Evolving URMC Studies Uphold Precision Radiation to Control Cancer

January 11, 2012

The University of Rochester Medical Center has been a leader in the study of stereotactic body radiation therapy (SBRT) for the past decade, and two of the latest research projects show that SBRT is emerging as an important tool for more people with advanced cancer.

Alan W. Katz, M.D., M.P.H., and Michael T. Milano, M.D., Ph.D., in separate studies in the International Journal of Radiation Oncology, Biology, Physics, report that SBRT can lead to long-term survival for liver cancer patients who are awaiting a transplant, and for select patients with early metastasis of many types of cancer.

Their work is the latest from a body of research conducted at the URMC’s James P. Wilmot Cancer Center, which was among the first institutions in the country to use SBRT. The therapy delivers high doses of radiation precisely to the tumor without harming adjacent tissues. Doctors use a coordinate system to map their target, and then deliver multiple, intersecting radiation beams at the spot, like several flashlights focused in one area. Because of their early use of this technology, Wilmot scientists have been able to study patients for longer periods under a variety of circumstances.

“Although we have known for quite some time that it is possible to treat metastatic disease, the technology needed to catch up to the concept,” said Milano, an associate professor of Radiation Oncology at Wilmot. “Now, physicians have a greater comfort level with SBRT due to treatment and imaging technology that can pinpoint smaller tumors, and data from our institution and others showing that SBRT works very well in certain cases.”

Katz, who is also an associate professor of Radiation Oncology, agreed. “Compared to older, more invasive treatments, stereotactic body radiation is usually very well tolerated, particularly as a bridge treatment,” he said. “And many people who develop liver cancer also have serious underlying conditions such hepatitis and cirrhosis of the liver, so often they are not candidates for chemotherapy and they are looking for novel, less-invasive ways to delay progression of their disease.”

In fact, SBRT is particularly useful for liver cancer. Patients seeking a liver transplant must meet the transplant criteria after a typical year-long waiting period. Bridge therapies are required during this time to keep the disease from spreading, and to improve chances for long-term survival.

Katz’s study was small, involving 18 patients initially and then only 12 who qualified for a transplant a few months after receiving SBRT between 2007 and 2009. However, the survival outcomes were significant: approximately 19 months after surgery all patients were doing well with no recurrences and no significant toxicities from the treatment, Katz said. (Average five-year survival rates for liver cancer vary greatly, ranging from 10 percent to 60 percent, depending upon the stage at diagnosis and other factors.)

Milano studied the long-term outcomes of 121 people who were treated with SBRT after being diagnosed with recurrences from a variety of cancers, including breast, prostate, lung and colon. Only people with five or fewer metastatic lesions were eligible. Breast cancer patients fared the best, perhaps because that cancer tends to be more indolent, he said.

For example, half of the 39 breast cancer patients with metastasis survived for more than four years after SBRT, and one-third of them were alive at seven-year follow-up visits. The study also noted that for the breast cancer patients who had bone metastasis, after SBRT none of their lesions recurred.

With other types of cancer, SBRT was less successful in terms of long-term survival but still was useful at controlling new lesions and thus delaying further spread of the disease in 74 percent of the patients. The two-year overall survival rate for 82 patients with metastasis from colon, lung, esophagus, or sarcomas, was 39 percent. Seven of 82 patients were alive after seven years.

When cancer spreads from the original site in the body to another site, the chances of a cure are slim. The primary goal is to slow the disease and relieve symptoms. Future research is aimed at investigating the newer, targeted treatments that might offer the best chance at prolonging life while maintaining quality of life.

Milano said further study of SBRT should address which subgroups of patients, aside from people with breast cancer, are likely to derive the most benefit from SBRT, and at what doses. When the URMC first began studying SBRT in 2001, 5-Gy fractions of radiation delivered to the organs was considered novel. Since then, however, researchers and clinicians have shown that doses of 10 to 20 Gy can be safe and effective, and the higher doses could potentially result in even better long-term survival.

For Media Inquiries:
Leslie Orr
(585) 275-5774
Email Leslie Orr

Source

NIH study to test treatment for fatty liver disease in children

For Immediate Release
Wednesday, January 11, 2012

Contact:
Leslie Curtis
Amy F. Reiter
301-496-3583

With the launch of a new clinical trial supported by the National Institutes of Health, researchers are working to determine whether treating children diagnosed with the most severe form of fatty liver disease with a drug called cysteamine will help improve the liver.

The trial, called Cysteamine Bitartrate Delayed-Release for the Treatment of Nonalcoholic Fatty Liver Disease in Children (CyNCh),will enroll 160 boys and girls ages 8 to 17 with nonalcoholic fatty liver disease (NAFLD). The participants will receive cysteamine or placebo by mouth twice a day for a year. There are no weight cutoffs or percentiles for the children participating in CyNCh. However, more than 90 percent of the children are expected to be overweight or obese. Participants need a baseline biopsy that confirms severe NAFLD to be eligible for the study. Children with poorly managed diabetes, heart disease, and other chronic liver diseases will be excluded.

NAFLD covers a range of severity from simple liver disease without injury, called steatosis, to the more concerning nonalcoholic steatohepatitis, or NASH, which includes fat accumulation, inflammation, and liver injury. Most children with fatty liver disease are overweight and resistant to insulin, a hormone that regulates energy. The only way to distinguish NASH from other forms of fatty liver disease is with a liver biopsy.

"We did not see fatty liver disease in children until recently," said Edward Doo, M.D., NASH Clinical Research Network project scientist and director of the Liver Diseases Program at NIH's National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), which is funding the study in collaboration with Raptor Pharmaceutical of Novato, Calif., which makes the drug and will provide it to the trial. "Fatty liver disease affects about 17 percent of children in the United States. This rise in the number of children with NAFLD most likely mirrors the increase in obesity, which affects more than 16 percent of American children and teens," Dr. Doo said.

Results from a small pilot study using cysteamine in 11 children with NASH suggest that it improves liver enzymes by reducing toxins that can damage the liver. Cysteamine is approved to treat cystinosis, a genetic disease that causes the amino acid cystine to accumulate in the kidneys, liver, eyes, brain, and white blood cells. Modest weight loss through diet and physical activity may help some children with fatty liver disease, but it is a treatment option that seldom helps people meet their goals. "We know that following a weight loss plan for many children and adults can be daunting, especially if they have limited access to healthy food options that are low in fat, added sugars, and calories, and infrequent opportunities for physical activity," said Joel E. Lavine, M.D., Ph.D., a CyNCh principal investigator and professor of pediatrics at Columbia University, New York City. "Hopefully, this trial will move us closer to finding a safe and effective treatment that helps children with fatty liver disease."

NAFLD can be a precursor to NASH, which may progress to cirrhosis, liver failure and liver cancer. NAFLD may also increase a patient’s risk of developing heart disease. A healthy liver helps the body remove harmful chemicals from the blood, fight infection and digest food. If too much scar tissue forms, the liver could fail. Then a liver transplant is required. "We are concerned that the disease may advance as children become adults and increase their risk for cirrhosis, liver failure, liver transplantation, and death as adults," said Stephen P. James, M.D., director of the NIDDK’s Digestive Diseases and Nutrition Division. "This multicenter, double-blind trial offers researchers and NIDDK an opportunity to rigorously assess how safe and effective cysteamine is in treating children with NASH, as well as to reveal new avenues worthy of scientific study."

The following clinical centers are conducting the CyNCh trial:

• Children's Memorial Hospital, Chicago
• Cincinnati Children’s Hospital Medical Center
• Columbia University, New York City
• Indiana University, Indianapolis
• Mount Sinai Medical Center, New York City
• St. Louis University
• Texas Children's Hospital, Houston
• University of California, San Diego
• University of California, San Francisco
• University of Washington, Seattle

For more information:

• NIDDK's NASH Clinical Research Network: https://jhuccs1.us/nash/open/centers/centers.htm
• NIDDK's Action Plan for Liver Disease Research: www.liverplan.niddk.nih.gov
• National Digestive Diseases Information Clearinghouse: http://digestive.niddk.nih.gov
• Weight-control Information Network: www.win.niddk.nih.gov
• ClinicalTrials.gov: www.clinicaltrials.gov

The NIDDK, a component of the NIH, conducts and supports research on diabetes and other endocrine and metabolic diseases; digestive diseases, nutrition and obesity; and kidney, urologic and hematologic diseases. Spanning the full spectrum of medicine and afflicting people of all ages and ethnic groups, these diseases encompass some of the most common, severe and disabling conditions affecting Americans. For more information about the NIDDK and its programs, see www.niddk.nih.gov. Education programs for diabetes and kidney disease offer information and resources for patients and health professionals.

About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.

Source

Minimal Transmission of HIV Despite Persistently High Transmission of Hepatitis C Virus in a Swedish Needle Exchange Program

From Journal of Viral Hepatitis

M. Alanko Blomé; P. Björkman; L. Flamholc; H. Jacobsson; V. Molnegren; A. Widell

Posted: 01/10/2012; J Viral Hepat. 2011;18(12):831-839. © 2011 Blackwell Publishing

Abstract and Introduction

Abstract

The aim of this study was to examine the prevalence and incidence of HIV and hepatitis B and C (HBV and HCV) among injecting drug users in a Swedish needle exchange programme (NEP) and to identify risk factors for blood-borne transmission. A series of serum samples from NEP participants enrolled from 1997 to 2005 were tested for markers of HIV, HBV and HCV (including retrospective testing for HCV RNA in the last anti-HCV-negative sample from each anti-HCV seroconverter). Prevalence and incidence were correlated with self-reported baseline characteristics. Among 831 participants available for follow-up, one was HIV positive at baseline and two seroconverted to anti-HIV during the follow-up of 2433 HIV-negative person-years [incidence 0.08 per 100 person-years at risk (pyr); compared to 0.0 in a previous assessment of the same NEP covering 1990–1993]. The corresponding values for HBV were 3.4/100 pyr (1990–1993: 11.7) and for HCV 38.3/100 pyr (1990–1993: 27.3). HCV seroconversions occurred mostly during the first year after NEP enrolment. Of the 332 cases testing anti-HCV negative at enrolment, 37 were positive for HCV RNA in the same baseline sample (adjusted HCV incidence 31.5/100 pyr). HCV seroconversion during follow-up was significantly associated with mixed injection use of amphetamine and heroin, and a history of incarceration at baseline. In this NEP setting, HIV prevalence and incidence remained low and HBV incidence declined because of vaccination, but transmission of HCV was persistently high. HCV RNA testing in anti-HCV-negative NEP participants led to more accurate identification of timepoints for transmission.

Introduction

Injecting drug use is an important route of HIV transmission worldwide,^[1,2] and hence targeting injecting drug users (IDUs) is a priority in HIV prevention. IDUs are also at risk of infection with other blood-borne pathogens, especially hepatitis B virus (HBV) and hepatitis C virus (HCV). Because these viruses share transmission routes, measures taken to prevent HIV might also be expected to reduce the spread of HBV and HCV. A wide range of strategies have been attempted to decrease blood-borne transmission among IDUs, as exemplified by harm reduction interventions such as methadone maintenance therapy (MMT) and needle exchange programmes (NEPs). Although NEPs are recommended by the World Health Organization (WHO), there is no unequivocal evidence from controlled studies demonstrating the protective efficacy of such schemes.^[3,4] Most evaluations of the effectiveness of NEPs regarding HIV compare populations or assess injection-related risk behaviour,^[5–7] and most studies of virological markers have been cross-sectional.^[8,9] HIV incidence studies among NEP participants have in general revealed low rates of seroconversion, especially when NEPs had been initiated before significant spread of HIV occurred in the target population.^[10–13] Such results agree with our earlier observations regarding NEP participants in Malmö, Sweden, in 1990–1993.^[14] However, a major concern in our Malmö NEP was ongoing transmission of HBV and HCV, which indicated blood-borne transmission despite access to clean injection equipment. We subsequently added HBV immunization to the program, as well as targeted health education concerning the risks of HCV transmission for both HCV-infected and HCV-uninfected participants.

The objective of the present study was to further investigate the recent epidemiology of HIV, HBV and HCV among new participants in the Malmö NEP, which is one of only two such programs in Sweden, and also to determine whether incident HCV infection was linked to baseline drug use–related risk factors.

Methods

Setting

In Sweden (pop. 9 million), approximately 4500 people had been diagnosed with HIV by the year 2005 (prevalence 0.04%), and, from 1995 to 2005, about 300 new cases were reported annually, with approximately 10% infected through injection drug use.^[15] The prevalence of previous HBV exposure in the general middle-aged population in urban areas was approximately 4% in 2000.^[16] Considering HCV, the prevalence in 1996–2006 was 0.5%, and injection drug use was reported to be the transmission route in 65% of the registered cases.^[17] No data are available regarding the incidence of HCV in Sweden.

The city of Malmö (pop. about 270 000) is located in Skåne County in the southernmost part of Sweden (pop. about 1 million), approximately 20 km from Copenhagen, Denmark. From 1997 to 2005, the average annual incidence of HIV in Skåne County was 39 (range 31–51), and most infections were acquired through sexual transmission. In 2005, approximately 500 people diagnosed with HIV were living in Skåne County.^[18] According to estimations,^[19] there were 1600 IDUs in Malmö in 1998 (1080 per 100 000 inhabitants aged 15–54 years). In 2006, there were 1000 HIV-infected IDUs in the entire country, and 6% of those IDUs lived in Malmö while the majority (72%) lived in the capital city of Stockholm.

The Malmö Needle Exchange Programme

The Malmö NEP was initiated in 1987, and it is located in the University Hospital compound at the Department of Infectious Diseases. The staff consists of two assistant nurses, a registered nurse, a social worker, a midwife and a physician. The NEP is open daytime during weekdays. A total of 3950 new participants enrolled in the Malmö NEP, and approximately 1150 persons were active in the programme each year during that period. Prerequisites for enrolment are self-reported injection drug use, age ≥20 years, signs of recent venipuncture and consent to HIV testing (which may be performed under code). About 140–200 new participants enrol annually. At the time of registration, structured data are collected and risk reduction counselling is given. A maximum of 20 needles and 10 syringes can be obtained per visit. Most participants who have initially chosen to be anonymous later decide to allow use of their unique national identity number (NIN) for management of data and test results, after which collected data are updated. NINs are used in all Swedish hospital and laboratory databases and in population registers.

Those susceptible to either HIV, HBV and/or HCV infection are serologically tested approximately every 3 months until seroconversion occurs. In addition, immunization against hepatitis B and A has been offered since 1994 and 1999, respectively. Educational videos aimed at both reducing infection and preventing overdose are shown in the waiting room, and participants are given barrier contraceptives, pregnancy screening and treatment for sexually transmitted infections. Basic medical care, psychosocial support and referral to detoxification or methadone/buprenorphine maintenance clinics are also offered, all free of charge.

Subjects

A total of 1661 participants registered in the Malmö NEP between 1 January 1997 and 31 December 2005 were eligible for inclusion in the present study, and a NIN was available for 1183 of those individuals. The remaining 478 subjects were mainly sporadic visitors who refused both use of their NINs and blood sampling (n = 454), or agreed only to blood sampling (n = 24), and thus identification of serological markers was not possible. Among the 1183 persons who allowed use of their NINs, 831 provided two or more samples and underwent two or more registered needle/syringe exchanges, and they were included in the analysis of incidence and risk factors prevalent at enrolment; this group is referred to as the longitudinal cohort. The 352 persons providing only one blood sample were analysed regarding prevalence of viral markers, demographics and risk profile; this group is called the baseline-only cohort.

Virological Testing

Serological Tests Virological results were retrieved from the mainframe computer at the hospital microbiology laboratory. During the study period, testing was progressively upgraded with new instruments and techniques [1997, chemiluminescence assay using avidin-coated tubes (Boehringer, Mannheim, Germany); 1998, bead-based ELISA (CobasCore; Roche, Mannheim, Germany); 2001, microparticle-based EIA (Abbott AxSym, Abbott Park, IL, USA)]. The markers studied were as follows: for HIV, anti-HIV antibodies followed by immunoblotting if needed; for HBV, hepatitis B surface antigen (HBsAg), core antibodies (anti-HBc) and surface antibodies (anti-HBs); for HCV, anti-HCV antibodies followed by immunoblotting if needed. All assays were continuously evaluated in international proficiency panels. Sera were routinely stored at −20 °C, which allowed retrospective retesting of relevant sera with the most sensitive anti-HCV assay (third generation Abbott AxSym).

Molecular Tests To define the time of HCV acquisition more exactly, all the latest available preseroconversion sera testing anti-HCV negative in the third-generation AxSym assay were retrospectively tested for HCV RNA in a Taqman48 Roche assay (Roche Diagnostics). Because the sample volumes were limited and the Taqman system requires 1 mL of starting material, participant sera were prediluted 1:10 in negative serum, which resulted in a detection limit of 150 IU/mL for HCV RNA.

Statistical Methods

Odds ratios, Mann–Whitney U-tests and Fisher's Exact tests were calculated to analyse differences between groups. Univariate and multiple logistic regression analyses were carried out to identify baseline risk factors associated for previous HCV exposure and with HCV seroconversion. Kaplan–Meier curves with log rank tests were plotted to visualize and test time to seroconversion between different year periods. The statistical tests were performed in spss 15.0 for Windows ( SPSS Inc., Chicago, IL, USA). P-values <0.05 were considered statistically significant. Odds Ratios (ORs) were considered as significant if the entire 95% confidence range either was above or below 1.0

The timepoint of seroconversion to HIV, HBV and HCV was defined as the midpoint between the last antibody-negative and the first antibody-positive sample. The timepoint of HCV infection was adjusted by the results of HCV RNA testing. The monitored follow-up period spanned from the first serum sample collected after registration in the NEP to the last sample taken before the end of 2005.

Ethical Considerations

After approval by the regional research ethics committee, the purpose and the procedure of our study were announced on posters in the NEP and in advertisements in the local press, including a widely distributed free daily newspaper. An opt-out strategy was used, assuming consent for NEP participants who did not actively object to study inclusion. All analyses were coded, with the exception of linking of the longitudinal laboratory results.

Results

Baseline Characteristics of Injecting Drug Users Who Did or Did Not Provide a National Identity Number

Participants with and without available NINs did not differ significantly with regard to gender, age or geographic origin (data not shown). However, only 50% of those with a NIN had spent time in prison prior to the enrolment in the NEP compared to 57% of those not providing a NIN (OR 0.76, CI 0.61–0.94: P = 0.013). Among those who did provide a NIN, injection of amphetamine only was less prevalent (OR 0.78, CI 0.62–0.98; P = 0.039), whereas cannabis use was significantly more common (OR 1.86, CI 1.41–2.45; P < 0.001).

Baseline Prevalence of HIV, HBV and HCV Markers in Injecting Drug Users Who Provided a National Identity Number

Longitudinal Cohort vs Baseline-only Cohort The baseline prevalence of serological markers for all identified patients was 0.34% (4/1183) for anti-HIV, 32% (380/1183) for anti-HBc and 64% (758/1183) for anti-HCV.

Markers of previous exposure to HBV and HCV were significantly more prevalent in the baseline-only cohort compared to the longitudinal cohort for HBV (OR 1.82, CI 1.40–2.37; P < 0.001) and for HCV (OR 1.85, CI 1.41–2.44; P < 0.001). The baseline-only cohort also had a significantly longer history of injecting both heroin and amphetamine before enrolling in the NEP (P < 0.001). Likewise, the use of cannabis (OR 2.01, CI 1.23–3.28; P = 0.004) and oral amphetamine (OR 2.70, CI 2.08–3.50; P < 0.001) was more prevalent in the baseline-only cohort. This group also reported having spent time in police custody more often (OR 1.69, CI 1.21–2.38; P = 0.002) or in prison (OR 1.50, CI 1.16–1.92; P = 0.002), or had been in care under the social services law (OR 1.73, CI 1.27–2.35; P = 0.001).

Longitudinal Cohort HIV. One of the 831 persons in the longitudinal cohort was anti-HIV positive at enrolment but had tested anti-HIV negative 3 months previously.

HBV. Markers of HBV exposure were detected at baseline in 236 persons (28%), 10 of whom developed chronic HBs antigenemia. Neither male gender (OR 1.30, CI 0.91–1.86) nor being born outside Sweden (OR 0.79, CI 0.54–1.14) was associated with a higher risk of HBV exposure. Exclusive use of heroin was associated with a significantly lower risk of HBV exposure compared to exclusive use of amphetamine or mixed use of those drugs (OR 0.48, 0.31–0.74; P = 0.0008). Furthermore, testing positive for HBV markers was strongly correlated with the presence of anti-HCV (OR 5.91, CI 3.97–8.80). Only seven persons had received full HBV vaccination and achieved protective levels of anti-HBs before NEP enrolment.

HCV. At baseline, anti-HCV was found in 499 (60%) participants. Univariate comparison of participants dichotomized for baseline anti-HCV status showed that presence of anti-HCV was associated with (Table 1, left section) older age (OR 1.09, CI 1.07–1.11; P < 0.001), longer duration of heroin injection (OR 1.11, CI 1.07–1.15; P < 0.001), longer duration of amphetamine injection (OR 1.11, CI 1.09–1.14; P < 0.001), parenteral use of both heroin and amphetamine (OR 1.65 CI 1.24–2.19; P = 0.001), use of oral amphetamine (OR 1.52, CI 1.13–2.04; P = 0.006), previous incarceration (OR 2.43, CI 1.82–3.25; P < 0.001), time in residential treatment centres (OR 1.39, CI 1.05–1.84; P = 0.021) and exposure to HBV (OR 5.72, CI 3.86–8.48; P < 0.001). Male gender (OR 0.68, CI 0.49–0.95; P = 0.023), intravenous heroin (OR 0.34, CI 0.24–0.48; P < 0.001) and oral heroin (OR 0.52, CI 0.33–0.82; P = 0.006) use were associated with a lower risk of anti-HCVseropositivity. By multivariate analysis, the following factors were significant: male gender (OR 0.39, CI 0.26–0.58; P < 0.001), higher age at entry (OR 1.03, CI 1.01–1.06; P = 0.007), longer duration of parenteral heroin (OR 1.06, CI 1.01–1.11; P = 0.011) and amphetamine (OR 1.06 CI 1.03–1.09; P < 0.001) use, previous incarceration (OR 1.59, CI 1.10–2.29; P = 0.013), residential treatment (OR 1.59, CI 1.01–2.51; P = 0.045) and markers of HBV exposure (OR 2.75, CI 1.76–4.32; P < 0.001).

Incidence of HIV, HBV and HCV Markers in the Longitudinal Cohort

HIV In 1999, seroconversion to anti-HIV occurred in two men (24 and 27 years of age, both anti-HCV positive). Anti-HIV were detected in one of those men 10 months after the first anti-HIV-negative registration sample; he had not visited the NEP for eight consecutive months during that period. The other man had tested anti-HIV negative 3 months prior to the first anti-HIV positive sample. Thus, the incidence of HIV was 0.082/100 pyr during a total time at risk of 2433 years (Table 2).

Hepatitis B Participants negative for HBsAg and/or anti-HBc were offered vaccination according to a standard three-dose schedule and using a postvaccination titre of anti-HBs >10 IU/mL as a criterion for protection. In the longitudinal cohort, 588 persons were susceptible to HBV. Three hundred and fifty-one of those individuals (60%) received at least three doses of vaccine, and protective levels of anti-HBs were achieved in 321 (91%).

HBV seroconversion occurred in 39 participants (21 with documented HBsAg and anti-HBc, 18 with anti-HBc only). The median interval between NEP enrolment and anti-HBc seroconversion was 17 months (range 2.0–101.0). The follow-up time was 1160 pyr, yielding a seroconversion rate of 3.36/100 pyr (Table 2). Nineteen (48%) of the incident HBV cases had begun vaccination with 11 having received only one dose and 2 two doses. Six subjects with HBV seroconversion had been fully vaccinated but had not achieved anti-HBs ≥10 IU/mL. No incident case of HBV occurred in vaccine responders. Five of the incident HBV cases developed chronic HBV infection. Thirteen (33%) of the 39 HBV seroconverters were susceptible to HCV, and 9 (69%) of those also seroconverted to anti-HCV. Drug use profiles did not differ significantly between those who were and those who were not infected with HBV during participation in the NEP.

Hepatitis C Seroconversion to anti-HCV. During 486 person-years at risk, 186 anti-HCV seroconversions occurred among 332 anti-HCV-negative individuals, resulting in an incidence of 38.3/100 pyr (Table 2). The majority of incident HCV infections occurred during the first 2 years after registration (Fig. 1a).

Figure 1. Time (years) elapsed before seroconversion to anti-HCV after enrolment in the Malmö needle exchange programme. The results are shown without (a) and with (b) adjustment for HCV viraemia in last anti-HCV-negative blood sample.

To assess potential trends over calendar time, we divided the entire cohort into three groups composed of all susceptible subjects registered in the NEP during three successive 3-year study periods. The time to event for those susceptible to HCV was calculated in Kaplan–Meier mode. Because the time of observation was shorter for the last group, events occurring later than the first 12 months after registration were censored. The corresponding time curves to HCV seroconversion are shown in Fig. 2. No significant differences were detected between these three groups.

Figure 2. Anti-HCV-free interval during the first 12 months of participation in the Malmö needle exchange programme among injecting drug users enrolled during three successive periods: 1997–1999, 2000–2002 and 2003–2005.

Risk Factors for anti-HCV Seroconversion. Univariate comparison of those who seroconverted to anti-HCV and those who remained anti-HCV negative showed that seroconversion was associated with the following (Table 1, right section): use of cannabis (OR 2.18, CI 1.02–4.65; P = 0.044), injection of both heroin and amphetamine (OR 1.60, CI 1.01–2.53; P = 0.044), and incarceration prior to enrolment (OR 1.79, CI 1.12–2.86; P = 0.015). Use of intravenous amphetamine (OR 0.55, CI 0.34–0.87; P = 0.012) only and oral amphetamine (OR 0.60, CI 0.38–0.96; P = 0.035) only was associated with a lower risk of seroconversion. Multivariate logistic regression analysis indicated that the duration of intravenous use of amphetamine before enrolment (OR 0.96 CI 0.92–1.00; P = 0.034), reported injection of both amphetamine and heroin (OR 1.87, CI 1.15–3.02; P = 0.011), and incarceration prior to enrolment (OR 1.89, CI 1.14–3.12; P = 0.013) were significant risk factors for HCV seroconversion after joining the programme.

Needle exchange programme participation was significantly longer and the number of visits significantly greater for the anti-HCV seroconverters than for those who remained anti-HCV negative. However, participants with detectable anti-HCV at baseline had a significantly lower median number of NEP visits, as well as a lower frequency of attendance than those who were anti-HCV negative at inclusion (Table 3).

HCV Incidence Adjusted for Serological Window Phase. Because anti-HCV antibodies appear months after infection, the high HCV incidence observed during the first months after enrolment might be explained by HCV infection acquired prior to registration. Among 186 persons who showed anti-HCV seroconversion following enrolment, HCV RNA was detected in the last available anti-HCV-negative sample in 67 cases (Fig. 1b). Thirty-seven of these were HCV viremic in their anti-HCV-negative enrolment sample, leading to a reclassification from incident to prevalent infection in those subjects, with an adjusted incidence of 31.5 per 100 pyr. Comparison of seroconverters who were in serological window phase at enrolment with subjects who acquired HCV after enrolment revealed no significant differences in relation to age or type or duration of drug use (data not shown).

Discussion

For more than two decades, the WHO has promoted needle exchange to prevent sharing of injection equipment and HIV transmission among IDUs. Despite this, many countries have pursued a restrictive policy and in Sweden only two NEPs exist. Furthermore, syringes and needles cannot be purchased legally without a prescription in Sweden.

Because the true efficacy of NEP cannot be demonstrated in randomized controlled trials, continuous evaluation of existing projects is critical. If the prevalence of HIV is very low in an IDU population under investigation, HIV seroconversion is not a reliable marker to detect blood-borne transmission. Like in our 1990–93 cohort, the incidence of HIV remained very low in the 1997–2005 cohort, and no new cases were detected after 1999.

We and others^[20,21] have used HBV and HCV as surrogate markers of the potential risk of spreading HIV. It is obvious that HBV immunization can confound the incidence of HBV and affect its usefulness as a surrogate marker. HCV is not effectively transmitted sexually and thus mainly reflects the injection risk, making this virus a more suitable marker of blood transmission.

Following our previous evaluation in 1990–1993, HBV immunization was introduced for unexposed NEP participants, which led to a sharp decline in HBV incidence from 11.7/100 to 3.36/100 pyr.

Our high HCV incidence is alarming (Table 2) and agrees with our previous results and those of others[22–24]. Several reasons may contribute to this phenomenon including the effects of a higher viral load and greater physical virion stability of HCV compared to HIV,^[25,26] as well as the much higher background prevalence of HCV among IDUs. Prevention of HCV transmission among IDUs is indeed a challenge, as demonstrated by a meta-analysis of 18 studies,^[27] which showed that neither NEPs nor MMT affected the incidence of HCV in IDUs. Researchers in the Netherlands recently found that only a combination of low-threshold NEPs and MMT could reduce HCV transmission among IDUs.^[28]

The majority of the participants in the Malmö NEP in 1997–2005 were already infected with HCV at baseline. Furthermore, we found that older age and longer duration of intravenous drug use was associated with HCV infection, and mixed use of heroin and amphetamine and incarceration prior to NEP enrolment were independent risk factors for HCV infection. Our data also show that most cases of HCV seroconversion occurred during the first year after enrolment, which is earlier than reported by Hagan et al.^[29]

Retrospective assessment of HCV RNA in frozen key samples from the longitudinal cohort revealed viraemia in 37/332 (12%) of the subjects who were anti-HCV negative at the time of enrolment. In an additional 30 individuals, a viraemic window-phase sample preceded anti-HCV seroconversion. Thus, it is likely that PCR analysis performed prospectively in anti-HCV-negative NEP participants would be a better method for detecting incident cases of HCV infection, permitting earlier and more effective interventions and tracing of transmission chains among such subjects.

After the initial phase of high HCV incidence following enrolment, new HCV infections became rarer in those still susceptible –a phenomenon which could be due both to behavioural and immunological factors.^[30]

Our study has limitations. Only NEP participants who were fully identified could be followed, which might have affected the results. However, demographic data reported by identifiable and nonidentifiable subjects were similar. Subjects with only one serum sample available had a higher risk profile compared to those in the longitudinal cohort, but they usually paid single or very few visits to the NEP making it questionable whether they should be regarded as NEP participants. Prospective assessment and monitoring of changes in drug injection risk profile was not consistently documented, nor were sexual risk factors. Furthermore, we were unable to objectively determine exact periods of and reasons for interruptions in NEP participation (e.g. imprisonment, travel or admission to detoxification clinics), and whether such interruptions were associated with changes in the rates of HCV seroconversion.

The effectiveness of a NEP depends on several factors, which, in addition to the number of needles and syringes exchanged,^[31] include acceptance and accessibility by the target population, as well as provision of adequate health education and medical services. In the Malmö NEP, limited opening hours and an age requirement of ≥20 years for participation may have been counterproductive, whereas the broad range of services offered probably had the opposite effect. A major advantage of NEPs is the possibility for surveillance of HIV seroepidemiology among IDUs and provide early warning as illustrated by the outbreak of HIV that occurred in 1994 in Vancouver,.^[32,33]

In conclusion, the persistently low incidence of HIV in the cohort we studied may be explained by a protective effect of the NEP combined with low background prevalence of HIV. Although NEPs conducted under these circumstances do not affect the incidence of HCV, they do contribute to surveillance and control of HIV transmission in the target population. Molecular testing focusing on participants with anti-HCV-negative samples may offer improved means of case finding.

References

1. WHO Regional Office for Europe and UNAIDS report on progress since the Dublin Declaration. Euro Surveill 2008; 13.
2. Mathers BM, Degenhardt L, Phillips B et al. Global epidemiology of injecting drug use and HIV among people who inject drugs: a systematic review. Lancet 2008; 372: 1733–1745.
3. WHO. Effectiveness of sterile needle and syringe programming in reducing HIV/AIDS among injecting drug users (evidence for action technical papers). WHO Library Cataloguing-in- Publication Data 2004.
4. Vlahov D, Junge B. The role of needle exchange programs in HIV prevention. Public Health Rep 1998; 113(Suppl. 1): 75–80.
5. Bruneau J, Daniel M, Kestens Y, Zang G, Genereux M. Associations between HIV-related injection behaviour and distance to and patterns of utilisation of syringe-supply programmes. J Epidemiol Community Health 2008; 62: 804–810.
6. Valente TW, Foreman RK, Junge B, Vlahov D. Needle-exchange participation, effectiveness, and policy: syringe relay, gender, and the paradox of public health. J Urban Health 2001; 78: 340–349.
7. Azim T, Hussein N, Kelly R. Effectiveness of harm reduction programmes for injecting drug users in Dhaka city. Harm Reduct J 2005; 2: 22.
8. Judd A, Hutchinson S, Wadd S et al. Prevalence of, and risk factors for, hepatitis C virus infection among recent initiates to injecting in London and Glasgow: cross sectional analysis. J Viral Hepat 2005; 12: 655–662.
9. Liu B, Sullivan SG, Wu Z. An evaluation of needle exchange programmes in China. AIDS 2007; 21(Suppl 8): S123–S128.
10. Huo D, Ouellet LJ. Needle exchange and injection-related risk behaviors in Chicago: a longitudinal study. J Acquir Immune Defic Syndr 2007; 45: 108–114.
11. Patrick DM, Tyndall MW, Cornelisse PG et al. Incidence of hepatitis C virus infection among injection drug users during an outbreak of HIV infection. CMAJ 2001; 165: 889–895.
12. Maher L, Jalaludin B, Chant KG et al. Incidence and risk factors for hepatitis C seroconversion in injecting drug users in Australia. Addiction 2006; 101: 1499–1508.
13. Ruan Y, Qin G, Yin L et al. Incidence of HIV, hepatitis C and hepatitis B viruses among injection drug users in southwestern China: a 3-year follow- up study. AIDS 2007; 21(Suppl 8): S39–S46.
14. Månsson AS, Moestrup T, Nordenfelt E, Widell A. Continued transmission of hepatitis B and C viruses, but no transmission of human immunodeficiency virus among intravenous drug users participating in a syringe/needle exchange program. Scand J Infect Dis 2000; 32: 253–258.
15. Swedish Institute for Disease Control S. Statistics for HIV-infection in Sweden. Available at http://www.smittskyddsinstitutet.se/statistik/hivinfektion/?t=com&p=8752#statistics-nav (accessed 090528).
16. Hoffmann G, Berglund G, Elmståhl S et al. Prevalence and clinical spectrum of chronic viral hepatitis in a middle-aged Swedish general urban population. Scand J Gastroenterol 2000; 35: 861–865.
17. Duberg A, Janzon R, Back E, Ekdahl K, Blaxhult A. The epidemiology of hepatitis C virus infection in Sweden. Euro Surveill 2008; 13(21): pii=18882.
18. Regional Centre for Communicable Disease Control S. Smittskydd Skåne,1:6. Available at http://www.skane.se/upload/Webbplatser/Smittskydd/Dokument/2006mars.pdf#page=2 (accessed 090528).
19. Federation of alcohol and drug awareness in Sweden C. Drug trends in Sweden 2006: report nr 98. 2006. Available at: http://www.can.se/documents/CAN/Rapporter/rapportserie/CAN-rapportserie-98-drogutvecklingen-i-sverige-2006.pdf (accessed 090528).
20. Aceijas C, Rhodes T. Global estimates of prevalence of HCV infection among injecting drug users. Int J Drug Policy 2007; 18: 352–358.
21. Des Jarlais DC, Arasteh K, McKnight C, Hagan H, Perlman D, Friedman SR. Using hepatitis C virus and herpes simplex virus-2 to track HIV among injecting drug users in New York City. Drug Alcohol Depend 2009; 101: 88–91.
22. Hernandez-Aguado I, Ramos-Rincon JM, Avinio MJ, Gonzalez-Aracil J, Perez-Hoyos S, de la Hera MG. Measures to reduce HIV infection have not been successful to reduce the prevalence of HCV in intravenous drug users. Eur J Epidemiol 2001; 17: 539–544.
23. Crofts N, Aitken CK, Kaldor JM. The force of numbers: why hepatitis C is spreading among Australian injecting drug users while HIV is not. Med J Aust 1999; 170: 220–221.
24. Muga R, Sanvisens A, Bolao F et al. Significant reductions of HIV prevalence but not of hepatitis C virus infections in injection drug users from metropolitan Barcelona: 1987–2001. Drug Alcohol Depend 2006; 82(Suppl 1): S29–S33.
25. Haber PS, Young MM, Dorrington L et al. Transmission of hepatitis C virus by needle-stick injury in community settings. J Gastroenterol Hepatol 2007; 22: 1882–1885.
26. Paintsil E, He H, Peters C, Lindenbach BD, Heimer R. Survival of hepatitis C virus in syringes: implication for transmission among injection drug users. J Infect Dis 2010; 202: 984–990.
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31. Des Jarlais DC, Perlis T, Arasteh K et al. HIV incidence among injection drug users in New York City, 1990 to 2002: use of serologic test algorithm to assess expansion of HIV prevention services. Am J Public Health 2005; 95: 1439–1444.
32. Strathdee SA, Patrick DM, Currie SL et al. Needle exchange is not enough: lessons from the Vancouver injecting drug use study. AIDS 1997; 11: F59–F65.
33. McInnes CW, Druyts E, Harvard SS et al. HIV/AIDS in Vancouver, British Columbia: a growing epidemic. Harm Reduct J 2009; 6: 5.

Source

Treatment of patients with genotype 3 chronic hepatitis C- current and future therapies

Liver International

Special Issue: Proceedings of the 5th Paris Hepatitis Conference. International Conference of the Management of Patients with Viral Hepatitis: Special Edition Hepatitis C

Volume 32, Issue Supplement s1, pages 141–145, February 2012

Review Article

Shiv K. Sarin, Chandan K. N. Kumar

Article first published online: 29 DEC 2011

DOI: 10.1111/j.1478-3231.2011.02715.x

© 2012 John Wiley & Sons A/S

Abstract

Genotype 3 is a common type of HCV infection, and standard therapy using pegylated interferon (PEG-IFN) and ribavirin (RBV) is quite effective in these patients. While a short course of 16 weeks may result in comparable end of therapy responses, relapse rates are often high. A 24-week course is therefore preferable, and is expected to result in sustained virological response (SVR) rates of more than 70%. The 24-week course is especially recommended in the presence of steatosis (often associated with Genotype 3 infection), fibrosis stage two or more, high BMI and high viral load. In patients who do not achieve a rapid viral response (RVR) with combination therapy, an extended course up to 48 weeks should be considered. While not as definite as for genotype 1 patients, the presence of the CC variant of IL28b could help in the initial prognosis and the need for additional treatment, if an RVR is not achieved. The role of directly acting antiviral agents (DAA) has not been fully evaluated in treatment naïve, non-responders and relapsers in genotype 3 patients. Initial results with the cyclophilin inhibitor Debio-025 are quite encouraging. There is an urgent need for large clinical trials using DAA and host modulators in patients with G3 infection.

According to WHO, around 130–170 million people are chronically infected with the hepatitis C virus (HCV) worldwide, reflecting the magnitude of this global health burden [1]. The estimated prevalence is around 2%. Epidemiological surveys have also shown a geographical variation in the prevalence and distribution of hepatitis C genotypes worldwide. Although HCV genotype 1 predominates in the Western countries, genotype 3 accounts for 35–80% of chronic HCV infections in regions such as the Indian subcontinent [2], Southeast Asia and Australia [3].

The standard of care (SOC) therapy for patients with chronic HCV infection has been the combination of peginterferon (PEG-IFN) and ribavirin (RBV). These drugs are administered for either 48 weeks (HCV genotypes 1, 4, 5 and 6) or 24 weeks (HCV genotypes 2 and 3), inducing sustained virological response (SVR) rates of 40–50% in those with genotype 1, and of 80% or more in those with genotypes 2 and 3 infections [4]. However, the rates of SVR in patients infected with genotype 3 are lower than those with genotype 2 [5]. Second, compared with other genotypes, genotype 3 is associated with a higher incidence of hepatic steatosis and the rapid progression of liver fibrosis [6]. We have previously shown that the median rate of the progression of fibrosis per year is 0.25 (0.0–1.5) fibrosis units in patients with genotype 3 in India and higher in patients who acquire infection after 30 years of age. The median time for progression to cirrhosis was 16 years [7]. According to a recent meta-analysis, the odds ratio for the association of genotype 3 infection and accelerated progression of liver fibrosis was 1.52 in single biopsy studies suggesting faster fibrosis progression compared with other genotypes [8].

In a retrospective study of 353 patients, Nkontchou et al. [9] showed that hepatitis C genotype 3 was associated with a higher incidence of hepatocellular carcinoma (HCC) in patients with ongoing cirrhosis. The risk factors for an increased risk of HCC were male gender, older age, higher body mass index, low platelet count and genotype 3. Probably because of the rapid progression to fibrosis, genotype 3 could predispose to HCC along with other defined risk factors. The HCV genotype 3 core protein causes steatosis [10, 11, 12] that can lead to oxidative stress and reactive oxygen species predisposing to carcinogenesis [13, 14]. Thus, better treatment must be found for this dreadful yet curable infection.

Present treatment for hepatitis C genotype 3

According to the recent AASLD guidelines [15], PEG-IFN α-2b (1.5 μg/kg/week) plus RBV (800–1400 mg/day) or PEG-IFN α-2a (180 μg/week) plus RBV (800 mg/day) for 24 weeks are the established SOC regimens for patients with chronic hepatitis C genotype 2 or 3. However, optimal administration of PEG-IFN/RBV, in particular, the duration and the dosage have still not been clearly established in relation to outcome in rapid and slow responders. Based on the concept of ‘response guided treatment,’a recent meta-analysis evaluated the issue of decreasing the duration of treatment to improve tolerance and cost effectiveness, and most importantly to decrease viral resistance to the standard bitherapy [16]. Treatment with PEG-IFN and weight-based RBV for 16 weeks in patients a with rapid virological response (RVR) resulted in an SVR of 76.3% and 86.4% with 24 weeks of treatment, unlike genotype 2 which was 83.8% and 89.3% respectively. This was because of increased relapse rates in patients with genotype 3. Manns et al. [17] showed that the relapse rate was 26% after 16 weeks of treatment and 18% after 24 weeks in genotype 3 patients. The increased relapse rates could be because of steatosis, and as already mentioned, the increased rate of fibrosis in thes patients. In a cohort of 932 treatment-naïve patients, investigators of the ACHIEVE-2/3 trial [18] showed that hepatic steatosis significantly increases the risk of relapse independent of HCV RNA levels in patients with genotype 3 who achieve an RVR with IFN-based regimens. This may be because of altered IFN-α signalling, increased intrahepatic RNA levels or increased quasispecies diversity. Other known risk factors for relapse are male gender, black race, age over > 40, increased viral load, presence of fibrosis, body weight > 85 kgs and presence of diabetes mellitus.

Predictors of response

IL28b polymorphism

There is recent evidence suggesting that polymorphisms near the IL28b gene, which codes for interferon (IFN)-λ3, predict response to PEG-IFN-α and RBV treatment in HCV genotype 1 infected patients. However, several studies have shown that this pathway is also applicable to genotype 3 patients and can help predict those who can achieve RVR. The single nucleotide polymorphism (SNP) rs12979860 (CC/CT/TT) is located 3 kb upstream of the IL28B gene on chromosome 19, which codes for IFN- λ3, and rs8099917 (TT/TG/GG) SNP is located 8 kb downstream of the IL28B gene and 6 kb upstream of the IL28A gene, which codes for IFN- λ2. Moghaddam et al. [19] found that factors that predicted RVR were IL 28B SNPs rs12979860 (CC allele), rs8099917 (TT allele), age < 40 years old and viral load (< 4 × 10^5 IU/ml). This was not associated with an SVR because of the increased rate of relapse with the CC allele along with higher pretreatment viral loads and ALT levels. Thus, the ‘host responder genotypes’, namely the rs12979860 CC allele and the rs8099917 TT allele were more likely to relapse after an early response. This is in contrast to the genotype 1 response in which host–responder genotypes are associated with a RVR and SVR as well as a decreased rate of relapse. Lindh et al. [20] studied the association between the IL28B gene variation at rs 12979860 and viral kinetics observed during treatment of chronic hepatitis C in a cohort of 345 treatment-naïve chronic hepatitis C patients (241 patients with genotype C). Viral response kinetics were assessed using viral RNA levels at days 0, 3, 7 and 29. The first phase of viral decline was a change in RNA levels from baseline to day 3. The decline rate for the second phase i.e. the slope, was calculated using HCV RNA values from days 3 and 7 in patients who were HCV RNA negative on day 29, and values from days 3, 7 and 29 for the remaining patients. This study found that the IL28b CC allele was strongly associated with a rapid early phase viral decline by a median of 5.68 log₁₀ IU/ml compared with 4.82 and 4.62 log₁₀ IU/ml in patients with CT or TT at rs12979860 respectively. Thus, the patients with a CC allele had a better chance of achieving an RVR (67%) than those with the CT (60%) or TT alleles (47%). In patients who received 24 weeks of antiviral treatment, the probability of achieving an SVR in those who did not achieve an RVR, was higher in those with the CC allele (74%) than with the CT (59%) or TT alleles (29%). Mangia et al. [21] reported that IL28B influenced treatment outcome in patients who did not achieve an RVR, with SVR rates of 29%, 67% and 87% in patients carrying the TT, CT or CC alleles at rs12979860 respectively. Another important conclusion of the study by Lindh et al. was that even though the IL28B CC allele was associated with a rapid early viral decline, it was not associated with an SVR when patients received a short course of 12 weeks of treatment. This was because of the high baseline viral load that is frequently observed in these patients. However, in a group with a baseline HCV RNA of 5.6 log₁₀ IU/ml, 33/38 patients (87%) treated for 12 weeks achieved an SVR if they carried the CC or CT SNP rs12979860 genotypes. As part of the lead-in phase of the HALT-C trial, Freedman et al. [22] showed fascinating evidence that the consumption of three or more cups of coffee per day was an independent predictor of response to standard bitherapy in chronic HCV patients. After adjustment for other predictors of response such as age, ethnicity, alcohol, cirrhosis, IL28b polymorphism rs12979860, the odds ratio for coffee drinkers vs non-drinkers was 2.0 for a response at week 12, 2.1 for a response at week 20, 2.4 for a response at the end of treatment and 1.8 for SVR.

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Other predictors of response

In a recent retrospective study by Amanzada et al. [23], a subgroup of patients with genotype 3, who were under the age of 40, who had an ‘ultrarapid’ virological response within 2 weeks (HCV RNA undetectable at week 2 of treatment), low ƴ-GT/ALT ratios and an absence of steatosis on liver biopsy, were found to achieve an SVR with IFN-α2A monotherapy 3–6 Million Units (MU) either daily or three times a week. Neither IL28b SNPs rs12979860 or rs8099917 genotypes, nor the duration therapy (24 weeks vs. 48 weeks) were related to treatment outcome. Moreover, this treatment was better tolerated because of the absence of the adverse effects of RBV. However, further randomized controlled trials are needed to validate these findings. A summary of the other predictors of response to standard treatment in chronic hepatitis C genotype 3 are given below (Table 1).

Future treatment options for patients with genotype 3

HCV is a 9.6-kb positive-sense, single-stranded RNA virus. It encodes a large single open reading frame corresponding to a poly-protein precursor of about 3000 amino acids, which is proteolytically processed by cellular signal peptidases and HCV-encoded proteases into at least 10 individual proteins, in the order of C-E1-E2-p7-NS2-NS3-NS4A-NS4B-NS5A-NS5B. Newer antivirals, more commonly known as directly acting antivirals (DAA), have mainly focused on two viral proteins, the NS3-4A serine protease and the NS5B RNA-dependent RNA polymerase, both of which have enzymatic activities essential for viral replication [24]. The peptidomimetic inhibitors of the NS3/4A serine proteases, telaprevir (VX-950) and boceprevir (SCH-503034) have created a revolution in the treatment of genotype 1 and have recently been recommended in combination with the standard bitherapy PEG-IFN/RBV for the treatment of patients with chronic hepatitis C genotype 1 [4]. However, these drugs have not shown to be of great benefit in the treatment of patients with genotype 3.

An alternative strategy is to target host factors that are also required for viral replication. Cyclophilins are a family of cellular peptidyl-prolyl isomerases required for HCV replication [25]. In an in vitro study by Mathy et al., combinations of a host factor (cyclophilin) inhibitor, NIM811, were studied with the three main classes of virus specific inhibitors: BILN2061 (ciluprevir), first NS3-4A protease inhibitor, a non-nucleoside NS5B polymerase inhibitor thiophene-2-carboxylic acid, and NM107, the active moiety of NM283 (valopicitabine), the first nucleoside NS5B inhibitor. Based on mathematical modelling, the effect of these combinations was shown to be synergistic for NIM811 with a nucleoside or a non-nucleoside viral polymerase inhibitor and additive for NIM811 with a viral protease inhibitor. The key advantages of targeting host factors are long lasting antiviral response and a greater genetic barrier to the emergence of viral escape mutants. The use of the oral cyclophilin B inhibitor Debio-025 was first investigated in a randomized double blind, placebo controlled trial of 19 patients co-infected with HIV and HCV [26]. Of the 19 co-infected patients, those treated with Debio-025 1200 mg twice daily for 15 days (n = 16) experienced a significantly greater maximum reduction of log₁₀ HCV RNA copies/ml (only in genotypes 1, 3 and 4) than placebo treated (n = 3) patients. The least squares mean of the maximum reduction of log₁₀ HCV RNA copies/ml for the Debio-025 group was −3.63 compared with −0.73 in the placebo group. The greatest response was observed in patients with genotype 3 who achieved a least squares mean maximum reduction of log₁₀ HCV RNA copies/ml of −4.46 log₁₀. None of the patients developed a viral breakthrough in the treatment arm, and time to relapse varied after the end of treatment. This was the first study to show the antiviral effects of oral cyclophilin inhibitors in a clinical study; however, larger studies are needed before this regimen can be clinically recommended. Another group of host factors was studied by Lupberger et al. [27]. The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase (RTK) that regulates a number of key processes, including cell proliferation, survival and differentiation during development, tissue homeostasis and tumorigenesis.

Ephrin receptor A2 (EphA2) mediates cell positioning, cell morphology, polarity and motility. HCV entry is a multistep process involving viral envelope glycoproteins and host cell factors. Attachment of the virus to the target cell is mediated through binding of HCV envelope glycoproteins to glycosaminoglycans. HCV is internalized in a clathrin-dependent endocytic process requiring CD81, scavenger receptor type B class I (SR-BI), claudin-1 (CLDN1) and occludin (OCLN). Inhibition of EGFR or EphA2 activity reduced CD81-CLDN1 association, hence hampering the cell entry process of HCV. The in vitro results showed that EGFR or EphA2 inhibition was associated with decreased cell entry, fusion, cell-to-cell transmission and subsequently decreased viral spread. This was extrapolated in in vivo studies conducted using an erlotinib (EGFR inhibitor) chimeric urokinase plasminogen activator–severe combined immunodeficiency (uPA-SCID) mouse model. Its treatment decreased steady-state HCV RNA levels by more than 90%. However, viral load increased, once the treatment was discontinued. Treatment was well-tolerated and did not induce any marked changes in safety parameters such as serum concentrations of alanine transaminase, albumin or body weight. These fascinating results provide a glimmer of hope, although there is a long way to go before they can be recommended in patients with chronic hepatitis C. There are many drugs in the pipeline, some of which are being studied in phase III trials (Table 2).

Conflicts of interest

The authors declare no conflicts of interest.

References

Source

What's new in HCV genotype 2 treatment

Liver International

Special Issue: Proceedings of the 5th Paris Hepatitis Conference. International Conference of the Management of Patients with Viral Hepatitis: Special Edition Hepatitis C

Volume 32, Issue Supplement s1, pages 135–140, February 2012

Review Article

Alessandra Mangia, Leonardo Mottola

Article first published online: 29 DEC 2011

DOI: 10.1111/j.1478-3231.2011.02710.x

© 2012 John Wiley & Sons A/S

Abstract

Genotype 2 (HCV-2) accounts for 8% of the patients with chronic hepatitis C virus in Europe. Because of the favourable response to interferon (IFN)-based treatment, this group is considered an ‘easy-to-treat’ genotype along with HCV-3. However, experimental and clinical data suggest possible differences between HCV-2 and -3. Recently, subtle differences in treatment efficacy have also been shown in response-guided treatment studies. In these studies, the duration of pegylated interferon (PEG-IFN) and ribavirin (RBV) treatment was tailored according to treatment response. Although SVR rates were similar between HCV-2 and HCV-3 patients after a rapid virological response (RVR), in the absence of RVR, the rates were lower in HCV-3 than in HCV-2. The triple combination treatment, including direct-acting antivirals (DAA) that will be commercialized in the coming months might increase SVR rates in this particular subgroup of patients. According to existing results, telaprevir might be beneficial in HCV-2 but not in HCV-3 patients. A nucleotide analogue polymerase inhibitor, PSI-7977 by Pharmasett has been shown to be active against both. The role of the IL28B polymorphism as a predictor of response to the current standard of care (SoC), PEG-IFN and RBV treatment is the subject of debate, but this mainly seems to be because of the small size of the samples in the studies performed so far. Existing results suggest that the genetic evaluation of IL28B may be useful in patients with HCV-2 for predicting response in patients without RVR.

Epidemiological background

In the European countries, the most frequent HCV genotype is genotype 1 followed by genotypes 3, then 2 (Table 1). Despite these epidemiological differences, HCV-2 and -3 are usually analysed together on the basis of similar favourable responses to IFN treatment. Studies exploring a reduction in treatment duration have recently highlighted potential differences between these two genotypes. A mean prevalence of 8.2% has been reported in Europe for genotype 2, ranging from a prevalence of 0.9% in Turkey to 27% in Italy [1]. In 1997, genotype 2 was observed in 38% of the HCV chronic infected patients referred to our centre [2]. Although the corresponding prevalence of genotype 3 in that study was less than 5%, a wave of genotype 3 infection is currently also increasing the proportion of HCV-3 infected patients in Italy [3]. The HCV-2 is observed in 3% and 9% of HCV patients, in Spain and in France respectively. Outside of Europe, a high frequency of HCV-2 has been reported in some Southern African and Asian areas where it accounts for 30% of chronic HCV infection overall [4].

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HCV genotype 2 treatment: PEG-IFN and ribavirin combination

The combination of PEG-IFN and RBV has been shown to be very successful in patients with genotype 2. The AASLD guidelines [5] advise treating HCV-2 and -3 patients for 24 weeks with combination treatment, including PEG-IFN alpha-2a or alpha-2b and a fixed dose of 800 mg of RBV [6]. With this treatment, more than 80% achieve SVR. However, because experimental and clinical data suggest possible differences between HCV-2 and -3 [7, 8, 9], it may be worthwhile to focus on response rates by genotype for the future scenario of the treatment of hepatitis C.

One trial by Zeuzem and the large ‘real-world’ WIN-R study reported a 9% difference between HCV-2 and -3 genotypes in SVR rates in favour of HCV-2 after 24 weeks of treatment [10, 11]. Recently, REDD 2/3 another ‘real-world’ study analysed HCV-2 and -3 separately in an evaluation of both a lower dose of PEG-IFN alpha-2b and a reduced duration of treatment [12]. This study reported somewhat higher rates of relapse in patients with HCV-3 than in those with HCV-2 after 24 weeks of PEG-IFN alpha-2b and weight-based RBV [12].

To reduce the costs and spare the side effects of combination treatment, several studies have investigated the effectiveness of treatment for less than 24 weeks after an RVR. Several studies in Europe and one study from Taiwan [13] have shown that a course of treatment with PEG-IFN and weight-based RBV for 12–16 weeks was not less effective or was cost-effective compared to the standard of 24 weeks [13, 14, 15, 16, 17]. However, one larger multicenter study, using a fixed dosage of RBV did not demonstrate that the two treatments were not less effective [18]. Based on the analysis of results in the literature, the updated European guidelines conclude that HCV-2 and -3 can be treated for 12–16 weeks when HCV RNA is undetectable after 4 weeks of treatment, as long as there is no advanced liver disease or obesity and RBV is weight-based [19]. The guidelines suggest that a short course of treatment may be slightly less effective in patients with HCV-3.

In a meta-analysis evaluating customized treatment of patients with HCV-2 and -3 in four studies, including 957 patients for whom separate data are available for both genotypes, we showed that SVR rates in HCV-3 patients with RVR were similar to those of HCV-2 patients [20]. The difference between the two genotypes is the probability of SVR in patients without RVR. In the absence of RVR [20], EASL guidelines advise 24 or 48 weeks of treatment depending on whether the patient is HCV RNA-negative or if there is a greater than 2 log₁₀ decline in HCV RNA at week 12 respectively. However, the recommended schedule for HCV-2 and HCV-3 patients is the same [19].

Rapid virological response, SVR and relapse rates for HCV-2 patients in studies on short treatment duration with separate analysis of HCV-2 and -3 are shown in Table 2. Patients with HCV-2 infection had extremely high RVR rates ranging from 68 to 87%. No significant differences were observed in the SVR rate after 12 or 24 weeks of treatment once RVR was achieved (Table 2). After 24 weeks of treatment, the risk of relapse in patients with HCV-2 is low and the increased risk as a result of a short treatment course appears to be clinically irrelevant. Indeed, only the Accelerate study reported relapse rates increase of more than 12% in the short treatment arm when compared with the standard duration. The analysis by Diago [21] took into account only the subgroup of patients with RVR. This result may be explained by a high proportion of patients with advanced liver disease were enrolled in the short treatment arm; 28% of patients who received 16 weeks of PEG-IFN plus fixed 800 mg doses of RBV had bridging fibrosis or cirrhosis [18].

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These results are supported by those of a recent meta-analysis evaluating six trials of standard or shortened treatment. Sensitivity analysis by genotype showed that an SVR was achieved by 84% of HCV-2 rapid responders with no significant differences between standard or shortened duration when weight-based dosages of RBV were used for 16 weeks. The corresponding rate in patients with HCV-3 was 81%, but the difference between short and standard duration was greater perhaps because of the use of fixed doses of RBV [22].

Table 3 reports the SVR rates in patients without RVR by genotype, in studies with data on 24 weeks of treatment. Unlike in HCV-3 patients, the SVR in HCV-2 patients who do not achieve RVR is above 60%. Increasing the SVR rate in patients without RVR is still an unresolved issue.

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Future therapies

Recently approved DAA inhibitors of HCV replication are expected to provide a major step forward in the treatment of HCV infection. Several small molecules, mainly inhibitors of HCV NS3/4A protease and NS5B polymerase are in the process of being commercialized in Europe.

Although DAA will improve virological response rates in patients with genotype 1, the development of small molecules effective against HCV genotypes other than one is in earlier stages [23]. Telaprevir, the first agent to directly target viral replication, has been shown to be active against HCV-2, but not against HCV-3. Telaprevir is a powerful oral protease inhibitor [24, 25] that can increase the SVR in genotype 1 HCV by about 30% compared to standard PEG-IFN/RBV. The activity of telaprevir was investigated in patients with HCV-2 and HCV-3 in the C209 study. The combination of telaprevir plus PEG-FN alpha-2a and RBV was evaluated in five patients with HCV-2 and compared to telaprevir alone in nine patients and to PEG-IFN and RBV in an additional nine patients in the control group. The triple combination therapy resulted in SVR rates of 100% which is remarkable considering the 89% rate observed in patients receiving standard PEG-IFN/RBV [26]. Conversely, telaprevir monotherapy had little or no activity in patients infected with HCV-3. In that study, telaprevir was administered as monotherapy or in combination with PEG-IFN for only 2 weeks, while the overall duration of treatment was 24 weeks in each arm. It should be noted that the histological diagnosis of cirrhosis was an exclusion criteria in this study.

Other NS3/4A protease inhibitors, nucleoside and non-nucleoside reverse replicase inhibitors as well as NS5A inhibitors have shown to have antiviral activity against HCV-2. One of the most promising drugs so far is PSI-7977, a nucleotide analogue polymerase inhibitor [27]. In the Proton study, an open label study, the drug was evaluated in 15 patients infected with HCV-2 and in 10 infected with HCV-3 as well as in a larger group of patients with HCV-1 infection [28]. That study, whose results were presented at the last EASL meeting, reported an RVR of 96% after the triple combination of 400 mg of PSI-7977 plus PEG-IFN/RBV. Twenty-four HCV-2 and -3 patients who completed the 12 weeks of treatment achieved SVR (96%). Patients with cirrhosis were excluded. The Electron study, an ongoing study, is currently evaluating this triple combination in an IFN sparing regimen strategy of only 8 weeks of triple combination treatment.

The role of IL28B to modify treatment strategies

The recent identification of a single nucleotide polymorphism (SNP) upstream from the IL28B gene associated with a response to IFN-based treatment is a landmark observation [29, 30, 31]. Genotype 1 patients with IL28B CC genotype had higher response rates compared to those with the rs12979860 TT alleles. Previous data proposed that interferon stimulated genes (ISGs) are up-regulated in non-responders prior to treatment [32, 33]. Genetic variation of the IL28B gene may explain the pre-activation of interferon stimulated genes (ISGs) in non-responder patients to IFN-based treatment, because the subjects with the unfavourable IL28B TT genotype have higher levels of activation of ISGs in the liver [34].

Distribution of CC genotypes in patients with HCV genotype 2

Numerous studies have investigated IL28B in patients with HCV-2 and -3 analysing both genotypes together. Separate analyses of the frequency of IL28B in patients with HCV-2 and -3 infections have only been performed in two studies, one by Sarrazin, and other by ours [35, 36] (Table 4). In both cases, the rs12979860 SNP was investigated [35].

Sarrazin et al. evaluated 378 patients with HCV-1, 77 with HCV-2 and 190 with HCV-3 [35]. They showed that the frequency of the CC genotype in patients with genotype 1 was 33.9%, whereas in patients with HCV-2 and HCV-3, it was 42.7%. When HCV-2 and -3 were analysed separately, the CC genotype was observed in 51.9% of those with HCV-2 compared to 38.9% of patients with HCV-3. When these frequencies were compared to those in the general population (49%), the difference between patients with HCV genotype 1 and healthy controls was high and statistically significant (P < 0.001). The difference in frequency between HCV-2 and the normal population was not statistically significant (P = 0.116). The frequency of the CC genotype in HCV-1 was significantly lower than that in HCV-2 patients (P = 0.045). No difference was observed in the frequency of CC between HCV-1 and -3 patients (P = 0.43).

Our group performed a study on the IL28B polymorphism in a cohort of 268 patients with HCV-2 (n = 215) (Table 4) and HCV-3 (n = 55) who were previously randomized in a multicenter-controlled trial to a treatment of variable or standard duration [36]. The favourable IL28B CC genotype was present in 37% of patients. When this group was compared to a cohort of HCV-1 patients in the same geographical area, the frequency of the CC genotype was slightly higher (37% vs 29% respectively). In the general population, the IL28B CC genotype was detected in 42% of cases. As in the study by Sarrazin, we observed a lower frequency of the CC genotype in patients with HCV-1 compared to the general population, but the difference was not significant. Differences between HCV-2 and control patients were not identified.

It is unclear if these variations in distribution are an effect of the functional mechanisms that lead to the development of chronic HCV infection, as previously suggested [37]. A prospective study in a large cohort of patients, including different HCV genotypes and subtypes in the presence of a specific IL28 genotype is required to clarify this issue.

SVR response in patients with HCV genotype 2 by IL28B

Several independent genome-wide association studies (GWAS) reported SNPs near the IL28B (IFN-λ3) locus that displayed association with treatment response, mainly in genotype 1 infected patients. Furthermore, in a mono-centric cohort of genotype 4 infected patients from three different ethnic groups (Egyptian, European and Sub-Saharan African), IL28Brs12979860 CC genotype was associated with a higher sustained virological response [38].

In contrast, available data on the predictive role of the IL28B polymorphism on SVR are conflicting for patients with HCV-2 and -3 infections. Some studies have failed to demonstrate any clear association between the IL28B polymorphism and SVR in patients with HCV-2 or -3 infection [39, 40]. Others have reported a positive association between the favourable rs12979860 CC or rs8099917 TT genotype, respectively, with RVR, but not SVR [41], suggesting an increased rate of relapse in this subset of patients. Finally, two European studies, including ours, examining HCV-2 and HCV-3 together, have shown that CC is associated with SVR [35, 36].

In our study, the association was largely driven by the subgroup of patients who did not achieve RVR [36]. Indeed, we observed that the IL28B CC genotype selects those who will respond to treatment among non-RVR patients. In contrast, the SVR rates in patients without RVR and with the TT genotype were negligible.

The CC genotype was not associated with RVR in the standard treatment arm or in patients who achieved RVR and were therefore treated for only 12 months. This lack of association may be a consequence of the rate of RVR observed in the different series of HCV-2 patients studied so far; larger numbers of patients would probably equalize the different results. In our cohort, CC genotype was an independent baseline predictor of SVR.

Our results suggest that IL28B may play a role in some patients, particularly those who do not achieve RVR, as defined by undetectable HCV RNA in serum after 4 weeks of treatment with an assay of sensitivity ≤ 50 IU/ml.

No association was found between RVR and IL28B genotype in the study by Sarrazin et al. evaluating 58 patients with HCV-2 and 147 with HCV-3 infection treated with PEG or standard IFN [35]. However the authors found an overall association with SVR, and with SVR in RVR patients, in particular. The main limitation of this study was the heterogeneity of previous treatment regimens, including IFN monotherapy. This may explain why the association with SVR was not statistically significant.

One difference between American patients and the HCV-2 patients evaluated in Sarrazin's and our study was that an intermediate degree of IFN sensitivity was observed in patients with the CT genotype.

Conclusions

Patients infected with genotype 2 HCV are an ‘easy-to-treat’ population. As a result of the very high successful response rate and the possibility of shortening the duration of treatment in nearly all patients who achieve an RVR in the absence of cirrhosis, treatment of HCV-2 with a standard combination of PEG-IFN/RBV may be continued.

The DAA potentially active against HCV-2 should be explored to increase the SVR response rates in the subgroup of patients without RVR whose SVR rates remain unsatisfactory, with the combination of PEG-IFN/RBV. In patients without RVR, IL28B might be a useful predictor of SVR after PEG-IFN/RBV combination treatment.

Conflicts of interest

The authors have no conflicts of interest to declare.

References

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China approves hepatitis E vaccine

Updated: 2012-01-11 20:31

BEIJING - China has approved a hepatitis E vaccine, claimed to be the world's first, said the Ministry of Science and Technology Wednesday.

The vaccine received the certificate for medicine production in December 2011, according to the State Food and Drug Administration.

A team of researchers from Xiamen University and Xiamen Innovax Biotech Co. Ltd. in southeast China's Fujian province had worked for 14 years to develop the vaccine, and the 863 program, the government-funded high-tech development initiative, began to sponsor the research in 2005, said the ministry statement.

The country will apply the vaccine to high-risk members of the population and work with international organizations to introduce it to other countries, the statement said.

The hepatitis E virus is shed in feces and spread via tainted water and food. According to the World Health Organization, one third of the global population is estimated to be infected by the virus and countries in South and East Asia report about 6.5 million infection cases every year.

In China, incidences of hepatitis E have increased notably and become the most common among all types of hepatitis infecting adults.

According to a research paper from the vaccine's development team published in The Lancet in August 2010, researchers conducted a trial involving 97,356 healthy participants in China. Half of them were given the vaccine and the other half a placebo.

The vaccine was given in three doses -- the second was given a month after the first and the third five months later.

Within a year of the third dose, 15 of the participants who were given placebos had contracted hepatitis E while no one in the vaccine group was infected, according to the report.

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