. Age 35–50 years, male sex, and sexual route of viral hepatitis transmission were associated with HIV co-infection with odds ratios of 4.42 [CI95% 1.40; 13.94], 2.21 [CI95% 1.74; 2.81], and 8.81 [CI95% 6.30; 12.33], respectively.
Conclusion
The prevalence of HIV co-infection among patients with newly diagnosed chronic viral hepatitis decreased concurrently with an increase in HIV testing prevalence.
... The progression of chronic hepatitis C (CHC) usually develops slowly, over several decades [14]. However, CHC may be accelerated by the presence of HIV coinfection [16], which promotes an accelerated progression of liver fibrosis and higher rates of cirrhosis, decompensation, and liver failure than patients monoinfected with HCV [17][18][19]. Additionally, CHC increases mortality both associated and not associated with HIV infection [20,21]. ...
Background: Advanced cirrhosis is related to alterations in immunity. We aimed to evaluate the levels of peripheral CD4+ T cells (Tregs) and plasma cytokine in patients coinfected with human immunodeficiency virus and hepatitis C virus (HIV/HCV) according to liver fibrosis stages [evaluated as liver stiffness measure (LSM)] and their linear relationship. Methods: We performed a cross-sectional study on 238 HIV/HCV-coinfected patients (119 had <12.5 kPa, 73 had 12.5–25 kPa, and 46 had >25 kPa). Peripheral T-cell subsets were phenotyped by flow cytometry, plasma biomarkers were assessed by multiplex immunoassays, and LSM was assessed by transient elastography. Results: We found HIV/HCV-coinfected patients had higher values of CD4+ Tregs (p < 0.001), memory Tregs (p ≤ 0.001), and plasma cytokine levels [IFN-γ (p ≤ 0.05) and IL-10 (p ≤ 0.01)] compared with healthy donors and HIV-monoinfected patients. In the multivariate analysis, higher LSM values were associated with reduced levels of IL-10 (adjusted arithmetic mean ratio (aAMR) = 0.83; p = 0.019), IL-2 (aAMR = 0.78; p = 0.017), TNF-α (aAMR = 0.67; p < 0.001), and IL-17A (aAMR = 0.75; p = 0.006). When we focus on HIV/HCV-coinfected patients analyzed by LSM strata, patients with ≥25 kPa had lower values of IL-2 (aAMR = 0.66; p = 0.021), TNF-α (aAMR = 0.565; p = 0.003), and IL-17A (aAMR = 0.58; p = 0.003) than patients with <12.5 kPa. Conclusion: HIV/HCV-coinfected patients showed an immunosuppressive profile compared to healthy controls and HIV-monoinfected patients. Additionally, HIV/HCV-coinfected patients with advanced cirrhosis (LSM ≥ 25 kPa) had the lowest plasma values of cytokines related to Th1 (IL-2 and TNF-α) and Th17 (IL-17A) response.
... Several factors may accelerate the risk of these complications such as age at infection, sex, route of infection, hepatitis C virus (HCV) genotype and obesity, among others (Ortiz et al., 2002;Rotman and Liang, 2009;Rueger et al., 2015). Additionally, human immunodeficiency virus (HIV) infection has a negative impact on the natural history of CHC in HIV/HCV coinfected patients, promoting the risk of fibrosis and cirrhosis, and being an significant cause of morbidity and death in this group of patients (Lopez-Dieguez et al., 2011;Macias et al., 2009). ...
Background:
TNFAIP3 is a crucial hepatoprotective factor due to its anti-inflammatory, anti-apoptotic, anti-oxidant and pro-regenerative functions. The aim of this study was to analyze the associations between genetic variants upstream of TNFAIP3 (rs675520, rs9376293 and rs6920220) and liver fibrosis severity and inflammation in HIV/HCV-coinfected patients.
Methods:
A cross-sectional study was carried out in 215 HIV/HCV-coinfected patients, who underwent a liver biopsy. TNFAIP3 polymorphisms were genotyped using GoldenGate® assay. Outcome variables were: a) liver fibrosis (Metavir score) [fibrosis stage (F0, F1, F2, F3 and F4) and advanced fibrosis and cirrhosis (F ≥ 3 and F4, respectively)]; b) non-invasive indexes [FIB-4, APRI, and their cut-offs (FIB-4 ≥ 3.25 and APRI≥1.5)]; c) inflammation-related biomarkers (leptin, HGF, NGF, sFasL, sFas, MIF, HA, Ang-2, TIMP1, MMP1 and MMP2).
Results:
Patients with rs675520 AG/GG genotypes had decreased odds of having cirrhosis (F4) and advanced fibrosis (FIB-4 ≥ 3.25 and APRI≥1.5) [adjusted Odd Ratio (aOR) = 0.30 (p = 0.025), aOR = 0.20 (p = 0.014), and aOR = 0.34 (p = 0.017), respectively] and lower levels of FIB-4 and APRI [adjusted arithmetic mean ratio (aAMR) = 0.76 (p = 0.003) and aAMR = 0.72 (p = 0.006), respectively]. Patients with rs9376293 CT/CC genotypes had decreased odds of APRI≥1.5 [aOR = 0.39 (p = 0.030)] and lower levels of APRI [aAMR = 0.77 (p = 0.018)]. Patients with rs6920220 AG/AA genotypes had higher odds of having FIB-4 ≥ 3.25 [aOR = 3.72 (p = 0.043)]. Moreover, rs675520 AG/GG genotypes, compared to AA genotype, were associated with lower levels of leptin and NGF (p = 0.002 and p = 0.001, respectively) and higher levels of sFas, MIF, TIMP1 and MMP2 (p = 0.004, p = 0.007, p = 0.020 and p = 0.036, respectively). Also, rs9376293 CT/CC genotypes were related to lower leptin levels (p = 0.026) and higher sFas, MIF, TIMP1 and MMP2 levels (p = 0.029, p = 0.040, p = 0.022 and p = 0.024, respectively).
Conclusions:
Genetic variants upstream of TNFAIP3 were associated with the liver fibrosis severity and inflammation in HIV/HCV-coinfected patients.
... However, antiretroviral therapy should be conducted carefully due to the high risk of liver toxicity caused by interactions between anti-HCV and anti-HIV drugs, especially in HIV/HCV-coinfected patients with progressed liver disease. 173,174 Antiretroviral therapy can be delayed in HIV treatment-naïve patients with a CD4+ lymphocyte count >500/mm 3 to prevent drug-drug interactions until HCV treatment is completed. In patients with a CD4 lymphocyte count <200/mm 3 , antiretroviral therapy should be initiated promptly, but HCV therapy can be delayed until the patient is stable on HIV treatment because no data are available on the efficacy of DAA treatment in severely immunosuppressed patients. ...
... Bei akuter Hepatitis-C-Monoinfektion entwickeln 30 -50 % der Patienten eine Spontanheilung, und eine Therapie in diesem Stadium erreicht deutlich höhere Ansprechraten als bei chronischer Hepatitis C (IIb) [595]. Im Vergleich dazu geht bei HIV-positiven Patienten die akute HCV-Infektion häufiger in eine chronische Hepatitis C über (IIb) [596,597], die dann infolge der Immunsuppression durch HIV beschleunigt zur Fibrose fortschreitet (III) [598,599]. ...
Hepatitis C virus (HCV) infection has been a major global health concern, with a significant impact on public health. In recent years, there have been remarkable advancements in our understanding of HCV and the development of novel therapeutic agents. The Saudi Society for the Study of Liver Disease and Transplantation formed a working group to develop HCV practice guidelines in Saudi Arabia. The methodology used to create these guidelines involved a comprehensive review of available evidence, local data, and major international practice guidelines regarding HCV management. This updated guideline encompasses critical aspects of HCV care, including screening and diagnosis, assessing the severity of liver disease, and treatment strategies. The aim of this updated guideline is to assist healthcare providers in the management of HCV in Saudi Arabia. It summarizes the latest local studies on HCV epidemiology, significant changes in virus prevalence, and the importance of universal screening, particularly among high-risk populations. Moreover, it discusses the promising potential for HCV elimination as a public health threat by 2030, driven by effective treatment and comprehensive prevention strategies. This guideline also highlights evolving recommendations for advancing disease management, including the treatment of HCV patients with decompensated cirrhosis, treatment of those who have previously failed treatment with the newer medications, management in the context of liver transplantation and hepatocellular carcinoma, and treatment for special populations.
Background:
People with HIV and hepatitis C virus (HCV) coinfection experience excess mortality due to multiple causes. Identification of biomarkers associated with mortality beyond that attributable to liver fibrosis may be relevant for prognostication. Fibroblast growth factor 23 (FGF23), a phosphotropic hormone, predicts adverse outcomes in several chronic conditions. We aimed to investigate whether elevated FGF23 predicts all-cause mortality in patients with HIV/HCV coinfection: Methods: We included patients with HIV/HCV coinfection from the Canadian Coinfection Cohort with available serum FGF23, fibrosis biomarker fibrosis-4 (FIB-4), and at least 1 year follow up. Elevated FGF23 and advanced liver fibrosis were defined as FGF23>241 reference unit/mL and FIB-4>3.25, respectively. All-cause mortality was analyzed using survival analysis. The effect of advanced liver fibrosis as a mediator on mortality was estimated by mediation analysis.
Results:
321 patients were included (24% with elevated FGF23, 19% with advanced liver fibrosis). During a mean follow-up period of 8.4 years, 34% of the cohort died. The incidence rate of all-cause mortality was higher in patients with elevated FGF23 (66.1 per 1000 person-years (PY), 95% CI 45.8-92.3) relative to patients without elevated FGF23 (37.5 per 1000 PY, 95% CI 29.6-46.9). After adjusting for potential confounders, elevated FGF23 was associated with significant direct and indirect effects (mediated through advanced liver fibrosis) on all-cause mortality, with 57% of deaths not mediated via advanced fibrosis.
Conclusions:
In patients with HIV/HCV coinfection, FGF23 may be used as prognostic biomarker for risk stratification accounting also for death causes other than those attributable to liver fibrosis.
Background:
Chronic liver disease has emerged as a leading cause of non-AIDS-related mortality in hepatitis C virus (HCV)/human immunodeficiency virus (HIV)-coinfected patients. The relationship between CD4 cell count and HIV-related opportunistic infections and tumors has been well characterized; however, it is unclear whether CD4 cell count is associated with HCV-related hepatic events.
Methods:
This observational cohort study enrolled HCV/HIV-coinfected patients from the National Free Antiretroviral Treatment Program of China from 2004 to 2019 in Guangzhou. The primary outcome was a composite of hepatic events, including cirrhosis complications, hepatocellular carcinoma (HCC), and liver-related mortality. Kaplan-Meier survival and multivariate logistic regression analyses were performed.
Results:
Among the 793 patients, 43 developed hepatic events during a median follow-up of 6.7 years, including 35 cirrhosis complications, 13 HCC cases, and 14 cases of liver-related mortality. The 5-year and 10-year cumulative incidences of hepatic events were 4.2% and 9.3%, respectively. Patients who developed hepatic events had a less satisfactory increase in CD4 cell count, lower peak CD4 (354.5/μL vs. 560.0/μL, P < 0.001), and lower percentage of peak CD4 > 500/μL (30.2% vs. 60.7%, P < 0.001) after the initiation of antiretroviral therapy (ART) than those who did not. The cumulative incidences of hepatic events were higher in patients with lower peak CD4 levels with adjusted odds ratios of 3.96 (95% confidence interval [CI]: 1.51-10.40), 2.25 (95% CI: 0.87-5.86), and 0.98 (95% CI: 0.35-2.74) for patients with peak CD4 at <200/μL, 200-350/μL, and 351 to 500/μL, respectively, relative to those with peak CD4 > 500/μL. Peak CD4 was negatively associated with the risk of hepatic events in a dose-response manner (P-value for trend = 0.004).
Conclusion:
Persistently low CD4 cell counts after ART are independently associated with a high risk of hepatic events in HCV/HIV-coinfected patients, highlighting the important role of immune reconstitution in improving liver outcomes.
Bacteria, viruses, and parasites are harmful microorganisms that cause infectious diseases. Early detection of diseases is critical to prevent disease transmission and provide epidemic preparedness, as these can cause widespread deaths and public health crises, particularly in resource-limited countries. Lateral flow assay (LFA) systems are simple-to-use, disposable, inexpensive diagnostic devices to test biomarkers in blood and urine samples. Thus, LFA has recently received significant attention, especially during the pandemic. Here, first of all, the design principles and working mechanisms of existing LFA methods are examined. Then, current LFA implementation strategies are presented for communicable disease diagnoses, including COVID-19, zika and dengue, HIV, hepatitis, influenza, malaria, and other pathogens. Furthermore, this review focuses on an overview of current problems and accessible solutions in detecting infectious agents and diseases by LFA, focusing on increasing sensitivity with various detection methods. In addition, future trends in LFA-based diagnostics are envisioned.
Resumen
El aumento de la esperanza de vida desde la introducción del tratamiento antirretroviral (TAR), junto con el envejecimiento de la población con infección por el VIH, ha motivado que en los últimos años haya crecido el interés por las complicaciones no infecciosas descritas en estos pacientes, en los que se ha detectado un incremento de la incidencia de tumores no asociados a SIDA, complicaciones hepáticas y cardiovasculares, entre otros eventos, y que actualmente se asocian con una importante morbimortalidad. En esta actualización, abordaremos los aspectos más relevantes de las principales complicaciones no infecciosas que presentan los pacientes con infección por el VIH en la actualidad y los aspectos clave a valorar durante el seguimiento.
We aimed to evaluate the association of plasma biomarkers linked to inflammation (bacterial translocation, inflammatory response, and endothelial dysfunction), coagulopathy, and angiogenesis with the severity of liver cirrhosis (assessed by the Child-Pugh-Turcotte score, CTP) and Child-Pugh B cirrhosis (CTP 7–9) in patients with advanced hepatitis C virus (HCV)-related cirrhosis. We carried out a cross-sectional study in 97 patients with advanced HCV-related cirrhosis (32 HCV-monoinfected and 65 HIV/HCV-coinfected). Plasma biomarkers were measured by ProcartaPlex multiplex immunoassays. The outcome variable was the CTP score and the Child-Pugh B cirrhosis (CTP 7–9). HIV/HCV-coinfected patients and HCV-monoinfected patients with advanced HCV-related cirrhosis had near-equivalent values of plasma biomarkers. Higher values of plasma biomarkers linked to an inflammatory response (IP-10, IL-8, IL-6, and OPG), endothelial dysfunction (sVCAM-1 and sICAM-1), and coagulopathy (D-dimer) were related to higher CTP values. The most significant biomarkers to detect the presence of Child-Pugh B cirrhosis (CTP 7–9) were IP-10 (p-value= 0.008) and IL-6 (p-value=0.002). The AUC-ROC values of IP-10, IL-6, and both biomarkers combined (IP-10+IL-6) were 0.78, 0.88, and 0.96, respectively. In conclusion, HIV infection does not appear to have a significant impact on the analyzed plasma biomarkers in patients with advanced HCV-related cirrhosis. However, plasma biomarkers linked to inflammation (inflammatory response and endothelial dysfunction) were related to the severity of liver cirrhosis (CTP score), mainly IP-10 and IL-6, which discriminated patients with Child-Pugh B concerning Child-Pugh A.
HIV co‐infection has been suggested to play a deleterious role on the pathogenesis of liver fibrosis among vertically HCV infected children. The aim of this study was to describe the longitudinal evolution of vertically acquired HIV/HCV co‐infection in youths, in comparison to HCV infection alone. This was a retrospective, multicenter study including vertically‐HIV/HCV co‐infected patients and age and sex‐matched vertically HCV mono‐infected patients. Progression to advanced liver fibrosis, defined as F3 or more by elastography or METAVIR biopsy staging and response to treatment were compared by means of uni and multivariate regression analysis and Cox regression models. Sixty‐seven co‐infected patients were compared to 67 matched HCV mono‐infected patients. No progression to advanced liver disease was observed during the first decade. At a median age of 20.0 [19.0, 22.0] years, 26.7% co‐infected vs. 20% mono‐infected had progressed to advanced fibrosis (p=0.617). Peg‐IFN/RBV for HCV treatment was given to 37.9% vs 86.6% (p‐value<0.001). At treatment initiation, co‐infected patients were older (16.9±4.1 vs. 11.7±4.5 years, p<0.001), and 47.1% vs. 7.1% showed advanced fibrosis (p<0.003), with no differences in hard‐to‐treat genotype distribution. Sustained viral response was comparable between groups (43.5% vs 44.0%, p=0.122). In vertically HIV/HCV co‐infected patients, the progression to liver fibrosis was rare during childhood. At the end of adolescence, over 25% of patients displayed advanced liver disease. Response to Peg‐IFN/RBV was poor and comparable in both groups, supporting the need for fast access to early treatment with direct acting antivirals against HCV for vertically co‐infected patients.
Due to shared routes of transmission, prevalence of hepatitis C virus (HCV) infection in human immunodeficiency virus (HIV)-infected patients is high.
Objectives:
To compare the efficacy of sofosbuvir/ledipasvir (SOF/LDV) for 8 weeks (SL8) versus a 12-week course of SOF/LDV (SL12) among HIV/HCV-coinfected patients in clinical practice. In addition we compared sustained virological response (SVR) rates achieved with SL8 in HCV-monoinfected and HIV/HCV-coinfected patients in a real life setting.
Methods:
HCV-infected patients were retrospectively selected from the HEPAVIR-DAA and GEHEP-MONO real-life prospective cohorts if they fulfilled the following criteria: 1) Infected with genotype 1; 2) Treatment with SL8 or SL12; 3) Treatment naïve prior to receiving SL8 or SL12; 4) Absence of cirrhosis; 5) Baseline HCV RNA<6 × 106 IU/mL; 6) Reached the scheduled time-point for SVR (SVR12) assessment. SVR12 and relapse rates of HCV-monoinfected and HIV/HCV-coinfected patients were compared on an intention to treat basis. The responses with SL8 and SL12 were also compared.
Results:
In the SL8 group, 107 (51%) HCV-monoinfected and 102 (49%) HIV/HCV-coinfected patients were included. One hundred and sixty-four (43%) HCV-monoinfected subjects and 220 (57%) HIV/HCV-coinfected patients received SL12. SVR12 rates for HIV/HCV-coinfected patients treated with SL8 vs SL12 were SVR12 92.2% vs. 97.3% (p = 0.044) and the respective relapse rates were 4.9% vs. 0.5% (p = 0.013). SVR12 rates for SL8 among HCV-monoinfected and HIV/HCV-coinfected patients were: 96.3% vs. 92.2% (p = 0.243), respectively. The corresponding relapse rates were 0.9% vs. 4.9% (p = 0.112).
Conclusion:
HIV/HCV-coinfected patients reach high rates of SVR12 with SL8, although lower than with SL12, mainly due to a higher probability of relapse. SVR12 rates with SL8 are numerically lower and the proportion of relapses higher in HIV/HCVcoinfected patients than in HCV-monoinfected subjects.
Lipodystrophy is a group of clinically heterogeneous, inherited or acquired, disorders characterized by complete or partial absence of subcutaneous adipose tissue that may occur simultaneously with the pathological, ectopic, accumulation of fat in other regions of the body, including the liver. Fatty liver adds significantly to hepatic and extra-hepatic morbidity in patients with lipodystrophy. Lipodystrophy is strongly associated with severe insulin resistance and related comorbidities, such as hyperglycemia, hyperlipidemia and nonalcoholic fatty liver disease (NAFLD), but other hepatic diseases may co-exist in some types of lipodystrophy, including autoimmune hepatitis in acquired lipodystrophies, or viral hepatitis in human immunodeficiency virus (HIV)-associated lipodystrophy. The aim of this review is to summarize evidence linking lipodystrophy with hepatic disease and to provide a special focus on potential therapeutic perspectives of leptin replacement therapy and adiponectin upregulation in lipodystrophy.
Objective:
To assess the impact of HIV-coinfection on the risk of developing liver related complications in HCV-infected patients with advanced fibrosis treated with direct-acting antivirals (DAA) after sustained virological response (SVR).
Design:
Prospective cohort study SETTING:: Multicenter SUBJECTS:: Patients from the GEHEP and HEPAVIR cohorts, were selected if they fulfilled the following criteria: 1) Treatment against HCV with all oral DAA combination; 2) SVR achievement, defined as undetectable plasma HCV RNA 12 weeks after the end of therapy; 3) Pre-treatment liver stiffness (LS) equal to or higher than 9.5 kPa; 4) LS measurement at the time of SVR.
Main outcome measure(s):
The primary variable was the time until the development of a liver complication or requiring liver transplant.
Results:
Seven hundred-seventeen patients were included and 507 (71%) were coinfected with HIV. After a median follow-up time of 21 (14-25) months, 15 (2.1%) patients developed a liver complication and/or underwent a liver transplant and 15 (2.0%) died. The probability of remaining free of hepatic complications or transplant at one and two years was, respectively, 99% and 96% in HCV-monoinfected patients and 99% and 98% in coinfected patients (p=0.648). In a multivariate analysis, in which non liver-related death was considered as a competing event, HIV coinfection was not associated with the appearance of hepatic complications or requiring liver transplant [HR=0.24; 95% CI (0.03-1.93) p=0.181]. Having presented hepatic decompensation prior to SVR [HR = 29.06; 95% CI (3.91-216.16) p < 0.001] and the value of LS at the SVR time-point (HR = 1.12; 95%CI (1.07-1.18) p < 0.001] were associated with a higher probability of development of liver events.
Conclusion:
HIV coinfection is not associated with a higher probability of developing liver complications in HCV-infected patients with advanced fibrosis, who achieved SVR with interferon-free regimens.
This update to the document on antiretroviral therapy (ART) in adults, which has been prepared jointly by GeSIDA and the Spanish National AIDS Plan for the last two decades, supersedes the document published in 2017.¹ The update provides physicians treating HIV-1-infected adults with evidence-based recommendations to guide their therapeutic decisions. The main difference with respect to the previous document concerns recommended initial ART regimens, only three of which are maintained as preferential. All three include dolutegravir or raltegravir, together with emtricitabine/tenofovir alafenamide or abacavir/lamivudine. Other differences concern the section on switching ART in patients with suppressed viral replication, which now includes new two- and three-drug regimens, and the antiretroviral drugs recommended for pregnant women and patients with tuberculosis. A recommendation has also been added for patients who present with acute HIV infection after pre-exposure prophylaxis.
Hepatotropic viruses induced hepatitis progresses much faster and causes more liver- related health problems in people co-infected with human immunodeficiency virus (HIV). Although treatment with antiretroviral therapy has extended the life expectancy of people with HIV, liver disease induced by hepatitis B virus (HBV) and hepatitis C virus (HCV) causes significant numbers of non-acquired immune deficiency syndrome (AIDS)-related deaths in co-infected patients. In recent years, new insights into the mechanisms of accelerated fibrosis and liver disease progression in HIV/HCV and HIV/HBV co-infections have been reported. In this paper, we review recent studies examining the natural history and pathogenesis of liver disease in HIV-HCV/HBV co-infection in the era of direct acting antivirals (DAA) and antiretroviral therapy (ART). We also review the novel therapeutics for management of HIV/HCV and HIV/HBV co-infected individuals.
Retrospective studies indicate that co-infection of hepatitis C virus (HCV) and human immunodeficiency virus (HIV) accelerates hepatic fibrosis progression. We have developed a co-culture system (MLH) comprising primary macrophages, hepatic stellate cells (HSC, LX-2), and hepatocytes (Huh-7), permissive for active replication of HCV and HIV, and assessed the effect of these viral infections on the phenotypic changes and fibrogenic gene expression in LX-2 cells. We detected distinct morphological changes in LX-2 cells within 24 hr post-infection with HCV, HIV or HCV/HIV in MLH co-cultures, with migration enhancement phenotypes. Human fibrosis microarrays conducted using LX-2 cell RNA derived from MLH co-culture conditions, with or without HCV and HIV infection, revealed novel insights regarding the roles of these viral infections on fibrogenic gene expression in LX-2 cells. We found that HIV mono-infection in MLH co-culture had no impact on fibrogenic gene expression in LX-2 cells. HCV infection of MLH co-culture resulted in upregulation (>1.9x) of five fibrogenic genes including CCL2, IL1A, IL1B, IL13RA2 and MMP1. These genes were upregulated by HCV/HIV co-infection but in a greater magnitude. Conclusion: Our results indicate that HIV-infected macrophages accelerate hepatic fibrosis during HCV/HIV co-infection by amplifying the expression of HCV-dependent fibrogenic genes in HSC.
It is widely accepted that HIV infection is a risk factor for increased severity of HCV liver disease. However, owing to better efficacy and safety of cART, and increased access to HCV therapy, whether this condition remains true is still unknown. 1,253 HCV mono‐infected patients and 175 HIV/HCV co‐infected cirrhotic patients, included in two prospective French national cohorts (ANRS CO12 CirVir and CO13 HEPAVIH) were studied. Cirrhosis was compensated (Child‐Pugh A), without prior history of complication, and assessed on liver biopsy. Incidences of liver decompensation, hepatocellular carcinoma (HCC) and death according to HIV status were calculated by a Fine‐Gray model adjusted for age. Propensity score matching was also performed to minimize confounding by baseline characteristics. At baseline, HIV/HCV patients were younger (47.5 vs. 56.0 years, p<0.001), more frequently males (77.1% vs. 62.3%, p<0.001), and had at baseline and at end of follow‐up, similar rates of HCV eradication than HCV mono‐infected patients. 80.4% of HIV/HCV patients had an undetectable HIV viral load. After adjustment for age, 5‐year cumulative incidences of HCC and decompensation were similar in HIV/HCV and HCV patients (8.5% vs. 13.2%, p=0.12 and 12.8% vs. 15.6%, p=0.40, respectively). Overall mortality adjusted for age was higher in HIV/HCV co‐infected patients (SHR=1.88; 95% CI: 1.15‐3.06, p = 0.011). Factors associated with liver decompensation and HCC were age, absence of SVR and severity of cirrhosis, but not HIV status. Using a propensity score matching 95 patients of each group according to baseline features, similar results were observed. In HCV‐infected cirrhotic patients, HIV co‐infection was no longer associated with higher risks of HCC and hepatic decompensation. Increased mortality however persisted, due to extra‐hepatic conditions. This article is protected by copyright. All rights reserved.
The two currently available types of pegylated interferon (peg-IFN) used to treat hepatitis C have different pharmacokinetic properties. It is unclear how these differences affect response to therapy. We compared the effectiveness and safety of peg-IFN-alpha2a and peg-IFN-alpha2b, both with ribavirin, against chronic hepatitis C virus (HCV) infection in HIV-infected patients.
From the GESIDA HIV/HCV cohort, we analysed patients treated with peg-IFN-alpha2a (n = 315) or peg-IFN-alpha2b (n = 242). The primary endpoint was a sustained virological response (SVR).
Both groups were well matched in baseline characteristics except for a higher frequency of injection drug users in the peg-IFN-alpha2b group than in the peg-IFN-alpha2a group (85% versus 76%; P = 0.01) and a higher frequency of bridging fibrosis and cirrhosis (F3-F4) in the peg-IFN-alpha2b group than in the peg-IFN-alpha2a group (42% versus 33%; P = 0.04). End-of-treatment response was significantly lower among patients treated with peg-IFN-alpha2b [40% versus 52%; odds ratio (OR), 1.63; 95% confidence interval (95% CI), 1.16-2.29; P < 0.01]. However, no significant differences were found in SVR between patients treated with peg-IFN-alpha2b and those treated with peg-IFN-alpha2a (31% versus 33%; OR, 1.09; 95% CI, 0.75-1.59; P = 0.655). Therapy was interrupted due to adverse events in 33 (14%) patients treated with peg-IFN-alpha2b and 47 (15%) patients treated with peg-IFN-alpha2a.
No differences in effectiveness and safety were found between peg-IFN-alpha2b and peg-IFN-alpha2a for the treatment of chronic HCV infection in HIV-infected patients.
Liver fibrosis is an important prognostic factor in patients with hepatitis C. The effect of pegylated (PEG) interferon alone or its combination with ribavirin on fibrosis has not been established.
We pooled individual data from 3010 naive patients with pretreatment and posttreatment biopsies from 4 randomized trials. Ten different regimens combining standard interferon, PEG interferon, and ribavirin were compared. The impact of each regimen was estimated by the percentage of patients with at least 1 grade improvement in the necrosis and inflammation (METAVIR score), the percentage of patients with at least 1 stage worsening in fibrosis METAVIR score, and by the fibrosis progression rate per year.
Necrosis and inflammation improvement ranged from 39% (interferon 24 weeks) to 73% (optimized PEG 1.5 and ribavirin; P < 0.001). Fibrosis worsening ranges from 23% (interferon 24 weeks) to 8% (optimized PEG 1.5 and ribavirin; P < 0.001). All regimens significantly reduced the fibrosis progression rates in comparison to rates before treatment. The reversal of cirrhosis was observed in 75 patients (49%) of 153 patients with baseline cirrhosis. Six factors were independently associated with the absence of significant fibrosis after treatment: baseline fibrosis stage (odds ratio [OR] = 0.12; P < 0.0001), sustained viral response (OR = 0.36; P < 0.0001), age < 40 years (OR = 0.51; P < 0.001), body mass index < 27 kg/m(2) (OR = 0.65; P < 0.001), no or minimal baseline activity (OR = 0.70; P = 0.02), and viral load < 3.5 millions copies per milliliter (OR = 0.79; P = 0.03).
PEG-interferon and ribavirin combination significantly reduces the rate of fibrosis progression in patients with hepatitis C.
A study was performed in 10 European health care centers in which 914 patients coinfected with hepatitis C virus (HCV) and
human immunodeficiency virus (HIV) who had elevated serum alanine aminotransferase (ALT) levels underwent liver biopsy during
the period of 1992 through 2002. Overall, the METAVIR liver fibrosis stage was F0 in 10% of patients, F1 in 33%, F2 in 22%,
F3 in 22%, and F4 in 13%. Predictors of severe liver fibrosis (METAVIR stage, F3 or F4) in multivariate analysis were age
of >35 years (odds ratio [OR], 2.95; 95% confidence interval [CI], 2.08–4.18), alcohol consumption of >50 g/day (OR, 1.61;
95% CI, 1.1–2.35), and CD4+ T cell count of <500 cells/mm3 (OR, 1.43; 95% CI, 1.03–1.98). Forty-six percent of patients aged >40 years had severe liver fibrosis, compared with 15%
of subjects aged <30 years. The use of antiretroviral therapy was not associated with the severity of liver fibrosis. In summary,
severe liver fibrosis is frequently found in HCV-HIV-coinfected patients with elevated serum ALT levels, and its severity
increases significantly with age. The rate of complications due to end-stage liver disease will inevitably increase in this
population, for whom anti-HCV therapy should be considered a priority.
The natural history of hepatitis C virus (HCV) infection remains uncertain. Previous data concerning rates of progression are from studies using estimated dates of infection and single liver biopsy scores. We prospectively studied the rate of progression of fibrosis in HCV infected patients by repeat liver biopsies without intervening treatment.
We studied 214 HCV infected patients (126 male; median age 36 years (range 5-8)) with predominantly mild liver disease who were prospectively followed without treatment and assessed for risk factors for progression of liver disease. Interbiopsy interval was a median of 2.5 years. Paired biopsies from the same patient were scored by the same pathologist.
Seventy of 219 (33%) patients showed progression of at least 1 fibrosis point in the Ishak score; 23 progressed at least 2 points. Independent predictors of progression were age at first biopsy and any fibrosis on first biopsy. Factors not associated with progression were: necroinflammation, duration of infection, alcohol consumption, alanine aminotransferase levels, current or past hepatitis B virus infection, ferritin, HCV genotype, and steatosis or iron deposition in the initial biopsy.
One third of patients with predominantly mild hepatitis C showed significant fibrosis progression over a median period of 30 months. Histologically, mild hepatitis C is a progressive disease. The overall rate of fibrosis progression in patients with hepatitis C was low but increased in patients who were older or had fibrosis on their index biopsy. These data suggest that HCV infection will place an increasing burden on health care services in the next 20 years.
Background
Recent studies strongly suggest that due to the limitations and risks of biopsy, as well as the improvement of the diagnostic accuracy of biochemical markers, liver biopsy should no longer be considered mandatory in patients with chronic hepatitis C. In 2001, FibroTest ActiTest (FT-AT), a panel of biochemical markers, was found to have high diagnostic value for fibrosis (FT range 0.00–1.00) and necroinflammatory histological activity (AT range 0.00–1.00). The aim was to summarize the diagnostic value of these tests from the scientific literature; to respond to frequently asked questions by performing original new analyses (including the range of diagnostic values, a comparison with other markers, the impact of genotype and viral load, and the diagnostic value in intermediate levels of injury); and to develop a system of conversion between the biochemical and biopsy estimates of liver injury.
Results
A total of 16 publications were identified. An integrated database was constructed using 1,570 individual data, to which applied analytical recommendations. The control group consisted of 300 prospectively studied blood donors. For the diagnosis of significant fibrosis by the METAVIR scoring system, the areas under the receiver operating characteristics curves (AUROC) ranged from 0.73 to 0.87. For the diagnosis of significant histological activity, the AUROCs ranged from 0.75 to 0.86. At a cut off of 0.31, the FT negative predictive value for excluding significant fibrosis (prevalence 0.31) was 91%. At a cut off of 0.36, the ActiTest negative predictive value for excluding significant necrosis (prevalence 0.41) was 85%. In three studies there was a direct comparison in the same patients of FT versus other biochemical markers, including hyaluronic acid, the Forns index, and the APRI index. All the comparisons favored FT (P < 0.05). There were no differences between the AUROCs of FT-AT according to genotype or viral load. The AUROCs of FT-AT for consecutive stages of fibrosis and grades of necrosis were the same for both moderate and extreme stages and grades. A conversion table was constructed between the continuous FT-AT values (0.00 to 1.00) and the expected semi-quantitative fibrosis stages (F0 to F4) and necrosis grades (A0 to A3).
Conclusions
Based on these results, the use of the biochemical markers of liver fibrosis (FibroTest) and necrosis (ActiTest) can be recommended as an alternative to liver biopsy for the assessment of liver injury in patients with chronic hepatitis C. In clinical practice, liver biopsy should be recommended only as a second line test, i.e., in case of high risk of error of biochemical tests.
Cohort studies have shown that highly active antiretroviral therapy (HAART) can improve liver-related mortality in HIV/hepatitis C virus (HCV)-coinfected patients. A reduction in the accelerated liver fibrosis progression observed in HIV infection induced by HAART could explain these findings. A few studies have assessed the impact of HAART on liver fibrosis, but with contradictory results. Therefore, we evaluated the associations between the use of different antiretroviral drug classes and HAART combinations, and liver fibrosis in HIV-infected patients with chronic hepatitis C. Six hundred and eighty-three HIV/HCV-coinfected patients, who underwent a liver biopsy and who had not received anti-HCV treatment were included. Age at HCV infection < 23years (adjusted odds ratio [AOR] = 0.7, 95% confidence interval [95% CI] = 0.3-0.9, P = 0.05) and protease inhibitor (PI)-based HAART versus no use of HAART (AOR = 0.5, 95% CI = 0.3-0.9, P = 0.01) were negatively associated with advanced fibrosis (> or = F3). PI-based HAART versus no use of HAART (AOR = 0.4, 95% CI = 0.2-0.7, P = 0.001) was negatively associated with fibrosis progression rate > or = 0.2 units/year and independently of age at HCV infection and CD4+ T-cell counts. Fifteen (17%) patients treated only with PIs and zidovudine plus lamivudine showed > or = F3, compared with 65 (37%) patients without HAART (P = 0.001). Forty (31%) patients on PI and stavudine plus lamivudine showed > or = F3 (P = 0.3, when compared with patients with no HAART). The use of PI-based HAART in HIV/HCV-coinfected patients is associated with less severe fibrosis and slower progression of fibrosis. The nucleoside analogue backbone in a HAART regimen may influence this association.
The availability of an increasing number of antiretroviral agents and the rapid evolution of new information has introduced extraordinary complexity into the treatment of HIV-infected persons. In 1996, the Department of Health and Human Services and the Henry J. Kaiser Family Foundation convened the Panel on Clinical Practices for the Treatment of HIV to develop guidelines for the clinical management of HIV-infected adults and adolescents. This report recommends that care should be supervised by an expert, and it makes recommendations for laboratory monitoring with particular emphasis on measurement of plasma levels of HIV RNA. It also provides guidelines for antiretroviral therapy, including when to start treatment, what drugs to initiate, when to change therapy, and therapeutic options when changing therapy. Special consideration is given to adolescents and pregnant women. As with decisions about treatment of other chronic conditions, therapeutic decisions about HIV disease require a mutual understanding between the patient and the health care provider regarding the benefits and risks of treatment. Like treatment for most chronic diseases, antiretroviral regimens are complex, have major side effects, pose difficulty with compliance, and carry serious potential consequences with the risk for resistance from nonadherence to the drug regimen or suboptimal levels of antiretroviral agents. Patient education and involvement in therapeutic decisions is important for all medical conditions but is considered especially critical for HIV infection and its treatment. With regard to specific recommendations, treatment should be offered to all patients with the acute HIV syndrome, those within 6 months of seroconversion, and all patients with symptoms ascribed to HIV infection. Recommendations for offering antiretroviral therapy to asymptomatic patients depend on virologic and immunologic factors. In general, treatment should be offered to individuals with fewer than 500 CD4+ T cells/mm3 or plasma HIV RNA levels exceeding 10 000 copies/mL (branched DNA assay) or 20 000 copies/mL (reverse transcriptase polymerase chain reaction assay). The strength of the recommendation to treat asymptomatic patients should be based on the patient's willingness to accept therapy, the probability of adherence with the prescribed regimen, and the prognosis in terms of time to an AIDS- defining complication as predicted by plasma HIV RNA levels and CD4+ T-cell counts, which independently help predict prognosis. Once the decision has been made to initiate antiretroviral therapy, the goal is maximum viral suppression for as long as possible. Results of clinical trials to data indicate that this may currently be best achieved with a potent protease inhibitor in combination with two nucleoside analogue reverse transcriptase inhibitors (NRTIs). Another option is the combination of saquinavir plus ritonavir combined with one or two NRTIs. Other currently available regimens may be used in selected settings but are considered by many to be less likely to produce maximum viral suppression. Results of therapy are evaluated primarily with plasma HIV RNA levels; these are expected to show a one-log (10-fold) decrease at 8 weeks and no detectable virus (<500 copies/mL) at 4 to 6 months after initiation of treatment. Failure of therapy (i.e., plasma HIV RNA levels >500 copies/mL) at 4 to 6 months may be ascribed to nonadherence, inadequate potency of drugs or suboptimal levels of antiretroviral agents, resistance, and other factors that are poorly understood. Patients whose therapy fails should change to at least two new agents that are not likely to show cross-resistance with drugs given previously; ideally, the regimen should be changed to a completely new regimen that is devoid of anticipated cross-resistance and for which clinical trial data support a high probability of viral response. Rational changes in therapy may be especially difficult to achieve for patients for whom the preferred regimen has failed, because of limitations in the available alternative antiretroviral regimens that have documented efficacy; these decisions are further confounded by problems with adherence, toxicity, and resistance. In some settings, it may be preferable for a patient to participate in a clinical trial with or without access to new drugs or to use a regimen that may not achieve the optimal virologic goal.
Background:
The natural history of hepatitis C virus (HCV) infection remains uncertain. Previous data concerning rates of progression are from studies using estimated dates of infection and single liver biopsy scores. We prospectively studied the rate of progression of fibrosis in HCV infected patients by repeat liver biopsies without intervening treatment.
Patients:
We studied 214 HCV infected patients (126 male; median age 36 years (range 5-8)) with predominantly mild liver disease who were prospectively followed without treatment and assessed for risk factors for progression of liver disease. Interbiopsy interval was a median of 2.5 years. Paired biopsies from the same patient were scored by the same pathologist.
Results:
Seventy of 219 (33%) patients showed progression of at least 1 fibrosis point in the Ishak score; 23 progressed at least 2 points. Independent predictors of progression were age at first biopsy and any fibrosis on first biopsy. Factors not associated with progression were: necroinflammation, duration of infection, alcohol consumption, alanine aminotransferase levels, current or past hepatitis B virus infection, ferritin, HCV genotype, and steatosis or iron deposition in the initial biopsy.
Conclusions:
One third of patients with predominantly mild hepatitis C showed significant fibrosis progression over a median period of 30 months. Histologically, mild hepatitis C is a progressive disease. The overall rate of fibrosis progression in patients with hepatitis C was low but increased in patients who were older or had fibrosis on their index biopsy. These data suggest that HCV infection will place an increasing burden on health care services in the next 20 years.
Unlabelled:
Human immunodeficiency virus (HIV) infection modifies the natural history of chronic hepatitis C, thus promoting more rapid progression to cirrhosis and end-stage liver disease. The objective of our study was to determine whether hepatitis C virus (HCV) clearance is associated with improved clinical outcomes in patients positive for HIV and HCV. It was an ambispective cohort study carried out in 11 HIV units in Spain and involved 711 consecutive patients positive for HIV/HCV who started interferon plus ribavirin therapy between 2000 and 2005. We measured sustained virologic response (SVR), i.e., undetectable HCV RNA at 24 weeks after the end of treatment, and clinical outcomes, defined as death (liver-related or non-liver-related), liver decompensation, hepatocellular carcinoma, and liver transplantation. Of 711 patients who were positive for HIV/HCV, 31% had SVR. During a mean follow-up of 20.8 months (interquartile range: 12.2-38.7), the incidence rates per 100 person-years of overall mortality, liver-related mortality, and liver decompensation were 0.46, 0.23, and 0.23 among patients with SVR and 3.12, 1.65, and 4.33 among those without SVR (P = 0.003, 0.028, and <0.001 by the log-rank test), respectively. Cox regression analysis adjusted for fibrosis, HCV genotype, HCV RNA viral load, Centers for Disease Control and Prevention clinical category, and nadir CD4+ cell count showed that the adjusted hazard ratio of liver-related events was 8.92 (95% confidence interval, 1.20; 66.11, P = 0.032) for nonresponders in comparison with responders and 4.96 (95% confidence interval, 2.27; 10.85, P < 0.001) for patients with fibrosis grade of F3-F4 versus those with F0-F2.Because this was not a prospective study, selection and survival biases may influence estimates of effect.
Conclusion:
Our results suggest that the achievement of an SVR after interferon-ribavirin therapy in patients coinfected with HIV/HCV reduces liver-related complications and mortality.
The extent of liver fibrosis is an important prognostic factor in patients infected with hepatitis C virus. Administration of a combination of interferon and ribavirin produces a superior viral clearance response rate than interferon alone. The effect of this combination regimen on hepatic fibrosis has not been established. To determine the impact of combination regimen or interferon alone on the progression of liver fibrosis we pooled individual data of 1,509 patients with pretreatment and post-treatment biopsies from 3 randomized trials. Fibrosis progression and regression rates between biopsies were calculated by the Kaplan-Meier method and by the fibrosis progression rate per year. The percentage of patients without significant fibrosis (stage 0 or 1) at 96 weeks was 68 +/- 4% (mean +/- SE) when treated by combination regimen for 48 weeks, 64 +/- 4% by interferon alone for 48 weeks, 42 +/- 7% by combination regimen for 24 weeks (lower than both 48-week regimens P <.001), and 24 +/- 9% interferon alone for 24 weeks (lower than the combination regimen for 24 weeks; P =.02). Three factors were independently associated with fibrosis reduction: sustained viral response, duration of treatment, and baseline fibrosis stage (all P <.001 in proportional hazards regression model). These results show that interferon and ribavirin combination therapy significantly reduces the rate of fibrosis progression in patients with hepatitis C. This effect was most prominent in patients who achieved a virologic response, those receiving 48 weeks of therapy, and in patients with significant fibrosis at baseline.
Studies have shown that rates of liver disease are higher in persons who are coinfected with human immunodeficiency virus
(HIV) and hepatitis C virus (HCV) than they are in persons with HCV alone, but estimates of risk vary widely and are based
on data for dissimilar patient populations. We performed a meta-analysis to quantify the effect of HIV coinfection on progressive
liver disease in persons with HCV. Eight studies were identified that included outcomes of histological cirrhosis or decompensated
liver disease. These studies yielded a combined adjusted relative risk (RR) of 2.92 (95% confidence interval [CI], 1.70–5.01).
Of note, studies that examined decompensated liver disease had a combined RR of 6.14 (95% CI, 2.86–13.20), whereas studies
that examined histological cirrhosis had a pooled RR of 2.07 (95% CI, 1.40–3.07). There is a significantly elevated RR of
severe liver disease in persons who are coinfected with HIV and HCV. This has important implications for timely diagnosis
and consideration of treatment in coinfected persons.
Hepatitis C virus (HCV)-related liver fibrosis progression is accelerated in human immunodeficiency virus (HIV)-infected patients. The effect of protease inhibitor (PI) therapy on liver fibrosis is unknown. The aim of this work was to analyze the impact of PI therapy on HCV-related liver fibrosis in HIV/HCV coinfected patients. We evaluated in a long-term follow-up retrospective cohort study the influence of antiretroviral therapy containing PI on liver fibrosis in 182 consecutive HIV/HCV coinfected patients. At liver biopsy, 63 patients had received PI and 119 patients had never been treated with PI. Relationships between liver histologic features, age, alcohol consumption, CD4 cell count, HIV-RNA load, and antiretroviral regimens were analyzed. Liver fibrosis stage was lower in patients receiving PIs by comparison with patients who had never received PIs (P =.03). The 5-, 15-, and 25-year cirrhosis rates were 2% versus 5%, 5% versus 18%, and 9% versus 27%, respectively, in patients who had received PIs compared with PI-untreated patients (P =.0006). Multivariate analysis identified 4 independent predictors of progression to cirrhosis: absence of protease inhibitor therapy (relative risk [RR] = 4.74, 95% confidence interval [CI], 1.34-16.67), heavy alcohol consumption (> or = 50 g daily) (RR = 4.71, 95% CI, 1.92-11.57), low CD4 cell count (<200/microL) (RR = 2.74, 95% CI, 1.17-6.41), and age at HCV contamination (> or = 20 years) (RR = 2.37, 95% CI, 1.04-5.38). In conclusion, protease inhibitor therapy might not accelerate progression to HCV-related cirrhosis. Furthermore, chronic use of antiretroviral therapy containing PI together with reduction of alcohol consumption and maintenance of high CD4 count could have a beneficial impact on liver fibrosis progression in HIV/HCV coinfected patients.
A sustained virological response (SVR) rate of 41% has been achieved with interferon alfa-2b plus ribavirin therapy of chronic hepatitis C. In this randomised trial, peginterferon alfa-2b plus ribavirin was compared with interferon alfa-2b plus ribavirin.
1530 patients with chronic hepatitis C were assigned interferon alfa-2b (3 MU subcutaneously three times per week) plus ribavirin 1000-1200 mg/day orally, peginterferon alfa-2b 1.5 microg/kg each week plus 800 mg/day ribavirin, or peginterferon alfa-2b 1.5 microg/kg per week for 4 weeks then 0.5 microg/kg per week plus ribavirin 1000-1200 mg/day for 48 weeks. The primary endpoint was the SVR rate (undetectable hepatitis C virus [HCV] RNA in serum at 24-week follow-up). Analyses were based on patients who received at least one dose of study medication.
The SVR rate was significantly higher (p=0.01 for both comparisons) in the higher-dose peginterferon group (274/511 [54%]) than in the lower-dose peginterferon (244/514 [47%]) or interferon (235/505 [47%]) groups. Among patients with HCV genotype 1 infection, the corresponding SVR rates were 42% (145/348), 34% (118/349), and 33% (114/343). The rate for patients with genotype 2 and 3 infections was about 80% for all treatment groups. Secondary analyses identified bodyweight as an important predictor of SVR, prompting comparison of the interferon regimens after adjusting ribavirin for bodyweight (mg/kg). Side-effect profiles were similar between the treatment groups.
In patients with chronic hepatitis C, the most effective therapy is the combination of peginterferon alfa-2b 1.5 microg/kg per week plus ribavirin. The benefit is mostly achieved in patients with HCV genotype 1 infections.
Fibrosis is the hallmark of hepatic cirrhosis, worsening of which is probably the best surrogate marker for progression of chronic liver disease. We evaluated a large cohort of patients with chronic hepatitis C (CHC) using liver histology to assess the rate and predictors of progression of fibrosis.
The cohort consisted of 123 patients with CHC who underwent 2 liver biopsies 4-212 months (mean, 44 months) apart without intervening treatment. Liver histology was graded using the histology activity index (score, 0-18) and fibrosis staged using a scoring system of 0 (no fibrosis) to 6 (cirrhosis).
Among 123 patients, 48 (39%) showed progression in fibrosis scores, 46 (37%) showed no change, and 29 (24%) showed improvement. Of those with worsening fibrosis, 75% had a 1-point increase and 25% a 2-point or greater increase in scores, and 9% showed progression to cirrhosis. The overall rate of progression was 0.12 fibrosis units per year, a rate that predicts progression to cirrhosis in 50 years if progression was linear. The rate of fibrosis progression was variable, and it was higher among older patients, those with higher serum alanine and aspartate aminotransferase levels, and those with the most extensive periportal necrosis on initial liver biopsy.
The best predictors of fibrosis progression in CHC are the extent of serum aminotransferase elevations and the degree of hepatocellular necrosis and inflammation on liver biopsy. These findings support the recommendation that patients with normal aminotransferase levels and mild liver histology can safely defer treatment.
Highly active antiretroviral therapy (HAART) has improved the prognosis of HIV infection. However, replication of hepatitis C virus (HCV) is not inhibited by HAART, and treatment-related hepatotoxicity is common. To clarify the effect of HAART in HIV/HCV-coinfected patients, we studied liver-related mortality and overall mortality in 285 patients who were regularly treated during the period 1990-2002 at our department.
Survival was analysed retrospectively by Kaplan-Meier and Cox's regression analyses after patients (81% haemophiliacs) had been stratified into three groups according to their antiretroviral therapy (HAART n=93, available after 1995; treatment exclusively with nucleoside analogues n=55, available after 1992; or no treatment, n=137).
Liver-related mortality rates were 0.45, 0.69, and 1.70 per 100 person-years in the HAART, antiretroviral-treatment, and untreated groups. Kaplan-Meier analysis of liver-related mortality confirmed the significant survival benefit in patients with antiretroviral therapy (p=0.018), and regression analysis identified HAART (odds ratio 0.106 [95% CI 0.020-0.564]), antiretroviral treatment (0.283 [0.103-0.780]), CD4-positive T-cell count (0.746 [0.641-0.868] per 0.05x10(9) cells/L), serum cholinesterase (0.962 [0.938-0.986] per 100 U/L), and age (1.065 [1.027-1.105] per year) as independent predictors of liver-related survival. Severe drug-related hepatotoxicity was seen in five patients treated with nucleoside analogues alone and 13 treated with HAART. No patient died from drug-related hepatotoxicity.
In addition to improved overall survival, antiretroviral therapy significantly reduced long-term liver-related mortality in our patients. This survival benefit seems to outweigh by far the associated risks of severe hepatotoxicity.
Relative risk is usually the parameter of interest in epidemiologic and medical studies. In this paper, the author proposes a modified Poisson regression approach (i.e., Poisson regression with a robust error variance) to estimate this effect measure directly. A simple 2-by-2 table is used to justify the validity of this approach. Results from a limited simulation study indicate that this approach is very reliable even with total sample sizes as small as 100. The method is illustrated with two data sets.
To assess survival in patients with HIV and viral hepatitis co-infection.
A prospective university clinic cohort of 472 patients with HIV infection who were followed for 8343 patient-months. The outcome measures were the survival from HIV or liver disease assessed by the Kaplan-Meier method. Multivariable analysis using a Cox regression model identified variables associated with mortality.
Patients were divided into four subgroups: HIV/hepatitis B virus (HBV) (n = 72), HIV/hepatitis C virus (HCV) (n = 256), multiple hepatitides (n = 18) and HIV alone (n = 126). One hundred and thirty-four patients (28.4%) died during follow-up. Liver mortality was noted in 55 patients, representing 12% of the cohort and 41% of the total mortality. Survival curves were similar in patients with HIV alone and those with any viral hepatitis co-infection. Liver deaths were more common in patients with multiple hepatitides (28%) HIV/HBV (15%), HIV/HCV co-infection (13%) versus HIV alone (6%). Liver mortality was comparable in HIV/HBV as in HIV/HCV co-infected patients and was not associated with gender, ethnicity, age, or mode of infection. HIV deaths were similar in patients co-infected with viral hepatitis compared with those with HIV alone. In patients with viral hepatitis co-infection, initial CD4 cell count > 200 x 10(6) cells/l and use of highly active antiretroviral therapy (HAART) were associated with significantly reduced liver mortality.
Patients with HIV and viral hepatitis had greater liver mortality than patients with HIV alone, but had comparable HIV mortality. Co-infection with hepatitis B is associated with hepatic outcomes similar to hepatitis C. Control of immunosuppression with HAART and CD4 counts > 200 x 10(6) cells/l are associated with better hepatic outcomes and should be the first priority in patients with HIV and viral hepatitis.
In the era of antiretroviral therapy (ART), liver disease has emerged as an important cause of death among persons with human immunodeficiency virus (HIV)/hepatitis C virus (HCV) coinfection. The objective of this study was to estimate the burden of liver disease and evaluate determinants of liver fibrosis and necroinflammatory activity among HIV/HCV coinfected patients receiving ART. We studied 112 randomly selected and 98 referred HCV-infected patients undergoing care in the Johns Hopkins University HIV clinic. Liver disease was characterized clinically and histologically. Of the 210 individuals studied--64% of whom had received ART within 2 years of liver disease assessment--33% had no fibrosis (F0), and 26% had bridging fibrosis or cirrhosis (> or =F3). The median necroinflammatory activity score was 3 (range, 0-9 of 18). ART was not associated with fibrosis; however, significantly less hepatic necroinflammatory activity was observed among persons who had received highly active antiretroviral therapy longer (P = .02) and more effectively (defined by HIV RNA suppression; P < .01). Twelve percent of individuals had previous ART-associated liver enzyme elevations (grades 3-4), but liver fibrosis was not more severe if the liver enzyme elevation resolved. On the other hand, liver fibrosis was more severe in persons with persistent liver enzyme elevations (grades 1-4). In conclusion, despite widespread exposure to ART and documented instances of ART-related hepatitis, we found no evidence that ART caused serious histological liver disease. Recognition of bridging fibrosis and cirrhosis in some but not most patients underscores the importance of identifying and treating liver disease in HIV/HCV coinfected persons.
HIV/HCV-coinfected patients reportedly have a faster fibrosis progression rate (FPR) than HCV-monoinfected patients. This study examined whether HIV suppression through highly active antiretroviral therapy (HAART) attenuates this accelerated fibrosis progression.
In two hepatitis C centers, a retrospective analysis identified 656 consecutive treatment-naïve HCV-infected patients who had undergone a liver biopsy, had a presumed date of HCV infection, and had been tested for HIV, 274 of them HIV-positive (95.2% on HAART) and 382 HIV-negative. The primary outcome measure was the FPR, defined as Ishak fibrosis score [0-6] over estimated duration of HCV infection.
Among HIV/HCV-coinfected patients, 51.2% had undetectable HIV RNA (< 400 copies/mL). There was no difference in FPR between HIV/HCV-coinfected and HCV-monoinfected patients (0.136 vs. 0.128 Ishak fibrosis units/year, P=0.29). However, HIV/HCV-coinfected patients with any detectable HIV viral load >400 copies/mL had a faster FPR (0.151) than HCV-monoinfected patients (0.128, P=0.015) and than HIV/HCV-coinfected patients with undetectable plasma HIV RNA (0.122, P=0.013) who in turn had the same FPR as HCV-monoinfected subjects (0.128, P=0.52). An accelerated FPR in HIV viremic patients was seen with CD4+ cells <500/mm(3) (0.162 vs. 0.123, undetectable HIV RNA, P=0.005) but not with CD4+ cells >500/mm(3) (0.118 vs. 0.121, P=0.89). In multivariable linear regression analysis of HIV/HCV-coinfected patients, log(10) HIV RNA level, necroinflammation, and age at HCV infection were independently correlated to FPR, but not alcohol use or CD4+ cell count (r(2)=0.45 for model).
HIV/HCV-coinfected patients with undetectable HIV RNA through HAART have a slower FPR than those with any HIV RNA level and an FPR similar to HCV-monoinfected individuals.
To find the survival and the predictors of death of HIV-infected patients with hepatitis C virus (HCV)-related end-stage liver disease (ESLD).
A prospective cohort study set in the infectious diseases units of four tertiary care public hospitals in Andalucía, Spain. From a multicentric cohort of 2664 HIV/HCV-co-infected patients, all consecutive patients with HCV-related cirrhosis who presented with the first hepatic decompensation from January 1997 to June 2004 were followed-up and 153 patients were included. The survival and the demographic, HIV-related and liver-related factors associated with death were evaluated.
Ninety-five (62%) patients died during the follow-up. In 79 (85%) individuals, the cause of death was liver related. The median survival time was 13 months. Independent predictors of survival were Child score [hazard ratio (HR), 1.2; 95% confidence interval (CI), 1.08-1.37; P = 0.001], CD4+ cell count at decompensation lower than 100 cells/microl (HR, 2.48; 95% CI, 1.52-4.06; P < 0.001) and hepatic encephalopathy as the first hepatic decompensation (HR, 2.45; 95% CI, 1.41-4.27; P = 0.001). HAART was prescribed to 101 (66%) patients. The cumulative probability of survival in patients under HAART was 60% at 1 year and 40% at 3 years, versus 38 and 18%, respectively, in patients not treated with HAART (P < 0.0001). The HR (95% CI) of death in patients on HAART was 0.5 (0.3-0.9), (P = 0.03). CONCLUSIONS The survival of HIV/HCV-co-infected patients with ESLD is extremely poor. Immunosuppression and markers of severe liver disease predict liver-related mortality in these patients. HAART seems to be associated with a reduced liver-related mortality.
To identify predictive factors for moderate/severe liver fibrosis and to analyse fibrosis progression in paired liver biopsies from HIV-positive patients with chronic hepatitis C virus (HCV) infection.
HIV/HCV coinfected patients followed at the 2nd Department of Infectious Diseases of L. Sacco Hospital in Milan, Italy, with at least one liver biopsy specimen were retrospectively evaluated.
A total of 110 patients were enrolled in the study. In a univariate analysis, predictive factors of Ishak-Knodell stage > or =3 were a history of alcohol abuse [odds ratio (OR) 3.6, P=0.004], alanine aminotransferase level >100 IU/L at biopsy (OR 2.4, P=0.05), necro-inflammatory grade > or =9 (OR 37.14, P<0.0001) and CD4 count <350 cells/microL at nadir (OR 5.3, P=0.05). In a multivariate analysis, age >35 years (OR 3.19, P=0.04) and alcohol abuse (OR 4.36, P=0.002) remained independently associated with Ishak-Knodell stage. Paired liver biopsies were available in 36 patients; 18 showed an increase of at least one stage in the subsequent liver biopsy. Either in a univariate or in a multivariate analysis, a decrease of CD4 cell count of more than 10% between two biopsies (OR 6.85, P=0.002) was significantly associated with liver fibrosis progression.
Our findings highlight the relevance of encouraging a withdrawal of alcohol consumption in people with chronic HCV infection and of carrying out close follow-up of patients, especially if they are more than 35 years old. It is therefore mandatory to evaluate HIV/HCV coinfected patients for anti-HCV treatment and to increase CD4 cell count through antiretroviral therapy in order to reduce the risk of fibrosis progression and to slow the evolution of liver disease.
Paired liver biopsies from patients enrolled in the multinational AIDS PEGASYS Ribavirin International Co-infection Trial were analysed to investigate a possible correlation between virological and histological responses.
A total of 860 HIV-hepatitis C virus (HCV)-co-infected patients were randomly assigned to receive pegIFNalpha-2a (40KD) 180 microg/week plus 800 mg daily ribavirin, pegIFNalpha-2a (40KD) plus placebo or conventional IFNalpha-2a 3 MIU three times a week plus ribavirin for 48 weeks. Paired biopsies were obtained from 401 patients and scored locally using the Ishak-modified histological activity index (HAI). The second biopsy was obtained, on average, 26 weeks or more after the end of treatment. Histological response was defined as a 2-point or greater reduction in the HAI score.
The histological response rate was significantly higher in patients receiving pegIFNalpha-2a (40KD) plus ribavirin (57%) than in patients receiving pegIFNalpha-2a (40KD) plus placebo (39%; P < 0.017) or IFNalpha-2a plus ribavirin (41%; P = 0.04). Histological response was correlated with virological response, with the histological response rate ranging from 62 to 74% in patients who achieved a sustained virological response (SVR). Histological response was also seen in 32-43% of patients not achieving an SVR. A higher total HAI score was the only prognostic factor for achieving histological response.
The histological response rate was significantly higher in HIV-HCV-co-infected patients who received pegIFNalpha-2a (40KD) plus ribavirin than in those receiving pegIFNalpha-2a (40KD) plus placebo or IFNalpha-2a plus ribavirin. Histological response was correlated with virological response, although a substantial proportion of patients who did not achieve an SVR experienced histological improvement.
Unlabelled:
The effect of achieving a sustained virological response (SVR) following interferon-alpha (IFNalpha) treatment on the clinical outcomes of patients with HCV-related cirrhosis is unknown. In an attempt to assess the risk of liver-related complications, HCC and liver-related mortality in patients with cirrhosis according to the response to IFNalpha treatment, a retrospective database was developed including all consecutive patients with HCV-related, histologically proven cirrhosis treated with IFNalpha monotherapy between January 1992 and December 1997. SVR was an undetectable serum HCV-RNA by PCR 24 weeks after IFNalpha discontinuation. HCC was assessed by ultrasound every 6 months. Independent predictors of all outcomes were assessed by Cox regression analysis. Of 920 patients, 124 (13.5%) were classified as achieving a SVR. During a mean follow-up of 96.1 months (range: 6-167) the incidence rates per 100 person-years of liver-related complications, HCC and liver-related death were 0, 0.66, and 0.19 among SVR and 1.88, 2.10, and 1.44 among non-SVR (P<0.001 by log-rank test). Multivariate analyses found that non-SVR was associated with a higher risk of liver-related complications (hazard ratio, HR, not applicable), HCC (HR 2.59; 95% CI 1.13-5.97) and liver-related mortality (HR 6.97; 95% CI 1.71-28.42) as compared to SVR.
Conclusion:
Thus, in patients with HCV-related, histologically proven cirrhosis, achievement of a SVR after IFNalpha therapy was associated with a reduction of liver-related mortality lowering both the risk of complications and HCC development. Irrespective of SVR achievement, all patients should continue surveillance because the risk of occurrence of HCC was not entirely avoided.
Unlabelled:
Little is known about the natural history of liver disease in human immunodeficiency virus (HIV)/hepatitis C virus (HCV)-coinfected subjects under highly active antiretroviral therapy (HAART). The objectives of this study were to obtain information about the mortality, the incidence of hepatic decompensations, and the predictors thereof in this population. In a multicenter cohort study, the time to the first hepatic decompensation and the survival of 1,011 antiretroviral naïve, HIV/HCV-coinfected patients who started HAART and who were followed prospectively were analyzed. After a median (Q1-Q3) follow-up of 5.3 (2.9-7.1) years, 59(5.83%) patients developed a hepatic decompensation and 69 (6.82%) died, 30 (43%) of them because of liver disease. The factors independently associated [HR (95% CI)] with the occurrence of hepatic decompensations were age older than 33 years [2.11 (1.18-3.78)], female sex [2.11 (1.07-4.15)], Centers for Disease Control stage C [2.14 (1.24-3.70)], a diagnosis of cirrhosis at baseline [10.86 (6.02-19.6)], CD4 cell gain lower than 100/mm3 [4.10 (2.18-7.69)] and less than 60% of the follow-up with undetectable HIV viral load [5.23 (2.5-10.93)]. Older age [2.97 (1.18-7.50)], lack of HCV therapy [11.32 (1.44-89.05)], hepatitis D virus coinfection [16.15 (2.45-106.48)], a diagnosis of cirrhosis at recruitment [13.69 (5.55-34.48)], hepatic encephalopathy [62.5 (21.27-200)] and lower CD4 cell gain [3.63 (1.45-9.09)] were associated with mortality due to liver failure.
Conclusion:
End-stage liver disease is the primary cause of death in HIV/HCV-coinfected patients under HAART. Higher increase of CD4 cell counts, lack of markers of serious liver disease and therapy against HCV are factors associated with better hepatic outcome.
In HIV/hepatitis C virus (HCV)-coinfected patients, it is recommended to repeat liver biopsy every 3 years when anti-HCV treatment is not indicated. We studied fibrosis progression in HIV/HCV-coinfected patients, who were not receiving anti-HCV treatment, on the basis of two successive liver biopsies. Thirty-two patients were retrospectively included. Twenty-six patients (79%) were on antiretroviral treatment at the first biopsy. The mean CD4 cell count was 470 +/- 283/mm(3). Three patients were staged F2 and the remainder F0/F1. The median interval between the two biopsies was 49 (24-80) months. At the second biopsy, the stage distribution was F0 0%, F1 41% (n = 13), F2 34% (n = 11), F3 19% (n = 6) and F4 6% (n = 2). The mean fibrosis progression rate (FPR) was 0.25 points/year. Nine patients (28%) were considered as rapid fibrosis progressors (progression by more than two points) and their FPR was 0.5 point/year; comparison of these subjects with the other 23 patients showed no relation between FPR and age, alcohol consumption, CD4+ cell count, HIV viral load, HCV genotype, aspartate aminotransferase or alanine aminotransferase. Analysis of the treatment received between the two liver biopsies did not find any correlation between liver FPR and a specific compound. Fifteen patients started anti-HCV therapy based on the second biopsy. Liver fibrosis in HIV/HCV-coinfected patients should be evaluated at least every 3 years, as nine of 32 (28%) of our patients progressed by at least two fibrosis points despite a high CD4+ cell count. The second biopsy showed that 15 patients (45%) qualified for anti-HCV therapy. Development of noninvasive methods of fibrosis evaluation should permit more frequent monitoring.
To define the incidence of fibrosis progression among hepatitis C virus (HCV)/HIV-co-infected adults, to assess whether HCV or HIV treatment alters the risk of progression, and to determine the utility of liver biopsy to predict future disease.
This prospective cohort evaluated 184 HIV/HCV-co-infected individuals who had at least two liver biopsies (median interval 2.9 years).
Biopsies were scored according to the Ishak modified histological activity index scoring system by a single pathologist blind to biopsy sequence. Significant fibrosis progression was defined as an increase of at least two Ishak fibrosis units between the first and second liver biopsy. Logistic regression analysis was used to assess determinants of fibrosis progression.
A total of 174 non-cirrhotic patients were eligible; the majority were African-American men undergoing HIV treatment. On initial biopsy, no or minimal fibrosis was identified in 136 patients (77%). Significant fibrosis progression occurred in 41 patients (24%). Measures of HIV disease and its treatment before and after initial biopsy were not significantly different in progressors and non-progressors. Fibrosis progression was not associated with HCV treatment, which was received by 37 patients (21%) but only three sustained HCV-RNA suppression. In adjusted analysis, only an elevated serum aspartate aminotransferase level between biopsies was associated with progression (odd ratio 3.4, 95% confidence interval 1.4-7.9).
Over a 3-year interval, significant fibrosis progression can occur in co-infected individuals even if minimal disease was detected on initial biopsy. In this context, factors other than treatment for HIV or HCV modify the risk of fibrosis progression.
We analyzed the effect of exposure to nonnucleoside reverse-transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs) on the progression of liver fibrosis in patients with human immunodeficiency virus (HIV) and hepatitis C virus coinfection.
We analyzed data and liver biopsy findings for 201 coinfected patients. Fibrosis was scored following the French METAVIR Cooperative Study Group. We used multinomial logistic regression analysis and the fibrosis progression rate to assess the association between cumulative exposure to antiretroviral drugs and stage of fibrosis.
The adjusted odds ratio (AOR) and 95% confidence interval (CI) of having a fibrosis stage score of 0 or 1, compared with 3 or 4, increased with each additional year of exposure to HAART (AOR, 1.32; 95% CI, 1.04-1,67), to NNRTIs as a class (AOR, 1.64; 95% CI, 1.18-2.27), to efavirenz (AOR, 1.54; 95% CI, 1.03-2.30), and to nevirapine (AOR, 1.72; 95% CI, 1.15-2.78). This effect was not found with PIs as a class. The AOR (95% CI) of having a fibrosis stage score of 2 versus 3 or 4 increased with each additional year of exposure to NNRTIs (AOR, 1.51; 95% CI, 1.08-2.10) and nevirapine (AOR, 1.58; 95% CI, 1.06-2.37). This effect was not found with highly active antiretroviral therapy, PIs, or efavirenz. The AOR (95% CI) of having a fibrosis progression rate < or = 0.1 versus > 0.1 increased with each additional year of exposure to highly active antiretroviral therapy (AOR, 1.31; 95% CI, 1.07-1.60), to NNRTIs (AOR, 1.33; 95% CI, 1.03-1.70), and to nevirapine (AOR, 1.44; 95% CI, 1.07-1.95). This effect was not found with PIs or with efavirenz.
In contrast with previous studies, we found that exposure to NNRTIs was clearly associated with a reduction in fibrosis progression, whereas exposure to PIs was not. Of note, exposure to nevirapine was more consistently associated with a reduction in fibrosis progression than was exposure to efavirenz. Prospective work is needed in this area.
Human immunodeficiency virus (HIV) coinfection increases hepatitis C virus (HCV)-related progression of hepatic fibrosis, increases HCV persistence, and decreases response rates to interferon-based anti-HCV therapy. It has remained unclear how HIV, a nonhepatotropic virus, accelerates the progression of liver disease by HCV.
We explored the possibility that circulating HIV and/or its proteins contribute to the pathogenesis of HCV through engagement of extracellular coreceptors on hepatocytes.
In this study, we found that inactivated HIV or gp120 increases HCV replication and enhances HCV-regulated transforming growth factor (TGF)-beta1 expression in both a replicon and an infectious model of HCV. This proviral effect of HIV and gp120 on HCV replication is neutralized by antibodies to CCR5 or CXCR4. However, HIV and gp120 did not alter type I interferon-mediated signaling in these HCV models, indicating that HIV regulates HCV replication through an alternative mechanism. Interestingly, we found that human TGF-beta1 also enhanced HCV replication. The effect of HIV on HCV replication was blocked by a neutralizing antibody to TGF-beta1, indicating that its effects on HCV replication are TGF-beta1 dependent.
These results suggest a novel mechanism by which HIV not only enhances HCV replication but also contributes to progression of hepatic fibrosis.
Sustained virological response to interferon plus ribavirin reduces liver-related complications and mortality in HIV/ HCV-co-infected patients
- J Berenguer
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- M Von-Wichman
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- Hiv Undetectable
- Yes
Undetectable HIV viremia*
Yes vs. No
0.61 (0.39-0.93)
0.028
CD4 cell counts change
Per 25 cells increase
1.0 (0.98-1.02)
0.87
Factors affecting liver fibrosis in human immunodeficiency virus-and
- Y Benhamou
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Sustained virological response to interferon plus ribavirin reduces liver-related complications and mortality in HIV/ HCV-co-infected patients
- J Berenguer
- J Alvarez-Pellicer
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