Tuesday, March 28, 2017

New report lays plan to eliminate 90,000 hepatitis B and C deaths by 2030

New report lays plan to eliminate 90,000 hepatitis B and C deaths by 2030

US could be rid of hepatitis B and C as public health problems, preventing nearly 90,000 deaths by 2030, with better attention to prevention, screening, treatment, and creative financing for medicines

National Academies of Sciences, Engineering, and Medicine

WASHINGTON - Hepatitis B and C kill more than 20,000 people every year in the United States. A new report from the National Academies of Sciences, Engineering, and Medicine presents a strategy to eliminate these diseases as serious public health problems and prevent nearly 90,000 deaths by 2030.

"Viral hepatitis is simply not a sufficient priority in the United States," said Brian Strom, chair of the committee that carried out the study and chancellor and university professor, Rutgers Biomedical and Sciences, Rutgers University, Newark, N.J. "Despite being the seventh leading cause of death in the world - and killing more people every year than HIV, road traffic accidents, or diabetes - viral hepatitis accounts for less than 1 percent of the National Institutes of Health research budget."

About 1.3 million people in the United States have chronic hepatitis B, and about 2.7 million have chronic hepatitis C. These infections also increase risk of liver cancer. Together, hepatitis B and C cause about 80 percent of the cases worldwide of liver cancer, which has been steadily increasing in both new cases and deaths in the United States since the early 2000s. The incidence of liver cancer in the United States increased 38 percent between 2003 and 2012, and liver cancer deaths increased 56 percent in the same time, primarily due to viral hepatitis.

The world has the tools to prevent these deaths. Hepatitis B is preventable with vaccination, and recent advances in treatment make hepatitis C curable with short and easily tolerable courses of medicines. The committee said the number of deaths from hepatitis B could be cut in half by 2030 by diagnosing 90 percent of the nation's chronic hepatitis B patients, bringing 90 percent of those to care, and treating 80 percent of those for whom treatment is warranted. These actions would avert more than 60,000 deaths and also reduce liver cancer and cirrhosis from hepatitis B infection by about 45 percent. Similarly, treating everyone with chronic hepatitis C would reduce new infections by 90 percent by 2030 and reduce hepatitis C deaths by 65 percent over the same time. These actions would avert 28,800 deaths by 2030 and depend on diagnosing 110,000 new cases a year between now and 2020, gradually dropping off to 70,000 a year by 2025.

The committee said eliminating hepatitis B and C as public health problems in the U.S. by 2030 will require a significant departure from the status quo - including aggressive testing, diagnosis, treatment, and prevention methods, such as needle exchange. It called for a coordinated federal effort to manage hepatitis elimination, and it recommended expanding syringe exchange for people who inject drugs, free hepatitis B vaccine in pharmacies and other easily accessible places, and unrestricted treatment for everyone with hepatitis C. Because the medicines that cure chronic hepatitis C are expensive, the committee gave considerable attention to novel ways to pay for them and recommended a voluntary licensing agreement between the federal government and a patent-holding pharmaceutical company as a way to make the drug more affordable for Medicaid beneficiaries and other underserved patient populations.

Prevention is the first step to eliminating the public health problems of hepatitis B and C, the committee said. About 90 percent of U.S. children were fully immunized against hepatitis B in 2013, but only about a quarter of adults over 19 were immunized. If states supported hepatitis B vaccination to the same level as the seasonal influenza vaccine, great improvements could be made. Offering vaccination in pharmacies is one way to reach a wider cross-section of society, but some states restrict the types of vaccines offered in pharmacies and the circumstances under which pharmacists may administer them. The committee recommended that states expand access to adult hepatitis B vaccination, removing barriers for free immunization in pharmacies and other easily accessible settings.

Hepatitis B virus can easily pass from mother to baby, and the committee was concerned with preventing such cases. Children born to women with chronic hepatitis B require immunization within 12 hours of birth, and other children should receive it within a day of birth. The committee recommended that the National Council on Quality Assurance monitor the delivery of the first dose of hepatitis B vaccine, thereby drawing attention to this essential service. There are also cases where preventive measures are not enough to stop the virus from passing from a mother to her child. Expectant mothers with hepatitis B should have testing early in pregnancy to measure viral DNA, the committee said. This would identify highly viremic women, allowing them and their doctors to weigh the pros and cons of additional medical intervention to prevent neonatal hepatitis B infection.

Until there is a vaccine for hepatitis C, prevention will be mostly a matter of limiting exposure to the virus. People who inject drugs account for 75 percent of the roughly 30,500 new hepatitis C infections every year in the United States, so ending transmission depends on reaching this population. The best strategies to prevent hepatitis C combine both safer injection and treatment for the underlying addiction. Opioid agonist therapy uses prescription medicines - one example is methadone - to relieve the symptoms of drug withdrawal. Such treatment can prevent drug overdose and transmission of blood-borne infections, but 30 million Americans live in places where no providers prescribe these medicines. Syringe exchange programs are also essential, but they currently do not have sufficient reach, even in cities. Rural and suburban areas are home to about half of the people who inject drugs in United States, but these areas have only 30 percent of the nation's syringe exchange programs and distribute 8 percent of the total syringes. Syringe exchange programs do not encourage new drug users or increase drug use among clients, but laws in some states impede their functioning. The committee recommended expanded access to syringe exchange and opioid agonist therapy in accessible venues. Pharmacies, for example, may be a promising setting for syringe exchange, as they are easy to reach in most of the country and reasonably well equipped to provide a confidential space for counseling. Exchanges operating from a van or bus could also reach people in remote areas and may face less community opposition than a fixed-site exchange.

The direct-acting antiviral drugs that cure hepatitis C make elimination feasible in the United States, but their cost is an obstacle to large-scale treatment, creating inequities. While these drugs are very expensive, they are also cost-effective, when compared to other health care interventions. A recent study found that almost half of Medicaid patients were refused hepatitis C treatment, compared to only 5 percent of Medicare patients and about 10 percent of patients with commercial insurance. Furthermore, less than 1 percent of prisoners with hepatitis C have been treated. Faced with the unenviable task of allocating scarce treatment, some payers give first priority to the sickest patients - those at immediate risk of cirrhosis or end-stage liver disease. But delaying treatment increases a patient's risk of cirrhosis, liver cancer, and death. It also hurts society, as the untreated patient can still transmit the virus. Treating everyone with chronic hepatitis C, regardless of disease stage, would avert considerable suffering in hepatitis C patients and would pay off in a reduction in new infections.

Unrestricted, mass treatment of hepatitis C is necessary to eliminate the disease as a public health problem by 2030, but no direct-acting agent will come off patent before 2029. Delaying mass treatment until generic medicines are available would result in tens of thousands of deaths and billions of dollars in wasted medical costs. At the same time, innovator drug companies have the right to compensation for the risk they took to bring a valuable product to market, and society benefits from the financial incentive for pharmaceutical breakthroughs that patent protection offers. In an effort to balance these competing needs, the committee recommended that the government purchase a license or assignment to the patent on a direct-acting antiviral drug, and use it only in those market segments where the government pays for treatment and access is now limited, such as Medicaid and prisons. The committee proposed a voluntary transaction where six innovator pharmaceutical companies bid to sell a license to the government for use in a narrow market that the companies would not otherwise reach. This limitation will also control costs, because the government should not have to pay as much as if it were compromising the lucrative private market. The voluntary nature of this process guarantees the drug company reasonable compensation, and the patent holder has the option to walk away if the price is too low.

The committee's calculations suggested a patent license should cost about $2 billion, after which states and the federal government would pay about $140 million to produce the medicines needed to treat about 700,000 neglected patients. For comparison, under the status quo, it would cost about $10 billion over the next 12 years to treat only 240,000 of the same people.

Another challenge of eliminating hepatitis B and C in the U.S. is that people who have or are at risk for contracting the diseases often are not engaged in care and can be difficult to reach, including people who are born abroad, are uninsured, have substance use problems, and are or have been imprisoned. The committee recommended that the U.S. Department of Health and Human Services work with states to build a comprehensive system of care and support for such patients on the scale of the Ryan White system, which brought HIV services to millions of poor HIV patients.

Working through primary care providers can also improve the reach of hepatitis services. There is precedent for managing hepatitis C in primary care, but treating viral hepatitis carries risks that providers in small practices may be reluctant to accept, causing a disparity where viral hepatitis care is out of reach for people in rural and underserved communities. The committee recommended that the American Association for the Study of Liver Diseases and the Infectious Diseases Society of America partner with primary care providers and their professional organizations to build capacity to treat hepatitis B and C in primary care.

People in jails and prisons bear a particularly high burden of viral hepatitis. The committee found an opportunity in this problem because correctional facilities are an ideal place to test and vaccinate for hepatitis B and to cure hepatitis C. Directly observed therapy is the norm and the risk of drug diversion is low. The committee recommended that the criminal justice system screen, vaccinate, and treat hepatitis B and C in correctional facilities according to national clinical practice guidelines.

The study was sponsored by the Centers for Disease Control and Prevention Division of Viral Hepatitis and Division of Cancer Prevention and Control; U.S. Department of Health and Human Services Office of Minority Health; American Association for the Study of Liver Diseases; Infectious Diseases Society of America; and National Viral Hepatitis Roundtable. The National Academies of Sciences, Engineering, and Medicine are private, nonprofit institutions that provide independent, objective analysis and advice to the nation to solve complex problems and inform public policy decisions related to science, technology, and medicine. The National Academies operate under an 1863 congressional charter to the National Academy of Sciences, signed by President Lincoln. For more information, visit http://national-academies.org. A roster follows.

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Clinical efficacy and tolerability of direct-acting antivirals in elderly patients with chronic hepatitis C

Clinical efficacy and tolerability of direct-acting antivirals in elderly patients with chronic hepatitis C
Sherigar, Jagannath M.; Gayam, Vijay; Khan, Arifa; Mukhtar, Osama; Arefiev, Yavgeniy; Khalid, Mazin; Siddiqui, Imran; Rangaraju, Ayyappa M.; Budhathoki, Nibash; Mansour, Mohammed; Guss, Debra; Mohanty, Smruti R.

European Journal of Gastroenterology & Hepatology: Post Author Corrections:
March 24, 2017 doi: 10.1097/MEG.0000000000000871

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Abstract
Background: There is a lack of evidence-based data on aged patients with newer direct-acting antivirals (DAAs) and with shorter duration of treatment regimens involving DAAs with or without ribavirin (RBV) and pegylated interferon (Peg IFN).

Patients and methods: Medical records of 240 patients treated with DAAs with or without Peg IFN and RBV between January 2013 and July 2015 were retrospectively analyzed. Patients were divided into two groups: patients aged 65 years and older (N=84) and patients aged younger than 65 years (N=156). Pretreatment baseline patient characteristics, treatment efficacy, factors affecting sustained virologic response at 12 weeks after treatment, and adverse reactions were compared between the groups.

Results: No statistically significant difference was observed with end of treatment response (98.8 vs. 98%, P=0.667) and sustained virologic response at 12 weeks after treatment (93.1 vs. 94.1%, P=0.767) between patients aged 65 and older and those younger than 65 years of age. Fatigue was the most common adverse event recorded (32.5%), followed by anemia (19.6%), leukopenia (11.7%), thrombocytopenia (10%), skin rash (8.3%), and headache (7.9%). The RBV dose was reduced in eight (8%) patients and four patients discontinued the RBV treatment because of severe anemia. RBV dose reduction or discontinuation did not reach statistical significance (P=0.913). Increased fibrosis, cirrhosis, aspartate aminotransferase, alanine aminotransferase, hemoglobin, and platelet levels seem to affect the sustained virologic response in the elderly. Twelve (6.28%) patients failed to respond to treatment and the failure rate was not significant (P=0.767) between the groups.

Conclusion: DAAs with or without IFN and RBV in the standard recommended 12 or 24-week treatment regimens are effective, well tolerated, and may be safely extended to elderly patients infected with chronic hepatitis C.

Introduction
Globally, chronic hepatitis C virus (HCV) infection has been estimated to affect 2–3% (about 170 million) of the world’s population [1]. A National Health and Nutrition Examination Survey 2003–2010 analysis estimated that ∼2.7 (1.0%) million USA residents have infection with chronic HCV [2]. Chronic HCV is the leading cause of cirrhosis, hepatocellular carcinoma (HCC), and its related complications, and thus elimination of HCV significantly reduces the risk of HCC, liver failure, and death [3].

An increased prevalence of chronic HCV infection is observed with advancing age. These patients are likely to have an advanced liver disease including cirrhosis of the liver and related complications [4,5]. In countries such as Japan, Taiwan, and some European countries, the prevalence of chronic hepatitis C infection is the highest in the aged population [6]. According to the USA Census Bureau, by 2030, more than 20% of USA residents are projected to be aged 65 years and older. The baby boomers (born between 1945 and 1965) began turning 65 in 2011 and currently account for three-fourth of all chronic HCV infections among adults in the USA [7].

Older individuals infected with chronic HCV are historically considered a difficult to treat category with less success and more treatment failures than the younger population. The pegylated interferon (peg IFN) and ribavirin (RBV) combination therapy was associated with a high discontinuation rate in the elderly because of the longer duration of treatment and associated adverse events [8]. With the recent introduction of IFN-free direct-acting antivirals (DAAs), the treatment success for chronic HCV infection has improved markedly, with the overall cure rate reaching above 90%. Even though some of the newer drug trials included aged populations, the numbers of elderly patients enrolled were limited. Although we have achieved considerable advancements in treatment with newer agents, the coadministration of RBV in combination with newer agents still exists in certain patient groups to achieve an acceptable response rate. A shorter duration of treatment with these regimens and better tolerability are expected in both younger and older populations. We, therefore, examined the effectiveness and tolerability of newer DAAs in older patients aged older than 65 years compared with younger patients. We also evaluated the factors associated with sustained virologic response (SVR) and the tolerability of DAAs in combination with Peg IFN, RBV, or both with a shorter duration of treatment in an aged population compared with younger patients aged younger than 65 years.

Patients and methods
This retrospective cohort study protocol was approved by the institutional review board of each hospital (New York Presbyterian Brooklyn Methodist Hospital New York and Interfaith Medical Center, New York).

Patients
A total of 279 consecutive patients with chronic HCV treated with either a combination of DAAs or at least one of the newer agents in combination with IFN and RBV between January 2013 and July 2015 at two institutions were retrospectively analyzed. Thirty-nine patients were excluded from the study for various reasons including insufficient documentation of viral load during the treatment and failure to attend follow-up after the end of treatment (Fig. 1). All the 240 patients included in this retrospective cohort study received at least eight weeks of treatment with one of the recommended combination regimens in standard doses for chronic HCV infection. Patients were divided into two groups: patients aged younger than 65 years (N=156) and those aged 65 years and older (N=84). The choice of treatment regimens used was made on the basis of the American Association of Study of Liver Disease guidelines during that period. During early 2013, treatment recommendation was triple therapy with a protease inhibitor, Peg IFN, and RBV. In the years 2014 and 2015, the rest of the regimens were used as they were approved one after the other by the Food and Drug Administration.

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The combination treatment regimens used were Peg IFN α-2a+RBV+sofosbuvir `(SOF), SOF+RBV, ledipasvir (LDV)+SOF (Harvoni; Gilead Sciences, Foster City, California, USA), LDV+SOF+ RBV (Harvoni+RBV), ombitasvir+paritaprevir+ritonavir+dasabuvir(ViekiraPak;AbbVie Inc, Illinois, NorthChicago, USA), ombitasvir+paritaprevir+ritonavir+dasabuvir+RBV (Viekira Pak+RBV), and simeprevir (SPV)+sofosbuvir. Only three patients were treated with Peg IFN+RBV+telaprevir andone patienteachreceivedthe PegIFN+RBV+boceprevir, Peg IFN+RBV+Harvoni, and SPV+SOF+RBV combination(Fig.2).

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Fig.2


The duration of the treatment periodranged from a minimum of 8weeks(N=3, all with Harvoni) to a standard 12 weeks (N=201) or 24 weeks (N=36) depending on their status of previous treatment and cirrhosis. All patients who received the IFN-based regimen received PegIFN at a standard dose of 180mg subcutaneously once a week. A weight-based RBV dose was used at 1200mg daily in two divided doses for those weighing 75kg and 1000mg for those weighing less than 75kg.

Study assessments
Pretreatment baseline characteristics (Table 1), laboratory studies, baseline HCV viral load, treatment efficacy with the end of treatment response (ETR), and sustained virologic response at 12 weeks after the completion of treatment (SVR12) were compared between the groups. We determined the factors associated with SVR on baseline characteristics by univariate analysis. A separate analysis was carried out in patients aged older than or equal to 65 years to determine the factors associated with SVR in the elderly group. The safety and tolerability of antiviral drug regimens were assessed by reviewing the documented common or serious adverse events, treatment completion rate, and reduction in the medication dosage or discontinuation of medications.

Assessment of liver fibrosis was performed with invasive liver biopsy in some cases and noninvasive testing with a fibrosure test or a fibroscore test and the aspartate aminotransferase (AST)-to-aspartate platelet ratio index (APRI) score. Patients who had clinical, laboratory, and radiologic evidence of cirrhosis were treated without any further assessment of fibrosis. Treatment response was assessed with HCV RNA viral load (IU/ml) at four weeks after initiation of treatment, at the end of treatment, and 12 weeks after the completion of treatment.

The test was performed using Cobas AmpliPrep/Cobas TaqMan HCV Quantitative Test, v2.0 (Roche Molecular Diagnostics, Pleasanton, California, USA) with a lower limit of quantification of HCV RNA 15IU/ml. ETR was defined as undetectable viral load at the end of completion of treatment. SVR12 was defined as undetectable viral load at 12 weeks after the end of treatment.

Statistical analysis
The SPSS statistics software package (IBM SPSS Statistics, version 21; IBM Corp, Armonk, New York, USA) was used for statistical analysis. Values were expressed as mean±SD and the mean quantitative values were analyzed using Student’s t-test. The χ2-test was used to analyze differences in qualitative values. All P values were two tailed and a P value of less than 0.05 was considered significant. One-way analysis of variance was used to determine whether there were differences among the group means. Univariate analysis was used to identify the factors related to SVR.

Results
Patients Sixty-five percent (N=156) of the total of 240 patients were younger than 65 years and patients aged 65 years or older comprised 35% (N=84) of treated patients, with the range being 22–94 years (59.96±10.89). Ninety-nine patients were men and 57 patients were women in the group younger than 65 years of age and 46 were men and 38 were women in the group 65 years of age and older, respectively. Most of the patients were Black (51%, 123/240), followed by White (23%, 56/240), Hispanic (11%, 27/240), and Asians (1%, 2/240). The 32 (13%) patients categorized as others were genotype (GT) 4 and were of Middle-Eastern or Egyptian origin. Also, 32 patients were coinfected with HIV and were receiving their antiretroviral therapy for HIV infection during HCV treatment; no dose adjustment was required. The basic clinical characteristics of all treated patients are summarized in Table 1.

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Table 1


GTs 1a and 1b was present in 78.3% of the treated patients. The next most common genotype was GT 4, found in 11.7% of patients. GTs 2 and 3 were present in 6.7 and 3.3% of all treated patients, respectively.

Seventy five patients were treatment experienced, 50 of whom were <65 years old and 25 patients who were ≥65 years. These treatment experienced patients had either previously failed treatment with the IFN and RBV combination or IFN and RBV in combination with newer DAAs. Model for end-stage liver disease (MELD) score was high in patients aged 65 years and older and was statistically significant (P=0.048). A significant difference was observed between the groups with baseline medical comorbidities HTN (P=0.004), coronary artery disease (P=0.041), and chronic kidney disease (P=0.008) in patients aged 65 years and older, and tended to have more comorbidities than younger age groups. Except for baseline hemoglobin (P=0.004) and alanine aminotransferase (ALT) (P=0.018), no difference was noted between the initial laboratory studies within the groups. The mean viral load remained similar in both groups (P=0.624). No statistical significance was observed with sex (P=0.189), BMI (P=0.713), APRI score (P=0.619), or status of previous treatment (P=0.715).

Response to therapy
In seven out of the total 240 patients, no end of treatment response was recorded; however, viral load was recorded as undetectable at 4 or 8 weeks on treatment, except one patient, who had a quantifiable viral load at 2 weeks. SVR12 was not reported in 49 patients, either because of pending follow-up or because it was not determined and recorded. With all the treatment regimens combined, the overall ETR rate was 98.2% (N=233) and SVR12 was 94% (N=191) (Figs 3 and 4).

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Figs 3 and 4


No statistically significant difference was observed with ETR (98.8 vs. 98%, P=0.667) and SVR12 (93.1 vs. 94.1%, P=0.767) between patients aged 65 years and older and those younger than 65 years of age. SVR12 for DAA with IFN and RBV treatment was 98% (49/50), higher than 91.4% (118/129) achieved with IFN-free DAA regimens, but was not statistically significant. A similar response rate was observed in patients older than or equal to 65 years, with 100% of the patients on the IFN-based regimen achieving an SVR compared with only 91.07% SVR with the IFNfree treatment regimen. ETR and SVR12 for GTs 1a, 1b, 2, 3, and GT 4 were 97.7, 100, 93.8, 100, and 100% and 92, 100, 92.9, 83.3, and 91.7%, respectively (Fig. 6).

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Fig. 6

Patients with GT 3 were the lowest responders, highlighting the fact that GT 3 is the most difficult to treat with DAA agents. The ETR rate and SVR12 rates for subgroups Peg IFN+RBV+SOF, SOF+RBV, Harvoni, Viekira Pak/ Viekira Pak+RBV, and SPV+SOF were 100, 96.7, 97.4, 100, 98.1%, and 97.8, 88, 94.1, 100, and 90.6%, respectively.

For patients who had previous treatment failure or were naïve to treatment, no significant difference in ETR (P=0.783) or SVR12 (P=0.947) was observed between the younger and the older age groups. The univariate analysis determined the factors associated with an SVR (Table 2). The SVR12 was significantly lower in patients with high APRI and a high MELD score, indicating that advanced fibrosis is a major factor in determining the response to treatment (P=0.001 and 0.008, respectively). Baseline ALT and AST were significantly higher in patients who failed to achieve an SVR than in patients who did achieve SVR12 (P=0.016 and 0.000, respectively). BMI was significantly higher in patients who achieved SVR12 (P=0.000) Table 2. Factors associated with SVR12 were analyzed separately for patients aged older than or equal to 65 years (Table 4).

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Table 4


The ratio of GT 1 patients who achieved an SVR12 was significantly lower compare to other genotypes (P=0.001). Cirrhosis and MELD score of more than ten were associated with a low SVR (P=0.001 and 0.042, respectively). Baseline ALT and AST tended to be higher in those who did not achieve an SVR (P=0.020 and 0.000, respectively) and BMI tended to be lower in patients who failed to respond to treatment. Only seven patients had the IL28B GT tested and hence were not included in the evaluation of factors predicting the SVR. There were 12(6.28%) patients(5≥65and7<65years) who failed to respond to treatment. Eight patients developed relapse after treatment, three responded partially, and one achieved a virologic breakthrough during the treatment period (Table 3). Nine out of 12 patients who did not respond to treatment were cirrhotic. The difference in the failure rate between the two groups was not significant statistically (P=0.767).

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Table 3


Safety and tolerability
None of the adverse reactions reported were severe, except severe anemia in two patients. Fatigue was the most common adverse event recorded (32.5%), followed by 65 years) patients discontinued the RBV treatment because of severe anemia (decrease in hematocrit >25% from baseline); however, they all achieved SVR12. RBV dose reduction or discontinuation did not reach statistical significance between the two groups (P=0.913) (Fig. 5).

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Fig. 5


Discussion
Eradication of HCV reduces the risk of progression to cirrhosis, HCC, and liver-related mortality, and thus leads to an improvement in overall survival and quality of life [9]. Historically, the standard longer duration of IFN and RBV treatment produced significant adverse events in elderly patients, necessitating dose reduction or discontinuation of medications [10,11]. The overall SVR rate was less than 50% with standard dual therapy with Peg IFN and RBV regimens. With the introduction of first DAAs in 2011, the triple therapy (boceprevir or telaprevir with Peg IFN and RBV) increased the SVR12 to 65–70% in GT 1 patients. Subsequent, substantial progress with further trials including combination NS5A and NS5B inhibitors, SVR12 approached more than 90%. Current guidelines do not specify the age limit for treating elderly patients.

The American Association of Study of Liver Disease recommends one of the six- DAA combination regimens for GT 1, the most common type of chronic HCV infection in the United States [12]. RBV is still an integral part of the treatment regimen and utilized in combination with DAAs in GT 4 and as an alternative treatment regimen in GTs 1 and 3 patients with compensated cirrhosis.

A recent meta-analysis by Yang et al. [8] concluded that the overall SVR in patients aged older than or equal to 65 years treated with a prolonged course of IFN/RBV regimens was significantly lower and had a significantly higher risk of relapse than in patients younger than 65 years of age. IFN and RBV discontinuation rate were also significantly higher in older patients than in younger patients.

We did not find any significant difference in RBV dose reduction or discontinuation rate (P=0.913) in patients aged 65 years and older compared with younger patients. These findings indicate that elderly patients are tolerating equally the shorter course of treatment involving better tolerated and can be administered to any age group safely with close monitoring during the treatment.

In most initial trials on protease inhibitors, a small number of patients older than 65 years of age were included. Although there was no upper age limit in NS5B nucleotide polymerase inhibitor SOF and NS3/4A second generation protease inhibitor simeprevir trials, the number of elderly patients included was too small to draw any conclusion [14,15]. In most of the trials involving SOF, most of the patients treated were in their 50s [16–21]. In our study, 54 (27 in each group) patients treated with SPV and the SOF regimen showed similar SVR12 rates (P=0.607) and adverse events profile. Overall, SVR12 treated with an SOF-based regimen was 91–98%, in agreement with the results observed from the major trials involving SOF [18–22]. In trials involving Viekira Pak, the study group involved were younger than 71 years, with a mean age in the 50s, and the SVR rate was well above 88% [22–26]. Overall, the response rate with Viekira Pak in our study was 100% (12<65 and 6> 65 years), with good tolerance to medication in elderly patients. Clinical trials involving IFN and RBV-free regimens also did not include enough patients aged 65 years and older to determine whether they respond differently from a younger population.

Trials involving the NS5A inhibitor LDV and SOF in ION1, 2, and 3 trials included only 117 patients aged65yearsandolder,andthepatientpopulationincluded in Lone Star Study involving the LDV and the SOF combination was younger than 70 years [27–30]. No overall difference in tolerability and effectiveness was observed with elderly patients, but the data available for the treatment of the aged population with newly approved therapies are still limited not only in registration trials but also in real-world treatments and community-based HCV regimens. Results of evaluation of 80 (52<65 and 28> 65 years) patients treated with Harvoni in our study yielded an ETR of 97% and an SVR12 of 94%, consistent with the results observed in clinical trials. No statistically significant difference was noted in our study with ETR (P=0.209) or SVR12 (P=0.120) between the two age groups, consistent with the recently published study by Saab et al. [31]. They analyzed the data from four open-label phase 3 clinical trials that evaluated the safety and efficacy of LDV+SOF and concluded that the combination of LDV and SOF is safe, effective,andwelltoleratedinpatientsolderthan65yearsof age who have GT 1 hepatitis C infection [31]. Of the 2293 patients enrolled in four phase 3 trials, 264 (12%) were older than or equal to 65 years of age, of whom 24 were aged older than or equal to 75 years. 97% of patients aged younger than 65 years achieved SVR12 (1965/2029) and 98% (258/264) of patients aged older than or equal to 65 years achieved SVR12. The most common adverse events in both age groups that occurred in 10% or more patients were headache and fatigue.

Most adverse events noted in our study were minor and did not require any intervention, comparable with the study reports from major trials involving similar treatment regimens (Table 5). Adverse events did not differ significantly between the groups, except abdominal pain (P=0.018). Ten (6.4%) patients, all younger than 65 years of age, complained of nonspecific abdominal pain on treatment. Considering that the population involved had significant pain issues at baseline, it appears that this symptom may not be entirely related to the medication agent used. There were two serious adverse reactions during treatment with the regimen involving RBV with severe anemia requiring a blood transfusion and two patients received darbepoietin infusion for correction of anemia. None of the patients discontinued the complete treatment regimen in our study because of adverse reactions, although four patients discontinued the RBV during the treatment; they all achieved SVR12. In 12% of the patients, the RBV dose was reduced during treatment.

A recent study by Pernas [32] raised a concern about possible drug interactions and RBV dose reduction because of adverse reactions in a significant number of patients after following 125 patients 65 years and older who were treated for hepatitis C with newer DAA agents. Of the 61.2% of patients who received RBV, in almost half, the dose was reduced during treatment [32].

Clinical trials involving a recently approved IFN-free regimen for GTs 1 and 4, elbasvir, and grazoprevir (Zepatier; Merck & Co Inc, Kenilworth, New Jersey, USA) with or without RBV included 187 patients aged 65 years or older [33]. The higher rate of late ALT elevation was observed in elderly patients; however, no dosage adjustment was required and the ALT level of most patients normalized after the completion of treatment. SVR differs with GTs. We found a statistically significant low SVR rate with GT 1 in an elderly age group. There are no data identifying which patients will achieve an SVR among older patients with a DDA-based treatment. Our analysis indicates that cirrhosis and increased MELD score are important factors for low SVR in general and in elderly patients. Univariate analysis showed that baseline BMI, ALT, AST, and hemoglobin are factors that are associated significantly with an SVR (P=0.020, 0.020, 0.000, and 0.013, respectively). In our study, 12 (6.28%) patients failed to respond to treatment (7<65 and 5≥65 years). Age was not a factor for the poor virologic response and the failure rate between the groups was not significant (P=0.767). All patients reported adherence to the medication regimen, and there was no clinical evidence of any reinfection in relapsed patients.

None of these patients had any pretreatment-resistant or post-treatment-resistant associated variants and are awaiting further treatment. Seventy-five (nine out of 12) percent of the patients who failed to respond to treatment were cirrhotic and 41% (five out of 12) were coinfected with HIV. Further studies are required to evaluate these significant numbers of relapses in HIV-coinfected patients. Nine patients who failed to treatment received one or the other SOF-based regimen.

Some of the limitations of this study are the retrospective nature of our study, the fact that documentation of the common adverse events may not be complete, and that elderly patients involved are still a small number compared with registration trials.

However, to our knowledge, our study is the first study involving a real-world community-based treatment comparing HCV patients younger than 65 years of age and 65 years of age and older. Going forward, the IFN-free regimens seem to be the standard of care in both age groups. RBV in combination with other DAAs may still be useful in treating some of the difficult to treat patient groups and in less developed countries, where the cost of newer antiviral medicines is a major hurdle. Shortened treatment course may reduce the drug-related adverse events in general including elderly patients. There is a pressing need to include older patients in future trials involving IFN-free agents. They require more complex decision-making because of their age and comorbid conditions with multiple medications.

Conclusion
The age of the patient does not seem to have a major impact on the virologic response rate when treating chronic HCV infection. Older patients (age 65 years and older) do not appear to have a higher frequency of adverse events compared with younger patients. Increased fibrosis, cirrhosis, some of the baseline laboratory studies including AST, ALT, Hemoglobin, and platelet levels seem to affect the SVR in the elderly and require further studies. More studies should be carried out in an older population of patients to assess the safety, efficacy, and adverse reactions of newer DAAs regimens. Treatment should not be withheld purely on the grounds of advanced age.

References

Monday, March 27, 2017

Would legalizing medical marijuana help curb the opioid epidemic?

Abstract
Drug and Alcohol Dependence
April 1, 2017 Volume 173, Pages 144–150

Medical marijuana policies and hospitalizations related to marijuana and opioid pain reliever
Yuyan Shi
DOI: http://dx.doi.org/10.1016/j.drugalcdep.2017.01.006

ArQule Announces Top-Line Results of Phase 3 Clinical Study of Tivantinib in Hepatocellular Carcinoma in Japan

ArQule Announces Top-Line Results of Phase 3 Clinical Study of Tivantinib in Hepatocellular Carcinoma in Japan

BURLINGTON, Mass.--(BUSINESS WIRE)--
March 27, 2017
ArQule, Inc. (ARQL) today reported that its partner, Kyowa Hakko Kirin, announced top-line results of the JET-HCC Phase 3 trial of tivantinib in Japan, and that the trial did not meet its primary endpoint of progression free survival (PFS).

JET-HCC is a randomized, double-blind placebo-controlled study that enrolled approximately 190 Japanese patients with c-Met diagnostic-high inoperable hepatocellular carcinoma (HCC) with a history of prior sorafenib therapy, to evaluate the efficacy and safety of tivantinib.

The primary endpoint of the trial is PFS, and the top-line results did not show a significant difference in PFS between the tivantinib group and the placebo group. There were no new safety issues observed in the trial.

The details of the study results will be presented in an upcoming scientific forum.

“I would like to thank our partner, Kyowa Hakko Kirin, and all the participants in their study,” said Paolo Pucci, Chief Executive Officer of ArQule. “The results are disappointing as there is a need for a second-line HCC therapy in Japan.”

Hepatitis C - Medicare Part D: High costs put some drugs out of reach

Medicare Part D: High costs put some drugs out of reach
March 27, 2017 12:45 PM
By Katie Wedell / Dayton Daily News
DAYTON, Ohio — High-priced prescription drugs are driving up the cost of Medicare Part D catastrophic coverage, which is bad news for both patients and taxpayers, according to a new report from the Department of Health and Human Services Office of Inspector General.

Patients on specialty drugs for cancer, hepatitis C, multiple sclerosis and other diseases are seeing higher out-of-pocket costs because of inflated list prices that accelerate their move into a coverage gap known as the “doughnut hole,” the report says.

The government’s spending is only going to grow, as 3 out of 4 hepatitis C patients are baby boomers who are aging into eligibility for Medicare Part D.

Drugs like Harvoni are extremely effective, he said, but are beyond reach for many of those afflicted with hepatitis C....
Continue reading... 

MSF joins Europe-wide action challenging patent on key hepatitis C drug

MSF joins Europe-wide action challenging patent on key hepatitis C drug

Patent opposition aims to increase affordable access to hepatitis C drug sofosbuvir for millions

State Health Registry issues ‘Cancer in Iowa: 2017’ report, highlights increase in liver cancer cases

Increase In Liver Cancer Cases

An excerpt from the report released by the Iowa State Health Registry is provided below, full press release available here

The report, based on data from the Iowa Cancer Registry and the Iowa Department of Public Health, is available online in the “Publications” section on the registry’s website or by calling the registry at 319-335-8609. The report includes county-by-county statistics, summaries of new research projects, and a special section focused on liver cancer.

Liver cancer is the 13th leading cause of cancer deaths in Iowa. However, unlike most other common cancers, both new cases of and deaths from liver cancer are on the rise in Iowa and throughout the U.S.

The rate of new liver cancer cases in Iowa has roughly tripled over the past 35 years, from two cases per 100,000 people in 1975 to 1979 to six cases per 100,000 in 2010 to 2014.

Michael Voigt, clinical professor of internal medicine and a specialist in gastroenterology and hepatology at University of Iowa Hospitals and Clinics, says that chronic infections of hepatitis B or hepatitis C are the major risk factors for liver cancer, and these infections are correlated with the increase in the number of cases.

“Liver cancer is predominantly due to hepatitis B or hepatitis C infection, and chronic viral hepatitis ultimately causes more deaths than breast cancer, heart failure, or prostate cancer,” Voigt says. “Deaths from hepatitis C are at an all-time high, and the number of cases in people under 30 years of age is increasing dramatically in Iowa.”

However, Voigt notes that because there is a vaccination for hepatitis B and effective treatment of both hepatitis B and C, liver cancer is highly preventable. “The Centers for Disease Control and Prevention (CDC) recommends that everyone born between 1945 and 1965 be tested for hepatitis C,” he says. “It is a silent killer, and the majority of people with hepatitis C are unaware of it.”

Though most cases of liver cancer prove to be fatal, national data show that in recent years deaths have been increasing slower than new cases. Iowa data shows a similar trend but has lower rates overall, possibly due to earlier detection and improvements in treatment of chronic hepatitis.

George Weiner, director of Holden Comprehensive Cancer Center at the University of Iowa, says that researchers consider the disease from all angles in order to reduce the number of cancer deaths.

“Cancer prevention, early detection, and therapy are all important as we seek to reduce the burden of cancer, including liver cancer,” Weiner says. “We are continuing to make progress through research in all of these areas.”

Continue reading....

The 2017 Hepatitis C Community Summit – a key step on the road to elimination

The 2017 Hepatitis C Community Summit – a key step on the road to elimination
In the lead-up to the annual International Liver Congress (ILC) in Amsterdam, Eberhard Schatz of the Correlation Network writes about the Hepatitis C Community Summit that will be held in Amsterdam on the 18-19th of April to focus on community related initiatives and their key role in the hepatitis C elimination movement. Read more about the Summit and register here.
Next month, April, brings the annual meeting of the European Association for the Study of the Liver (EASL), the International Liver Congress (ILC) 2017 in Amsterdam. The ILC serves as one of the most important international meetings on liver research in the calendar year. This year, also in Amsterdam just prior to the opening day of the ILC, the Correlation Network Hepatitis C Initiative has organized the two-day Hepatitis C Community Summit on the 18th and 19th of April.
It is now critically important to reach out to risk groups, such as networks of people who inject drugs, to involve and inform them about treatment options, to provide barrier-free access, and to meet people where they are.
To face the challenges ahead and to effectively provide access to all patients in need, we think the medical world, hepatologists, and consequently the International Liver Congress, must take into account crucial aspects of public health and community involvement to reach global hepatitis elimination goals.

Due to the fact that treatment with new direct-acting antivirals is quick and effective, it is now critically important to reach out to risk groups, such as networks of people who inject drugs, to involve and inform them about treatment options, to provide barrier-free access, and to meet people where they are: in community centres, harm reduction and low-threshold service settings, opioid substitution treatment centres, etc.

The Hepatitis C Community Summit fills a gap in the world of hepatitis C virus (HCV) research, bringing together diverse partners from Europe to provide a platform for community inclusion with all those involved in HCV treatment, most notably civil society. The Summit will bring attention to bear on hepatitis C from the perspectives of medical experts and researchers, as well as patients and representatives of harm reduction and community services in order.
The Summit aims to provide an overview on existing (community related) initiatives, to address challenges and barriers ahead, and provide a platform for exchange across professional borders.
The Summit aims to provide an overview on existing (community related) initiatives, to address challenges and barriers ahead, and provide a platform for exchange across professional borders. In this regard, we are very happy that EASL, WHO, and other important stakeholders and speakers will be contributing to the event.

In addition to attending community members, patient representatives, service providers in community and harm reduction settings, researchers, and several policy makers, we invite ILC participants to join the two-day programme. There will be a welcome, keynote, short plenary speeches from the full spectrum of knowledge in the hepatitis field, and roundtable discussions on the first day as well as two plenary sessions, parallel workshop-style sessions, and a final reception during the second day.

The Summit will be concluded with the launch of a ‘Community Declaration’, a consensus statement highlighting the importance of community involvement in the process of eliminating HCV. This declaration will initially be endorsed by the Hepatitis C Community Summit organizing partners:
We look forward to seeing you in Amsterdam!

Source - http://blogs.biomedcentral.com/on-health/2017/03/23/the-2017-hepatitis-c-community-summit-a-key-step-on-the-road-to-elimination/

HIV and Hepatitis C are No Longer the Most Serious Infectious Threats to People Who Inject Drugs

Paul E. Sax, MD
Contributing Editor
NEJM Journal Watch
Infectious Diseases


HIV and ID Observations
An ongoing dialogue on HIV/AIDS, infectious diseases,
all matters medical, and some not so medical.

In Case You Missed It

HIV and Hepatitis C are No Longer the Most Serious Infectious Threats to People Who Inject Drugs

I had dinner with my daughter Mimi the other evening, and was ruminating about how things have changed since I started work as an Infectious Diseases doctor around 25 years ago.

Here’s an excerpt of our chat:

Me:  There are way more cases of endocarditis in young people than there used to be, a complication of injecting drugs. People in their 20s and 30s with life-threatening infections, getting admitted to the hospital, needing antibiotics for weeks, sometimes surgery … it’s awful. [I didn’t mean for this to sound like a cautionary speech to my 21-year-old daughter, but reading it now — guilty as charged.]
Mimi:  Endocarditis?
Me:  Infection of the heart valves. It’s an incredibly serious problem, much more difficult to treat than HIV and HCV. Even with our best antibiotics, some people need major heart surgery — their lives are never the same. And sometimes the infection spreads through the blood to the lungs, spine, brain… Some even die!

Continue reading....

Treat All - Are we nearing the end in the fight against hepatitis C?

Journal: Expert Review of Gastroenterology & Hepatology

Are we nearing the end in the fight against hepatitis C?
Joel V. Chua & Shyam Kottilil
Received 09 Jan 2017, Accepted 17 Mar 2017
Accepted author version posted online: 24 Mar 2017

http://dx.doi.org/10.1080/17474124.2017.1309287

View Article
Download PDF

With a robust choice of DAA regimens available, even patients that were in the past considered hard to treat such cirrhotic patients, or those previously excluded from treatment due to chronic kidney disease, now have therapeutic options.  For example, elbasvir-grazoprevir is preferred to be used in HCV-infected patients with chronic kidney disease; while decompensated HCV cirrhotic patient are able to be treated with sofosbuvir-ledipasvir-ribavirin, or sofosbuvirvelpatasvir-ribavirin, or sofosbuvir-daclatasvir-ribavirin regimens.  In addition, highly effective and safe pangenotypic DAA regimens such as the once daily fixed dose combination sofosbuvirvelpatasvir, as well as daclatasvir plus sofosbuvir, increases the breath of those that can be treated and cured.  These advancement in drug therapy against HCV, coupled with increasing availability of generic DAAs [6] outside of the U.S. will increase access to these highly efficacious cure drugs worldwide.

Though having safe and highly effective drug regimens that can “virtually” cure all HCV infected individuals is an integral part of any hepatitis C eradication strategy, it still is just one component to achieving disease elimination..
Continue reading....

Gilead hepatitis C drug patent faces European challenge

Gilead hepatitis C drug patent faces European challenge
International groups representing doctors and patients have launched a fresh challenge to the patent on Gilead Sciences' hepatitis C drug sofosbuvir at the European Patent Office in order to increase access to the treatment.

MSF and MdM, who have been joined by 28 groups from across Europe, said key patents on sofosbuvir had already been revoked in China and Ukraine, and decisions were pending in other countries, including Argentina, India, Brazil, Russia and Thailand.

Continue reading...

Saturday, March 25, 2017

Hep C Weekend Reading: Favorite quote of the week “Fight to treat your patients as early as possible.”

HCV Weekend Reading
Hope you all had a wonderful week, sit back and catch up on what you may have missed over the last week in this issue of Weekend Reading.

In a recent article published in Clinical Infectious Diseases, data suggested that delaying hepatitis C treatment regardless of fibrosis stage may be detrimental to patients, ya think?  Reuters Health reported: "Mortality is increased in patients with moderate or severe liver disease related to chronic hepatitis C, and progression from mild/moderate to severe disease cannot be predicted reliably." Here is a quote from Dr. Cepeda, a key author of the study; “Fight to treat your patients as early as possible.” Read the rest of the article, here.

However, according to a report released this month from Trio Health, after patients are prescribed HCV therapy insurance companies are denying coverage, interim data from the study showed HCV treatment non-starts are up, from eight percent in 2014, to over 30 percent in 2016, for the most part because of payer coverage denials. The HCV regimens evaluated in the study include the following: Sovaldi®/Harvoni® (Gilead), Viekira Pak™ (Abbvie), Zepatier™ (Merck), Daklinza™ (BMS) and Epclusa® (Gilead). Read commentary on the report here, Trio press release here.

Annals of Internal Medicine, reported high cure rates, with few side effects, in a review article on various FDA approved regimens to treat chronic hepatitis C. Sustained virologic response (SVR) for genotype 1 (using different approved HCV regimens) was reported at over 95%. Sofosbuvir plus velpatasvir  or daclatasvir for 12 weeks in genotype 3 patients without cirrhosis appeared to seem most effective, for geno 3's with cirrhosis, a regimen of velpatasvir-sofosbuvir had higher response rates, the latter is  also highly effective (99% response rate) for genotypes 2, 4, 5, and 6, this summary was published in NEJM Journal Watch, read the full text article; Hepatitis C: Down but Not Out - Oral Direct-Acting Agent Therapy for HCV.

Weekly News Coverage
HEP offers hepatitis C research with daily news, a great place to start learning about HCV.
Over at HepCBC, each Friday a nice summary of news is available, read this weeks: Weekly Bull.

Healio
Daily news, updates and more over at Healio.
Check out the following March publications as well.
HCV Next
Healio Gastroenterology
Infectious Disease News

News Re-Cap
Author: Richard Pizzi Family Practice News
Publish date: March 21, 2017 - Hepatitis Outlook Late February 2017
Here’s a quick look at some notable news items and journal articles published over the past month, which cover a variety of the major hepatitis viruses.

Week Ending March 22, 2017
Hepatitis C | MD Magazine
Infectious Disease Special Edition
Don't miss recent articles written by your favorite bloggers over at HEP blogs.
HepatitisC.net is a great site for patient resources and personal stories with daily articles.

In Case You Missed It

MD Whistleblower
Medical Marijuana Use - Ready, Fire, Aim!
Michael Kirsch, MD
Promoting medical marijuana use is hot – smokin’ hot. States are racing to legalize this product, both for recreational and medical use. In my view, there’s a stronger case to be made for the former than the latter.

Presently, marijuana is a Schedule I drug, along with heroin, LSD and Ecstasy. The Food and Drug Administration (FDA) defines this category as drugs with no acceptable medical use and a high potential risk of addiction. Schedule I contains drugs that the FDA deems to be the least useful and most dangerous. Schedule V includes cough medicine containing codeine.

Hepatitis C Foundation
How to Find a Liver Specialist Who Really Knows Hepatitis B
March 22, 2017
By Christine Kukka
If you have chronic hepatitis B or are newly-diagnosed, it’s important to see a liver specialist who has experience with hepatitis B.

Having a specialist with hepatitis B expertise on your team not only safeguards your health, it also lessens the stress of having a chronic liver disease. “My specialist gave me all the possible scenarios, but most importantly, he gave me my life back,” one hepatitis B patient recalled.

Podcast
Date Released: Mar 8 2017
HCV Management In Liver Transplantation
Dr. Robert Brown discusses management of hepatitis C infection in patients undergoing liver transplantation, Dr. Nancy Sokol hosts.
Listen here...

Learning Activity
Watch - Release Date: 3/15/2017
Hepatitis C: New Paradigms for Evaluation & Management
Dr. Naudia Jonassaint discusses the new paradigms in regards to the evaluation and management of Hepatitis C. She reviews the basic epidemiology & scope of Hepatitis C, appropriate screening for Hepatitis C, basic Hepatitis C treatment options , identification of special populations, and post SVR Monitoring
Quick View, watch here...



Healthy You

Behind The Headlines
Overweight young men 'more likely to get severe liver disease'
"Men who are overweight in their late teens have a higher risk of developing liver cancer in later life, new research suggests," reports ITV News. Swedish researchers also found a link to other serious types of liver disease…

Updates On This Blog
HCV vaccines—back to the future?
Effects of Melatonin on Liver Injuries and Diseases
Resistance testing for the treatment of chronic hepatitis C with direct acting antivirals: when and for how long?
Future of liver disease in the era of direct acting antivirals for the treatment of hepatitis C
Study - Statin use may lead to: Decreased fibrosis and Reduced risk of developing liver cancer
Watch - Hepatitis C Overview
Chronic Hepatitis C And Functional Dyspepsia (FD) - A Feeling Of Discomfort In The Upper Abdomen
HCV - Fatty liver disease and genotype 3
HCV Genotypes/Treatment
Is There A Natural Way To Improve Liver Fibrosis?

Check back for updates, enjoy the rest of your weekend.

HCV vaccines—back to the future?

Editorial
HCV vaccines—back to the future

Paul Klenerman

Received: 12 February 2017; Accepted: 15 February 2017; Published: 16 March 2017.
doi: 10.21037/aob.2017.02.01


View Full Text Article Online

HCV is a huge global problem. Major advances have been made in recent years in the drug therapy for chronic HCV infection (1). If patients have access to such directly acting antiviral agents, there is a very high chance of cure in most settings, even in patients with advanced disease or with previous treatment failures. However, in order to effectively get on top of the epidemic, such therapy is likely only one weapon, as there is still a substantial amount of ongoing transmission and undiagnosed disease, often in populations that are hard to reach. Virologic cure through the new agents does not lead to host immunity, so approaches to prevention of new or repeat infections are still needed. For this reason, a vaccine for HCV still has an important place at the table (2,3).

The classical approach to vaccines has been to use either a live strain with attenuated pathogenicity—as in the case of smallpox vaccine—or to use a killed or inactivated vaccine. Both approaches have been very effective. Live strains—such as the yellow fever vaccine—produce long lasting immunity, and combine typically cellular immunity with humoral responses. While this is advantageous, for many pathogens there is no clear way of safely attenuating the virus, so the risks outweigh the benefits. Inactivated vaccines, for example the Salk polio vaccine, similar to the toxoids used for tetanus, induce a strong antibody response, although the induction of cytotoxic T cells is limited. In the end, the efficacy of the vaccine depends on the dominant form of protection. In the case of HBV vaccines, a recombinant protein approach is highly effective, as the levels of antibody generated are sufficient to provide robust immunity (4). Recombinant protein approaches mimic the killed vaccines in providing a non-replicating antigen, together with sufficient adjuvant to activate the innate immune responses needed for immunologic priming. For HBV the field is relatively well off as the antibodies represent a clear “correlate of protection”—i.e., their presence predicts efficacy (4). Unfortunately, we do not have very well defined correlates of protection in HCV infection, although there is a wealth of data that innate and adaptive immune responses are important, including a role for T cells. This includes studies of animal models, host immunogenetics, viral evolution and numerous correlative studies in acute and chronic disease, as well as challenge studies (5-7).

For HCV, there have been limited attempts to date to develop preventive vaccines, compared for example to HIV, and there are no simple live-attenuated avenues to explore (3,8,9). HCV is persistent, highly mutable, and difficult to grow in culture. It is also in many patients a relatively poor inducer of immune responses, partly because of its hepatotropism. In common with other complex infections such as HIV and malaria, a viral vector approach has been taken by a few groups, using HCV antigens expressed in the context of another virus, such as a poxvirus or adenovirus. This allows the immunogen to be presented in an optimal form to generate cellular immune responses, and in humans, adenoviral vectors have been shown to be quite effective at priming both CD4+ and CD8+ T cell responses (10,11). Currently a preventive HCV vaccine based on priming with a chimpanzee adenoviral vector expressing HCV non-structural proteins 3-5B, and boosting with a modified vaccinia Ankara (MVA) vector expressing the same proteins is in phase 2 trials in the USA (https://clinicaltrials.gov/ct2/show/NCT01436357).

Antibodies also have a role to play in protection against HCV, and in an ideal world a vaccine that induced a high-titre antibody response capable of blocking infection of a wide range of HCV strains—so-called broadly neutralising antibody (bNAbs)—would be very effective. Attempts have been made to generate antibodies using recombinant HCV envelope proteins, and bNAbs have been generated with this approach (12,13). However, high level production of these protein targets is not trivial and so this area is still open for development, including attempts to focus the antibody response on targets within envelope which are highly conserved and block infection (14).

On this background the recent study by Yokokama et al. in Gut is of interest as it combines new and old approaches to try and induce protective immunity against HCV (15). While it is not possible to routinely culture HCV, certain strains—notably JFH, first generated by Wakita, a co-author on the current study—can replicate in specific cell lines, and this technology has been further developed to allow different genotypes to be cultured (16). The authors were able to make high level stocks of a cell culture strain (HCVcc), purify it and then inactivate it using UV light for safe use as a vaccine. In order to improve its immunogenicity, they combined it with different adjuvants, one the classical album, and a second, based on stimulation by DNA motifs known as CpG presented in nano-particulate form. CpG motifs bind Toll like receptor 9 (TLR9) and induce strong innate immune activation, enhancing immunogenicity—in particular when presented in nanoparticulate form (17). They analysed immunogenicity of such a vaccine in mice and then in marmosets.

The study showed a number of important features. Animals receiving vaccinations using the alum based vaccine did generate some antibodies against HCV, although the levels of neutralisation were overall quite low. However, using the CpG based nanoparticle adjuvant K3-SPG, the same inactivated HCVcc preparation did induce neutralising antibody which was able to block infection. The levels of neutralisation in vitro reached around 60%, so blockade was not complete, but interestingly the sera did block infection by strains bearing envelopes from diverse genotypes, which would be an important attribute of any vaccine. There was also some evidence of T cell responses against components of the vaccine, capable of making interferon-gamma (IFNg). Analyses of marmoset T cell responses is difficult, so the overall levels of such responses are hard to gauge compared to human studies, but once again they were much more evident using the CpG based nanoparticle adjuvant K3-SPG. Induction of IFNg in response to HCV antigens does correlate with successful immune control of HCV in many human studies, was an important readout in the challenge studies performed previously using virally vectored vaccines, and remains the major measure immunogenicity in the development of HCV T cell vaccines in human trials (11).

This vaccine approach therefore is in many ways classical, but also relies heavily on the new adjuvant for its immunogenicity. The issue is to assess the potential for protection. This was not addressed in the marmoset model, although such animals can be infected with chimeric HCV/GBV-C viruses and that may be one possible approach (18). Additional pre-clinical models also include transgenic mouse strains which support HCV infection, some of which are immunologically intact (19). Given the lack of a clear correlate of protection, it would be very valuable to have more preclinical data before engaging in human studies. However, if it is possible to scale up and provide a highly robust safety profile for such a vaccine, immunogenicity studies in humans, followed by trials in populations at risk are really the only way to answer the question regarding protection. Possibly the blend of old and new approaches used in this study could pave the way for such future vaccines.