Hepatitis C virus (HCV) infection has been associated with liver disease including liver cirrhosis and hepatocellular carcinoma (HCC) in chronically-infected persons. However, in HIV/HCV co-infected patients, increased rate of progression to cirrhosis and HCC has been reported. Limited information exists regarding genetic variants of HCV circulating among co-infected patients, which could be important in the design of broadly protective vaccine and management of the disease. Here, we determined the genotypes of HCV isolates circulating among HIV/HCV co-infected patients in Ibadan, southwestern Nigeria. One hundred and twenty-five HIV/HCV IgM positive samples obtained from HIV laboratory, University of Ibadan were used for this study. HCV NS5B gene was amplified using polymerase chain reaction (PCR). The amplified NS5B gene was sequenced using gene specific primers. Twenty isolates were amplified, out of which 13 were successfully sequenced. Phylogenetic analysis of the 13 sequenced isolates showed three HCV subtypes 1a, 3a and 5a belonging to genotypes 1, 3 and 5 respectively. Ten isolates (77%) belong to subtype 5a, followed by 2 isolates (15%) subtype 1a and 1 isolate (8%) was subtype 3a. The predominant HCV genotype was 5, followed by genotype 1 (subtype 1a). The findings, as well as the observed mutations in NS5B gene, indicate the need for screening and monitoring of HIV/HCV co-infected patients. Further study to determine the phylogeny of isolates circulating in other parts of Nigeria will be carried out.

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.

Even after attainment of sustained viral suppression following implementation of highly active antiretroviral therapy, HIV-infected persons continue to experience persistent, low-grade, systemic inflammation. Among other mechanisms, this appears to result from ongoing microbial translocation from a damaged gastrointestinal tract. This HIV-related chronic inflammatory response is paralleled by counteracting, but only partially effective, biological anti-inflammatory processes. Paradoxically, however, this anti-inflammatory response not only exacerbates immunosuppression but also predisposes for development of non-AIDS-related, non-communicable disorders. With respect to the pathogenesis of both sustained immunosuppression and the increased frequency of non-AIDS-related disorders, the anti-inflammatory/profibrotic cytokine, transforming growth factor-β1 (TGF-β1), which remains persistently elevated in both untreated and virally suppressed HIV-infected persons, may provide a common link. In this context, the current review is focused on two different, albeit related, harmful activities of TGF-β1 in HIV infection. First, on the spectrum of anti-inflammatory/immunosuppressive activities of TGF-β1 and the involvement of this cytokine, derived predominantly from T regulatory cells, in driving disease progression in HIV-infected persons via both non-fibrotic and profibrotic mechanisms. Second, the possible involvement of sustained elevations in circulating and tissue TGF-β1 in the pathogenesis of non-AIDS-defining cardiovascular, hepatic, pulmonary and renal disorders, together with a brief comment on potential TGF-β1-targeted therapeutic strategies.

Studies have shown that hepatitis C virus (HCV) RNA levels remain stable over time in HIV/HCV-coinfected individuals taking combination antiretroviral therapy (cART), while spontaneous clearance of HCV RNA during the persistent infection phase has been documented only rarely among those with the CC interleukin (IL)-28B genotype. This study describes HCV RNA profiles and factors associated with changes over time in HCV RNA levels in the ESPRIT study.

HIV/HCV-coinfected individuals positive for HCV RNA were included in the study. Follow-up was counted from the first HCV RNA positive test and censored at the initiation of interferon-based treatment. HCV RNA and IL-28B measurements were performed in the same reference laboratory. Random effects mixed models were used to analyse changes over time in HCV RNA.

A total of 312 ESPRIT patients were included in the study (151 in the arm receiving subcutaneous recombinant IL-2 and 161 in the control arm). Most of the patients were white (89%) and male (76%), and they had a median of 5 HCV RNA measurements per person [interquartile range (IQR) 3-6; range 1-9]. Median follow-up was 5 years (IQR: 2-6 years). At baseline, 96% of patients were taking cART and 93% had undetectable HIV RNA. Mean HCV RNA levels decreased by 13% per year over the study period [95% confidence interval (CI) 8-18%; P < 0.0001]. Baseline HCV RNA levels and the change over time in HCV RNA did not differ by randomization arm (P = 0.16 and P = 0.56, respectively). Nine individuals spontaneously cleared HCV RNA during follow-up [IL-28B genotypes: CC, five patients (56%); CT, four patients (44%)].

HCV RNA levels decreased over time in this population with well-controlled HIV infection. Spontaneous clearance of HCV RNA was documented in five individuals with IL-28B genotype CC and four with the CT genotype.

Antibody responses have not been fully characterised in chronically HIV/HCV patients receiving antiretroviral therapy (ART). Seventeen HIV/HCV patients receiving ART were followed for a median (range) interval of 597 (186-766) weeks. Prior to ART, HIV/HCV patients had lower levels of antibodies reactive with HCV core and JFH-1, and lower genotype cross-reactive neutralising antibodies (nAb) titres, than HCV patients. Levels of JFH-1 reactive antibody increased on ART, irrespective of CD4⁺ T-cell counts or changes in serum ALT levels. The appearance of nAb coincided with control of HCV viral replication in five HIV/HCV patients. In other patients, HCV viral loads remained elevated despite nAb responses. Sustained virological responses following HCV therapy were associated with reduced antibody responses to JFH-1 and core but elevated responses to non-structural proteins. We conclude that nAb responses alone may fail to clear HCV, but contribute to control of viral replication in some HIV/HCV patients responding to ART.

Due to high prevalence rates, the hepatitis C virus (HCV) and the HIV cause two viral infections of global importance. Shared routes of transmission lead to a high number of dually infected individuals especially in specific populations such as intravenous drug users or people from highly endemic regions for both viruses. Treatment progress made in the field of HIV in the past three decades diminished the number of HIV patients who die from opportunistic infections and enabled a rise of HCV-associated liver disease in the HIV-HCV-coinfected population.

An HIV-HCV coinfection is mainly characterized by a faster progression to liver cirrhosis that may lead to hepatic decompensation or the development of hepatocellular carcinoma (HCC). The treatment of HIV with highly active antiretroviral therapy (HAART) may only partly reverse this effect by the restoration of the immune system. Although no clear deleterious effect of HCV on the course of HIV infection is described, an increased HIV-associated and non-HIV-associated mortality has been described in patients not cured from their HCV infection.

In this article, we review the latest knowledge on the natural course of HCV in the HIV-infected population, the role of HIV treatment, and the possible effects of HCV on HIV disease progression.

Dendritic cell (DC) numbers and functions can be affected by HIV and HCV disease, but the effects of antiretroviral therapy (ART) on DC and the implications of these changes are unclear. We examined circulating DC in samples from Indonesian patients beginning ART with advanced HIV disease and documented mild/moderate HCV hepatitis. Frequencies of myeloid and plasmacytoid DC increased after 6 months on ART, but frequencies of DC producing IL-12 or IFNα following stimulation with TLR agonists (CL075, CpG) did not change. IFNγ responses to CL075, HCV and other antigens rose over this period. Hence increased IFNγ responses during ART may be associated with increased DC frequencies rather than changes in their functional capacity.

Due to shared routes of transmission, acute and chronic infection with hepatitis C virus is common among persons living with HIV infection in many regions of the world. In the era of effective antiretroviral therapy, acute HCV infection has been increasingly recognized in HIV-infected persons, particularly men who have sex with men, and liver disease, including hepatocellular carcinoma, has emerged as a leading cause of morbidity and mortality in those with chronic HCV infection, particularly older adults with long-standing coinfection. Over the past decade, the foundation for the management of acute and chronic HCV infection has been interferon alfa. However, due the high burden of treatment-related side effects and low likelihood of sustained virologic response, the impact of treatment with peginterferon/ribavirin on the burden of HCV disease in has been limited. However, the anticipated availability of safe, tolerable and highly efficacious interferon-free, oral HCV direct-acting antiviral combination therapies promise to dramatically change the management of acute and chronic HCV infection in HIV-infected persons. Preliminary data from studies of such oral DAA regimens in HIV/HCV coinfected patients suggest that coinfection with HIV will not impair HCV cure with these regimens. Indeed, in the coming era of high effective oral HCV DAA treatments, the only special feature concerning treatment of acute and chronic HCV infection in HIV-infected patients may be drug interactions between the antiretroviral drugs for HIV infection and direct-acting antiviral drugs for HCV infection.

When severely immunodeficient HIV/HCV co-infected patients are treated with antiretroviral therapy, it is important to know whether HCV-specific antibody responses recover and whether antibody profiles predict the occurrence of HCV-associated immune restoration disease (IRD). In 50 HIV/HCV co-infected patients, we found that antibody reactivity and titres of neutralising antibodies (nAb) to JFH-1 (HCV genotype 2a virus) increased over 48 weeks of therapy. Development of HCV IRD was associated with elevated reactivity to JFH-1 before and during the first 12 weeks of therapy. Individual analyses of HCV IRD and non-HCV IRD patients revealed a lack of an association between nAb responses and HCV viral loads. These results showed that increased HCV-specific antibody levels during therapy were associated with CD4(+) T-cell recovery. Whilst genotype cross-reactive antibody responses may identify co-infected patients at risk of developing HCV IRD, neutralising antibodies to JFH-1 were not involved in suppression of HCV replication during therapy.

Human immunodeficiency virus (HIV) and hepatitis C virus (HCV) cause substantial mortality, especially in persons chronically infected with both viruses. HIV infection raises plasma HCV RNA levels and diminishes the response to exogenous alpha interferon (IFN). The degree to which antiretroviral therapy (ART) control of infection overcomes these HIV effects is unknown. Participants with HIV-HCV coinfection were enrolled in a trial to measure HCV viral kinetics after IFN administration (ΔHCVIFN ) twice: initially before (pre-ART) and then after (post-ART) HIV RNA suppression. Liver tissue was obtained 2-4 hours before each IFN injection to measure interferon stimulated genes (ISGs). Following ART, the ΔHCVIFN at 72 hours (ΔHCVIFN,72 ) increased in 15/19 (78.9%) participants by a median (interquartile range [IQR]) of 0.11 log10 IU/mL (0.00-0.40; P < 0.05). Increases in ΔHCVIFN,72 post-ART were associated with decreased hepatic expression of several ISGs (r = -0.68; P = 0.001); a 2-fold reduction in a four-gene ISG signature predicted an increase in ΔHCVIFN,72 of 0.78 log10 IU/mL (95% confidence interval [CI] 0.36,1.20). Pre- and post-ART ΔHCVIFN,72 were closely associated (r = 0.87; P < 0.001). HCV virologic setpoint also changed after ART (ΔHCVART ): transient median increases of 0.28 log10 IU/mL were followed by eventual median decreases from baseline of 0.21 log10 IU/mL (P = 0.002). A bivariate model of HIV RNA control (P < 0.05) and increased expression of a nine-gene ISG signature (P < 0.001) predicted the eventual decreased ΔHCVART .

ART is associated with lower post-IFN HCV RNA levels and that change is linked to reduced hepatic ISG expression. These data support recommendations to provide ART prior to IFN-based treatment of HCV and may provide insights into the pathogenesis of HIV-HCV coinfection.

Coinfection with HIV adversely impacts every stage of hepatitis C (HCV) infection. Liver damage in HCV infection results from host antiviral responses rather than direct viral pathogenesis. Despite depressed cellular immunity, coinfected patients show accelerated hepatic fibrosis compared with HCV monoinfected patients. This paradox is poorly understood. T-regulatory (Treg) cells (CD4+ and FOXP3+) are hypothesized to limit hepatic damage in HCV. Our hypothesis was that reduced frequency of hepatic Treg in HIV/HCV coinfection compared with HCV monoinfection may explain poorer outcomes. We quantified FOXP3+, CD4+, CD8+ and CD20+ cells in liver biopsies of 35 male subjects matched by age and ISHAK fibrosis score, 12 HIV monoinfected, 11 HCV monoinfected and 12 HIV/HCV coinfected. Cell counts were performed using indirect immunohistochemical staining and light microscopy. HIV/HCV coinfected subjects had fewer hepatic FOXP3+ (P = 0.031) and CD4+ cells (P = 0.001) than HCV monoinfected subjects. Coinfected subjects had more hepatic CD8+ cells compared with HCV monoinfected (P = 0.023), and a lower ratio of FOXP3+ to CD8+ cells (0.08 vs 0.27, P < 0.001). Multivariate analysis showed number of CD4+ cells controlled for differences in number of FOXP3+ cells. Fewer hepatic FOXP3+ and CD4+ cells in HIV/HCV coinfection compared with HCV monoinfection suggests lower Treg activity, driven by an overall loss of CD4+ cells. Higher number of CD8+ cells in HIV/HCV coinfection suggests higher cytotoxic activity. This may explain poorer outcomes in HIV/HCV coinfected patients and suggests a potential mechanism by which highly active antiretroviral therapy may benefit these patients.

The objectives of the study are to characterize the cellular immune response in hepatitis C virus (HCV) genotype 1 and HIV co-infected patients with hemophilia in southern China during treatment with interferon and ribavirin and to study its correlation with the virologic response (VR). Thirty-six HCV genotype 1 and HIV co-infected patients with hemophilia in southern China were enrolled into the study. Using an ELISpot assay, HCV antigen-specific interferon (IFN) γ, interleukin (IL) 2, IL-4, and IL-10 secreting cells were measured in peripheral blood mononuclear cells. Single nucleotide polymorphisms of IL28B were determined, and immunological, virologic, and clinical variables were collected to identify factors associated with HCV-sustained VR (SVR) at week 72 after treatment. At baseline, there were no significant differences in IFN-γ and IL-2 mediated immune responses in subjects with VR versus non-responders. Higher IL-10 specific responses to NS3 were observed in VR patients. Subjects who had significant decreases in IL-10 responses at week 72 compared with baseline for NS3 and NS5 were more likely to be VR. In SVR, IL-2 production decreased moderately, and the levels of IL-4 were low throughout. The main correlation for SVR in genotype-l infected subjects was sustained HCV-specific IFN-γ responses through the whole 72-week period. In subjects with HIV and HCV co-infection combined with hemophilia, IL28B genotype CC, a decrease in HCV specific IL-l0 and IL-2 responses, and the maintenance of IFN-γ responses during treatment were associated with a 12- or 72-week VR.

We investigated changes in biomarkers of liver disease in HIV-HCV-coinfected individuals during successful combination antiretroviral therapy (cART) compared to changes in biomarker levels during untreated HIV infection and to HIV-monoinfected individuals.

Non-invasive biomarkers of liver disease (hyaluronic acid [HYA], aspartate aminotransferase-to-platelet ratio index [APRI], Fibrosis-4 [FIB-4] index and cytokeratin-18 [CK-18]) were correlated with liver histology in 49 HIV-HCV-coinfected patients. Changes in biomarkers over time were then assessed longitudinally in HIV-HCV-coinfected patients during successful cART (n=58), during untreated HIV-infection (n=59), and in HIV-monoinfected individuals (n=17). The median follow-up time was 3.4 years on cART. All analyses were conducted before starting HCV treatment.

Non-invasive biomarkers of liver disease correlated significantly with the histological METAVIR stage (P<0.002 for all comparisons). The mean ±sd area under the receiver operating characteristic (AUROC) curve values for advanced fibrosis (≥F3 METAVIR) for HYA, APRI, FIB-4 and CK-18 were 0.86 ±0.05, 0.84 ±0.08, 0.80 ±0.09 and 0.81 ±0.07, respectively. HYA, APRI and CK-18 levels were higher in HIV-HCV-coinfected compared to HIV-monoinfected patients (P<0.01). In the first year on cART, APRI and FIB-4 scores decreased (-35% and -33%, respectively; P=0.1), mainly due to the reversion of HIV-induced thrombocytopaenia, whereas HYA and CK-18 levels remained unchanged. During long-term cART, there were only small changes (<5%) in median biomarker levels. Median biomarker levels changed <3% during untreated HIV-infection. Overall, 3 patients died from end-stage liver disease, and 10 from other causes.

Biomarkers of liver disease highly correlated with fibrosis in HIV-HCV-coinfected individuals and did not change significantly during successful cART. These findings suggest a slower than expected liver disease progression in many HIV-HCV-coinfected individuals, at least during successful cART.

Clearance of infections caused by the hepatitis C virus (HCV) correlates with HCV-specific T cell function. We therefore evaluated therapeutic vaccination in 12 patients with chronic HCV infection. Eight patients also underwent a subsequent standard-of-care (SOC) therapy with pegylated interferon (IFN) and ribavirin. The phase I/IIa clinical trial was performed in treatment naive HCV genotype 1 patients, receiving four monthly vaccinations in the deltoid muscles with 167, 500, or 1,500 μg codon-optimized HCV nonstructural (NS) 3/4A-expressing DNA vaccine delivered by in vivo electroporation (EP). Enrollment was done with 2 weeks interval between patients for safety reasons. Treatment was safe and well tolerated. The vaccinations significantly improved IFN-γ-producing responses to HCV NS3 during the first 6 weeks of therapy. Five patients experienced 2-10 weeks 0.6-2.4 log10 reduction in serum HCV RNA. Six out of eight patients starting SOC therapy within 1-30 months after the last vaccine dose were cured. This first-in-man therapeutic HCV DNA vaccine study with the vaccine delivered by in vivo EP shows transient effects in patients with chronic HCV genotype 1 infection. The interesting result noted after SOC therapy suggests that therapeutic vaccination can be explored in a combination with SOC treatment.

Infection with hepatitis C virus (HCV) is a major cause of chronic liver disease. High HCV RNA levels have been associated with poor treatment response. This study aimed to examine the natural history of HCV RNA in chronically HCV/HIV-coinfected individuals.

Mixed models were used to analyse the natural history of HCV RNA changes over time in HIV-positive patients with chronic HCV infection.

A total of 1541 individuals, predominantly White (91%), male (73%), from southern (35%) and western central Europe (23%) and with HCV genotype 1 (58%), were included in the analysis. The median follow-up time was 5.0 years [interquartile range (IQR) 2.8 to 8.3 years]. Among patients not on combination antiretroviral therapy (cART), HCV RNA levels increased by a mean 27.6% per year [95% confidence interval (CI) 6.1-53.5%; P = 0.0098]. Among patients receiving cART, HCV RNA levels were stable, increasing by a mean 2.6% per year (95% CI -1.1 to 6.5%; P = 0.17). Baseline HCV RNA levels were 25.5% higher (95% CI 8.8 to 39.1%; P = 0.0044) in individuals with HCV genotype 1 compared with HCV genotypes 2, 3 and 4. A 1 log HIV-1 RNA copies/mL increase in HIV RNA was associated with a 10.9% increase (95% CI 2.3 to 20.2%; P = 0.012) in HCV RNA.

While HCV RNA levels increased significantly in patients prior to receiving cART, among those treated with cART HCV RNA levels remained stable over time.

HIV-1/hepatitis C virus (HCV) coinfection accelerates the progression of liver disease to cirrhosis, particularly in individuals with low CD4 T-cell counts. Highly active antiretroviral therapy (HAART) can significantly increase HCV-specific T-cell responses; however, it remains unclear whether the restoration of HCV-specific T cells by HAART is associated with liver injury in these coinfection patients.

A total of 32 HIV-1/HCV coinfected patients and 14 HCV monoinfected patients were enrolled, and 13 coinfected patients were initialized HAART and followed up for 6 months. HCV-specific interferon-γ responses to HCV core and NS3A proteins were examined by enzyme-linked immunosorbent spot.

HCV-specific interferon-γ responses to HCV core and NS3A proteins were impaired in HIV-1/HCV-coinfected patients as compared with those in HCV monoinfected patients. The impaired HCV-specific T-cell responses could be efficiently restored during the early phase of HAART, independent of HCV status, and were positively associated with increased CD4 T-cell counts. In addition, this recovery of HCV-specific T-cell responses occurred simultaneously with elevated serum alanine aminotransferase levels in HCV viremic patients and in patients with HCV rebound, but not in HCV nonviremic patients after 6 months of HAART.

The recovery of HCV-specific T-cell responses by HAART may lead to transient liver injury in patients with HIV-1/HCV coinfection, suggesting that early anti-HCV therapy before HAART may reduce the risk of liver injury and therefore may be beneficial to HIV-1/HCV-coinfected patients.

Hepatitis C and brucellosis are infectious diseases that occur worldwide, and both are endemic in Egypt. Co-infection with both agents is possible, and this can involve the liver in various ways. In this study, we investigated serum tissue inhibitor metalloproteinase-1 (TIMP-1), viral load, and liver functions in patients co-infected with hepatitis C virus (HCV) before and after brucellosis treatment. Over 3 years, 241 consecutive HCV patients (before interferon therapy was received) with recurrent fever who had occupational contact with animals were tested for brucellosis co-infection by a standard tube agglutination test. In patients with dual infection, viraemia (RT-PCR), TIMP-1 measured by ELISA, and liver functions were assessed and re-evaluated 2 months after brucellosis treatment. The number of patients with HCV/brucellosis co-infection was 32 out of 241 (13.3%). TIMP-1, viraemia, AST, ALT and bilirubin showed significant decrease (improvement) after brucellosis treatment (p < 0.001) but an insignificant difference (p > 0.05) with regard to serum albumin and prothrombin concentration. The study revealed that brucellosis is an important infection in HCV-infected patients and can aggravate the course of disease, suggesting that early treatment and prevention are important.

It is estimated that 4-5 million HIV-infected patients are coinfected with HCV. The impact of HIV on the natural course of HCV infection is deleterious. This includes a higher rate of HCV persistence and a faster rate of fibrosis progression. Coinfected patients show poor treatment outcome following standard HCV therapy. Although direct antiviral agents offer new therapeutic options, their use is hindered by potential drug interactions and toxicity in HIV-infected patients under HAART. Overtime, a large reservoir of HCV genotype 1 patients will accumulate in resource poor countries where the hepatitis C treatment is not easily affordable and HIV therapy remains the primary health issue for coinfected individuals. HCV vaccines represent a promising strategy as an adjunct or alternative to current HCV therapy. Here, the authors review the pathogenesis of hepatitis C in HIV-infected patients, with a focus on the impact of HIV on HCV-specific immune responses and discuss the challenges for vaccine development in HIV-HCV coinfection.

The influence of HIV coinfection on plasma hepatitis C virus (HCV) RNA load has not been reliably evaluated. We analyzed plasma HCV RNA load in 396 HCV-monoinfected and 467 HIV/HCV-coinfected patients. Median HCV RNA concentrations (interquartile range) in HCV-monoinfected patients were 5.88 (5.3-6.2) log(10)IU/mL versus 5.96 (5.6-6.5) log(10)IU/mL in HIV/HCV-coinfected individuals (p=0.033) as determined with the Cobas Amplicor Test and 6.06 (5.4-5.7) log(10)IU/mL versus 6.3 (5.5-6.9) log(10)IU/mL (p=0.026) using the Cobas TaqMan System. The plasma HCV RNA load in patients with HIV infection and undetectable plasmatic HIV RNA was similar to that observed in HCV-monoinfected individuals [6.02 (5.45-6.61) log(10)IU/mL versus 6.01 (5.36-6.59) log(10)IU/mL, respectively (p=1.0)]. In conclusion, HIV coinfection tends to be associated with higher plasma HCV RNA load, however, the magnitude of the differences is small and this effect can be counterbalanced with antiviral therapy.

Up to one-third of HIV-infected patients is infected with hepatitis C virus (HCV). It is now widely accepted that HIV accelerates the course of HCV-related chronic liver disease. The improved survival of HIV patients after successful antiretroviral therapy (ART) has led to a significant decline in HIV-related morbidity, and liver disease caused by HCV infection has emerged as a major threat to the survival of HIV patients. HIV/HCV coinfected patients have a more rapid progression to cirrhosis and its complications than HCV monoinfected patients. Even though the effect of HCV on HIV infection and disease progression is less clear, most advocate early anti-HCV treatment to reduce the risk of chronic liver disease.

Recent studies support current recommendations to begin ART early in the course of HIV infection in order to limit progression of liver disease in coinfected patients. HIV coinfection has a negative impact on HCV pathogenesis, and despite increased risk of drug-related hepatotoxicity, successful response to ART might lessen progression of chronic liver disease and improve response to anti-HCV therapy.

HIV infection affects rate of liver disease progression in those with HCV coinfection. Treatment of HIV may result in slower rates of progression and liver mortality.

Liver disease is an important cause of morbidity and mortality in the era of combination antiretroviral therapy in HIV/hepatitis C virus (HCV) co-infected patients. This review highlights the role of pegylated interferon-alpha (peg-IFN) and ribavirin (RBV) therapy and examines factors associated with response and strategies to maximize responses.

HCV viral clearance is lower in HIV co-infected patients than in HCV mono-infected patients. However, in patients who attain sustained response there is clinical benefit in terms of liver disease associated morbidity and mortality and treatment is costeffective. Predictors of response appear similar, although there are a number of modifiable patient-associated and HIV-associated factors that could be addressed. Moreover, the use of weight-based RBV and treatment length guided by early viral responses improve response rate. Avoidance of drug-drug interactions and use of haematopoietic growth factors reduce adverse events and dose reductions and ultimately increase response rates. Very early prediction of treatment futility is promising. Induction dosing strategies have not yielded positive results, though twice weekly peg-IFN-alpha-2a induction therapy merits further investigation.

Peg-IFN/RBV therapy plays an important role in the management of HCV in HIV-infected patients. Efforts to maximize response to current therapy need to continue while we await new therapies.

The goal of this study is to review key recent findings related to the immunopathogenesis of hepatitis C virus (HCV) infection, especially in regards to T lymphocytes. It aims to complement other reviews in this issue on the roles of host genetics (IL-28B), acute HCV infection (when disease outcome is determined) and other factors that may influence fibrosis progression (microbial translocation). The main focus is on specific immunity and T cells in the context of success and failure to control viral infection.

This review focuses on two areas of intense interest in the recent literature: the relationship between the human leukocyte antigen (HLA), class I-restricted T-cell responses and the evolution of the virus and the role of inhibitory markers on T cells in the immunopathogenesis of HCV. When appropriate, we compare findings from studies of HIV-specific immunity.

From examining the virus and the mutational changes associated with T-cell responses and from analyzing the markers on T cells, there have been numerous advances in the understanding of immune evasion mechanisms employed by HCV.

Highly active antiretroviral therapy (HAART)-related hepatotoxicity, a relevant side effect in HIV/hepatitis C virus (HCV) co-infected patients, has evolved over time. Antiretroviral therapy might have a positive effect on the liver of HIV/HCV co-infected patients, but data are conflicting.

HIV treatments have evolved and we have currently a drug armamentarium with a good liver safety profile. Most of the current first-line HAART regimens recommended by guidelines fit well to HIV/HCV co-infected patients. There are now multiple retrospective studies that suggest a possible benefit of HIV control and protection of CD4 cell counts to the liver of HIV/HCV co-infected patients. However, data are conflicting at times. This factor along with the methodological limitations of these studies prevent us from drawing definitive conclusions. Even assuming a positive effect, HAART does not appear to fully correct the adverse effect of HIV infection on HCV-related outcomes. In the era of HCV direct antiviral agents, the timing of HIV and HCV therapies has to be individualized in HIV/HCV co-infected patients given the variety of scenarios.

With current HIV drug armamentarium it is possible to construct HAART regimens with optimal liver safety profile for HCV co-infected patients. The possible positive effect of HAART on the HCV-infected liver should not distract from the main intervention, which is HCV eradication with specific treatment.

Interferon-gamma release assays (IGRA) are more specific than the tuberculin skin test (TST) for the diagnosis of Mycobacterium tuberculosis infection. Data on sensitivity are controversial in HIV infection.

IGRA (T-SPOT.TB) was performed using lymphocytes stored within 6 months before culture-confirmed tuberculosis was diagnosed in HIV-infected individuals in the Swiss HIV Cohort Study.

64 individuals (69% males, 45% of non-white ethnicity, median age 35 years (interquartile range [IQR] 31-42), 28% with prior AIDS) were analysed. Median CD4 cell count was 223 cells/μl (IQR 103-339), HIV-RNA was 4.7 log10 copies/mL (IQR 4.3-5.2). T-SPOT.TB resulted positive in 25 patients (39%), negative in 18 (28%) and indeterminate in 21 (33%), corresponding to a sensitivity of 39% (95% CI 27-51%) if all test results were considered, and 58% (95% CI 43-74%) if indeterminate results were excluded. Sensitivity of IGRA was independent of CD4 cell count (p = 0.698). Among 44 individuals with available TST, 22 (50%) had a positive TST. Agreement between TST and IGRA was 57% (kappa = 0.14, p = 0.177), and in 34% (10/29) both tests were positive. Combining TST and IGRA (at least one test positive) resulted in an improved sensitivity of 67% (95% CI 52-81%). In multivariate analysis, older age was associated with negative results of TST and T-SPOT.TB (OR 3.07, 95% CI 1,22-7.74, p = 0.017, per 10 years older).

T-SPOT.TB and TST have similar sensitivity to detect latent TB in HIV-infected individuals. Combining TST and IGRA may help clinicians to better select HIV-infected individuals with latent tuberculosis who qualify for preventive treatment.

Liver disease is a major cause of morbidity and mortality in HIV-infected persons. The long-term beneficial versus potentially harmful influence of antiretroviral therapy (ART) on the liver is debated. We review current data on factors contributing to liver disease in HIV-monoinfected as well as in HIV/viral hepatitis-coinfected patients, highlighting the role of ART, HIV itself, immunodeficiency, patient characteristics, and lifestyle risk factors.

New ART-related clinical syndromes, including noncirrhotic portal hypertension and nonalcoholic fatty liver disease, have emerged, and observational data suggest long-term ART-associated liver injury. Recently, there is increasing evidence that HIV itself and immunosuppression are contributing to liver injury in both HIV-coinfected and HIV-monoinfected patients. In HIV-positive persons, ART attenuates progression of chronic viral hepatitis.

Current expert guidelines recommend earlier treatment of HIV infection in persons coinfected with hepatitis B virus and possibly hepatitis C virus. It is unknown whether an earlier start of ART is beneficial for the liver in HIV-monoinfected patients. Future research should focus on long-term ART-related hepatotoxicity.

To examine the association between maternal hepatitis B and C mono- and co-infections with singleton pregnancy outcomes in the state of Florida.

We analysed all Florida births from 1998 to 2007 using birth certificate records linked to hospital discharge data. The main outcomes of interest were selected pregnancy outcomes including preterm birth, low birth weight (LBW), small for gestational age (SGA), fetal distress, neonatal jaundice and congenital anomaly.

The study sample consisted of 1,670,369 records. Human immunodeficiency virus co-infection and all forms of substance abuse were more frequent in mothers with hepatitis B and C infection. After using multivariable modelling to adjust for important socio-demographical variables and obstetric complications, women with hepatitis C infection were more likely to have infants born preterm [odds ratio (OR), 1.40; 95% confidence intervals (CI), 1.15-1.72], with LBW (OR, 1.39; 95% CI, 1.11-1.74) and congenital anomaly (OR, 1.55; 95% CI, 1.14-2.11). In addition, women with hepatitis B infection were less likely to have infants born SGA (OR, 0.79; 95% CI, 0.66-0.95).

Our findings provide further understanding of the association between maternal hepatitis B or C carrier status and perinatal outcomes. Infants born to women with hepatitis C infection appear to be at risk for poor birth outcomes, including preterm birth, LBW and congenital anomaly.

Cellular responses against hepatitis C virus (HCV) are impaired in HIV/HCV-coinfected patients showing uncontrolled viral replication and immune suppression. Very few studies have explored to what extent HCV-specific response improves as a consequence of control of HIV replication by highly active antiretroviral therapy. We compared HCV-specific T-cell responses between HIV/HCV-coinfected patients, showing complete viral suppression, and HCV-monoinfected patients.

HCV-specific T-cell responses were examined in 50 interferon-naive patients with chronic hepatitis C: 27 HCV-mono-infected and 23 HIV/HCV-coinfected on highly active antiretroviral therapy and undetectable HIV load. Production of interferon-γ and tumor necrosis factor-α was simultaneously measured in response to genotype-matched overlapping peptides spanning the whole HCV proteome by flow cytometry. Differences between groups were tested using nonparametric tests.

More than half of patients presented CD4+ (60%) or CD8+ (57%) response to at least one HCV protein with no significant differences between both groups. Intensity and breadth of response were also similar between groups. The functional profile of response was represented, in both groups, mainly by monofunctional subsets, although there were some differences between CD4+ and CD8+ T-cell response. CD8+ response was mediated almost exclusively by monofunctional interferon-γ+ cells, whereas bifunctional interferon-γ+ tumor necrosis factor-α+ cells showed a moderate contribution to CD4+ response. Most of the CD8+ response was mediated by interferon-γ, whereas tumor necrosis factor-α was the highest contributor to CD4+ response.

Our study demonstrates that in HIV/HCV-coinfected patients with maximal HIV suppression under highly active antiretroviral therapy, several characteristics of anti-HCV T-cell response are similar to those found in HCV-monoinfected patients, suggesting that control of HIV replication might improve HCV-specific T-cell response in HIV/HCV-coinfected patients.

Infection with the polyoma virus BK (BKV) is a major cause of morbidity following renal transplantation. Limited understanding of the anti-viral immune response has prevented the design of a strategy that balances treatment with the preservation of graft function. The proven utility of interferon-gamma enzyme-linked immunospot (ELISPOT) assays to measure T cell responses in immunocompetent hosts was the basis for trying to develop a rational approach to the management of BKV following renal transplantation. In a sample of transplant recipients and healthy controls, comparisons were made between T cell responses to the complete panel of BKV antigens, the Epstein-Barr virus (EBV) antigens, BZLF1 and EBNA1, and the mitogen phytohaemagglutinin (PHA). Correlations between responses to individual antigens and immunosuppressive regimens were also analysed. Antigen-specific T cell responses were a specific indicator of recent or ongoing recovery from BKV infection (P < 0·05), with responses to different BKV antigens being highly heterogeneous. Significant BKV immunity was undetectable in transplant patients with persistent viral replication or no history of BKV reactivation. Responses to EBV antigens and mitogen were reduced in patients with BKV reactivation, but these differences were not statistically significant. The T cell response to BKV antigens is a useful and specific guide to recovery from BKV reactivation in renal transplant recipients, provided that the full range of antigenic responses is measured.