Hospital-based screening outperforms primary care screening as a means of achieving hepatitis C virus micro-elimination.

AIM: To assess the respective performances of a HCV screening program in a hospital setting and a HCV screening model applied concomitantly in a primary care centre. METHODS: Adult patients consecutively admitted to hospital for ambulatory surgery were screened for anti-HCV antibodies (hospital screening cohort, HPSC), as were patients receiving blood tests for medical reasons in a primary care centre (primary care screening cohort, PCSC). Serum anti-HCV and HCV RNA levels were tested by ELISA and real-time PCR, respectively. RESULTS: Seroprevalence of HCV infection was 2.2 % in the HPSC and 1.4 % in the PCSC (p = 0.044). All viraemic patients (0.2 % in HPSC and 0.1 % in PCSC) were treated with direct-acting antivirals and 85.7 % experienced a sustained virological response. CONCLUSIONS: Hospital-based HCV screening outperformed primary care-centered screening, significantly increasing HCV case findings.

Patient-centered and integrated outreach care for chronic hepatitis C patients with serious mental illness in Taiwan.

Patients with serious mental illness have a higher risk of hepatitis C virus (HCV) infection but suboptimal HCV care. The current study aimed to facilitate HCV treatment uptake by implementing an integrated outreach care model. Multidisciplinary outreach screening followed by HCV reflex testing and onsite treatment for schizophrenia patients was accomplished through the coordination of nongovernmental organizations, remote specialists, and local care providers. The objective was microelimination effectiveness, defined as the multiplication of the rates of anti-HCV antibodies screening, accurate HCV RNA diagnosis, treatment allocation, treatment completion, and sustained virological response (SVR12; no detectable HCV RNA throughout 12 weeks in the post-treatment follow-up period). A total of 1478 of the 2300 (64.3%) psychiatric patients received HCV mass screening. Seventy-three (4.9%) individuals were seropositive for anti-HCV antibodies. Of the 73 anti-HCV seropositive patients, all (100%) received HCV reflex testing, and 29 (37.7%) patients had HCV viremia. Eight patients (34.8%) had advanced liver disease, including 3 with liver cirrhosis and 2 with newly diagnosed hepatocellular carcinoma. Twenty-three of the 24 (95.8%) patients who stayed in the healthcare system received and completed 8 weeks of glecaprevir/pibrentasvir treatment and post-treatment follow-up without significant DDIs or adverse events. The SVR12 rate was 100%. The microelimination effectiveness in the current study was 61.6%. Individuals with serious mental illness are underserved and suffer from diagnostic delays. This patient-centered and integrated outreach program facilitated HCV care in this marginalized population.

Multi-disciplinary cooperation for the micro-elimination of hepatitis C in China: a hospital-based experience.

BACKGROUND: Hepatitis C virus (HCV) infection is one of the main causes of liver cancer and imposes an enormous social and economic burden. The blood-borne virus screening policy for preventing iatrogenic infections renders hospitals important for identifying individuals infected with hepatitis C. Therefore, we aimed to investigate the establishment of a multi-disciplinary cooperation model in medical institutions to leverage the screening results of patients with hepatitis C. Our objective is to ensure that patients receive timely and effective diagnosis and treatment, thereby enabling the elimination of hepatitis C by 2030. METHOD: A multi-disciplinary cooperation model was established in October 2021. This retrospective study was based on the establishment of antibody-positive and HCV RNA-positive patient databases. A Chi-square test was used to compare the HCV RNA confirmation rate in anti-HCV-positive patients, as well as the hepatitis C diagnosis rate and treatment rate in RNA-positive patients before and after the multi-disciplinary cooperation. A multivariable logistic regression was used to analyse the factors affecting the treatment of patients with hepatitis C. In addition, we examined changes in the level of hepatitis C knowledge among medical staff. RESULTS: After the implementation of the multi-disciplinary cooperation model, the RNA confirmation rate of hepatitis C antibody-positive patients increased from 36.426% to 88.737%, the diagnostic accuracy rate of RNA-positive patients increased from 67.456% to 98.113%, and the treatment rate of patients with hepatitis C increased from 12.426% to 58.491%. Significant improvements were observed among the clinicians regarding their ability to understand the characteristics of hepatitis C (93.711% vs. 58.861%), identify people at high risk (94.340% vs. 53.797%), manage patients with hepatitis C after diagnosis (88.679% vs. 67.089%), and effectively treat hepatitis C (84.277% vs. 51.899%). Multi-disciplinary cooperation in medical institutions was the most important factor for patients to undergo HCV treatment (odds ratio: 0.024, 95% confidence interval: 0.007-0.074). CONCLUSIONS: This study showed that the use of a multi-disciplinary cooperation model to utilise the results of HCV antibody screening fully in patients through further tracking, referral, and treatment may facilitate the detection and treatment of patients with hepatitis C and accelerate the elimination of HCV in China.

Global, regional, and country-level coverage of testing and treatment for HIV and hepatitis C infection among people who inject drugs: a systematic review.

BACKGROUND: People who inject drugs are disproportionately affected by HIV and hepatitis C virus (HCV) infections, while there is little global data on HIV and HCV testing and treatment coverage of this population. We conducted a systematic review to evaluate country-level, regional, and global coverage of HIV and HCV testing and treatment among people who inject drugs. METHODS: We did a systematic review, and searched bibliographic databases (MEDLINE, Embase, and PsycINFO) and grey literature for studies published between Jan 1, 2017, and April 30, 2022, that evaluated the proportion of people who inject drugs who received testing or treatment for HIV or HCV. For each country, we estimated the proportion of people who inject drugs tested for HIV antibodies in the past 12 months (recent), people who inject drugs ever tested for HCV antibodies and HCV RNA, people who inject drugs with HIV currently receiving antiretroviral therapy, and people who inject drugs with HCV ever receiving HCV antiviral treatment. Regional and global estimates, weighted by the population size of people who inject drugs, were generated where sufficient data were available. This study is registered with PROSPERO (CRD42020173974). FINDINGS: 512 documents reported data eligible for analyses, including 337 peer-reviewed articles, 27 conference abstracts or presentations, and 148 documents from grey literature or supplementary searches. Data of recent HIV antibody testing were available for 67 countries and ever having had HCV antibody testing were available for 49 countries. Globally, an estimated 48·8% of people who inject drugs were recently tested for HIV antibodies (95% uncertainty interval [UI] 43·3-54·2%; range 0·9-86·0%), and 47·1% had ever been tested for HCV antibodies (95% UI 43·4-51·0%; range 0·0-93·3%). HCV RNA testing data were available from three countries. Coverage of HIV antibody testing was high (>75%) in four countries and for HCV antibody testing in 15 countries. The estimated uptake of current HIV treatment (18 countries) ranged from 2·6% to 81·9%, and the estimated uptake of ever having HCV treatment (23 countries) ranged from 1·8% to 88·6% across countries. Uptake of HIV treatment was high in two countries, and of HCV treatment in one country. INTERPRETATION: HIV and HCV testing and treatment uptake among people who inject drugs was highly variable, and suboptimal in most countries. Strategies to improve access to HIV and HCV care among people who inject drugs and the availability of public health surveillance are urgently required. FUNDING: Australian National Health and Medical Research Council and UK National Institute for Health and Care Research Health Protection Research Unit in Behavioural Science and Evaluation.

Guillain-Barré syndrome as clinical presentation of a recently acquired hepatitis C.

About 40% of the Guillain-Barré syndrome (GBS) cases are associated with prodromal infections; occasionally, it has been associated to chronic hepatitis C or its reactivation. A 38-year-old man came to our attention after transaminase elevation occurred during recovery from GBS. All the possible causes of acute hepatitis were excluded except for the positivity of HCVRNA, and a diagnosis of new onset hepatitis C was made. Recalling patient history, we observed that (i) anti-HCV antibodies were negative and liver enzymes were normal 7 weeks before GBS onset; (ii) in the early stages of ICU admission, liver enzymes started to rise, but the elevation remained mild under steroid treatment; (iii) serum aminotransferase peak occurred 11 weeks after GBS onset; and (iv) HCV RNA was already significantly high when anti-HCV antibodies became positive, consistent with an acute hepatitis. Furthermore, anti-HCV seroconversion was likely delayed or blurred by steroids and immunoglobulin infusions. The interval of time between GBS onset and transaminase elevation compared with the patient clinical history allows us to establish a cause-effect relationship between the two diseases. All patients with GBS should be tested for hepatitis C, or its reactivation if already present, and followed up for an early diagnosis and treatment.

A single site study to investigate the current prevalence of anti-hepatitis C virus antibody among substance use disorder patients in Hiroshima-Insufficient testing and diagnosis.

AIMS: Hepatitis C virus (HCV) infection among drug users presents an important public health problem; however, little recognition and few approaches to address this issue in Japan. This study was conducted to investigate the current disease status by assessing anti-HCV antibody (Ab) seroprevalence among people who inject drugs (PWIDs) and people who use drugs (PWUDs) in Hiroshima, Japan. METHODS: This study was a psychiatric single-site chart review in patients with drug abuse problems in the Hiroshima region. The primary outcome was anti-HCV Ab prevalence among PWIDs who underwent anti-HCV Ab testing. The secondary outcomes included the prevalence of anti-HCV Ab among PWUDs who underwent anti-HCV Ab testing and the proportion of patients who underwent anti-HCV Ab examination. RESULTS: A total of 222 PWUD patients were enrolled. Among these, 16 patients (7.2%) had records of injection drug use (PWIDs). Eleven (68.8%) of the 16 PWIDs received anti-HCV Ab tests, and 4 (36.4%, 4/11) were anti-HCV Ab-positive. Among 222 PWUDs, 126 (56.8%) patients received anti-HCV Ab tests, and 57 of these patients (45.2%, 57/126) were anti-HCV Ab-positive. CONCLUSION: The prevalence of anti-HCV Ab among PWIDs and PWUDs who visited the study site was higher than the general population, which was 2.2% among hospitalized patients between May 2018 and November 2019. Considering the World Health Organization's (WHO) elimination goal and recent advances in HCV treatment, patients with drug abuse experience should be encouraged to take HCV tests and consult hepatologists for further investigations and treatment if they are positive for anti-HCV Ab.

Misunderstanding of hepatitis C virus (HCV) infection status by non-specialized medical doctors in patients who achieved sustained virologic response to anti-HCV therapy.

INTRODUCTION: With the increase in the number of patients with sustained virologic response (SVR) in whom hepatitis C virus (HCV) was eradicated by the anti-HCV therapy, there are now many individuals in whom serum HCV RNA is absent despite positive serum HCV antibodies. However, in general clinical practice, HCV infection remains usually screened by measurement of serum HCV antibodies and patients with SVR can be misunderstood regarding HCV infection status. METHODS: In the multicenter study, we conducted interviews with administered questionnaires to SVR individuals who had regular hospital visits after SVR. The prevalence of experiencing an incorrect diagnosis of HCV infection after SVR was assessed. Individuals who experienced this misunderstanding were further asked where they experienced it and how it made them feel. RESULTS: In a survey of 2,246 SVR individuals, 197 individuals (8.8%) were misunderstood as having persistent HCV infection by medical doctors due to positive HCV antibody, despite the absence of HCV viremia. These misunderstandings occurred most prevalently at a private clinic (55.3%). More than half (53.3%) of these individuals felt anxious about their HCV infection with becoming unsure about their HCV eradication status. CONCLUSIONS: Misunderstanding HCV status is commonly occurred in SVR individuals. Specialists in hepatology and infectious diseases should broadly emphasize the fact that most patients with HCV antibodies are now HCV-free because of the use of anti-HCV therapy.

Treating people where they are: Nurse-led micro-elimination of hepatitis C in supported housing sites for networks of people who inject drugs in Victoria, Canada.

To achieve the World Health Organization's goal of eliminating hepatitis C (HCV) by 2030 requires enhanced HCV testing and treatment among people who use drugs (PWUD). Micro-elimination of HCV is a strategy to target HCV testing and treatment efforts to specific segments of the population. From February to December 2018 nurses initiated a "seek & treat" micro-elimination approach, increasing outreach and removing barriers to accessing HCV treatment in a clinic setting by testing and treating individuals, including PWUD, where they live. The aim of this study was to evaluate the proportion of clients with HCV antibodies and HCV RNA and the response to direct acting agent (DAA therapy) among people who live at or have social connections to local supportive housing sites through this nurse-led micro-elimination project in Victoria, Canada. A chart review of electronic medical records and case management documentation was used to collect relevant data of participants treated with DAA therapy, identified through specific housing site testing and outreach interventions. In total, 180 people were tested for HCV antibodies, 72 (40%) were antibody positive: 51 (28%) were RNA positive, 13 (7%) had spontaneously cleared and 8 (4%) had been previously treated. Of the 51 that were currently living with HCV, 43 people were started on treatment, 39 have achieved sustained virologic response (SVR). By providing treatment to clients in their homes and with their friends, clinicians have been able to treat clients, including those with limited contact with the health care system.

Negative impact of HIV infection on broad-spectrum anti-HCV neutralizing antibody titers in HCV-infected patients with advanced HCV-related cirrhosis.

OBJECTIVES: The current study aimed to assess the impact of HIV on the production of anti-HCV antibodies in HCV-infected individuals with advanced HCV-related cirrhosis before and 36 weeks after the sustained virological response (SVR) induced by direct-acting antivirals (DAAs) therapy. METHODS: Prospective study on 62 patients (50 HIV/HCV-coinfected and 12 HCV-monoinfected). Plasma anti-E2 and HCV-nAbs were determined respectively by ELISA and microneutralization assays. RESULTS: At baseline, the HCV-group had higher anti-E2 levels against Gt1a (p = 0.012), Gt1b (p = 0.023), and Gt4a (p = 0.005) than the HIV/HCV-group. After SVR, anti-E2 titers against Gt1a (p < 0.001), Gt1b (p = 0.001), and Gt4a (p = 0.042) were also higher in the HCV-group than HIV/HCV-group. At 36 weeks post-SVR, plasma anti-E2 titers decreased between 1.3 and 1.9-fold in the HIV/HCV-group (p < 0.001) and between 1.5 and 1.8-fold in the HCV-group (p ≤ 0.001). At baseline, the HCV-group had higher titers of HCV-nAbs against Gt1a (p = 0.022), Gt1b (p = 0.002), Gt2a (p < 0.001), and Gt4a (p < 0.001) than the HIV/HCV-group. After SVR, HCV-nAbs titers against Gt1a (p = 0.014), Gt1b (p < 0.001), Gt2a (p = 0.002), and Gt4a (p = 0.004) were also higher in the HCV-group. At 36 weeks post-SVR, HCV-nAbs decreased between 2.6 and 4.1-fold in the HIV/HCV-group (p < 0.001) and between 1.9 and 4.0-fold in the HCV-group (p ≤ 0.001). CONCLUSIONS: HIV/HCV-coinfected patients produced lower levels of broad-spectrum anti-HCV antibodies than HCV-monoinfected patients.

Current status of hepatitis C virus among people living with human immunodeficiency virus in Egypt.

BACKGROUND: Human immunodeficiency virus (HIV)-hepatitis C virus (HCV) co-infection is increasing due to their similar routes of transmission. Co-infection poses a big challenge. Information on the prevalence of HCV infection in Egyptian HIV individuals is scarce. METHODS: A cross-sectional study was conducted on 1004 HIV individuals who were recruited from July 2018 to March 2019. Blood samples obtained from HIV individuals were subsequently screened for HCV antibodies using the Murex anti-HCV (version 4) enzyme-linked immunosorbent assay test. HCV RNA was performed only on anti-HCV antibody-positive samples. Logistic regression was used to identify factors associated with HCV seroprevalence using SPSS (IBM, Armonk, NY, USA). RESULTS: Among 1004 participants, 349 exhibited a positive result for anti-HCV antibodies (34.8% [95% confidence interval 31.81 to 37.8]). The most commonly self-reported risk factor of HIV infection by the co-infected participants was intravenous drug use (IDU) (303/349 [86.8%]). In multinomial analysis, risk factors identified as statistically associated with HCV seroprevalence include IDU, history of surgical operations and dental procedures and HIV viral load (p<0.001, 0.032, <0.001 and 0.006, respectively). Under combination antiretroviral therapy (cART), the proportion of HIV mono-infected individuals with an undetectable HIV viral load was significantly higher than those with co-infection (p<0.0007). We also found that HIV-HCV co-infected participants exhibited significantly higher CD4+ cell counts than those with HIV mono-infection (p=0.04). CONCLUSIONS: The prevalence of HIV-HCV co-infection is higher in Egypt compared with other countries in Africa. It is essential to screen all HIV-infected patients for HCV infection for early identification, counselling and initiation of anti-HCV treatment.

Prevalence and undiagnosed fraction of hepatitis C infection in 2018 in Spain: results from a national population-based survey.

BACKGROUND: A national strategy against hepatitis C virus (HCV) was implemented in Spain in 2015 with the aim of reducing associated morbidity and mortality. In order to improve our understanding of the epidemiology of HCV, we analysed the prevalence of HCV antibodies and active infection overall and by age and sex in the general population aged 20-80 years. We also aimed to report the undiagnosed fraction. METHODS: A national population-based seroprevalence survey was conducted in 2017-2018. A representative sample from the general population was selected using two-stage sampling. The prevalence of total HCV antibodies and of HCV RNA was calculated using inverse probability weighting based on bootstrapping. RESULTS: Overall, we approached 17 496 persons; 9103 agreed to participate and met the eligibility criteria and 7675 were aged 20-80. We obtained a prevalence of HCV antibodies of 0.85% [95% confidence interval (CI): 0.64-1.08%] and of active infection of 0.22% (95% CI: 0.12-0.32%). The prevalence of active HCV infection was highest in men aged 50-59 (0.86%; 95% CI: 0.28-1.57%) and in men aged 60-69 years (0.72%; 95% CI: 0.27-1.28%). Prevalence was below 0.20% in the remaining age groups. The undiagnosed fraction for active HCV infection was 29.4%. CONCLUSION: This study shows that prevalence of HCV in the general population in Spain is low and reflects the impact of scaling up treatment with direct acting antivirals, together with other prevention strategies, from 2015 onwards. The data reported can guide subsequent public health actions.

Defining Breadth of Hepatitis C Virus Neutralization.

Extraordinary genetic diversity is a hallmark of hepatitis C virus (HCV). Therefore, accurate measurement of the breadth of antibody neutralizing activity across diverse HCV isolates is key to defining correlates of immune protection against the virus, and essential to guide vaccine development. Panels of HCV pseudoparticle (HCVpp) or replication-competent cell culture viruses (HCVcc) can be used to measure neutralizing breadth of antibodies. These in vitro assays have been used to define neutralizing breadth of antibodies in serum, to characterize broadly neutralizing monoclonal antibodies, and to identify mechanisms of HCV resistance to antibody neutralization. Recently, larger and more diverse panels of both HCVpp and HCVcc have been described that better represent the diversity of circulating HCV strains, but further work is needed to expand and standardize these neutralization panels.

A novel neutralizing human monoclonal antibody broadly abrogates hepatitis C virus infection in vitro and in vivo.

Infections with hepatitis C virus (HCV) represent a worldwide health burden and a prophylactic vaccine is still not available. Liver transplantation (LT) is often the only option for patients with HCV-induced end-stage liver disease. However, immediately after transplantation, the liver graft becomes infected by circulating virus, resulting in accelerated progression of liver disease. Although the efficacy of HCV treatment using direct-acting antivirals has improved significantly, immune compromised LT-patients and patients with advanced liver disease remain difficult to treat. As an alternative approach, interfering with viral entry could prevent infection of the donor liver. We generated a human monoclonal antibody (mAb), designated 2A5, which targets the HCV envelope. The neutralizing activity of mAb 2A5 was assessed using multiple prototype and patient-derived HCV pseudoparticles (HCVpp), cell culture produced HCV (HCVcc), and a human-liver chimeric mouse model. Neutralization levels observed for mAb 2A5 were generally high and mostly superior to those obtained with AP33, a well-characterized HCV-neutralizing monoclonal antibody. Using humanized mice, complete protection was observed after genotype 1a and 4a HCV challenge, while only partial protection was achieved using gt1b and 6a isolates. Epitope mapping revealed that mAb 2A5 binding is conformation-dependent and identified the E2-region spanning amino acids 434 to 446 (epitope II) as the predominant contact domain. CONCLUSION: mAb 2A5 shows potent anti-HCV neutralizing activity both in vitro and in vivo and could hence represent a valuable candidate to prevent HCV recurrence in LT-patients. In addition, the detailed identification of the neutralizing epitope can be applied for the design of prophylactic HCV vaccines.

[Advanced Testing and Laboratory for HBV, HCV, and HIV Infection].

Most target substances for immunoassay of infectious disease are antigens or antibodies which do not exist in the human body. Therefore, the method to set reference values is different from chemistry or hematology testing. High sensitivity is required for infectious disease testing, particularly for screening. Also, its reference values (cut-off values) are set as low as possible. Therefore, a false-positive reaction can be caused due to slightly non-specific reactions in infectious disease reagents. The specificities for infectious disease reagents were evaluated with 9 kinds of HCV antibody test kit and 9 kinds of HIV screening kit. The frequencies of false-positive results were 0.2-1.8 and 0.2-1.3%, respectively, and even a kit with a high specificity showed a false-positive result for 1 in 500 samples. The sensitivities for infectious disease reagents were evaluated with a newly developed super-high- sensitive HBs antigen assay kit and 8 kinds of chemiluminescence HBs antigen assay kit which are highly sensitive conventional kits. As a result, the super-high-sensitive kit was 10 to 40 times more sensitive than conventional kits. After introducing the super-high-sensitive kit to routine assays, 16 HBV-infected patients, who were not identified with the conventional kits, were detected for six months. On the other hand, we confirmed false-positive results due to contamination between specimens after introducing the super-high-sensitive kit. It is recommended to use the super-high-sensitive kit in a well-controlled environment to prevent contamination between specimens in order to generate highly reliable test results.

Immunoglobulin with High-Titer In Vitro Cross-Neutralizing Hepatitis C Virus Antibodies Passively Protects Chimpanzees from Homologous, but Not Heterologous, Challenge.

The importance of neutralizing antibodies (NAbs) in protection against hepatitis C virus (HCV) remains controversial. We infused a chimpanzee with H06 immunoglobulin from a genotype 1a HCV-infected patient and challenged with genotype strains efficiently neutralized by H06 in vitro. Genotype 1a NAbs afforded no protection against genotype 4a or 5a. Protection against homologous 1a lasted 18 weeks, but infection emerged when NAb titers waned. However, 6a infection was prevented. The differential in vivo neutralization patterns have implications for HCV vaccine development.

The past, present and future of neutralizing antibodies for hepatitis C virus.

Hepatitis C virus (HCV) is a major cause of liver disease and hepatocellular carcinoma worldwide. HCV establishes a chronic infection in the majority of cases. However, some individuals clear the virus, demonstrating a protective role for the host immune response. Although new all-oral drug combinations may soon replace traditional ribavirin-interferon therapy, the emerging drug cocktails will be expensive and associated with side-effects and resistance, making a global vaccine an urgent priority. T cells are widely accepted to play an essential role in clearing acute HCV infection, whereas the role antibodies play in resolution and disease pathogenesis is less well understood. Recent studies have provided an insight into viral neutralizing determinants and the protective role of antibodies during infection. This review provides a historical perspective of the role neutralizing antibodies play in HCV infection and discusses the therapeutic benefits of antibody-based therapies. This article forms part of a symposium in Antiviral Research on "Hepatitis C: next steps toward global eradication."

The spectrum of undiagnosed hepatitis C virus infection in a US HIV clinic.

United States guidelines endorse one-time HCV antibody screening at HIV diagnosis. Rescreening HCV-seronegative patients on a regular basis is still not policy, although HIV-infected persons have reasonably substantial HCV incidence. We evaluated routine risk factor-independent HCV antibody re-testing in a Rhode Island HIV clinic. We instituted annual HCV antibody testing for HCV-seronegative patients who had not been rescreened in a year or more. Testing based on clinical suspicion continued. We conducted a chart review of new antibody-positive cases in the first year of rescreening, July 2006 to June 2007. Of 245 rescreened patients, 11 (4.5%) seroconverted. Five (45%) were female. Median time between last negative and first positive result was 32 months (range 8-98 months). Six (55%) had documented risk factors and 6 (55%) elevated ALT (> 45 IU/L) between antibody tests; none prompted re-testing. One seroconverter died of hepatocellular carcinoma 3.7 years after HCV diagnosis. A twelfth was rescreened for suspected acute HCV based on ALT of 515 IU/L. He had newly detectable HCV RNA then seroconversion, and achieved SVR following 6 months of treatment in the acute phase for genotype 1 infection. Incident HCV is not uncommon among HIV-infected patients in care. Rescreening identified undiagnosed HCV in this population. HCV RNA should be checked promptly in HCV-seronegative persons with ALT elevation. We observed consequences of late diagnosis (hepatocellular carcinoma) and benefits of early diagnosis (cure with treatment of acute HCV). Adding annual rescreening to the Ryan White Program would facilitate earlier identification of undiagnosed HCV and create an instant widespread surveillance system, providing HCV incidence data.

New therapeutic options for HCV infection in the monoclonal antibody era.

Hepatitis C virus (HCV) infection is a leading cause of chronic liver disease and the most common indication for liver transplantation. Current therapies are ineffective in a relevant percentage of patients raising the urgent medical need to develop adequate therapies for this infection. Broadly neutralizing human monoclonal antibodies (mAbs) directed against the HCV E2 glycoprotein (HCV/E2), the major target of the neutralizing humoral immune response, are considered as a possible novel therapeutic strategy for this infection. In the last few years, several anti-HCV/E2 human mAbs have been described in literature to be possibly used for therapeutic or prophylactic purposes. In this review, we illustrate the best candidates for an anti-HCV mAb-based therapy, considering their cross-neutralization profiles and their ability to overcome possible viral escape mechanisms.

Human monoclonal antibody HCV1 effectively prevents and treats HCV infection in chimpanzees.

Hepatitis C virus (HCV) infection is a leading cause of liver transplantation and there is an urgent need to develop therapies to reduce rates of HCV infection of transplanted livers. Approved therapeutics for HCV are poorly tolerated and are of limited efficacy in this patient population. Human monoclonal antibody HCV1 recognizes a highly-conserved linear epitope of the HCV E2 envelope glycoprotein (amino acids 412-423) and neutralizes a broad range of HCV genotypes. In a chimpanzee model, a single dose of 250 mg/kg HCV1 delivered 30 minutes prior to infusion with genotype 1a H77 HCV provided complete protection from HCV infection, whereas a dose of 50 mg/kg HCV1 did not protect. In addition, an acutely-infected chimpanzee given 250 mg/kg HCV1 42 days following exposure to virus had a rapid reduction in viral load to below the limit of detection before rebounding 14 days later. The emergent virus displayed an E2 mutation (N415K/D) conferring resistance to HCV1 neutralization. Finally, three chronically HCV-infected chimpanzees were treated with a single dose of 40 mg/kg HCV1 and viral load was reduced to below the limit of detection for 21 days in one chimpanzee with rebounding virus displaying a resistance mutation (N417S). The other two chimpanzees had 0.5-1.0 log(10) reductions in viral load without evidence of viral resistance to HCV1. In vitro testing using HCV pseudovirus (HCVpp) demonstrated that the sera from the poorly-responding chimpanzees inhibited the ability of HCV1 to neutralize HCVpp. Measurement of antibody responses in the chronically-infected chimpanzees implicated endogenous antibody to E2 and interference with HCV1 neutralization although other factors may also be responsible. These data suggest that human monoclonal antibody HCV1 may be an effective therapeutic for the prevention of graft infection in HCV-infected patients undergoing liver transplantation.

Understanding the switchbacks: the impact of direct antivirals on the minimization of hepatitis C virus recurrence after transplantation.

KEY POINTS: 1. Interferon (IFN) and ribavirin can be used in select patients before or after liver transplantation, and they can reduce the risk of recurrence or effect a cure in these settings. 2. Currently licensed direct-acting antiviral drugs are used with IFN and ribavirin, so the safety and tolerability of triple therapy will be worse than those of double therapy in pretransplant and posttransplant settings. 3. Drug-drug interactions [exemplified by the interactions of protease inhibitors (PIs) with tacrolimus and cyclosporine] and the need for dose modifications (exemplified by the need to modify ribavirin doses in patients with renal dysfunction) challenge the safe use of antiviral drugs after transplantation. 4. Experience with the use of human immunodeficiency virus PIs and emerging data about hepatitis C virus (HCV) PIs show that this class of drugs can be used with care after transplantation. 5. Attempts to prevent HCV graft infections through the use of HCV immunoglobulin immediately after transplantation have been largely unsuccessful. 6. The blockade of cell surface HCV receptors with antibodies or small molecules appears to limit HCV cell entry in vivo and in a mouse model, and this may suggest a novel approach to limiting HCV recurrence at the time of transplantation.