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1.  Impaired Hepatitis C Virus-Specific T Cell Responses and Recurrent Hepatitis C Virus in HIV Coinfection 
PLoS Medicine  2006;3(12):e492.
Background
Hepatitis C virus (HCV)-specific T cell responses are critical for spontaneous resolution of HCV viremia. Here we examined the effect of a lymphotropic virus, HIV-1, on the ability of coinfected patients to maintain spontaneous control of HCV infection.
Methods and Findings
We measured T cell responsiveness by lymphoproliferation and interferon-γ ELISPOT in a large cohort of HCV-infected individuals with and without HIV infection. Among 47 HCV/HIV-1-coinfected individuals, spontaneous control of HCV was associated with more frequent HCV-specific lymphoproliferative (LP) responses (35%) compared to coinfected persons who exhibited chronic HCV viremia (7%, p = 0.016), but less frequent compared to HCV controllers who were not HIV infected (86%, p = 0.003). Preservation of HCV-specific LP responses in coinfected individuals was associated with a higher nadir CD4 count (r2 = 0.45, p < 0.001) and the presence and magnitude of the HCV-specific CD8+ T cell interferon-γ response (p = 0.0014). During long-term follow-up, recurrence of HCV viremia occurred in six of 25 coinfected individuals with prior control of HCV, but in 0 of 16 HIV-1-negative HCV controllers (p = 0.03, log rank test). In these six individuals with recurrent HCV viremia, the magnitude of HCV viremia following recurrence inversely correlated with the CD4 count at time of breakthrough (r = −0.94, p = 0.017).
Conclusions
These results indicate that HIV infection impairs the immune response to HCV—including in persons who have cleared HCV infection—and that HIV-1-infected individuals with spontaneous control of HCV remain at significant risk for a second episode of HCV viremia. These findings highlight the need for repeat viral RNA testing of apparent controllers of HCV infection in the setting of HIV-1 coinfection and provide a possible explanation for the higher rate of HCV persistence observed in this population.
HIV infection impairs the immune response to HCV. Even individuals who have cleared HCV infection remain at significant risk for a second episode of HCV viremia.
Editors' Summary
Background.
Because of shared transmission routes (contaminated needles, contaminated blood products, and, to a lesser extent, unprotected sex), a large proportion of HIV-infected individuals (estimates range between 25% and 33%) are also infected with the hepatitis C virus (HCV). In most but not all individuals infected with HCV, the virus infection is chronic and causes liver disease that can eventually lead to liver failure. Disease progress is slow; it often takes decades until infected individuals develop serious liver disease. In people infected with both HCV and HIV, however, liver disease caused by HCV often appears sooner and progresses faster. As highly active antiretroviral therapy (HAART) and prophylaxis of opportunistic infections increase the life span of persons living with HIV, HCV-related liver disease has become a major cause of hospital admissions and deaths among HIV-infected persons.
Why Was This Study Done?
A sizable minority of people who are infected with HCV manage to control the virus and never get liver disease, and scientists have found that these people somehow mounted a strong immune response against the hepatitis C virus. CD4+ T cells, the very immune cells that are infected and destroyed by HIV, play an important role in this immune response. The goal of the present study was to better understand how infection with HIV compromises the specific immune response to HCV and thereby the control of HCV disease progression.
What Did the Researchers Do and Find?
The researchers recruited four groups of patients, 94 in total, all of whom were infected with HCV. Two groups comprised patients who were infected with HIV as well as HCV, with either high or undetectable levels of HCV (30 patients in each group). The two other groups included patients not infected with HIV, either with high or undetectable levels of HCV (17 patients in each group). The researchers focused on the individuals who, despite coinfection with HIV, were able to control their HCV infection. They found that those individuals managed to maintain relatively high levels of CD4+ T cells that specifically recognize HCV. However, a quarter of these patients (six out of 25) failed to keep HCV levels down for the entire observation period of up to 2.5 years; their blood levels of HCV rose substantially, most likely due to recurrence of the previously suppressed virus (the researchers could not be certain that none of the patients had become infected again after a new exposure to HCV-contaminated blood, but there was no evidence that they had engaged in risky behavior). The rise of HCV levels in the blood of the relapsed patients coincided with a drop in overall CD4+ T cell numbers. Following relapse in these individuals, HCV did not return to undetectable levels during the study. During the same period none of the 16 HIV-uninfected people with controlled HCV infection experienced a recurrence of detectable HCV.
What Do These Findings Mean?
Despite the relatively small numbers of patients, these results suggest that recurrence of HCV after initial control of the virus is more likely in people who are coinfected with HIV, and that HCV control is lost when CD4+ T cell counts fall. This is one more reason to test all HIV-positive patients for HCV coinfection. Coinfected patients, even those who seem to be controlling HCV and would not automatically receive HCV treatment, should be regularly tested for a rise of HCV levels. In addition, maintaining CD4+ T cells at a high level might be particularly important for those patients, which means that doctors might consider starting HAART therapy earlier than is generally recommended for HIV-infected individuals. Additional studies are needed to support these recommendations, however, especially as this study did not follow the patients long enough to determine the consequences of the observed loss of control of HCV.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0030492.
AIDS Treatment Data Network factsheet on HIV/HCV coinfection
US CDC factsheet on HIV/HCV coinfection
American Liver Foundation, information on HIV and HCV
MedlinePlus pages on HCV
doi:10.1371/journal.pmed.0030492
PMCID: PMC1705826  PMID: 17194190
2.  Significance of hepatitis B virus surface antigen, hepatitis C virus expression in hepatocellular carcinoma and pericarcinomatous tissues 
AIM: To investigate the correlation between hepatitis B virus surface antigen (HBsAg), hepatitis C virus (HCV) expression in hepatocellular carcinoma (HCC), the HAI score of the noncancerous region of the liver and the serum Alpha fetoprotein (AFP) level.
METHODS: The patterns of HBsAg and HCV in 100 cases of HCC and their surrounding liver tissues were studied on paraffin-embedded sections with immuno-histochemistry, the histological status was determined by one pathologist and one surgeon simultaneously using the hepatitis activity index (HAI) score, and AFP was detected by radioimmunity. The study included 100 consecutive patients who underwent curative resection for HCC. Based on HBsAg and HCV expression, the patients were classified into 4 groups: patients positive for HBsAg (HBsAg group), patients positive for HCV (HCV group), patients negative for both HCV and HBsAg (NBNC group) and patients positive for both HBsAg and HCV (BC group).
RESULTS: The BC group had significantly higher HAI scores than the other three groups. (BC > HCV > HBsAg > NBNC). HBV and HCV virus infection was positively correlated with HAI (rs = 0.39, P = 0.0001). The positive rate of AFP (85.7%) and the value of AFP (541.2 ng/mL) in the group with HBV and HCV co-infection were the highest among the four groups. The positive rate (53.3%) of AFP and the value of AFP ( 53.3 ng/mL) in the group with none-infection of HBV and HCV were the lowest. HBV and HCV virus infection was positively correlated with AFP(rs = 0.38, P = 0.0001).
CONCLUSION: The AFP increase in patients with liver cancer was positively correlated with the infection of HBV and HCV. The serum AFP elevation by the infection of HBV and HCV is one of mechanisms which lead to hepatocarcinogenesis, and the antivirus intervening treatment of hepatitis is significant for the prognosis of liver cancer. From our Spearman’s rank correlation analysis, we can conclude that the severity of virally induced inflammation is correlated with HBsAg and HCV expression in HCC tissues and noncancerous tissues. Prior co-infection of HBV in HCV patients may be an adverse risk factor for intrahepatic inflammation.
doi:10.3748/wjg.v13.i12.1870
PMCID: PMC4149970  PMID: 17465484
Hepatitis B virus surface antigen; Hepatitis C virus antigen; Histological activity index; Immunohisto-chemistry; Hepatocellular carcinoma; Alpha-fetoprotein.
3.  Clinical experience with nonstandard doses ofinterferon alfa-2b and ribavirin in the treatment of chronic hepatitis C infection: A retrospective analysis 
Background:
Hepatitis C virus (HCV) infection is the most common blood-borne virus in the United States. Several mono- and combination therapies have been approved by the US Food and Drug Administration for the treatment of HCV, but their routes of administration, dosing approaches, eras of introduction, and actual use in clinical practice and resulting effectiveness have not yet been reported.
Objectives:
The aim of this article was to characterize clinical use and virologic response (VR) of the HCV treatments interferon alfa-2b plus ribavirin (IFN + RBV) and peginterferon alfa-2b plus ribavirin (peg-IFN + RBV).
Methods:
This retrospective chart review of office-based practices in theUnited States was conducted at 200 physicians' offices across the United States. We collected data concerning dosing patterns, VR (HCV RNA load, ≤1000 IU/mL or “negative” on polymerase chain reaction qualitative analysis), and adverse events (AEs) from the medical records of a geographically diverse sample of patients receiving treatment for chronic HCV infection in the United States from July 2001 to June 2002. For efficacy assessment, factors that were statistically different at baseline were adjusted using logistic regression. Providers also reviewed the medical records for symptoms or signs consistent with HCV treatment-related AEs.
Results:
Data from the records of 675 patients (423 men, 252 women; mean [SD] age of 45.5 [8.2] years; mean [SD] body weight, 80.8 [19.4] kg) were analyzed. At baseline, the IFN + RBV treatment group (330 patients) had significantly higher percentages of black patients (22.1% vs 15.7%; P = 0.032) and patients with hepatic disease based on clinician-reported cirrhosis and liver dysfunction (18.8% vs 9.9%; P < 0.001), and a significantly lower percentage of white patients (60.3% vs 69.6%; P = 0.012) compared with the peg-IFN + RBV treatment group (345 patients). The difference in log-transformed baseline HCV RNA loads between the 2 treatment groups in this study was <1 log unit. A significantly higher percentage of IFN + RBV-treated patients compared with peg-IFN + RBV-treated patients were prescribed HCV therapy on diagnosis (37.3% vs 29.9%; P = 0.041), and the mean (SD) duration of treatment was significantly different between the 2 treatment groups (52.5 [37.0] vs 27.5 [15.0] weeks; P < 0.001). Peg-IFN + RBV was associated with a higher rate of VR compared with IFN + RBV on univariate analysis (28.5% vs 17.5%; P = 0.018). Recommended doses of peg-IFN and higher-than-recommended doses of RBV were associated with an increased likelihood of VR. Higher-than-recommended doses of peg-IFN without a concomitant increase in RBV was not associated with an increased likelihood of VR. The incidences of the 3 most commonly reported AEs in the IFN + RSV group were significantly higher compared with those in the peg-IFN + RSV group: fatigue, 217 (65.8%) versus 185 (53.6%) patients (P = 0.001); depression, 147 (44.5%) versus 120 (34.8%) (P = 0.009); and anxiety, 87 (26.4%) versus 64 (18.6%) (P = 0.014). Nausea, however, was reported in a significantly higher number of patients in the peg-IFN group compared with the IFN + RBV group (74 [21.4%] vs 51 [15.5%]; P = 0.045). The frequencies of dose modification and treatment discontinuation due to AEs were similar between the 2 treatments and were similar to or less than those reported in other studies.
Conclusions:
In this retrospective data analysis of US office-based practicesconcerning HCV treatment, clinicians were observed to prescribe IFN + RBV at doses that differ from recommendations in the product information (PI), as well as prescribe the RBV component of peg-IFN + RBV at doses that differed from PI recommendations. Although patients treated with peg-IFN + RBV appeared to achieve higher VR compared with those treated with IFN + RBV in our analysis of data from clinical practice, peg-IFN + RBV was associated with lower VR rates compared with those reported in clinical studies.
doi:10.1016/j.curtheres.2005.10.005
PMCID: PMC4003805  PMID: 24790244
hepatitis C; pegylated interferon; interferon alfa-2b and ribavirin; ribavirin; dosing; outcomes
4.  IL28B, HLA-C, and KIR Variants Additively Predict Response to Therapy in Chronic Hepatitis C Virus Infection in a European Cohort: A Cross-Sectional Study 
PLoS Medicine  2011;8(9):e1001092.
Vijayaprakash Suppiah and colleagues show that genotyping hepatitis C patients for the IL28B, HLA-C, and KIR genes improves the ability to predict whether or not patients will respond to antiviral treatment.
Background
To date, drug response genes have not proved as useful in clinical practice as was anticipated at the start of the genomic era. An exception is in the treatment of chronic hepatitis C virus (HCV) genotype 1 infection with pegylated interferon-alpha and ribavirin (PegIFN/R). Viral clearance is achieved in 40%–50% of patients. Interleukin 28B (IL28B) genotype predicts treatment-induced and spontaneous clearance. To improve the predictive value of this genotype, we studied the combined effect of variants of IL28B with human leukocyte antigen C (HLA-C), and its ligands the killer immunoglobulin-like receptors (KIR), which have previously been implicated in HCV viral control.
Methods and Findings
We genotyped chronic hepatitis C (CHC) genotype 1 patients with PegIFN/R treatment-induced clearance (n = 417) and treatment failure (n = 493), and 234 individuals with spontaneous clearance, for HLA-C C1 versus C2, presence of inhibitory and activating KIR genes, and two IL28B SNPs, rs8099917 and rs12979860. All individuals were Europeans or of European descent. IL28B SNP rs8099917 “G” was associated with absence of treatment-induced clearance (odds ratio [OR] 2.19, p = 1.27×10−8, 1.67–2.88) and absence of spontaneous clearance (OR 3.83, p = 1.71×10−14, 2.67–5.48) of HCV, as was rs12979860, with slightly lower ORs. The HLA-C C2C2 genotype was also over-represented in patients who failed treatment (OR 1.52, p = 0.024, 1.05–2.20), but was not associated with spontaneous clearance. Prediction of treatment failure improved from 66% with IL28B to 80% using both genes in this cohort (OR 3.78, p = 8.83×10−6, 2.03–7.04). There was evidence that KIR2DL3 and KIR2DS2 carriage also altered HCV treatment response in combination with HLA-C and IL28B.
Conclusions
Genotyping for IL28B, HLA-C, and KIR genes improves prediction of HCV treatment response. These findings support a role for natural killer (NK) cell activation in PegIFN/R treatment-induced clearance, partially mediated by IL28B.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
About 170 million people harbor long-term (chronic) infections with the hepatitis C virus (HCV) and 3–4 million people are newly infected with the virus every year. HCV—a leading cause of chronic hepatitis (inflammation of the liver)—is spread though contact with infected blood. Transmission can occur during medical procedures (for example, transfusions with unscreened blood or reuse of inadequately sterilized medical instruments) but in developed countries, where donated blood is routinely screened for HCV, the most common transmission route is needle-sharing among intravenous drug users. HCV infection can cause a short-lived illness characterized by tiredness and jaundice (yellow skin and eyes) but 70%–80% of newly infected people progress to a symptom-free, chronic infection that can eventually cause liver cirrhosis (scarring) and liver cancer. HCV infections can be treated with a combination of two drugs—pegylated interferon-alpha and ribavirin (PegIFN/R). However, PegIFN/R is expensive, causes unpleasant side-effects, and is ineffective in about half of people infected with HCV genotype 1, the commonest HCV strain.
Why Was This Study Done?
It would be extremely helpful to be able to identify which patients will respond to PegIFN/R before starting treatment. An individual's genetic make-up plays a key role in the safety and effectiveness of drugs. Thus, pharmacogenomics—the study of how genetic variants affects the body's response to drugs—has the potential to alter the clinical management of many diseases by allowing clinicians to provide individually tailored drug treatments. In 2009, scientists reported that certain single nucleotide polymorphisms (SNPs, a type of genetic variant) lying near the IL28B gene (which encodes an immune system protein made in response to viral infections) strongly influence treatment outcomes and spontaneous clearance in HCV-infected people. This discovery is now being used to predict treatment responses to PegIFN/R in clinical practice but genotyping (analysis of variants of) IL28B only correctly predicts treatment failure two-thirds of the time. Here, the researchers investigate whether genotyping two additional regions of the genome—the HLA-C and KIR gene loci—can improve the predictive value of IL28B genotyping. Human leukocyte antigen C (HLA-C) and the killer immunoglobulin-like receptors (KIRs) are interacting proteins that have been implicated in HCV viral control.
What Did the Researchers Do and Find?
The researchers genotyped 417 patients chronically infected with HCV genotype 1 whose infection had been cleared by PegIFN/R treatment, 493 patients whose infection had not responded to treatment, and 234 patients whose infection had cleared spontaneously for two HLA-C variants (C1 and C2), the presence of several KIR genes (individuals carry different combinations of KIR genes), and two IL28B SNPs (rs8099917 and rs12979860). Carriage of “variants” of either IL28B SNP was associated with absence of treatment-induced clearance and absence of spontaneous clearance. That is, these variant SNPs were found more often in patients who did not respond to treatment than in those who did respond, and more often in patients who did not have spontaneous clearance of their infection than those who did. The HLA-C C2C2 genotype (there are two copies of most genes in the genome) was also more common in patients who failed treatment than in those who responded but was not associated with spontaneous clearance. The rate of correct prediction of treatment failure increased from 66% with IL28B genotyping alone to 80% with combined IL28B and HLA-C genotyping. Finally, carriage of specific KIR genes in combination with specific HLA-C and IL28B variants was also associated with an altered HCV treatment response.
What Do These Findings Mean?
These findings show that the addition of HCL-C and KIR genotyping to IL28B genotyping improved the prediction of HCV treatment response in the patients investigated in this study. Because all these patients were European or of European descent, these findings need confirming in people of other ethnic backgrounds. They also need confirming in other groups of Europeans before being used in a clinical setting. However, the discovery that the addition of HLA-C genotyping to IL28B genotyping raises the rate of correct prediction of PegIFN/R treatment failure to 80% is extremely promising and should improve the clinical management of patients infected with HCV genotype 1. In addition, these results provide new insights into how PegIFN/R clears HCV infections that may lead to improved therapies in the future.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001092.
The World Health Organization provides detailed information about hepatitis C (in several languages)
The US Centers for Disease Control and Prevention provides information on hepatitis C for the public and for health professionals (information is also available in Spanish)
The US National Institute of Diabetes and Digestive and Kidney Diseases provides basic information on hepatitis C (in English and Spanish)
The Hepatitis C Trust is a patient-led, patient-run UK charity that provides detailed information about hepatitis C and support for patients and their families; a selection of personal stories about patients' experiences with hepatitis C is available, including Phil's treatment story, which details the ups and downs of treatment with PegIFN/R
MedlinePlus provides links to further resources on hepatitis C
The Human Genome Project provides information about medicine and the new genetics, including a primer on pharmacogenomics
doi:10.1371/journal.pmed.1001092
PMCID: PMC3172251  PMID: 21931540
5.  Viral Hepatitis among Somali Immigrants in Minnesota: Association of Hepatitis C with Hepatocellular Carcinoma 
Mayo Clinic Proceedings  2012;87(1):17-24.
Objective
To study the frequencies of chronic viral hepatitis B (HBV), hepatitis C (HCV), and their associations with hepatocellular carcinoma (HCC) in immigrant Somalis seen at Mayo Clinic, Rochester, Minnesota.
Methods
We investigated the frequencies of HBV and HCV infection and HCC in immigrant Somalis seen at Mayo Clinic, Rochester, Minnesota between July 1, 1996 and October 31, 2009. Non-Somali Olmsted County residents served as controls.
Results
For Somali males and females, age-adjusted proportions (per 1000) were 209 and 123 for HBV surface antigen (HBsAg), 644 and 541 for HBV core antibody (HBcAb) and 99 and 66 for anti-HCV. The comparative proportions in non-Somalis were 20 and 9 for HBsAg, 126 and 97 for HBcAb, and 32 and 17 for anti-HCV. HCV RNA confirmed that 93% (68/73) of Somalis and 93% (282/303) of non-Somalis with positive anti-HCV tests had active HCV infection. Of 30 Somali patients with HCC, 22 (75.9%) were anti-HCV-positive [odds ratio (95% CI): 31.3 (12.95 – 75.52), p<0.0001 compared to anti-HCV-negative Somalis]; 5 (17.9%) were HBsAg-positive [OR 1.38 (0.52–3.69), p=0.53]; and 18 (69.2%) were HBcAb-positive [OR 1.80 (0.77–4.20), p=0.16]. Viral hepatitis was diagnosed coincident with HCC in 45% (9/20) of HCV-associated HCCs. Only 20% (4/20) of HCCs were detected during surveillance.
Conclusions
HBV and HCV occurred frequently in this sample of Somali immigrants. HCV was the major risk factor for HCC. Screening Somali immigrants for HCV infection may enhance the prevention, early detection, and optimal treatment of HCC.
doi:10.1016/j.mayocp.2011.08.001
PMCID: PMC3337857  PMID: 22212964
Somali; Hepatitis C; Hepatitis B; Hepatocellular carcinoma
6.  Effects of a 24-week course of interferon-α therapy after curative treatment of hepatitis C virus-associated hepatocellular carcinoma 
AIM: To assess whether a 24-wk course of interferon (IFN) could prevent hepatocellular carcinoma (HCC) recurrence and worsening of liver function in patients with hepatitis C virus (HCV)-infected patients after receiving curative treatment for primary HCC.
METHODS: Outcomes in 42 patients with HCV infection treated with IFN-α, after curative treatment for primary HCC (IFN group), were compared with 42 matched curatively treated historical controls not given IFN (non-IFN group).
RESULTS: Although the rate of initial recurrence did not differ significantly between IFN group and non-IFN group (0%, 44%, 61%, and 67% vs 4.8%, 53%, 81%, and 87% at 1, 3, 5, and 7 years, P = 0.153, respectively), IFN group showed a lower rate than the non-IFN group for second recurrence (0%, 10.4%, 28%, and 35% vs 0%, 30%, 59%, and 66% at 1, 3, 5 and 7 years, P = 0.022, respectively). Among the IFN group, patients with sustained virologic response (SVR) were less likely to have a second HCC recurrence than IFN patients without an SVR, or non-IFN patients. Multivariate analysis identified the lack of SVR as the only independent risk factor for a second recurrence, while SVR and Child-Pugh class A independently favored overall survival.
CONCLUSION: Most intrahepatic recurrences of HCV-related HCC occurred during persistent viral infection. Eradication of HCV is essential for the prevention of HCC recurrence and improvement of survival.
doi:10.3748/wjg.v13.i40.5343
PMCID: PMC4171324  PMID: 17879404
Hepatitis C virus; Hepatocellular carcinoma; Recurrence; Survival; Sustained virological response
7.  Kidney and liver organ transplantation in persons with human immunodeficiency virus 
Executive Summary
Objective
The objective of this analysis is to determine the effectiveness of solid organ transplantation in persons with end stage organ failure (ESOF) and human immunodeficiency virus (HIV+)
Clinical Need: Condition and Target Population
Patients with end stage organ failure who have been unresponsive to other forms of treatment eventually require solid organ transplantation. Similar to persons who are HIV negative (HIV−), persons living with HIV infection (HIV+) are at risk for ESOF from viral (e.g. hepatitis B and C) and non-viral aetiologies (e.g. coronary artery disease, diabetes, hepatocellular carcinoma). Additionally, HIV+ persons also incur risks of ESOF from HIV-associated nephropathy (HIVAN), accelerated liver damage from hepatitis C virus (HCV+), with which an estimated 30% of HIV positive (HIV+) persons are co-infected, and coronary artery disease secondary to antiretroviral therapy. Concerns that the need for post transplant immunosuppression and/or the interaction of immunosuppressive drugs with antiretroviral agents may accelerate the progression of HIV disease, as well as the risk of opportunistic infections post transplantation, have led to uncertainty regarding the overall benefit of transplantation among HIV+ patients. Moreover, the scarcity of donor organs and their use in a population where the clinical benefit of transplantation is uncertain has limited the availability of organ transplantation to persons living with ESOF and HIV.
With the development of highly active anti retroviral therapy (HAART), which has been available in Canada since 1997, there has been improved survival and health-related quality of life for persons living with HIV. HAART can suppress HIV replication, enhance immune function, and slow disease progression. HAART managed persons can now be expected to live longer than those in the pre-HAART era and as a result many will now experience ESOF well before they experience life-threatening conditions related to HIV infection. Given their improved prognosis and the burden of illness they may experience from ESOF, the benefit of solid organ transplantation for HIV+ patients needs to be reassessed.
Evidence-Based Analysis Methods
Research Questions
What are the effectiveness and cost effectiveness of solid organ transplantation in HIV+ persons with ESOF?
Literature Search
A literature search was performed on September 22, 2009 using OVID MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, EMBASE, the Cumulative Index to Nursing & Allied Health Literature (CINAHL), the Cochrane Library, and the International Agency for Health Technology Assessment (INAHTA) for studies published from January 1, 1996 to September 22, 2009.
Inclusion Criteria
Systematic review with or without a Meta analysis, RCT, Non-RCT with controls
HIV+ population undergoing solid organ transplantation
HIV+ population managed with HAART therapy
Controls include persons undergoing solid organ transplantation who are i) HIV− ii) HCV+ mono-infected, and iii) HIV+ persons with ESOF not transplanted.
Studies that completed and reported results of a Kaplan-Meier Survival Curve analysis.
Studies with a minimum (mean or medium) follow up of 1-year.
English language citations
Exclusion Criteria
Case reports and case series were excluded form this review.
Outcomes of Interest
i) Risk of Death after transplantation
ii) Death censored graft survival (DCGS)
iii) HIV disease progression defined as the post transplant incidence of:
- opportunistic infections or neoplasms,
- CD4+ T-cell count < 200mm3, and
- any detectable level of plasma HIV viral load.
iv) Acute graft rejection,
v) Return to dialysis,
vi) Recurrence of HCV infection
Summary of Findings
No direct evidence comparing an HIV+ cohort undergoing transplantation with the same not undergoing transplantation (wait list) was found in the literature search.
The results of this review are reported for the following comparison cohorts undergoing transplantation:
i) Kidney Transplantation: HIV+ cohort compared with HIV− cohort
ii) Liver Transplantation: HIV+ cohort compared with HIV− negative cohort
iii) Liver Transplantation: HIV+ HCV+ (co-infected) cohort compared with HCV+ (mono-infected) cohort
Kidney Transplantation: HIV+ vs. HIV−
Based on a pooled HIV+ cohort sample size of 285 patients across four studies, the risk of death after kidney transplantation in an HIV+ cohort does not differ to that of an HIV− cohort [hazard ratio (HR): 0.90; 95% CI: 0.36, 2.23]. The quality of evidence supporting this outcome is very low.
Death censored graft survival was reported in one study with an HIV+ cohort sample size of 100, and was statistically significantly different (p=.03) to that in the HIV− cohort (n=36,492). However, the quality of evidence supporting this outcome was determined to be very low. There was also uncertainty in the rate of return to dialysis after kidney transplantation in both the HIV+ and HIV− groups and the effect, if any, this may have on patient survival. Because of the very low quality evidence rating, the effect of kidney transplantation on HIV-disease progression is uncertain.
The rate of acute graft rejection was determined using the data from one study. There was a nonsignificant difference between the HIV+ and HIV− cohorts (OR 0.13; 95% CI: 0.01, 2.64), although again, because of very low quality evidence there is uncertainty in this estimate of effect.
Liver Transplantation: HIV+ vs. HIV−
Based on a combined HIV+ cohort sample size of 198 patient across five studies, the risk of death after liver transplantation in an HIV+ cohort (with at least 50% of the cohort co-infected with HCV+) is statistically significantly 64% greater compared with an HIV− cohort (HR: 1.64; 95% CI: 1.32, 2.02). The quality of evidence supporting this outcome is very low.
Death censored graft survival was reported for an HIV+ cohort in one study (n=11) however the DCGS rate of the contemporaneous control HIV− cohort was not reported. Because of sparse data the quality of evidence supporting this outcome is very low indicating death censored graft survival is uncertain.
Both the CD4+ T-cell count and HIV viral load appear controlled post transplant with an incidence of opportunistic infection of 20.5%. However, the quality of this evidence for these outcomes is very low indicating uncertainty in these effects. Similarly, because of very low quality evidence there is uncertainty in the rate of acute graft rejection among both the HIV+ and HIV− groups
Liver Transplantation: HIV+/HCV+ vs. HCV+
Based on a combined HIV+/HCV+ cohort sample size of 156 from seven studies, the risk of death after liver transplantation is significantly greater (2.8 fold) in a co-infected cohort compared with an HCV+ mono-infected cohort (HR: 2.81; 95% CI: 1.47, 5.37). The quality of evidence supporting this outcome is very low. Death censored graft survival evidence was not available.
Regarding disease progression, based on a combined sample size of 71 persons in the co-infected cohort, the CD4+ T-cell count and HIV viral load appear controlled post transplant; however, again the quality of evidence supporting this outcome is very low. The rate of opportunistic infection in the co-infected cohort was 7.2%. The quality of evidence supporting this estimate is very low, indicating uncertainty in these estimates of effect.
Based on a combined HIV+/HCV+ cohort (n=57) the rate of acute graft rejection does not differ to that of an HCV+ mono-infected cohort (OR: 0.88; 95% CI: 0.44, 1.76). Also based on a combined HIV+/HCV+ cohort (n=83), the rate of HCV+ recurrence does not differ to that of an HCV+ mono-infected cohort (OR: 0.66; 95% CI: 0.27, 1.59). In both cases, the quality of the supporting evidence was very low.
Overall, because of very low quality evidence there is uncertainty in the effect of kidney or liver transplantation in HIV+ persons with end stage organ failure compared with those not infected with HIV. Examining the economics of this issue, the cost of kidney and liver transplants in an HIV+ patient population are, on average, 56K and 147K per case, based on both Canadian and American experiences.
PMCID: PMC3377507  PMID: 23074407
8.  Effect of HIV infection-related factors on SVR rate in HCV treatment in HIV-infected patients 
Journal of the International AIDS Society  2014;17(4Suppl 3):19635.
Introduction
Factors that have an effect on the rate of sustained virological response (SVR) in chronic hepatitis C (CHC) patients include: genotype of hepatitis C virus (HCV); level of HCV RNA replication and rate of its reduction in the course of treatment; original hepatic fibrosis level; genotype of Interleukin-28B (especially for Genotype 1 HCV – G1); daily ribavirin (RBV) dose. This study evaluated the effect of the HIV infection-related factors on the SVR rate in HCV treatment in patients with concurrent infection (HIV/HCV).
Methods
The follow-up included 232 HIV/HCV-infected patients. Ninety-nine of 232 patients with HIV/HCV-infection received antiretroviral therapy (ART) for at least three months before the initiation of the CHC treatment. Before the HCV therapy, the median of CD4+cells was 406/mm3 (with ART) and 507/mm3 (without ART). Patients received HCV treatment with pegylated interferon (PEG-IFN) and RBV (1000/12,000 mg/day) during 24–48 weeks.
Results
SVR was received in 50% of patients with G1 HCV, and 80.1% of patients with Genotypes 2/3 (G2/3; p<0.0001). The SVR rate in the group of patients without ART was reliably higher, 74.4% (with ART – 58.6%; p=0.0053). No significant differences in the SVR rate (62.3% and 69.6%, accordingly) were detected after the differentiation of patients based on the initial absolute values of CD4+cells count (<350 cells/mm3 and >350 cells/mm3). In 127 patients with the HIV/HCV-infection, the percentage of CD4+cells before the CHC treatment was >25% and more (Group 1 [Gr. 1]), and in 105 patients ≤25% (Group 2 [Gr. 2]). The SVR rate for Gr. 1 patient was 74.6%, and for Gr. 2 patients –58.1% (p=0.0023). The SVR rate in patients with G1 HCV was 56.8% (Gr. 1) and 44.2% (Gr. 2; p=0.1095), whereas the rate for G2 and 3 was 85.5% and 71.7%, accordingly (p=0.0242). Forty patients in Gr. 1 and 59 patients in Gr. 2 received ART. The comparison of the SVR rate for these patients showed no significant differences: 60% and 57.6%, accordingly. SVR rate in the patients without ART demonstrated that for Gr.1 patients (CD4+>25%) was reliably higher, 82.8% (compared to Gr.2 with 58.7%; p=0.0012).
Conclusions
Along with factors related to HCV and the patient, the SVR rate in the HCV treatment with PEG-IFN and RBV may be affected in patients with the concurrent infection by the use of ART and original relative content of CD4+cells. The maximum SVR rate was achieved in the patients without ART and with the CD4+cells >25% (baseline). When indicted, it is reasonable to provide HCV treatment to HIV-infected patients as long as the percentage of CD4+cells remains high and there is no need of ART.
doi:10.7448/IAS.17.4.19635
PMCID: PMC4224794  PMID: 25394139
9.  Comparative Evaluation of the Total Hepatitis C Virus Core Antigen, Branched-DNA, and Amplicor Monitor Assays in Determining Viremia for Patients with Chronic Hepatitis C during Interferon Plus Ribavirin Combination Therapy 
Journal of Clinical Microbiology  2003;41(7):3212-3220.
An assay prototype designed to detect and quantify total hepatitis C virus [HCV] core antigen (HCV core Ag) protein in serum and plasma in the presence or absence of anti-HCV antibodies has been recently developed by Ortho-Clinical Diagnostics. The aim of the study was to evaluate the sensitivity, specificity, and reproducibility of the Total HCV core Ag assay in comparison with two quantitative assays for HCV RNA: Quantiplex HCV RNA 2.0 (bDNA v2.0) or Versant HCV RNA 3.0 (bDNA v3.0) assays and the Cobas Amplicor HCV Monitor version 2.0 (HCM v2.0) test. We have studied samples of a well-characterized panel and samples from patients with chronic hepatitis C treated with interferon alone or with ribavirin. We have also compared the kinetics of HCV core Ag and HCV RNA in the follow-up of treated patients. The HCV core Ag assay exhibited linear behavior across samples from different genotypes. The coefficients of variation for intra- and interassay performance were 5.11 and 9.95%, respectively. The specificity of the assay tested in blood donors was 99.5%. Samples from HCV-infected patients showed that the correlation between the HCV core Ag and the two HCV RNA quantitative assays (bDNA and HCM v2.0) was 0.8 and 0.7, respectively. This correlation was maintained across different genotypes of HCV (r2 = 0.64 to 0.94). Baseline HCV core Ag values were significantly lower in sustained responders to interferon (IFN) than in other groups of patients (5.31 log10 [104 pg/ml] versus 5.99 log10 [104 pg/ml]; P < 0.001). In patients treated with IFN or combination therapy, we found an association between a decrease of more than 2 log IU/ml in viral load, undetectable HCV core Ag, and sustained response. Among sustained responders to IFN alone or combination therapy and among relapsers after IFN alone, 84 out of 101 (83.2%) had undetectable HCV core Ag, and 76 out of 96 (79.2%) had a viral load decrease of ≥2 log IU/ml, after 1 month of treatment. In conclusion, the Total HCV core Ag assay is a new useful test for the detection of HCV viremia and the monitoring of patients treated with IFN alone or in combination with ribavirin.
doi:10.1128/JCM.41.7.3212-3220.2003
PMCID: PMC165326  PMID: 12843066
10.  Survival rates of early-stage HCV-related liver cirrhosis patients without hepatocellular carcinoma are decreased by alcohol 
Although alcohol abuse is the most common cause of liver cirrhosis in the United States, the enhancing effects of alcohol on the long-term prognosis of hepatitis C virus (HCV) related liver cirrhosis has not been clarified. To investigate how alcohol abuse influences the prognosis of hepatitis virus related liver cirrhosis, we studied 716 Japanese patients. Cumulative survival and hepatocellular carcinoma (HCC) development rates were analyzed in alcohol abusive, cirrhotic patients with or without hepatitis virus infection. Patients who abused alcohol were younger (p<0.0001) than HCV infected, non-abusive patients. The overall survival rate among patients with alcoholic cirrhosis (Al group), HCV related cirrhosis (HCV group), and HCV infected + alcoholic cirrhosis (HCV + Al group), showed no significant differences, although the 10-year cumulative survival rate of Al group was the highest of the three groups. The HCC development rate of Al group was the lowest. In addition, alcohol abuse decreased the survival rates of HCV group in the early stage with no HCC (p = 0.0028). In conclusion, alcohol abuse might affect the progression of liver damage in HCV infected patients with liver cirrhosis in the early stage, although the influence of alcohol abuse on the long term prognosis seems to be rather small.
doi:10.3164/jcbn.09-119GFR
PMCID: PMC3045691  PMID: 21373271
prognosis of liver cirrhosis; alcoholic liver disease; hepatitis C virus; hepatocellular carcinoma
11.  A Novel Diagnostic Target in the Hepatitis C Virus Genome 
PLoS Medicine  2009;6(2):e1000031.
Background
Detection and quantification of hepatitis C virus (HCV) RNA is integral to diagnostic and therapeutic regimens. All molecular assays target the viral 5′-noncoding region (5′-NCR), and all show genotype-dependent variation of sensitivities and viral load results. Non-western HCV genotypes have been under-represented in evaluation studies. An alternative diagnostic target region within the HCV genome could facilitate a new generation of assays.
Methods and Findings
In this study we determined by de novo sequencing that the 3′-X-tail element, characterized significantly later than the rest of the genome, is highly conserved across genotypes. To prove its clinical utility as a molecular diagnostic target, a prototype qualitative and quantitative test was developed and evaluated multicentrically on a large and complete panel of 725 clinical plasma samples, covering HCV genotypes 1–6, from four continents (Germany, UK, Brazil, South Africa, Singapore). To our knowledge, this is the most diversified and comprehensive panel of clinical and genotype specimens used in HCV nucleic acid testing (NAT) validation to date. The lower limit of detection (LOD) was 18.4 IU/ml (95% confidence interval, 15.3–24.1 IU/ml), suggesting applicability in donor blood screening. The upper LOD exceeded 10−9 IU/ml, facilitating viral load monitoring within a wide dynamic range. In 598 genotyped samples, quantified by Bayer VERSANT 3.0 branched DNA (bDNA), X-tail-based viral loads were highly concordant with bDNA for all genotypes. Correlation coefficients between bDNA and X-tail NAT, for genotypes 1–6, were: 0.92, 0.85, 0.95, 0.91, 0.95, and 0.96, respectively; X-tail-based viral loads deviated by more than 0.5 log10 from 5′-NCR-based viral loads in only 12% of samples (maximum deviation, 0.85 log10). The successful introduction of X-tail NAT in a Brazilian laboratory confirmed the practical stability and robustness of the X-tail-based protocol. The assay was implemented at low reaction costs (US$8.70 per sample), short turnover times (2.5 h for up to 96 samples), and without technical difficulties.
Conclusion
This study indicates a way to fundamentally improve HCV viral load monitoring and infection screening. Our prototype assay can serve as a template for a new generation of viral load assays. Additionally, to our knowledge this study provides the first open protocol to permit industry-grade HCV detection and quantification in resource-limited settings.
Christian Drosten and colleagues develop, validate, and make openly available a prototype hepatitis C virus assay based on the conserved 3' X-tail element, with potential for clinical use in developing countries.
Editors' Summary
Background.
About 3% of the world's population (170 million people) harbor long-term (chronic) infections with the hepatitis C virus (HCV) and about 3–4 million people are newly infected with this virus every year. HCV—a leading cause of chronic hepatitis (inflammation of the liver)—is spread through contact with the blood of an infected person. Globally, the main routes of transmission are the use of unscreened blood for transfusions and the reuse of inadequately sterilized medical instruments, including needles. In affluent countries, where donated blood is routinely screened for the presence of HCV, most transmission is through needle sharing among drug users. The risk of sexual and mother-to-child transmission of HCV is low. Although HCV infection occasionally causes an acute (short-lived) illness characterized by tiredness and jaundice (yellow eyes and skin), most newly infected people progress to a symptom-free, chronic infection that can eventually cause liver cirrhosis (scarring) and liver cancer. HCV infections can be treated with a combination of two drugs called interferon and ribavirin, but these drugs are expensive and are ineffective in many patients.
Why Was This Study Done?
An effective way to limit the global spread of HCV might be to introduce routine screening of the blood that is used for transfusions in developing countries. In developed countries, HCV screening of blood donors use expensive, commercial “RT-PCR” assays to detect small amounts of HCV ribonucleic acid (RNA; HCV stores the information it needs to replicate itself—its genome—as a sequence of “ribonucleotides”). All the current HCV assays, which can also quantify the amount of viral RNA in the blood (the viral load) during treatment, detect a target sequence in the viral genome called the 5′-noncoding region (5′-NCR). However, there are several different HCV “genotypes” (strains). These genotypes vary in their geographical distribution and, even though the 5′-NCR sequence is very similar (highly conserved) in the common genotypes (HCV genotypes 1–6), the existing assays do not detect all the variants equally well. This shortcoming, together with their high cost, means that 5′-NCR RT-PCR assays are not ideal for use in many developing countries. In this study, the researchers identify an alternative diagnostic target sequence in the HCV genome—the 3′-X-tail element—and ask whether this sequence can be used to develop a new generation of tests for HCV infection that might be more appropriate for use in developing countries.
What Did the Researchers Do and Find?
The researchers determined the RNA sequence of the 3′-X-tail element in reference samples of the major HCV genotypes and showed that this region of the HCV genome is as highly conserved as the 5′-NCR. They then developed a prototype X-tail RT-PCR assay and tested its ability to detect small amounts of HCV and to measure viral load in genotype reference samples and in a large panel of HCV-infected blood samples collected in Germany, the UK, Brazil, South Africa, and Singapore. The new assay detected low levels of HCV RNA in all of the genotype reference samples and was also able to quantify high RNA concentrations. The viral load estimates it provided for the clinical samples agreed well with those obtained using a commercial assay irrespective of the sample's HCV genotype. Finally, the X-tail RT-PCR assay gave similar results to a standard assay at a fraction of the cost when used to measure viral loads in a Brazilian laboratory in an independent group of 127 patient samples collected in Brazil.
What Do These Findings Mean?
These findings suggest that the HCV 3′-X-tail element could provide an alternative target for screening blood samples for HCV infection and for monitoring viral loads during treatment, irrespective of HCV genotype. In addition, they suggest that X-tail RT-PCR assays may be stable and robust enough for use in laboratories in emerging countries. Overall, these findings should stimulate the development of a new generation of clinical HCV assays that, because the protocol used in the X-tail assay is freely available, could improve blood safety in developing countries by providing a cheap and effective alternative to existing proprietary HCV assays.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000031.
The World Health Organization has a fact sheet about hepatitis C (in English and French)
The US Centers for Disease Control and Prevention provides information on hepatitis C for the public and for health professionals (information is also available in Spanish)
The US National Institute of Diabetes and Digestive and Kidney Diseases provides basic information on hepatitis C (in English and Spanish)
The MedlinePlus Encyclopedia has a page on hepatitis C; MedlinePlus also provides links to further information on hepatitis C (in English and Spanish)
doi:10.1371/journal.pmed.1000031
PMCID: PMC2637920  PMID: 19209955
12.  Seroprevalence of hepatitis B and C viruses and risk factors in HIV infected children at the felgehiwot referral hospital, Ethiopia 
BMC Research Notes  2014;7(1):838.
Background
Liver hepatitis due to Hepatitis B (HBV) and hepatitis C virus (HCV) co-infection is the leading cause of morbidity and mortality in HIV infected children and it is more severe in resource poor settings. Data on seroprevalence of HBV and HCV among HIV infected children are scarce in Ethiopia. This study was conducted to determine seroprevalence and risk factors of HBV and HCV and its effect on liver enzyme among HIV-positive children aged 18 months to 15 years attending the paediatric HIV care and treatment clinic at Felege Hiwot referral hospital, Ethiopia.
Methods
A cross-sectional study was conducted in May, 2014. Demographic and risk factors were collected using a structured questionnaire. Hepatitis B surface antigen (HBsAg) and anti-HCV antibodies were detected using an enzyme linked immunosorbent assay (ELISA). Alanine aminotransferase (ALT) levels were determined. The results were analyzed using descriptive and logistic regression.
Results
A total of 253 HIV positive children, boys (52.5%) and girls (47.5%) took part in the study. The median age of the children was 11 years. Overall, 19 (7.5%) of HIV infected children were positive either for HBsAg or anti-HCV antibodies. The seroprevalence of HBV and HCV were 2.0% and 5.5%, respectively. All HBsAg positive children were in older age groups (11-15years). Seroprevalence of HCV was higher in children from urban (7.7%) than rural (1.2%) residents (P = 0.02). Overall, 29 (12.1%) of children had elevated ALT. Of these, 31.5% were from HBsAg or anti-HCV antibody positive children whereas 9.8% were from hepatitis B or C virus negative children (P = 0.001). Multivariate logistic regression showed that being positive for HBsAg or anti-HCV antibody (AOR: 4.7(95% CI: 1.5-13.5) was significantly associated with elevated ALT.
Conclusion
HBV and HCV co-infections are common in HIV positive children. In HIV positive children, HBV and HCV co-infection were associated with elevate ALT. Routine screening for HBV and HCV in HIV infected children should be implemented.
doi:10.1186/1756-0500-7-838
PMCID: PMC4255438  PMID: 25421947
HBV; HCV; HIV; ALT; Children
13.  Prevalence of Occult Hepatitis B Virus in Plasma and Peripheral Blood Mononuclear Cell Compartments of Patients With Chronic Hepatitis C Infection in Tehran-Iran 
Hepatitis Monthly  2013;13(5):e10134.
Background
Occult hepatitis B virus (HBV) infection (OBI) is frequently reported in patients with chronic hepatitis C virus (HCV) infection. An association between OBI and more liver damage, cirrhosis, hepatocellular carcinoma, and reduced response to interferon therapy in patients with HCV infection is suggested.
Objectives
The aim of this study was to determine the prevalence of occult HBV, and evaluate its clinical influence on patients with chronic HCV.
Patients and Methods
A cohort study including50 patients with positive results for HCV, and negative results for HBsAg tests was performed. The patients were divided into two groups: one group had positive results for both HCV and occult HBV tests (n = 18), and the other had positive results for HCV, but negative findings for occult HBV (n = 32). All were treated with PEG-IFN alpha-2a and Ribavirin. Presence of HCV RNA was followed in these patients.
Results
HBV-DNA was detected using nested-PCR in 20% of plasma and 32.6% of peripheral blood mononuclear cell (PBMC) compartments. No significant differences were observed between patients with and without occult HBV for sex, age, duration of HCV infection, histological markers, presence of anti-HBc, HCV viral load, and HCV genotype. The response rate was significantly higher in patients with positive results for HBV-DNA test compared to those with negative findings (100% vs. 71.9 %, P < 0.05).
Conclusions
In conclusion, occult HBV was found in 36% of patients with negative results for HBsAg, but positive results for HCV. Detection of HBV-DNA in both PBMCs and plasma together in comparison with plasma alone provided more true identification of OBI.The SVR rate was significantly higher in coinfected patients than mono-infected ones.
doi:10.5812/hepatmon.10134
PMCID: PMC3741907  PMID: 23967017
Hepatitis B; Hepatitis C Virus; Peripheral Blood Mononuclear Cell
14.  Additive effect modification of hepatitis B surface antigen and e antigen on the development of hepatocellular carcinoma. 
British Journal of Cancer  1996;73(12):1498-1502.
To assess the role of hepatitis B e antigen (HBeAg) and its interaction with hepatitis B surface antigen (HBsAg) on the development of hepatocellular carcinoma (HCC), this case-control study included 361 age- and sex-matched pairs of patients with histologically proven HCC and healthy control subjects. HBsAg, HBeAg and antibody to HBeAg (anti-HBe) were detected by radioimmunoassay. Antibodies to hepatitis C virus (anti-HCV) were detected by second-generation enzyme immunoassay. The prevalences of HBeAg (20.2%), HBsAg (80.3%) and anti-HCV (29.5%) in cases were higher than in controls (1.9%, 20.7%, and 2.7% respectively; each P < 0.0001). Using patients negative for HBsAg, HBeAg and anti-HBe as a referent group, univariate analysis indicated that HBsAg alone or HBsAg and HBeAg were risk factors for HCC (P for trend < 0.0001). Calculation of incremental odds ratio indicated that there was additive interaction between HBsAg and HBeAg. Multivariate analysis indicated that HCC development was strongly associated with the presence of HBeAg (odds ratio, 8.1; 95% confidence interval, 2.4-27.1), HBsAg (odds ratio, 68.4; 95% confidence interval, 20.5-227.8) and anti-HCV (odds ratio, 59.3; 95% confidence interval, 13.6-258.4). In conclusion, HBsAg, HBeAg and anti-HCV are independent risk factors for HCC. There is additive and independent effect modification between HBsAg and HBeAg on the development of HCC.
PMCID: PMC2074539  PMID: 8664119
15.  Sustained virological response: A milestone in the treatment of chronic hepatitis C 
AIM: To evaluate the long-term eradication of hepatitis C virus (HCV) infection and liver-related complications in chronically infected patients that have achieved sustained virological response.
METHODS: One hundred and fifty subjects with chronic hepatitis C (CHC) or cirrhosis and sustained virological response (SVR) between the years of 1989 and 2008 were enrolled in a long-term clinical follow-up study at the Gastrointestinal and Liver Unit of the University Hospital of Naples “Federico II”. At the beginning of the study, the diagnosis of HCV infection was made on the basis of serum positivity for antibodies to HCV and detection of HCV RNA transcripts, while a diagnosis of chronic hepatitis was formulated using imaging techniques and/or a liver biopsy. SVR was achieved by interferon-based therapy, both conventional and pegylated, with and without ribavirin treatment. The patients were evaluated for follow-up at a median length of 8.6 years, but ranged from 2-19.9 years. Among them, 137 patients had pre-treatment CHC and 13 had cirrhosis. The patients were followed with clinical, biochemical, virological, and ultrasound assessments on a given schedule. Finally, a group of 27 patients underwent a liver biopsy at the beginning of the study and transient elastography at their final visit to evaluate changes in liver fibrosis.
RESULTS: The median follow-up was 8.6 years (range 2-19.9 years). HCV RNA remained undetectable in all patients, even in patients who eventually developed liver-related complications, indicating no risk of HCV recurrence. Three liver-related complications were observed: two cases of hepatocellular carcinoma and one case of bleeding from esophageal varices resulting in an incidence rate of 0.23%/person per year. Further, all three complications took place in patients diagnosed with cirrhosis before treatment began. Only one death due to liver-related causes occurred, resulting in a mortality rate of 0.077% person per year. This amounts to a 99.33% survival rate in our cohort of patients after therapy for HCV infection. Finally, of the 27 patients who underwent a liver biopsy at the beginning of the study, a reduction in liver fibrosis was observed in 70.3% of the cases; only three cases registering values of liver stiffness indicative of significant fibrosis.
CONCLUSION: Patients with CHC and SVR show an excellent prognosis with no risk of recurrence and a very low rate of mortality. Our data indicate that virus-eradication following interferon treatment can last up to 20 years.
doi:10.3748/wjg.v19.i18.2793
PMCID: PMC3653153  PMID: 23687416
Antiviral therapy; Cirrhosis; Hepatitis C virus; Sustained virological response; Fibrosis
16.  The natural history of HCV in a cohort of haemophilic patients infected between 1961 and 1985 
Gut  2000;47(6):845-851.
AIM—This study describes the long term follow up of haemophilic patients infected with hepatitis C virus (HCV) between 1961 and 1985.
METHODS—Clinical and treatment records from 310 patients with inherited coagulation disorders treated with blood product before 1985 were reviewed. Standard survival analysis methods were used to model progression to liver failure and death.
RESULTS—A total of 298/305 (98%) patients tested were anti-HCV positive. Twenty seven (9%) individuals consistently HCV polymerise chain reaction negative were considered to have cleared the virus. By 1 September 1999, 223/310 (72%) were alive, 26 (8%) had died a liver related death, and 61 (20%) had died from other, predominantly human immunodeficiency virus (HIV) related, causes. Kaplan-Meier progression rates to death from any cause and liver related deaths 25 years after exposure to HCV were 47% (95% confidence intervals (CI) 34-60) and 19% (95% CI 10-27), respectively. After 13.3 years from 1985, by which time all patients had seroconverted to HIV, progression rates to death from any cause and liver related deaths were, respectively, 8% (95% CI 4-13) and 3% (95% CI 0.4-6) for those HIV negative, and 57% (95% CI 48-66) and 21% (95% CI 13-31) for those HIV positive (p=0.0001). Using Cox proportional hazard models, the adjusted relative hazard of death for individuals coinfected with HIV compared with those infected with HCV alone was 19.47 (95% CI 9.22-41.10), 0.99 (95% CI 0.39-2.53), 3.47 (95% CI 1.40-8.63), and 9.74 (95% CI 3.91-24.26) for the age groups at infection 10-19 years, 20-29 years, and >30 years, respectively, compared with the age group <10 years. The adjusted relative hazard for genotype 1 compared with other genotypes was 2.7 (95% CI 1.36-5.15) .
CONCLUSIONS—While 25 year follow up of 310 haemophilic patients has shown the potentially lethal combination of HIV and HCV coinfection, HCV singly infected individuals show slow progression of liver disease.


Keywords: hepatitis C virus; human immunodeficiency virus; haemophilia
doi:10.1136/gut.47.6.845
PMCID: PMC1728144  PMID: 11076885
17.  Chronic Hepatitis C Virus Infection is Associated with All-Cause and Liver-Related Mortality in a Cohort of HIV-Infected Patients with Alcohol Problems 
Addiction (Abingdon, England)  2013;109(1):62-70.
Aims
To assess the association between hepatitis C virus (HCV) infection and overall and liver-related death in human immunodeficiency virus (HIV)-infected patients with alcohol problems.
Design
We analyzed data from a cohort of HIV-infected adults with current or past alcohol problems enrolled between 2001 and 2003, searching for causes of death until 2010 using the National Death Index.
Setting and participants
Participants were HIV-infected adults with current or past alcohol problems, recruited in Boston, MA from HIV clinics at two hospitals, homeless shelters, drug treatment programs, subject referrals, flyers, and another cohort study with comparable recruitment sites.
Measurements
The primary and secondary outcomes were all-cause and liver-related mortality, respectively. The main independent variable was HCV RNA status (positive vs. negative). Mortality rates and Kaplan-Meier survival curves were calculated by HCV status for both overall and liver-related mortality. Cox proportional hazards models were used to assess the association between HCV infection and overall and liver-related death, adjusting for alcohol and drug use over time.
Findings
397 adults (50% HCV-infected) were included. As of December 31, 2009, 83 cohort participants had died (60 HCV-infected, 23 HCV-uninfected; log rank test p<0.001), and 26 of those deaths were liver-related (21 HCV-infected, 5 HCV-uninfected; log rank test p<0.001). All-cause and liver-related mortality rates were 4.68 and 1.64 deaths per 100 person-years for HCV-infected patients and 1.65 and 0.36 per 100 person-years for those without HCV, respectively. In the fully adjusted Cox model, HCV infection was associated with both overall [HR 2.55 (95%CI:1.50–4.33), p<0.01], and liver-related mortality [HR 3.24 (95%CI:1.18–8.94), p=0.02].
Conclusion
Hepatitis C virus infection is independently associated with all-cause and liver-related mortality in human immunodeficiency virus-infected patients with alcohol problems, even when accounting for alcohol and other drug use.
doi:10.1111/add.12367
PMCID: PMC3947001  PMID: 24112091
18.  Viral Hepatitis Among Somali Immigrants in Minnesota: Association of Hepatitis C With Hepatocellular Carcinoma 
Mayo Clinic Proceedings  2012;87(1):17-24.
Objective
To study the frequencies of chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infection, and their associations with hepatocellular carcinoma (HCC) in immigrant Somalis seen at Mayo Clinic in Rochester, Minnesota.
Patients and Methods
We determined the frequencies of HBV and HCV infection and HCC in immigrant Somalis seen at Mayo Clinic from July 1, 1996, through October 31, 2009. Non-Somali Olmsted County residents served as controls.
Results
For Somali males and females, age-adjusted proportions (per 1000 population) were 209 and 123 for hepatitis B surface antigen (HBsAg), 644 and 541 for hepatitis B core antibody (HBcAb), and 99 and 66 for anti-HCV. The comparative proportions in non-Somalis were 20 and 9 for HBsAg, 126 and 97 for HBcAb, and 32 and 17 for anti-HCV. Hepatitis C virus RNA confirmed that 68 of 73 Somalis (93.2%) and 261 of 282 non-Somalis (92.6%) with positive anti-HCV test results had active HCV infection. Of 30 Somali patients with HCC, 22 (73.3%) tested anti-HCV positive (odds ratio [OR], 31.3; 95% confidence interval [CI], 13.0-75.5; P<.001; compared with anti-HCV–negative Somalis), 5 (16.7%) were HBsAg positive (OR, 1.4; 95% CI, 0.5-3.7; P=.53), and 18 (60.0%) were HBcAb positive (OR, 1.8; 95% CI, 0.8-4.2; P=.16). Viral hepatitis was diagnosed coincident with HCC in 9 of 20 patients (45.0%) with HCV-associated HCCs. Only 4 of 24 cases of HCC (16.7%) were detected during surveillance.
Conclusion
Both HBV and HCV occurred frequently in this sample of Somali immigrants. However, HCV was the major risk factor for HCC. Screening Somali immigrants for HCV infection may enhance the prevention, early detection, and optimal treatment of HCC.
doi:10.1016/j.mayocp.2011.08.001
PMCID: PMC3337857  PMID: 22212964
19.  Current therapy for hepatitis C or D or immunodeficiency virus concurrent infection with chronic hepatitis B 
Hepatology International  2008;2(3):296-303.
Concurrent hepatitis C virus (HCV), hepatitis delta virus (HDV), or human immunodeficiency virus (HIV) infection with chronic hepatitis B virus (HBV) appears to increase the risk of progressive liver disease including liver cirrhosis and hepatocellular carcinoma. There is a 10% prevalence of HCV infection in chronic HBV or HDV infection. Serological evidence of previous exposure to HBV is found in more than 80% of HIV-positive patients in the high risk group. Notably, the most recently acquired virus tends to suppress the pre-existing virus. In chronic HBV infection acquired perinatally or in early childhood, usually HCV is dominant and may suppress or even displace HBV and HDV. Less frequently, HBV or HDV suppresses HCV. It is generally agreed that the dominant virus should be identified in order to make appropriate treatment decisions. Studies with standard interferon (IFN) to treat patients with HCV dominantly dual HBV/HCV infection have showed only limited virological response. But high dose of IFN has been demonstrated with better response rate. Combined ribavirin with standard or pegylated IFN therapy could achieve a sustained HCV clearance rate comparable with those infected with HCV alone. On the contrary, patients with HBV dominantly dual viral infection might indicate more appropriate addition of lamivudine to IFN than ribavirin. Additionally, patients with concurrent infection of HBV and HDV, IFN seems to be the only effective agent. However, the efficacy of IFN is related to the dose. High dose of IFN [9 MU tiw (thrice per week)] and longer treatment duration (at least 2 years) have been shown to achieve adequate virological response. In patients with concurrently infected HBV and HIV, anti-HBV therapy should be considered for all patients with evidence of liver disease, irrespective of the CD4 cell count. In patients not requiring antiretroviral therapy, HBV therapy should be preferentially based on IFN, adefovir, or telbivudine. In contrast, in patients with CD4 cell counts <350 cells/μl or those already on antiretroviral therapy, agents with double anti-HBV and anti-HIV activity are preferred. At present, the evidence of therapeutic efficacy is not sufficient to make a recommendation in treating patients with dual HBV/HCV or HBV/HDV or HBV/HIV infection. Further studies of the well-designed, larger scale are needed to elucidate the role of different regimens or combination in the treatment of dual viral infection.
doi:10.1007/s12072-008-9066-1
PMCID: PMC2716893  PMID: 19669257
Hepatitis B virus; Hepatitis C virus; Hepatitis delta virus; Human immunodeficiency virus; Concurrent infection
20.  Chemoprevention of hepatocellular carcinoma in patients with hepatitis C virus related cirrhosis 
World Journal of Hepatology  2013;5(10):521-527.
Interferon (IFN) therapy has been reported to decrease the risk of hepatocellular carcinoma (HCC) and improve survival by preventing liver-related deaths in patients with chronic hepatitis C virus (HCV) infection, while the role of IFN therapy on the natural history of hepatitis C related cirrhosis is still under debate. The ideal goal of therapy is to prevent the progression into end-stage disease. The use of IFN in patients with HCV compensated cirrhosis reduces the negative clinical evolution independently of the type of laboratoristic and virological response. In our experience, IFN therapy in HCV compensated cirrhosis is barely useful in prevention of HCC, as cirrhosis itself represents a risk of cancer. Some authors noted that IFN treatment reduces the risk of HCC independently of the virological response. It would probably be interesting to evaluate the efficacy of weekly low-dose pegylated (PEG)-IFN therapy in patients with HCV cirrhosis and to assess potential benefits of long-term PEG-IFN plus Ribavirin treatment.
doi:10.4254/wjh.v5.i10.521
PMCID: PMC3812454  PMID: 24179611
Chemoprevention; Cirrhosis; Hepatitis C virus; Hepatocellular carcinoma
21.  Combined IFN-α and 5-FU treatment as a postoperative adjuvant following surgery for hepatocellular carcinoma with portal venous tumor thrombus 
The efficacy of combination therapy with subcutaneous interferon (IFN)-α and intra-arterial 5-fluorouracil (5-FU) as a postoperative adjuvant for resectable advanced hepatocellular carcinoma (HCC) invading the major branches of the portal vein (PVTT) was examined. The prognosis of HCC with PVTT (Vp3 or 4) is extremely poor. Recently, we reported the possibility of combination therapy with IFN-α and intra-arterial 5-FU for intractable HCC with PVTT as a postoperative adjuvant and this is the second report. Patients with HCC with PVTT were included (n=50). Thirty consecutive patients with HCC and PVTT were treated with 3 cycles of a combination therapy consisting of arterial 5-FU infusion (300 mg/mm3/day, 5 days/week, for the initial 2 weeks) and IFN subcutaneous injection (5 MIU, 3 times/week, 4 weeks) as a postoperative adjuvant following hepatic resection; another 20 patients receiving no IFN/5-FU chemotherapy acted as controls. Results for the IFN/5-FU adjuvant treatment group were as follows: disease-free survival (n=9, 15–109 months), survival with recurrence (n=6, 30–92 months), cancer death (n=9, 14–60 months), death from other causes but no recurrence (n=5, 13–87 months) and death from other causes with recurrence (n=1, 22 months). The 1-year survival rate was 100% in patients treated with IFN/5-FU, and 30% in those without IFN/5-FU as historical controls (n=20). There was a significant difference in disease-free and overall survival rates between the two groups (P<0.0001). In conclusion, IFN/5-FU combination therapy may be a very promising postoperative adjuvant treatment for HCC with PVTT.
doi:10.3892/etm.2012.736
PMCID: PMC3524132  PMID: 23251233
HCC; PVTT; IFN; chemotherapy; surgery
22.  Cirrhosis and Chronic Viral Hepatitis as Risk Factors for Hepatocellular Carcinoma: Romanian Single-clinic Experience 
Mædica  2010;5(4):265-270.
ABSTRACT
Introduction: Hepatocellular carcinoma (HCC) represents the fifth most common cancer worldwide, while being the third leading cause of death by cancer. The primary risk factor for HCC seems to be liver cirrhosis. A large majority of these patients have a history of viral hepatitis.
Materials and methods: We selected a study lot consisting of 244 patients diagnosed with HCC, admitted between 2006 and October 2009 in the Emergency County Hospital of Craiova, Romania along with an age and gender matched control group, consisting of patients with no history of HCC or other malignancies. We interviewed all subjects regarding their alcohol consumption and background environment. All subjects underwent hepatitis B surface antigen (Hbs Ag) and anti-HCV antibodies (Anti-HCV Atb) serological determinations.
Results: The study group consisted of 148 males and 96 females. Liver cirrhosis (LC) was present in 84% of the study lot, 10% associated viral B hepatitis (HBV) and 6% viral C hepatitis (HCV), with no signs of LC. We found LC to be an important risk factor for HCC (RR 6.53, CI 95% 3.18–13.38). The RR and 95% CI of HCC were 4.51 (2.48–8.21) for HbsAg positivity. We noticed a strong correlation (Chi-square test, p<0.001) between the rural environment and the association with LC. HVB was also more present in patients coming from rural areas (p< 0.01). Alcohol intake was present in 89% of the whole lot, being more correlated with the presence of LC as well as with HbsAg positivity (RR 9.165, CI 95% 4.43–18.92).
Conclusion: Cirrhosis proved to be the primary risk factors for HCC. We underline the fact that HCC was found to be directly associated with viral hepatitis, without evident LC. Further studies are needed in order to establish if intensified HCC screening, especially in rural areas, is required in patients with newly diagnosed viral hepatitis. The increased prevalence of HBV infections might encourage HBV vaccinations as an efficient tool to prevent HCC.
PMCID: PMC3152834  PMID: 21977168
Hepatocellular carcinoma; liver cirrhosis; viral hepatitis; HbsAg positivity; Anti-HCV Atb positivity; alcohol abuse; background environment
23.  Impact of antibody to hepatitis B core antigen on the clinical course of hepatitis C virus carriers in a hyperendemic area in Japan: a community-based cohort study 
Aim
Subjects positive for antibody to hepatitis B core antigen (HBcAb) and negative for hepatitis B surface antigen (HBsAg) are considered to have occult hepatitis B virus (HBV) infection. The aim of this study was to determine the impact of occult HBV infection on aggravation of the clinical course in hepatitis C virus (HCV) carriers.
Methods
A prospective cohort study was performed in 400 subjects who were positive for anti-HCV antibody and negative for HBsAg. Among these subjects, 263 were HCV core antigen-positive or HCV RNA-positive (HCV carriers). We examined whether the presence of HBcAb affected the clinical course in these HCV carriers from 1996 to 2005.
Results
The HBcAb-positive rates were 53.6% and 52.6% in HCV carriers and HCV RNA-negative subjects, respectively. There were no differences in the incidence of hepatocellular carcinoma (HCC) and cumulative mortality associated with liver-related death between HCV carriers who were positive and negative for HBcAb. In multivariate analysis, age (≥65 years old) and alanin aminotransferase level (≥31 IU/L) emerged as independent risk factors for HCC development and liver-related death, but the HBcAb status was not a risk factor. In addition, increased serum hepatic fibrosis markers (measured from 2001 to 2004) were not associated with HBcAb status.
Conclusion
In our cohort study, the presence of HBcAb had no impact on HCC development, liver-related death and hepatic fibrosis markers in HCV carriers. Thus, our results indicate that occult HBV infection has no impact on the clinical course in HCV carriers.
doi:10.1111/hepr.12075
PMCID: PMC3710530  PMID: 23413835
antibody to hepatitis B core antigen; occult hepatitis B virus infection; hepatitis C virus; hepatocellular carcinoma; mortality; hepatic fibrosis
24.  Effect of Previous Interferon-based Therapy on Recurrence after Curative Treatment of Hepatitis C Virus-related Hepatocellular Carcinoma 
Previous reports have shown that interferon (IFN)-based therapy decreases the risk of development of hepatocellular carcinoma (HCC) in patients with chronic hepatitis C virus (HCV) infection. However, it remains to be fully elucidated whether elimination of HCV by IFN-based therapy inhibits HCC recurrence after curative treatment, such as surgical resection and local ablation therapies. In this study, we aimed to clarify the influence of a sustained virological response (SVR) after IFN-based therapy on recurrence and survival after curative treatment of HCC. Fifty-one patients who underwent curative treatment of HCV-related HCC after receiving IFN-based therapy were analyzed retrospectively. They were classified into SVR (N = 14) and non-SVR groups (N = 37). In the SVR group, serum levels of aspartate aminotransferase and alanine aminotransferase, the indocyanine green retention rate at 15 min, and the percentages of patients with liver cirrhosis and HCV serotype 1 were significantly lower, whereas serum albumin level and platelet count were significantly higher upon HCC occurrence. Recurrence-free survival (RFS) for the first recurrence was significantly higher in the SVR group (P < 0.01). Multivariate analysis showed that SVR at initial HCC treatment (P < 0.01) and multiple tumors (P < 0.01) are prognostic factors for RFS. Moreover, RFS for the second recurrence showed a similar trend to that for the first recurrence. In conclusion, patients who underwent IFN-based therapy before initial curative treatment of HCC had a favorable clinical outcome compared with non-SVR patients.
doi:10.7150/ijms.8764
PMCID: PMC4025170  PMID: 24843320
HCC; HCV; IFN; recurrence; SVR.
25.  Liver Fibrosis, Host Genetic and Hepatitis C Virus Related Parameters as Predictive Factors of Response to Therapy against Hepatitis C Virus in HIV/HCV Coinfected Patients 
PLoS ONE  2014;9(7):e101760.
Objective
To establish the role of liver fibrosis as a predictive tool of response to pegylated interferon alpha (Peg-IFN) and ribavirin (RBV) treatment in human immunodeficiency (HIV)/hepatitis C virus (HCV) coinfected patients, in addition to recognized predictive factors (HCV load, HCV genotype, IL-28B polymorphism).
Patients and Methods
A sample of 267 HIV/HCV coinfected patients was treated with Peg-IFN and RBV. Predictive factors of rapid (RVR) and sustained (SVR) virological response were analyzed. Independent variables were age, sex, IL28B, −238 TNF-α and −592 IL-10 polymorphisms, HCV genotype, HCV-RNA levels, significant fibrosis or cirrhosis and CD4+ T cell count.
Results
Patients infected by HCV genotype 1 (n = 187) showed RVR and SVR in 12% and 39% of cases, respectively. The parameters associated with RVR were IL28B genotype CC and plasma HCV-RNA levels <600000 IU/ml. Advanced liver fibrosis was negatively associated with SVR in patients without RVR. A SVR was obtained in 42% of subjects with HCV genotype 4, and the independent factors associated with SVR were IL28B genotype CC and an HCV-RNA <600000 IU/ml. A SVR was obtained in 66% of patients with HCV genotypes 2/3; in this case, the independent parameter associated with SVR was the absence of significant liver fibrosis. TNF-α and IL-10 polymorphisms were not associated with SVR, although a significantly higher percentage of −238 TNF-α genotype GG was detected in patients with significant liver fibrosis.
Conclusions
In HIV/HCV coinfected patients with HCV genotypes 1 or 4, RVR, mainly influenced by genotype IL28B and HCV-RNA levels, reliably predicted SVR after 4 weeks of therapy with Peg-IFN plus RBV. In patients infected by HCV genotype 3, an elevated relapse rate compromised the influence of RVR on SVR. Relapses were related to the presence of advanced liver fibrosis. Liver cirrhosis was associated with a −238 TNF-α polymorphism in these patients.
doi:10.1371/journal.pone.0101760
PMCID: PMC4094489  PMID: 25013899

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