Back to Newsletters
Download printable version
In This Issue:
AASLD 2009 - Part 1
Alan Franciscus, Editor-in-Chief
HealthWise: Hepatitis C Update
Lucinda Porter, RN
How Do Targeted Anti-HCV Drugs Work?
C.D. Mazoff, PhD, Managing Editor/Webmaster
HCV among Truck Drivers
Alan Franciscus, Editor-in-Chief
HCV Advocate Eblast
Stay informed on the latest news ..click here to register for email alerts
Back to top
AASLD 2009 - Part 1
Alan Franciscus, Editor-in-Chief
The American Association for the Study of Liver Diseases (ASSLD) conference was recently held in Boston, MA. As expected the majority of information about HCV was from studies on the new drugs being developed to treat hepatitis C. That’s the good news about the conference. The not so good news about the conference is that the information about HCV epidemiology, disease progression and disease management was minimal, which is unfortunate (to say the least) because of all the unanswered questions about these important issues. Having said this, the news about all of the new therapies to treat hepatitis C is very exciting and inspiring especially since we are moving closer to the eventual approval of drugs that will improve the treatment response rates. It is, however, important to keep in mind that most of the studies reviewed in this report include only a small number of participants and the period of time the drugs are being taken by people is short. Larger clinical trials with a diverse HCV population using a new drug over a longer period of time will give a much better picture of the safety, tolerability and efficacy of a study drug.
This is the first clinical trial of the combination of an HCV polymerase inhibitor, RG7128, and an HCV protease inhibitor, RG7227. What is noteworthy is the absence of interferon and ribavirin. The theory behind this clinical trial is that by combining two different types of direct HCV antiviral medications there is a different mechanism of action to attack the virus at different parts of the replication process to help to prevent the virus from becoming resistant to either medication. Also of note is that the drugs are eliminated differently from the body—one from the kidneys and one from the liver. Another compelling reason for hoping this combination will work is that both are oral medications that only have to be taken twice a day—which will make adherence much easier compared to taking a shot of interferon, multiple doses of ribavirin and possibly 3 daily doses of an HCV direct antiviral a day.
All patients in this study were HCV genotype 1 patients who did not have cirrhosis. Treatment relapsers, partial responders and null responders as well as treatment-naïve patients were included in the trial.
In April 2009 the results from part 1 of the phase I study were released. In part 1 the combination dosing for 14 days produced a median reduction of HCV RNA of -4.8 to -5.2 log10 IU/ml in the highest doses; all doses of the combination produced HCV RNA reductions (less than 40 IU/mL) in 63% of the trial participants The drugs were well-tolerated over the 14-day dosing period with no serious treatment-related adverse events, dose reductions or discontinuations
The objective of the second part of the study was to assess the safety and tolerability of a combination of the two drugs for up to 13 days.
All of the study medications were dosed at BID (twice a day) and in each group two patients received a placebo (sugar pill). A total of 24 patients were randomized to one of three treatment arms; the RNA decline is listed after the dosing regimen below:
- 8 patients who were treatment failure but NOT null-responders received 1000 mg RG7128 plus 600 mg RG7227
- -4.0 log10 IU/ml (range -6.0 to -2.5); HCV RNA < 15 IU/mL = 1 patient
- 8 patients who were null-responders received 1000 mg RG7128 and 900 mg RG7227.
- -4.9 log10 IU/mL (range -5.3 to -3.5); HCV RNA <15 IU/mL = 2 patients
- 8 patients who were treatment-naïve received 1000 mg RG7128 and 900 mg RG7227.
- -5.1 log10 IU/mL (range -5.9 to -3.0); HCV RNA <15 IU/mL – 5 patients
Similar to part 1 of the study results released earlier this year, headache was the most common side effect followed by nausea, diarrhea, and rash that were possibly related to the study drugs. There were no treatment discontinuations due to side effects. One person dropped out of the study due to personal reasons.
There was no treatment-emergent resistance identified. One patient in the low dose group had a rebound of HCV RNA viral load, but it was suppressed with treatment of pegylated interferon plus ribavirin.
The authors noted that this is the first interferon-free study to demonstrate that HCV RNA could be suppressed to the same extent as that shown with the use of the combination of HCV protease inhibitors, pegylated interferon and ribavirin over a two week period.
The results from this study are remarkable although it is important to remember that the number of people who actually took the drugs was very small and the people were only given the study drugs for a short period of time. The next steps (INFORM-2) are to study the combination of RG7128 and RG7227 with and without pegylated interferon and ribavirin for a longer period of time. The companies expect to start the studies in the first half of 2010.
Telaprevir is currently in phase III studies, but other on-going studies are being conducted and data is being released. Included in this report are results from three different telaprevir studies.
Final SVR results from PROVE3 were released that confirmed that SVR12 data is the same as SVR data—at least in this study. PROVE3 was a study conducted in people who did not achieve an SVR with a previous course of pegylated interferon and ribavirin. The study was composed of 4 treatment arms, but the arm that resulted in the highest response rate and lowest relapse rate was the 48-week treatment arm that included 24 weeks of telaprevir, pegylated interferon, and ribavirin followed by 24 weeks of pegylated interferon plus ribavirin. In this arm the SVR12 results ranged from 53 to 76% depending on the type of prior non-response. This group also had the lowest relapse rate (4%), which is pretty remarkable. The results comparing the SVR12 results to standard SVR (HCV RNA negative 24 weeks after the end of treatment) were the same except that one person was lost to follow-up.
This is an important finding since the shorter period of SVR will, hopefully, speed up the future development.
Study C208 is an important study because it compared a telaprevir dose taken every 8 hours (current phase III study) to a dose taken every 12 hours.
In the current study there were a total of 161 HCV genotype 1 treatment-naïve patients divided into 4 treatment arms. All patients received the triple combination listed below for 12 weeks followed by an additional 12 weeks with pegylated interferon (Pegasys, PegIntron) plus ribavirin. Listed below are the dosing arms as well as the SVR rates:
Arm A: 40 patients received telaprevir 750 mg every 8 hours plus Pegasys and ribavirin.
Arm B: 42 patients received telaprevir 750 mg every 8 hours plus PegIntron plus ribavirin.
Arm C: 40 patients received telaprevir 1125 mg every 12 hours with Pegasys and ribavirin.
Arm D: 39 patients received telaprevir 1125 mg every 12 hours with PegIntron plus ribavirin.
*Note: The daily dose or exposure of telaprevir was the same across all treatment arms = 2250 mg
The percentage of people who achieved a rapid virological response (undetectable viral load after 4 weeks) and went on to achieve an SVR was similar across all treatment arms—91 to 93%.
There were 14 people who discontinued treatment due to side effects—7 people due to rash; 2 people due to pruritus (itching). Of note, unlike in previous studies there was a rash management plan that included provider education and recommendations for over-the-counter medications to control the rash; this is believed to have contributed to the lower incidence of rashes in this study.
This study is important because it shows that the drug efficacy of the every 12 hours dosing schedule is the same as the every 8 hours dosing schedule. The two drugs that are furthest along in development are telaprevir and boceprevir—both dosing schedules are for taking the protease inhibitor every 8 hours, ribavirin twice a day and pegylated interferon one time a week. Maintaining 100% adherence for many patients will be a struggle with the new triple therapy. Failure to follow a dosing schedule or missing doses of the new direct antivirals will lead to drug resistance and, of course, lower treatment response rates. A regime with drugs taken every day from every 8 to every 12 hours will be a huge step forward in improving adherence and treatment outcomes. But since the phase III studies are using the 3 times a day dose, the immediate implications are unclear.
Results from Study 107, an on-going study of people who failed to achieve an SVR with a previous course of pegylated interferon plus ribavirin therapy in prior telaprevir studies (SOC or standard of care arms), were released at AASLD. The interim results were from 94 patients who were rolled over to treatment with telaprevir, pegylated interferon plus ribavirin for 12 weeks followed by either an additional 12 or 36 weeks of pegylated interferon plus ribavirin.
The sustained virological response rates between the two groups (total treatment duration) was not broken down so the results below are listed by type of response:
1. Prior null responders (patients who had a viral load reduction < 1 log10 at week 4 or < 2 log10 at week 12). A total of 28 of whom 16 (57%) achieved an SVR.
2. Prior partial responders (patients who had a viral load reduction > 2 log10 at week 12, but who had detectable HCV RNA at week 24. A total of 29 patients of whom 16 (55%) achieved an SVR.
3. Prior relapsers (patients who had an undetectable viral load during treatment, but had detectable viral load after treatment ended. A total of 29 patients of whom 26 (90%) achieved an SVR.
4. Prior viral breakthrough (patients who had undetectable viral load during treatment, but detectable viral load before the end of treatment. A total of 8 patients of whom 6 (75%) achieved an SVR.
*The SVR rates are combined for both treatment durations by type of non-response, but it was noted that the optimal treatment duration is 48 weeks.
According to a company press release the side effect profile was similar to what has been seen in previous telaprevir studies.
This important but small study is encouraging for improving the SVR rates in people who have been previously treated with pegylated interferon plus ribavirin therapy. The larger phase III studies of people who did not achieve an SVR with a previous course of pegylated interferon plus ribavirin will give us a much better picture of the future of retreatment in the HCV population that is in the most need of treatment options.
The SPRINT-1 was a phase II study of HCV genotype 1 treatment-naïve patients. In the current retrospective study, data from patients from the original study who achieved less than a 1 log10 drop in HCV RNA viral load (called null-responders in this analysis) after 4 weeks of PegIntron plus ribavirin (lead-in phase) was analyzed. All the patients received either 24 or 44 weeks of additional treatment with boceprevir, PegIntron and ribavirin. A total of 206 patient records were analyzed. In both groups of null-responders the SVR rate was 38% (16 out of 50 patients). In the group that was treated for 28 weeks the SVR rate was 25% (7 out of 28 patients) and 55% (12 out of 22 patients) in the group that received 48 weeks of therapy.
Another analysis of the SPRINT-1 clinical trial noted that people who achieved a rapid virological response after treatment with boceprevir, PegIntron and ribavirin were able to achieve an SVR rate of 82% (54 out of 66 patients) in the 28 week treatment arm. In the patients who did not achieve an RVR but who were HCV RNA negative by week 16 and were treated for 48 weeks there was a 79% (15 out of 19 patients) SVR. These results support the rationale for response-guided therapy.
While these results are impressive a couple of caveats need to be made: the findings are from an analysis of previous data which can prove to be a slippery slope, and there were small patient numbers as well. The phase III studies of boceprevir will yield much more accurate information about response-guided therapy.
In part 2 of AASLD conference coverage I will discuss the results from more than a dozen studies of the new agents that are being developed to treat hepatitis C.
Back to top
HEALTWISE: Hepatitis C Update
Lucinda K. Porter, RN
It’s a tradition. Every November, I scan the HCV Advocate website for the latest news from the American Association for the Study of Liver Diseases (AASLD) meeting. This year there were some juicy morsels, six of which I will review.
In the first study, Hepatitis C and Menopause: Interplay of Age, Gender, HCV Replication and Activity in Progression and Consequence for Therapy, Trépo, Bailly, Moreno, Lemmers, Adler, and Pradat investigate the differences in fibrosis progression among HCV patients. Previous studies revealed the possibility that estrogen may have anti-fibrogenic effects, so researchers specifically looked at fibrosis development in the light of gender, age, and menopause.
They looked at 163 enrollees, ages 23 to 84 years with a mean age of 55; 56% were male. Slightly more than half (55%) had progression of fibrosis, measured by a METAVIR fibrosis score of at least F3. Overall, males had higher progression rates at 66% versus 41% for women. However, for those under the age of 50, fibrosis progression was 51% for males versus 11% for females. Over age 50, the rate jumps to 77% for males versus 61% for females.
These data show a strong relationship between gender and fibrosis progression. The researchers surmise that estrogen may have a protective benefit for younger women with HCV. They recommend the use of estrogen replacement therapy for menopausal women.
Another interesting discovery appeared in this study. In general, viral loads dropped with age except in the group of post-menopausal women. There was no explanation for this.
The second study examined similar issues. Early Loss of Exposure to Estrogens is Critical in Determining Entity of Fibrosis and Response to IFN in Women with Hepatitis C is the title of a poster presented by Karampatou, Pazienza, Lei, Di Leo, Francavilla, and Villa. After observing that post-menopausal women with HCV had increased progression of fibrosis, these researchers wondered whether the correlation was due to aging and/or longer durations of infection or to menopause.
They analyzed data from 945 HCV-treatment patients of evenly-distributed genotype—541 men and 404 women. In the female group, 252 were menopausal. Most of these were spontaneously menopausal although 50 were surgical. Body weight was lower in pre-menopausal women; however histological steatosis (fatty liver) was not significantly different between the two groups.
Pre-menopausal women had the highest response to HCV-therapy. The sustained virologic response (SVR) was 63% versus 51% of males and post-menopausal women. In short, post-menopausal women responded similarly to treatment as men did.
The researchers concluded that menopause plays a significant role in determining the progression of fibrosis along with response to treatment. Estrogens have a powerful role in the regulation of inflammation and immunity. They recommended that interferon-based therapy be initiated at the youngest possible age, preferably prior to menopause.
The third item to catch my attention appeared in a 2009 supplement published by Hepatology and is also pertinent to women with HCV. Hepatitis C Virus (HCV) Infected Females Are at Higher Risk of Graft Loss after Liver Transplantation was presented by Jennifer Lai, MD and team of the University of California San Francisco. Data showed that women who had HCV-related liver transplantation have poorer long-term survival rates than men do. Women are also more likely to reject the donor liver. Lai also reported that women had a greater risk of advanced recurrent HCV after liver transplantation.
More research is needed to understand the reasons for the differences. Although she confirmed the need for further studies, Lai speculated that the differences may be due to:
- Aging differences between genders
- Gender mismatching of organs between donors and recipients
- Higher risk of kidney impairment in women prior to liver transplantation
Aging and HCV is the fourth item I will cover. In a poster titled, Aging of Hepatitis C Infected Persons in the United States: A Multiple Cohort Model of HCV Prevalence and Disease Progression, Davis, Alter, El-Serag, Poynard, and Jennings examine the aging HCV population.
The number of new HCV infections has been dropping, but those who acquired HCV during its peak years, are aging. The questions are these: 1) Will there be a rise in cirrhosis and other HCV-related problems, or 2) Has the burden of HCV reached a plateau?
Analyzing existing data from National Health and Nutrition Examination Survey (NHANES), Davis and team showed that the prevalence of HCV peaked in 2001 at 3.6 million. They project the number to be about half of this by 2030. They calculated that the likelihood of cirrhosis occurs between ages 60 to 80, regardless of the age of initial infection. Davis et al., project that of those with HCV, cirrhosis will reach 25% in 2010 and 45% in 2030, peaking at 1 million in 2020 (30.5%). They estimate that those with the severest form of cirrhosis (decompensation) will rise until 2022. HCV-related liver cancer will peak in 2019 at 14,000 annual cases.
A note about NHANES: Many HCV statistics are gleaned from this survey. Some experts believe that the NHANES estimates are low because certain populations with a high incidence of HCV were not counted, such as prisoners, homeless, military and those in institutions. Therefore, the number of those projected to experience HCV-related complications is likely to be significantly higher.
Davis and colleagues conclude that there will be a decline in chronic HCV as patients die of other non-HCV causes. The next two decades will experience a burden of HCV-related complications due to the long durations patients have had HCV. The researchers suggest that this impact could be reduced if more people are successfully treated for HCV.
The fifth study examined risk factors for HCV-associated fibrosis progression. The title of the poster was: Age, Insulin Resistance and Steatosis are Independent Risk Factors for Fibrosis Progression in Untreated Patients with Mild Chronic Hepatitis C: A Prospective Study with Repeat Biopsies and was conducted by Stern, Cardoso, Moucari, Martinot-Peignoux, Ripault, Boyer, Bedossa, and Marcellin.
Stern and colleagues looked at 265 patients with mild HCV who had never been treated and saw that the rate of fibrosis progression is low (27% in 6 years). However, factors that are associated with an increased rate of fibrosis are: older age, insulin resistance and the presence of fat in the liver (steatosis).
The final study I will discuss is my favorite. Titled, Resilience Affects the Quality of Life in Patients with Chronic Hepatitis C; it was conducted by Selmi, Giorgini, Cocchi, Meda, Marta, Monticelli, Magrin, Podda, and Zuin. They looked at the resilience of patients with HCV, meaning the ability to recover from or adjust easily to the diagnosis.
This study enrolled 149 HCV patients, none with cirrhosis or mood or anxiety disorders: 55% were female, 42% had previously undergone HCV treatment and were either non-responders or relapsers. They used multiple questionnaires, surveying psychological well-being, health, quality of life, family and social relationships, job satisfaction, and other factors.
Selmi and colleagues found that HCV patients are quite resilient. Our social relationships and psychological well-being are generally strong and we maintain a good quality of life. However, quality of life is affected by individual factors, particularly by the length of time one is infected. Selmi, et al. conclude, “informing patients regarding the disease natural history is critical to patient quality of life and should not be overlooked when new treatments are proposed.”
Summarizing these studies, I learned this:
- To avoid later complications, HCV treatment may help
- Treatment done early may have a better chance of success, particularly for pre-menopausal women
- Those with HCV should consider reducing the chances of acquiring fat around the liver by adopting a healthy lifestyle
Finally, I learned that as a group, HCV patients are quite resilient. However, that I already knew. You’ve been proving this for decades.
Back to top
How Do Targeted Anti-HCV Drugs Work?
Drugs that attack the hepatitis C virus (HCV) directly—dubbed specifically-targeted antiviral therapy for hepatitis C, or “STAT-C”—represent a paradigm shift in the management of the disease.
The current standard of care for chronic hepatitis C treatment, pegylated interferon plus ribavirin, works by stimulating the body’s immune response against the virus. Interferons are natural chemical messengers (cytokines) that regulate immune function. Ribavirin, an IMPDH inhibitor (Inosine monophosphate dehydrogenase), has the ability to inhibit viral replication by interfering with ribonucleic acid (RNA) production, but in practice appears to work primarily as an immune modulator.
Several new anti-HCV drugs now in development work another way—by blocking or interfering with specific steps in viral replication. In order to understand the potential of these novel agents, it is useful to look at the HCV life cycle and various ways it can be disrupted.
THE HCV LIFE CYCLE
HCV is a small virus consisting of a genome encased in a capsid shell and surrounded by an outer envelope.
HCV life cycle:
a) Virus binding and internalization, b) cytoplasmic release and uncoating, c) IRES-mediated translation and polyprotein processing, d) RNA replication, e) packaging and assembly, f) virion maturation and release. The topology of HCV structural and nonstructural proteins at the endoplasmic reticulum membrane is shown schematically. HCV RNA replication occurs in a specific membrane alteration, the membranous web. Note that IRES-mediated translation and polyprotein processing as well as membranous web formation and RNA replication, illustrated here as separate steps for simplicity, may occur in a tightly coupled fashion (from Moradpour D. et al. Nat. Rev. Microbiol. 2007;5:453-463.) http://www.chuv.ch/imul/imu_recherche
Click Here to view an animation of the HCV Life Cycle
The HCV genome, or genetic material, takes the form of positive single-strand RNA, which serves as a “blueprint” for the production of proteins and enzymes that make up the virus.
In order to replicate, or reproduce, HCV must enter a host cell and take over its machinery. The virus first attaches itself to receptors on the host cell’s surface, penetrates the cell membrane, and uncoats itself by shedding its outer layers.
Using the cell’s ribosomes tiny protein-production factories the RNA is translated, or used to create new viral proteins. The viral genome copies itself using genetic building blocks present in the host cell. Finally, these newly produced proteins and RNA are assembled to form complete virus particles that bud out of the host cell and go on to infect additional cells.
Specific viral enzymes are required to carry out certain steps in the replication process. Compounds that interfere with the action of these enzymes can therefore slow or halt viral reproduction. The STAT-C drugs furthest along in development target the HCV protease and polymerase enzymes.
When viral RNA is translated, it initially produces a single large polyprotein containing about 3,000 amino acids. This polyprotein must then be cleaved, or cut up into smaller pieces that can be used to assemble new viral particles. This is the job of protease enzymes, which act as “molecular scissors.”
The hepatitis C drug candidates expected to emerge first from the development pipeline, Vertex’s telaprevir and Schering-Plough’s boceprevir, are both covalent NS3/4A serine protease inhibitors. These compounds interfere with the HCV non-structural NS3 serine protease and the NS4A cofactor that facilitates protease function. The “next-generation” protease inhibitor narlaprevir belongs to the same class. These agents bind covalently to an active site on the protease enzyme, preventing it from carrying out its normal activity.
Other promising agents, including RG7227 (also known as ITMN-191) and MK-7009, work similarly, but with non-covalent binding to the HCV protease. Many other protease inhibitor candidates are in earlier stages of development.
Different enzymes are needed to copy viral RNA, the other crucial component of new virus particles. Genetic material is composed of a chain of building blocks known as nucleotides. HCV’s positive RNA strand is used as a template to produce a complementary negative (antisense) strand, which in turn is used to make more positive strands. HCV accomplishes this using an enzyme called RNA-dependent RNA polymerase, meaning it uses RNA to produce RNA (human cells, in contrast, use DNA to produce DNA, while retroviruses like HIV use RNA to produce DNA).
The HCV NS5B RNA-dependent RNA polymerase produces new RNA by adding successive nucleotides in a chain. Nucleoside or nucleotide analog drugs act as defective building blocks, or chain terminators. When added to a growing RNA chain, they prevent the addition of further nucleotides, thereby bringing production to a halt.
Some promising experimental agents, including RG7128, are nucleoside analog HCV polymerase inhibitors, as was the now-discontinued valopicitabine. (Ribavirin and successors like taribavirin are also nucleoside analogs but, as noted, seem to work by other mechanisms in anti-HCV therapy). The experimental agents PSI-7851 and IDX184 are examples of nucleotide analogs, which require less processing in the body than nucleoside analogs before they can be used.
Drugs may also interfere with polymerase activity in a different way, by binding to the enzyme and preventing it from working properly. Several non-nucleoside HCV polymerase inhibitors are in earlier stages of development, including Abbott’s ABT-072, Anadys Pharmaceuticals’ ANA598, Japan Tobacco’s JTK-003, and Vertex’s VCH-916.
OTHER DRUG TARGETS
While protease and polymerase inhibitors are furthest along in development, agents targeting other steps in the HCV life cycle are also being studied.
Compared with other viruses, researchers know relatively little about how HCV enters host cells. Nevertheless, drug developers are working on agents that interfere with viral attachment to cells by blocking either cell receptors or viral envelope proteins.
Once inside a host cell, HCV sheds its outer layers to release its genetic material. Agents that interfere with this uncoating process are also potential drug candidates. Unlike some other viruses, HCV does not integrate its genetic material into the host cell’s genome, so integrase inhibition is not a potential drug target.
In order to produce new proteins, HCV uses the host cell’s ribosomes and a replication complex where gene translation takes place. The viral genome contains an internal ribosomal entry site (IRES) at one end to enable this process. Companies are working on early development of various agents that interfere with IRES and HCV messenger RNA, including antisense oligonucleotides, ribozymes, and short interfering RNA sequences (siRNA).
After the HCV polyprotein is cleaved by a protease, some of the component pieces must be further processed before they can be used to assemble new virus particles. Various compounds such as castanospermine and its derivative celgosivir disrupt these processes. Helicase enzymes are “motor” proteins that separate strands of genetic material. The function of the HCV helicase is not fully understood, but it represents another potential drug target. Finally, anti-HCV agents could interfere with the final step of replication, inhibiting viral assembly or budding from host cells.
Drugs that specifically target HCV are less likely to cause systemic or whole body side effects such as those seen with interferon, which affects immune response rather than the virus itself. However, experience with antiretroviral therapies for HIV which work by some of the same mechanisms as anti-HCV agents indicates a need for caution.
HCV protease inhibitors, for example, have the potential to mimic the activity of human protease inhibitors. Nucleoside or nucleotide analogs could potentially interfere with copying of human as well as viral genetic material. Though the underlying mechanisms are not fully understood, drugs targeting HIV protease and reverse transcriptase (a form of polymerase) have been linked to a variety of metabolic and mitochondrial toxicities, so researchers should be on the lookout for similar side effects with anti-HCV agents.
PREVENTING DRUG RESISTANCE
Compared with DNA viruses, RNA viruses like HCV mutate frequently as they replicate, and lack a “proofreading” mechanism to eliminate such errors. Many viral mutations are either irrelevant or detrimental, but others can enable the virus to overcome the action of drugs. For example, a small change in the structure of the HCV protease binding pocket can mean protease inhibitors no longer fit into the pocket to disrupt protease function.
For all protease and polymerase inhibitors in development, single amino acid changes have been identified that reduce viral sensitivity to the drug. But combining agents that work by different mechanisms can slow or prevent such resistance. To overcome the effects of multiple drugs, HCV would have to produce multiple mutations, which tends to reduce viral fitness.
Pharmaceutical companies are testing several STAT-C combinations to determine whether the drugs have synergistic activity. Furthest along is a combination of the HCV protease inhibitor RG7227 plus the polymerase inhibitor RG7128. In the Phase 1 INFORM-1 trial, the two drugs demonstrated potent antiviral activity over 14 days in both treatment-naïve and interferon-experienced genotype 1 chronic hepatitis C patients.
In the future, it is likely that hepatitis C treatment will come to increasingly resemble therapy for HIV or hepatitis B virus, using combinations of small oral agents that attack the virus from multiple angles simultaneously, thereby improving the chances of disrupting viral replication over the long term.
Back to top
C.D.Mazoff, PhD, Managing Editor/Webmaster
It may be just a coincidence, or maybe the timing was just right, but this week the Journal of the American Medical Association (JAMA) published an interesting article on viral hepatitis. The article, “The Silent Epidemic of Viral Hepatitis May Lead to Boom in Serious Liver Disease,” 1 doesn’t really say much that we didn’t know before, especially after the release of the Milliman Report, officially known as Consequences of Hepatitis C Virus (HCV): Costs of a Baby Boomer Epidemic of Liver Disease in May of this year.
But now there is a Bill before Congress, the Viral Hepatitis and Liver Cancer Control and Prevention Act of 2009 (H.R. 3974), introduced by Mike Honda and others in October, and of course there is the also the newer H.R. 3962, The Affordable Health Care for America Act, revealed at just about the same time. Looks like a triple whammy to me. But it’s anyone’s guess.
The JAMA article basically summarizes the state of hepatic epidemiology in the US:
- More than 5 million US residents have viral hepatitis
- Prevention efforts have drastically reduced the incidence
- HCV down to 19,000 in 2006 from 180,000 in1982
- HBV down to 60,00 in 2004 from 200,000 in 1980
There is no doubt that this is quite impressive, and many health and medical organizations deserve congratulations—even the CDC. But, now there is another problem looming on the horizon: baby boomers and immigrants.
Although the rate of new infections of hepatitis C has dropped drastically in the general population, thanks to more screening of the blood supply and better practices, many of those who do have hepatitis C have had it for just long enough for it to become nasty. Most people with hepatitis C are asymptomatic, and few will progress to serious liver disease; but those who will (the 20% of the 180,000 in 1982 etc.) are beginning to knock on the doctor’s door. Furthermore, the statistics used to calculate the amount of people infected were seriously flawed because they didn’t take into account the homeless, the poor, the incarcerated and the mentally ill and others who slip through the cracks in the healthcare system because they don’t have medical insurance.
As far as hepatitis B goes, infant and adolescent vaccination programs have really helped. Not to mention other programs such as screening of pregnant women and educational campaigns. But the problem with HBV is that there are over 400 million people worldwide with HBV and many of them are knocking at the door as well. According to Dr. Hu, “50% to 70% of US residents with chronic HBV infections were born in another country, and more than half of new cases identified are in Asians or Pacific Islanders.” The majority of these persons are asymptomatic, and without screening and education, they are at risk of spreading the disease.
So, even though we are stopping many new infections, the problem is that 15-40% of people with chronic HBV develop cirrhosis or liver cancer, while the figures for those with HCV are slightly less.
And there are other complications: those with liver disease often have other illnesses—heart disease, kidney disease, autoimmune disorders, and depression particularly with hepatitis C. Lifestyle also plays a very important part: some with HCV are on the street and use drugs and share needles. Many use alternative forms of medication including alcohol which are bad for the liver; many cannot afford a low fat diet, and are reduced to eating junk and fast foods.
Of interest in the JAMA article is evidence of an apparent argument or kerfuffle between the US Preventive Services Task Force (USPSTF) and members of the AGA (American Gastroenterology Association), CDC and others because the USPSTF has recommended not only against increased screening in the asymptomatic but also in at risk populations. In my opinion the decision of the USPSTF is patently absurd if not criminally negligent considering that 80 percent of people who are infected with HCV do not know it because they have no symptoms and have never been tested!
It is encouraging to know that many doctors and institutions are actually on the patient’s side and trying very hard to change the state of the health of the nation, in more ways than one. Only time will tell; but for many, time is running out.
A report from the Institute of Medicine of the National Academies on ways to reduce the incidence of viral hepatitis is due out in 2010.
1“Silent Epidemic of Viral Hepatitis May Lead to Boom in Serious Liver Disease,” by Bridget M. Kuehn. JAMA. 2009;302(18):1949-1954 (doi:10.1001/jama.2009.1588)
Back to top
HCV Among Truck Drivers
Alan Franciscus, Editor-in-Chief
In many countries around the world the spread of infectious diseases can be traced to highway transportation routes. In Africa, Southeast Asia, Eastern Europe, and South America, for instance, the spread of sexually transmitted diseases has been linked to long-distance truck drivers and commercial sex workers. In the U.S. it has long been suspected that outbreaks of infectious diseases occur along certain highway routes frequented by truckers, but there has not been any good data to back it up.
However, a recent study published data collected from mobile clinic vans which were parked at a large truck terminal in Albuquerque, New Mexico (NM), along Interstate 40 (running east to west), and 10 other truck stops in the southern part of NM along Interstate 25, Interstate 10, and the intersection of Interstates 285 and 360.1
Truck stops carry a variety of services geared toward long-distance truck drivers such as food, showers, supplies, truck repairs, social networking, high-speed internet services, cash services and more. Many truck stops are also frequented by sex workers.
A total of 652 truckers, aged 21 yo or older (591 males; 61 females) were interviewed for 15 to 30 minutes and received $35.00 for their interview. The interviews were conducted from December 2004 through March 2006. Data was collected on driver demographics, driving history (years working as a truck driver), sexual behavior such as condom use, and a history of any sexually transmitted diseases. At the end of the interview, blood and urine samples were collected from the drivers and tested for syphilis, HIV, hepatitis B markers, and HCV antibody markers (including a signal to cut-off ratio to confirm HCV antibody status).
Since the interviews were anonymous the authors compared the age, gender, race, ethnicity, marital status, number of years driving and home state of all of the interviews to rule out any potential duplicates. The authors reported that they did not identify any duplicate results.
Twenty-one percent had sex with sex workers or with casual partners in the previous year. High risk sexual activity was associated with driving solo, history of injection drug use, and a history of a sexually transmitted infection (STI). Fourteen percent reported drug use in the previous year and 11% reported having a history of injection drug use.
A total of 97% of the drivers were tested of whom 8.5% (54 people) tested positive for hepatitis C antibodies (4.3% in people aged 40—49 yo), 10.4% (66 people) had hepatitis B core antibodies (a marker of past HBV infection), 1.3% (8 people) people were positive for chlamydia, and one each (.2%) had gonorrhea, syphilis, and HIV. Injection drug use and history of hepatitis B core antibodies were associated with HCV infection.
The authors noted that their results “suggest a need for hepatitis C screening and STI risk-reduction interventions in this population.”
Risk Assessment and Screening for Sexually Transmitted Infections, HIV, and Hepatitis Virus Among Long-Distance Truck Drivers in New Mexico, 2004-2006. Salway et al., November 2009, Vol 99, No. 11, American Journal of Public Health.
Back to top
Back to Newsletters