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Alan Franciscus, Editor-in-Chief
Treating Hepatitis C in Injection Drug Users
HealthWise: Hepatitis C and Sleep
Lucinda K. Porter, RN, CCRC
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Alan Franciscus, Editor-in-Chief
The European Association for the Study of the Liver (EASL) was recently held in Paris, France on April 13th through April 17th. There was limited amount of news on hepatitis C at the conference, but there was some exciting new data on various HCV drugs in clinical development as well as some interesting data on Pegasys and PegIntron that will be discussed in this article. In May 2005, the Digestive Disease Weekly (DDW) conference will take place in Chicago, IL and some of the studies presented at DDW will contain information from EASL that will be updated and covered on the HCV Advocate Web site and subsequent articles in the HCV Advocate newsletter.
HCV Investigational Therapies
Reports on a number of new drugs in development for treating hepatitis C were presented at EASL. Those which looked the most promising as future HCV medical treatments were viramidine, albuferon, and NM283.
Ribavirin induced hemolytic anemia is reported in about a quarter of HCV patients taking the combination therapy of pegylated interferon plus ribavirin. Preliminary data on the safety and tolerability of viramidine (in combination with pegylated interferon) was presented at the 2004 American Association for the Study of Liver Disease (AASLD). It was reported that the incidence of hemolytic anemia was dramatically lower in the viramidine arm of the study compared to the ribavirin arm (4% vs. 27% respectively).
The data on the sustained virological response (SVR-undetectable HCV during and 24 weeks post treatment) from the same clinical trial was presented at this year’s EASL conference.
One hundred seventy-one previously untreated patients received the full dose of 400 mg (47 patients), 600 mg (43 patients), and 800 mg (44 patients) twice a day (BID) of viramidine versus 1000/1200 mg/day ribavirin (37 patients) in combination with pegylated interferon. Treatment duration was 48 weeks for genotype 1, and 24 weeks for genotypes 2 and 3 with a follow-up period of 24 weeks. The patient characteristics were male (64%), Caucasian (76%), and genotype 1 (72%). The median HCV viral load was 6.5 log10 copies/mL. In the viramidine group, the highest SVR rate was in the patients that received 600 mg BID dose.
SVR viramidine 600 mg/ BID
|Genotypes 2, 3
It is difficult to draw any concrete conclusions about the SVR rates since the study included a limited number of patients. Phase III trials (with a much larger patient population) of viramidine vs. ribavirin are underway and the results from this study should give us a better understanding of the effectiveness of viramidine compared to ribavirin. However, since the response rates were similar between the different study arms, it does appear that viramidine may produce similar treatment response rates but with less of the ribavirin-induced hemolytic anemia.
Albuferon is a form of time-released interferon that is produced by fusing human serum albumin to interferon. In a previous phase I/II clinical trial of 119 adults (HCV positive non-responders to previous interferon therapy) who received albuferon, it was found that the drug was safe and well-tolerated with no discontinuations due to side effects. The side effects from the treatment were found to be transient (temporary) and mild to moderate in severity. The authors of this study found that the HCV RNA (viral load) decline was dose-dependent and concluded that albuferon has the potential to address an unmet need for HCV therapy with less frequent dosing (injections).
Data from a new phase II trial on 56 previously untreated genotype 1 patients also found that albuferon was safe and well-tolerated. Furthermore, it was reported that after 4 weeks of albuferon therapy there was a 99.9 percent decrease in viral load in the patients who received the two highest doses of albuferon. After 42 days, 23% of the same patients remained HCV negative. The authors concluded, based on this study, that albuferon could be dosed (injected) every 2-4 weeks and that it showed a strong antiviral activity after two doses. A larger 48-week combination study of albuferon plus ribavirin in previously untreated HCV patients is being planned.
Valopicitabine is an oral nucleoside analog, a new class of drugs that block the hepatitis C virus from replicating (reproducing) by inhibiting the HCV RNA polymerase. HCV polymerase is the enzyme of the hepatitis C virus that is critical in the replication process of hepatitis C. The data presented at EASL on valopicitabine is noteworthy because this is the first time that 24 week data has been reported on an HCV drug with direct antiviral properties against the hepatitis C virus.
Preliminary data from a phase II study was presented at EASL on the genotype 1 patients (previously untreated) who completed 24 weeks of treatment of valopicitabine combined with pegylated interferon. So far 9 out of 30 patients have completed 24 weeks of therapy. It was found that the HCV RNA (viral load) reduction was more than 99.0% in the 9 patients. The HCV viral load declined in 8 out of 9 patients to below the level of detection of < 600 IU/mL (Amplicor PCR)—six of the patients had a reduction of HCV viral load to below the level of detection by a more sensitive viral load test with a lower limit of 10 IU/mL (TaqMan PCR). The authors reported that there were no serious adverse events (side effects) and no patient was required to discontinue therapy due to valopicitabine-related side effects. A larger trial of 171 HCV genotype 1 patients who failed a previous course of pegylated interferon plus ribavirin is currently underway. The patients will receive valopicitabine monotherapy, valopicitabine plus pegylated interferon or pegylated interferon plus ribavirin. Enrollment in the new trial is expected to be completed by June 2005.
The EPIC3 (Evaluation of PegIntron in Control of Hepatitis C Cirrhosis) is an on-going clinical trial that is evaluating PegIntron plus Rebetol (ribavirin) for previous interferon based treatment non-responders and relaspers. The study will evaluate the effectiveness of PegIntron combination therapy in this patient population. There is also a PegIntron long term maintenance phase in this study that will evaluate whether the use of low dose PegIntron monotherapy can delay or prevent cirrhosis.
Preliminary results from the EPIC study involving over 2,200 HCV patients worldwide were released at EASL. In this study on people who failed a previous course of interferon based therapy, patients were treated with weight based PegIntron (1.5 mcg/kg/week) plus Rebetol (ribavirin-800-1400 mg/day) for up to 48 weeks. Twenty-one percent of the 978 patients who had completed up to 48 weeks of therapy achieved an SVR. Breaking it down by genotype, patients with genotype 1 achieved a 14% SVR compared to a 56% SVR in patients with genotypes 2 or 3. As expected it was found that treatment relapsers achieved higher SVR rates (41% SVR compared to 14% SVR in the treatment non-responders group) and that people with mild to moderate fibrosis achieved a higher SVR compared to people with more advanced scarring (26% vs. 15%).
Generally, people with persistently normal ALT levels have a milder course of HCV disease progression. However, about 30% of people with persistently normal ALT levels will progress on to advanced fibrosis and/or cirrhosis. Clinical trials have found that people with normal ALT levels can be treated successfully and achieve similar treatment response rates as people with elevated ALT levels. Data from a previous study using Pegasys plus Copegus (ribavirin) combination therapy for treatment of HCV in patients with persistently normal ALT levels was analyzed to find out if there was a relationship between the age and baseline characteristics of patients and response to therapy.
In this retrospective study, information on 422 patients was analyzed. It was found that people under 40 years old were more likely to achieve an SVR—54% in the group under 40 years old compared to 34% in the group that was over 40 years old. The authors concluded that age appears to be an important factor in treatment response. It was also pointed out that other confounding factors such as male gender, African American race and high HCV RNA (viral load) play an important role in treatment response.
Adherence to HCV medicines is also an important factor in achieving an SVR and data from another clinical trial was examined. A retrospective analysis of 569 patients who received Pegasys plus Copegus (ribavirin) found that the dose of Copegus was an important factor in treatment response. It was found that 66% of the patients in this group who took greater than 97% of their ribavirin dose achieved an SVR compared to the SVR rate of 33% for patients who took less than 60% of their ribavirin dose. The authors concluded that patients in this trial were more likely to maintain the Pegasys dose compared to the ribavirin dose and that avoiding ribavirin dose reductions and dose discontinuations will likely improve the overall SVR rates.
Weight is also another poor prognostic factor for achieving a successful treatment response, but a study presented at EASL reported that it appears that body weight is not solely responsible for the lower treatment response rates. Studies from two multinational phase III studies of 2,404 patients were analyzed and it was reported that the heavier patients were more likely to be male, black, cirrhotic and infected through intravenous drug use, which are all factors associated with a lower treatment response rate. The authors concluded: “This clustering of poor prognostic characteristics may explain the lower SVR rates observed in heavier patients.”
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Treating Hepatitis C in Injection Drug Users
Injection drug users (IDUs) traditionally have been considered poor candidates for hepatitis C treatment, and have been excluded from most clinical trials for new therapies. In particular, it was commonly assumed that IDUs tend to adhere poorly to therapy and are at high risk for HCV reinfection. The previous (1997) National Institutes of Health (NIH) consensus guidelines recommended that IDUs should abstain from drugs and alcohol for at least six months before being considered for hepatitis C treatment.
Attitudes have begun to change in recent years, in view of the fact that a large proportion of HCV positive people have a history of injection drug use. The latest NIH consensus guidelines, updated in 2002, recommend that “treatment of [patients with] active injection drug use be considered on a case-by-case basis, and that active injection drug use in and of itself not be used to exclude such patients from antiviral therapy.”
But treatment of hepatitis C in IDUs remains a challenge. The April 15 supplemental issue of Clinical Infectious Diseases was devoted to this topic, focusing on medical management and models of integrated care.
Often the first challenge is access to care. Despite changing attitudes, some providers remain reluctant to refer IDUs for hepatitis C treatment. As reported in the March 28, 2005 Archives of Internal Medicine, Lin Ding and colleagues found that physicians with “negative attitudes” toward IDUs – about 25% – were significantly less likely to prescribe antiretroviral therapy for HIV; it would not be surprising if a similar situation exists with regard to hepatitis C.
Steffanie Strathdee and colleagues, who surveyed young (age 18-35) IDUs in three U.S. cities, found that while more than 80% were interested in hepatitis C treatment, only 27% had seen a healthcare provider since they tested HCV positive. Patients whose doctors told them that having HCV put them at risk for liver cirrhosis or cancer were seven times more likely to express an interest in treatment. In a survey of Australian IDUs, many still believed active drug use barred them from government-funded HCV treatment (this exclusion was removed in 2001). Describing their experience treating HIV/HCV coinfected patients at Boston Medical Center (more than 30% of them active IDUs), Catherine Fleming and colleagues characterized several barriers to successful HCV therapy, including patients’ limited ability to navigate the healthcare system or pay for services.
A second challenge concerns management of psychiatric side effects of HCV therapy – particularly depression – in a population that has a high rate of co-existing psychiatric conditions. In a study of 293 patients at a Portland veterans’ hepatology clinic, Marian Fireman and colleagues found that 93% had a current or past history of at least one psychiatric disorder, most often depression (81%), post-traumatic stress disorder (62%), substance use disorders (58%), moderate-to-severe depression (35%), and/or bipolar disorder (20%); 73% had two or more conditions. Neuropsychiatric side effects are common in patients taking interferon, and research suggests that people with a history of substance use and/or pre-existing psychiatric conditions may have more trouble tolerating therapy. But for some individuals, apprehension may be part of the problem. In Fleming’s study, anxiety about side effects was one of the reasons given for not initiating hepatitis C treatment, but some patients who initially declined therapy changed their minds after ongoing education. Both Fireman and Fleming noted that advance treatment with antidepressants before starting interferon can in many cases prevent or ameliorate treatment-limiting depression.
Some former and active IDUs may have trouble maintaining good adherence to hepatitis C therapy, but others can be treated successfully. In a research overview, Markus Backmund and colleagues noted that in some studies patients receiving opiate drug substitution e.g., (methadone or buprenorphine maintenance) responded as well as non-IDUs. Gail Matthews and colleagues from Australia found that even individuals who continue to inject drugs on occasion can still achieve sustained virological response to interferon-based therapy.
“Many of these barriers to treatment are potentially modifiable,” Fleming and colleagues concluded, “leading to the possibility that, with appropriate interventions, treatment rates may be increased.” Research and clinical experience alike suggest that the key to such success is providing extra support before and during HCV treatment.
Strathdee and colleagues emphasized the need for improved communication between patients and providers – for example, discussing realistic expectations may help patients deal with side effects. Backmund and colleagues stressed the importance of interdisciplinary collaboration among hepatologists, addiction specialists, social workers, and psychotherapists. And according to Fleming’s team, “Linkages to psychiatric care and substance abuse programs may also facilitate the treatment of patients with more complex needs.”
Brian Edlin and colleagues presented an overview of how successful models – in settings ranging from primary care clinics to methadone maintenance programs to clinics in correctional facilities – can integrate HCV testing, counseling and education, substance-abuse treatment, psychiatric care, social support, liver disease evaluation, and medical management of hepatitis C. Indeed, Holly Hagan and colleagues found that of 95 methadone programs surveyed, all require medical evaluation (most of which include liver function testing and screening for liver disease) and nearly all provide referral to medical care for those testing HCV positive (among abstinence-based drug treatment programs, 50% required medical evaluation and 75% provided HCV medical referrals). Given that an estimated one-third of HCV-infected individuals pass through the correctional system each year, according to Amy Boutwell and colleagues, “[t]esting, education, and, when appropriate, treatment of prisoners should be a cornerstone of the public health response to the hepatitis C epidemic in the United States.”
The special issue of Clinical Infectious Diseases provided two examples of successful programs. Lynn Taylor described how an HIV clinic funded by the Ryan White CARE Act integrated care for HIV/HCV-coinfected IDUs. Patients were given directly administered pegylated interferon at weekly clinic visits, plus a week’s worth of ribavirin in pill boxes to take with them. She reported 99% attendance at clinic visits; none of the patients had to stop therapy due to continued drug use, addiction relapse, or psychiatric complications. From another angle, Alain Litwin and colleagues described the integration of HCV care within a methadone maintenance program, including HCV screening, substance abuse counseling, psychiatric services, HCV support groups, directly observed HCV therapy, and referrals for diagnostic procedures. “Our approach has led to high levels of adherence, with liver biopsy and substantial rates of initiation of antiviral therapy,” the authors concluded.
Together, these articles add to the evidence that the barriers to hepatitis C treatment in IDUs are, in Fleming’s words, “substantial, but not insurmountable,” and offered strategies for the successful integration of multidisciplinary care.
Hepatitis C Virus Infection and Substance Abuse: Medical Management and Developing Models of Integrated Care. Clinical Infectious Diseases 40 (supplement 5). April 15, 2005 (entire issue).
Ding, L. Predictors and consequences of negative physician attitudes toward HIV-infected injection drug users. Archives of Internal Medicine 165: 618-623. March 28, 2005.
Liz Highleyman (email@example.com) is a freelance medical writer and editor. She studied at Harvard School of Public Health and is an emergency medical technician. She has written for numerous publications including POZ and the Bulletin of Experimental Treatments for AIDS.
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HealthWise: Hepatitis C and Sleep
Lucinda K. Porter, RN, CCRC
People living with chronic hepatitis C virus (HCV) infection commonly complain of fatigue. However, there are many causes of fatigue, with insufficient sleep being one cause. Before blaming everything on HCV, it’s important to rule out other factors that may be causing or contributing to fatigue.
The majority of adults in this country report sleep problems. Most of us have had a night of poor sleep. But too many nights of insufficient sleep can be harmful. Sleep experts say that adults need between 7 and 9 hours of sleep every night. The function of sleep is to restore your body. Inadequate or poor quality sleep can lead to daytime tiredness. Insufficient sleep can have a negative impact on daily performance and immune function, and has been linked to traffic accidents.
Start by talking to your doctor. Sleep problems can be caused by medical issues. One example is sleep apnea. Sleep apnea interferes with people’s breathing while they sleep and can cause serious health problems. People with sleep apnea often do not know they have it. Sleep apnea can be treated.
Tell your health provider about all the drugs you are taking. Some of these may be causing your sleep problems. For instance, certain cold medicines can keep people awake. Current treatment for HCV can also create sleep difficulties. Withdrawal from substances you have become dependent on can also cause insomnia.
Getting too stirred up before bedtime can make it hard to fall asleep. Worrying can cause us to toss and turn. Watching the news or exercising before bedtime can be over stimulating. Sleep experts recommend leaving the TV out of the bedroom. Turn off the TV and your computer an hour or two before bedtime.
The following can interfere with a good night’s sleep:
• Caffeine – coffee, sodas, tea, chocolate
• A room that is too hot or too cold
• An uncomfortable bed
• Using alcohol before bedtime
• Being hungry
• Eating a large meal close to bedtime
• Drinking too many liquids before sleep
• A snoring bed partner
• A pet in the bedroom
Some tips that promote sleep:
• It’s important to make 8 hours of sleep a regular habit. Sleeping less during the week and trying to catch up on the weekend doesn’t work.
• Try to go to bed at the same time every night.
• If you have a clock that is always lit up, turn it so you can’t see the time.
• Exercise every day.
• If you nap, keep it short and early in the day.
• Try reading before bedtime, but use a low-watt bulb.
• Do not eat a few hours before bedtime but don’t go to bed hungry. If you eat something, choose food that is light and nutritious. Avoid spicy or greasy food.
• Take a hot bath before retiring.
• If you feel you need to worry, tell yourself that you will only worry in the daytime. Make your bedroom a fret-free zone. Learn relaxation techniques to reduce stress and worrying.
• Listen to relaxation tapes before retiring.
• Do not lay awake in bed for more than 20 to 30 minutes. Get up and do something boring for a little while and then go back to bed.
• Your bed is for sleep and sex. If you are not doing either of these, stay out of bed.
Sometimes herbal teas can be used to aid relaxation. The downside of herbal teas is that some people are awakened by the need to urinate. Chamomile tea is one of the more widely used herbs for sleep promotion. The scent of lavender on linens or near the bed is thought to promote relaxation. If you use herbs for sleep, be very cautious. People with HCV should avoid some herbs, especially if they are undergoing HCV treatment.
If sleep problems persist, your medical provider may want to prescribe medication for sleep. Both prescription and over-the-counter drugs can be very effective for this problem. Some medications can be habit-forming, so it’s important to tell your provider if you have a history of substance abuse. With sufficient and accurate information, your medical provider is likely to find a medication that is suited to your situation. If the medication you try does not work well for you, report this to your provider. There are many drugs that can be used and sometimes it’s a matter of finding a good fit.
Insomnia can be a drain on your quality of life. Don’t lay awake thinking about it. Get some help.
• The National Sleep Foundation
729 15th St., NW, 4th Floor, Washington, D.C. 20005
Copyright, May 2005 Lucinda Porter, RN and the Hepatitis C Support Project / HCV Advocate www.hcvadvocate.org – All Rights Reserved.
Reprint is granted and encouraged with credit to both the author and the Hepatitis C Support Project.
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