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In This Issue:
Retrovirus Conference Report on HIV/HCV Coinfection
Alan Franciscus, Editor-in-Chief
HealthWise: HCV Treatment and Sexual Dysfunction
Lucinda Porter, RN
HCV Treatment after Liver Transplantation
Alan Franciscus, Editor-in-Chief
HCV Advocate Eblast
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Retrovirus Conference Report
on HIV/HCV Coinfection
The 16th Conference on Retroviruses and Opportunistic Infections (CROI 2009) last month in Montreal featured several presentations on HIV/HCV coinfection, covering aspects including epidemiology, disease progression, and hepatitis C treatment. (Reports on sexually transmitted HCV among HIV positive gay/bisexual men will be covered in the next issue.)
72-week Extended Treatment
R. Chung and colleagues (abstract 103LB) reported the latest data from the SLAM-C trial (ACTG A5178), designed to look at interferon maintenance therapy and extended combination therapy in HIV/HCV coinfected patients (standard duration for coinfected patients is 48 weeks regardless of genotype). Initially, 329 coinfected individuals were treated with 180 mcg/week pegylated interferon alfa-2a (Pegasys) plus 1000-1200 mg/day weight-adjusted ribavirin for 12 weeks. At that point, participants who did not achieve early virological response (EVR) – at least a 2-log drop in HCV RNA – stopped ribavirin and continued on pegylated interferon alone (as reported at last year’s Retrovirus conference, maintenance therapy essentially demonstrated no benefit).
Of the 183 participants who achieved EVR, 169 opted to continue the combination regimen for a total duration of 72 weeks (data were available for 146); 78% had HCV genotypes 1 or 4, 29% had prior interferon experience, and 9% had cirrhosis. Overall, 51% of patients who achieved EVR went on to achieve sustained virological response (SVR) 24 weeks after completing therapy. But patients who achieved complete EVR – undetectable HCV RNA (< 600 IU/mL) at week 12 – were almost four times as likely to achieve SVR (62%) than partial early responders who had a 2-log drop but still detectable HCV viral load (17%). Overall, African-Americans had a lower SVR rate than non-black patients (38% vs. 57%). Among complete early responders, however, SVR rates no longer differed significantly according to race (65% for whites vs. 54% for blacks). About one-third of study participants stopped treatment before 72 weeks, with a majority of early discontinuations and dose reductions occurring during the final 24 weeks. The researchers concluded that patients who achieve complete EVR “do very well,” whereas those with partial EVR have “very limited responses.”
Gender and Side Effects
D. Bhattacharya and colleagues (abstract 845) conducted a meta-analysis to study the effect of gender and other predictors of adverse events in the pivotal APRICOT, ACTG A5071, and French RIBAVIC trials. Out of 1376 total participants, 21% were women. Overall, 50% of patients experienced adverse events (AEs) necessitating dose reduction, while 17% required premature treatment discontinuation. Women were significantly more likely than men to experience AEs leading to either dose reduction (61% vs. 48%) or discontinuation (24% vs. 16%), and these events also occurred earlier in women. However, the types of AEs leading to treatment changes were similar in both sexes. Constitutional symptoms such as fatigue and headache were the most common reasons for dose reduction (49%) or discontinuation (74%); the second leading causes were neutropenia for dose modification (26%) and depression for discontinuation (18%). Older patients experienced more side effects overall, but other factors differed between sexes. Men with lower body mass and women taking antiviral drugs in the NNRTI class were more likely to discontinue therapy, while women taking AZT (Retrovir) – which can cause anemia – had a high rate of dose reduction. In women, the researchers concluded, “antiretroviral regimen may be an important predictor of adverse events requiring treatment discontinuation during HCV therapy.”
Studies presented at the conference continued to produce conflicting data about whether HIV/HCV coinfected patients experience accelerated liver fibrosis compared to those with HCV alone. Looking at 92 coinfected and 128 HCV monoinfected hemophiliac men at 34 U.S. treatment centers who underwent liver biopsies, M. Ragni and colleagues (abstract 830) found that fibrosis was significantly more common in the coinfected compared with the monoinfected group (47% vs. 32.0%); average fibrosis scores were also higher in the former group (Ishak 2.3 vs. 1.9), despite a similar duration of HCV infection. Nearly half of HIV/HCV coinfected hemophilic men had a fibrosis score of 3 or higher, a 1.5-fold higher prevalence than in HCV monoinfected men, the researchers concluded.
In contrast, M. Jain and colleagues (abstract 831) performed a retrospective cross-sectional analysis of liver biopsies obtained from 180 HIV/HCV coinfected and 407 HCV monoinfected patients between 1998 and 2008. The HIV positive participants had relatively well-preserved immune function, with a median CD4 count of 459 cells/mm3. Coinfected and HCV monoinfected patients had a similar distribution of mild (39% vs. 34%), moderate (41% vs. 49%), and severe fibrosis (18% vs. 16%); the coinfected participants, however, tended to be younger (average age 43 vs. 47 years). Liver steatosis (fat accumulation) was less common among HIV positive individuals (37% vs. 59%). In a multivariate analysis, older age, steatosis, and elevated AST were independent risk factors for moderate-to-severe fibrosis, but HIV infection was not.
Using the non-invasive transient elastometry method (FibroScan), J. Pineda and colleagues (abstract 824) conducted another cross-sectional analysis of liver fibrosis among 1310 HIV/HCV coinfected participants in the Spanish GRAFIHCO study. Of these, 40% had a liver stiffness measurement of 9 kiloPascals (kPa) or greater, indicating significant fibrosis, while 19% had liver stiffness of 14 kPa or more, indicating cirrhosis. Significant predictors of advanced fibrosis were older age, heavy alcohol consumption, and longer duration of HCV infection. Having a CD4 count below 200 cells/mm3 was also marginally associated with worse fibrosis, which the researchers suggested supports earlier initiation of antiretroviral therapy for coinfected patients.
In another transient elastometry analysis, J. Del Valle and colleagues (abstract 826) studied 50 HIV/HCV coinfected and 30 HCV monoinfected patients who started pegylated interferon plus ribavirin. Liver stiffness measurements fell with therapy, from a median 7.6 kPa at baseline to 6.6 kPa 24 weeks after completion of treatment – a median decrease of 0.50 kPa. “Liver stiffness decreases significantly in HCV-infected patients treated with pegylated interferon and ribavirin, especially in those with higher liver stiffness prior to treatment and those who achieved sustained virological response,” the investigators concluded.
Past research has also yielded mixed data about the effect of HCV on CD4 cells in coinfected individuals. F. Ewings and colleagues (abstract 851) analyzed differences in how long it took after HIV seroconversion for the CD4 count to fall below 350 and 250 cells/mm3, as well as CD4 cell gains after starting combination antiretroviral therapy. The analysis included 1622 participants in the U.K. Register of HIV Seroconverters, of whom 85% were persistently HCV negative, 11% were HCV positive, and 4% seroconverted from HCV negative to positive. Before antiretroviral therapy initiation, HIV/HCV coinfected patients had 54 fewer cells/mm3 than HIV monoinfected individuals, even though they started anti-HIV treatment at about the same time. There was some evidence that CD4 counts declined faster in coinfected versus HIV monoinfected patients (1.2 vs. 2.4 years to fall below 350 cells/mm3; 3.5 vs. 5.6 years to fall below 250 cells/mm3), but the differences did not reach statistical significance. Among 823 individuals with data available after antiretroviral therapy initiation, there were no significant differences in time to HIV suppression or rate of CD4 cell recovery. “HCV co infected individuals may require frequent monitoring to ensure timely combination antiretroviral therapy initiation, but appear to experience the same benefits of combination antiretroviral therapy as those HCV uninfected,” the investigators concluded.
HCV Viral Load and Mortality
J. Rockstroh and colleagues (abstract 101) assessed the influence of HCV viral load and genotype on HIV and hepatitis C disease progression among 1952 coinfected participants in the EuroSIDA cohort. Within this group, 1537 patients (79%) had detectable HCV RNA (> 615 IU/mL), including 821 (53%) with HCV RNA of 500,000 IU/mL or higher and 716 (37%) with low HCV RNA (< 500,000 IU/mL). Individuals with undetectable HCV viral load and those with low HCV RNA had a similar incidence of all-cause and liver-related death, but patients with high HCV RNA had significantly higher mortality of both types; this relationship has not previously been observed in HCV monoinfected individuals. After adjusting for potential confounding factors, patients with HCV genotypes 2 or 3 had a lower all-cause death rate than those with genotypes 1 or 4, though the difference was only significant for genotype 3. HCV viral load did not affect virological or immunological response to antiretroviral therapy, but patients with HCV genotype 4 appeared to respond less well.
Hospitalization and Disability
Finally, B. Linus and colleagues (abstract 102) analyzed healthcare utilization among 359 HIV/HCV coinfected and 2723 HIV monoinfected patients in the ACTG Longitudinal Linked Randomized Trials (ALLRT) cohort (ACTG A5001), which is following participants enrolled in selected antiretroviral therapy trials. Participants provided annual self-reports about nights spent in the hospital, emergency department visits, and disability days (days spent in bed and days forced to cut back on work or other daily activities). Most patients were not receiving interferon-based therapy, so this did not influence disability rates.
HIV/HCV coinfected patients at all CD4 cell count levels spent more time hospitalized, made more emergency department visits, and experienced more disability days. After adjusting for potential confounding factors, coinfection remained a significant predictor of worse healthcare outcomes in all three areas. Differences between coinfected and HIV monoinfected patients were not statistically significant in the lowest CD4 cell strata, which the investigators attributed to “competing risks” in severely immunocompromised patients, and differences also diminished at the highest CD4 cell level. These findings led the investigators to conclude that “HIV programs serving a high proportion of HIV/HCV coinfected patients can expect 1.5 to 2 times higher rates of hospitalizations, emergency department visits, and disability days than would be expected from a similar population of HIV monoinfected patients.”
- Chung, R. et al. SLAM-C (ACTG A5178): Role of Early Virologic Response in Extended Therapy with Peg-Interferon and Weight-Based Ribavirin in HCV/HIV Co-Infection. 16th Conference on Retroviruses and Opportunistic Infections (CROI 2009). Montreal, Canada. February 8-11, 2009. Abstract 103LB.
- Morello, J et al. Ribavirin Plasma Levels at Week 4 Predicts Hepatitis C Virus Relapse in HIV/HCV-co-infected Patients Treated for Hepatitis C. CROI 2009. Abstract 842.
- Tural, C. et al. Effect of Ribavirin Plasma Trough Concentrations on Virological Response in Co-infected Patients on 4-Week Induction Dose of Ribavirin (1600 mg/day) and Peg-interferon a-2a (270 mg/week): Results from the CORAL-2 Study. CROI 2009. Abstract 841.
- Bhattacharya, D. et al. Women Experience Higher Rates of Adverse Events during HCV Therapy in HIV Infection. CROI 2009. Abstract 845.
- Ragni, M. et al. Cytokines and Liver Fibrosis in HIV/HCV Co-infection. CROI 2009. Abstract 830.
- Mamta, J. et al. Prevalence of Fibrosis Similar in Those with HIV/HCV Compared to HCV Alone. CROI 2009. Abstract 831.
- Pineda, J. et al. Prevalence and Factors Associated with Significant Liver Fibrosis Measured by Transient Elastometry in HIV/HCV-co-infected Patients. CROI 2009. Abstract 824.
- Del Valle, J. et al. Evolution of Liver Stiffness Evaluated by Transient Elastometry in Patients Treated with Pegylated Interferon + Ribavirin. CROI 2009. Abstract 826.
- Ewings, F. et al. HIV-infected Individuals Co-infected with HCV Appear to Have Faster CD4 Decline in the Absence of ART but Similar Response Once Combination ART Is Initiated. CROI 2009. Abstract 851.
- Rockstroh. J, et al. High Hepatitis C Viremia Is Associated with an Increased Risk of Mortality in HIV/HCV-Co-Infected Individuals. CROI 2009. Abstract 101.
- Linas, B. et al. The effect of HCV Co-infection on Health Care Utilization among HIV-Infected Subjects: the ACTG Longitudinal Linked Randomized Trials, Study 5001. CROI 2009. Abstract 102.
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Alan Franciscus, Editor-in-Chief
HCV & Cell Death
A new report from the University of Alberta is helping scientists understand the relationship between the hepatitis C virus and what causes the damage to the liver cell. In the past it was believed that the hepatitis C virus indirectly caused damage to liver cells—that is, that the virus itself didn’t kill the liver cell, but that the body’s adaptive immune system would attack and kill the entire liver cell that was infected with hepatitis C. In a study published in the February edition of PLoS Pathogens, Michael Joyce and colleagues transplanted human liver cells into mice and infected the liver cells with the hepatitis C virus. What they found was that the virus directly damaged the liver cell which could eventually lead to the death of the liver cell. This is noteworthy because mice do not have an adaptive immune system and proves that the virus itself can cause cell inflammation and death.
Source: PLoS Pathogens
In a somewhat related news story to the above, a new class of drugs believed to prevent the hepatitis C virus from entering the liver cell has just recently entered into a clinical trial. A new study of ITherX’s HCV inhibitor, ITX5061, is the first study of this type of inhibitor. The trial is a proof of concept study that will enroll about 40 HCV positive people who are treatment-naïve or treatment-experienced. The aim of the study is to test the safety, pharmacokinetic properties, and measure the effect of the drug on HCV RNA (viral load). The study will be conducted at various European sites.
Source: Company press release
Brazil: HCV among Athletes
The risk of sharing injection equipment is the most common transmission route of hepatitis C. However, very little has been reported about the incidence of HCV in athletes who have used injectable vitamins or performance enhancing drugs. In Brazil, a study1 was conducted by Dr. Passos and colleagues in which 208 former professional and amateur soccer and basketball players from the region of Ribeirdao Preto, Brazil answered a questionnaire about their use of injectable stimulants and other risk factors when they were participating in sporting activities. Of the 208 who answered the questionnaires, 24.5% of all the participants had used injectable stimulants—50.8% among the participants who were professional athletes. All of the participants were tested for hepatitis C by the ELISA antibody test. Those who tested antibody positive were confirmed with a viral load test (PCR) and a genotype test. The overall prevalence of HCV in the entire group was 7.2% (11% of the professional athletes, and 5.5% of the amateur athletes). It is interesting that, when the HCV positive results were paired with the questionnaires about injection use, there was a high correlation between those who self-reported stimulant injection (36% of those who tested HCV positive self-reported injection use) and HCV infection compared to those who did not report injecting stimulants (0.8%).
1Mem Inst Oswaldo Cruz, Rio de Janeiro, Vol. 103(8): 809-812, December 2008.
Cost of Digestive Disease
A report sponsored by the National Institutes of Health was released in Gastroenterology in February. The lead author of the study, J. E. Everhart, MD, MPH reported that the costs of digestive disease in the United States was estimated at 100 million outpatient visits and 13 million hospitalizations every year at a cost of $141.8 billion. The annual deaths from combined digestive diseases was estimated at 230,000. The price tag for viral hepatitis (hepatitis A, B, & C) was $3.3 billion dollars (direct and indirect costs). The top ten digestive disease costs (by type of disease) for both direct and indirect costs were estimated at:
- Digestive cancer – $24.1 billion
- Liver disease – $13.1 billion
- Gastro esophageal reflux disease (GERD) – $12.6 billion
- Gallstones – $6.2 billion
- Abdominal wall hernia – $6.1 billion
- Diverticular disease – $4.0 billion
- Pancreatitis—$3.7 billion
- Viral hepatitis (A, B, C) – $3.3 billion
- Peptic ulcer disease – $3.1 billion
- Appendicitis – $2.6 billion
Source: American Gastroenterological Association – www.gastrojournal.org
A research paper in the journal Hepatology about weight loss and fatty liver is yielding a wealth of information on the role of weight in the management of fatty liver and liver health in general. The study was conducted by S.A. Harrison and colleagues to find out if treatment with orlistat (brand name – Alli – an inhibitor of fat absorption in the intestines) when combined with calorie restriction (1,400 Kcal/day) and vitamin E (800 IU) would improve fatty liver and general liver health in people who are overweight. There were 41 participants in the 9 month study and they were divided into two groups – group A received orlistat (120 mg three times a day), diet restriction and vitamin E (800 IU); group B received vitamin E (800 IU) and diet restriction (no orlistat).
The researchers reported that group A had an 8.3% reduction in body weight compared to 6.0% in group B which did not receive the orlistat – the results were not considered statistically significant. However, when the results of the two groups were combined it was found that, in those who decreased their weight by greater than or equal to 5%, there were improvements in insulin sensitivity, fatty liver, and liver inflammation compared to those who lost less than 5% of their body weight. In addition, those who lost greater than or equal to 9% of their body weight also improved liver histology (health). The take home message of this study is that moderate weight loss can lead to dramatic improvement in the overall health of the liver.
Source: Hepatology, Volume 49, Issue 1, Pages 80-86
Fibromyalgia is believed to be an extrahepatic manifestation of HCV. There has long been a debate on the cause of and symptoms of fibromyalgia, but recent research has been pointing to a disorder that may be associated with the brain. Researchers at Louisiana State University conducted a study of 16 fibromyalgia patients to study the effect of stress on the brain by conducting brain imaging of the hippocampus region of the brain – the area that normalizes the effects of stress. What they found was that the hippocampus in the participants was not able to inhibit certain brain activity that helps to regulate the effects of stress.
The bottom line on this study is that it is important to control stress for everyone – especially those with fibromyalgia.
Romark made a couple of announcments recently about nitazoxanide (NTZ) – the company’s drug that they are testing as an add-on drug to the current standard of therapy – pegylated interferon plus ribavirin. The data from a Phase II study of treatment-naïve genotype 4 patients taking a controlled release version of nitazoxanide in combination with pegylated interferon plus ribavirin was recently released at the Asian Pacific Association for the Study of Liver Disease (APASL). The aim of the study was to determine the safety and effectiveness of two doses of controlled release NTZ (675 or 1350 mg twice a day (bid)) as a 4 week lead-in, followed by triple therapy (NTZ, PegIFN alfa-2A (Pegasys), ribavirin). There were three treatment arms:
- Placebo - 4 weeks; Pegasys plus ribavirin - 48 weeks (8 patients)
- NTZ-675 mg bid for 4 weeks; NTZ 675 mg bid, Pegasys, ribavirin for 36 weeks (17 patients)
- NTZ-1350 mg bid for 4 weeks; NTZ 1350 mg bid, Pegasys, ribavirin for 36 weeks (16 patients)
The interim analysis found that the rapid virological response (less than 12 IU/mL after 4 weeks), complete early virological response (less than 12 IU/mL after 12 weeks) and early virological response (greater than or equal to 2 log10 after 12 weeks) was higher in all of the groups that included controlled release NTZ. In addition, 82% in the 675mg dose group and 100% in the 1350 mg dose group were HCV RNA undetectable after 12 weeks. The drugs were shown to be safe and well-tolerated without any type of serious adverse events or treatment discontinuations.
In related news Romark announced that it had entered into an agreement with Chugai Pharmaceutical Co. Ltd., a member of the Roche Group, to license the development and commercialization of nitazoxanide as a treatment for hepatitis C in Japan.
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HealthWise: HCV Treatment and Sexual Dysfunction
—Lucinda Porter, RN
Ask any hepatitis C (HCV) patient who ever had treatment and you will likely learn that treatment is rough on one’s sex life. This includes male and female patients as well as their partners. Reports of sexual dysfunction are so common that researchers looked at this issue.
At the 2008 American Association of the Study of Liver Diseases meeting, Dove and colleagues1 designed a study to define the problem. While undergoing treatment with peginterferon and ribavirin, 260 men in 8 U.S. centers, completed sexual health questionnaires. Women were not included in this study.
Everything got worse during treatment. Impairment of sexual desire increased from a baseline of 37% to 53%. Erectile dysfunction increased from 26% to 39%. Ejaculatory dysfunction went from 21% to 31%. Overall sexual dissatisfaction jumped 44% to 54%. At the end of 48 weeks of treatment, more than half the participants reported that their sex life was worse than before treatment.
The men’s sexual health returned to baseline about 6 months after treatment ended. However, a small fraction continued to have ejaculatory and erectile problems that did not resolve during the 6 month post-treatment period.
Researchers found that sexual dysfunction began around 4 weeks after treatment started, gradually worsened, and resolved 6 months after treatment ended for all except the small number who continued to have some dysfunction. Dove and colleagues noted, “Initial impairment as well as worsening of sexual desire, function and satisfaction was associated with the presence of, and increase in depressive symptoms.” They recommend education and counseling.
“Note: Ribavirin, one of the medications used to treat HCV, has been associated with birth defects and fetal death. Pregnancy is to be avoided by women and female partners of men during and six months post-treatment. All patients, female and male are advised to use two reliable forms of birth control – in case one method fails. Pregnancy should be ruled out before starting HCV treatment. Practice contraception during and 6 months after completing treatment – even if pregnancy is only a remote possibility.”
The reasons for decline in sexual function were not specifically discussed. However, over the years of working with patients, coupled with my own experience on treatment, I have observed a variety of factors that may affect one’s sex life.
First, there is the issue that sometimes treatment feels like an out of body experience. This is not painful but it is weird. Being out of touch is rough on intimacy. Another problem is fatigue. The old joke about being too tired for sex can readily apply to HCV-treatment patients. When getting up from the couch takes too much effort, being amorous may seem like running a marathon.
Depression is another issue as it is a common side effect of HCV treatment. This alone may lower one’s libido or sex drive. Antidepressant medications may offer tremendous relief for depression but some of these drugs wreak havoc on the libido.
Treatment is hardly an aphrodisiac. Nausea, headache, and other adverse events crowd out thoughts of sex. The cosmetic side effects such as hair loss, dry itchy skin, rashes and brittle nails may contribute to a feeling of lack of attractiveness. Vaginal dryness is common, which can cause painful intercourse. Men report erectile and ejaculatory dysfunction while on treatment. If this is cause for despair, read on. There may be ways to minimize some of these treatment-induced problems.
If treatment is affecting your sex life, start by acknowledging the problem. We can’t fix what we don’t admit is broken. Next, talk to your medical provider. This may not be easy to do. Keep in mind that sex is a basic need. Sex and intimacy are part of being healthy.
Although treatment may cause sexual problems, your medical provider will want to rule out other causes. Exercise, sufficient sleep and general happiness are important elements of sexual health. Medications, substance abuse, diabetes and other diseases may cause sexual dysfunction. Hormones can also cause problems, sometimes easily fixed by taking replacement hormones.
“Note: Oil-based lubricants can break down condoms and diaphragms. When using latex birth control products, only use water-based lubricants as petroleum-based ones may eat holes through your protection.”
Erectile problems may be treated with medications, such as tadalafil (Cialis), sildenafil (Viagra) or vardenafil (Levitra). These work by increasing blood flow to the penis. Vaginal dryness can be treated with lubricants.
If antidepressants are the cause, your provider may recommend a different medication or suggest ways to take antidepressants that may relieve the problem. Some patients report good results when they take a few days off from antidepressants. However, this should only be done under medical supervision.
Not everyone feels the same about sex and our individual needs change with time and circumstances. It may not bother you that you don’t feel sexual. However, it may trouble your partner. Honest, open communication is critical. Perhaps you can explore new ways for your partner’s needs to be met. You may find ways to be intimate without sexual intercourse.
Experiment with massage or a candlelit evening at home watching a romantic movie. There are all sorts of ways to spice up life when it feels dull. If this feels too much for you to undertake, ask your partner to take the initiative.
Although it is common to experience treatment-induced sexual problems, it may surprise you to learn that the precise opposite experience has occurred. While discussing HCV treatment side effects, a nurse told me that two of her male patients told her that ribavirin intensified their sexual performance so much that they pleaded to stay on the drug. This anecdote certainly throws a Spanish fly in to the ointment.
Treatment-induced sexual problems are almost always temporary. If you still have problems six months after treatment has stopped, talk to your medical provider. Again, it is important to rule out other causes for the dysfunction.
Although it feels lousy, no one has ever died from sexual dysfunction. Remember treatment-induced sexual problems are temporary. Hang on to the reasons why you are undergoing HCV therapy. Remind yourself that you are taking care of yourself and that the side effects will pass. Get support and extra hugs. You deserve it.
1Decline in Sexual Desire, Function and Satisfaction in Men During Peginterferon and Ribavirin Therapy for Chronic Hepatitis C. L. M. Dove; R. C. Rosen; D. Ramcharran; A. S. Wahed; S. H. Belle; R. S. Brown; J. H. Hoofnagle. 2008, American Association of the Study of Liver Diseases meeting.
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HCV Treatment after Liver Transplantation
Alan Franciscus, Editor-in-Chief
Hepatitis C is the number one reason for liver transplantation in the United States. Unfortunately, since the hepatitis C virus is in the blood the new liver will become re-infected. In addition, the disease process can be much faster due to many factors, such as the use of immunosuppressive drugs to prevent the body’s rejection of the new liver but which also increase the rate of HCV replication and disease progression. The faster disease progression can lead to decompensated cirrhosis and the possibility of the need for another liver transplant. HCV treatment is urgently needed in these cases to eliminate HCV, and thereby help slow down or stop disease progression. However, treatment success rates in people who are waiting for a transplant or have recently received a transplant are historically low. This article will summarize a report conducted by F.D. Gordon and colleagues published in Liver Transplantation that reviewed available data on HCV treatment in post liver transplant patients with conventional interferon (with and without ribavirin) and pegylated interferon (with and without ribavirin).
The approach to treating hepatitis C after a liver transplant usually consists of two options:
Prophylactic: treat HCV immediately after transplantation to eliminate the virus before it has a chance to establish infection and damage the liver, or
Established infection: watch and wait using various screening tools and criteria to guide when and if treatment is needed
One approach is to start treatment soon after receiving the liver transplant. A review of literature found various studies using conventional (or standard) interferon (with and without ribavirin), and pegylated interferon (with and without ribavirin). Treatment was started two to six weeks after transplantation. In one study the sustained virological response rate (SVR – undetectable 24 weeks following treatment) was 4.5% in the patients who received conventional interferon or pegylated interferon monotherapy and 18.2% in the patients who received pegylated interferon (with and without ribavirin). Due to the difficulty of using ribavirin in liver transplant patients the ribavirin dose was started at 600 mg/day and raised to 1000 to 1200 mg/day after 4 weeks with the goal of maintaining the ribavirin dose throughout treatment (note: only 9% were able to achieve this goal). In another study using pegylated interferon monotherapy for 48 weeks only 8% of patients achieved an SVR. These results are not very encouraging especially considering the high rate of side effects. One of the reasons for the lower treatment response rates is the difficulty in maintaining the optimal dose of ribavirin since transplanted patients are already at risk for anemia. There are also other issues that affect the lower treatment response rates such as the use of immunosuppressive drugs to prevent the body from rejecting the new liver, and the body’s need to recover from a major surgery.
- In 2000 there were 5000 liver transplants performed – 37% because of hepatitis C
- After transplantation: 10 to 20% of HCV patients will develop cirrhosis – the likelihood of developing decompensated cirrhosis within 12 months is 42% in those with cirrhosis
- The 3 year survival rate is considerably lower in people with hepatitis C who have received a liver transplant compared to those who had a liver transplant but who do not have hepatitis C (78.5% vs. 81.4%)
- The 5-year survival rate is 30% for those with HCV who have had a liver transplant and have progressed to cirrhosis
In patients treated after evidence of established infection the use of conventional interferon or pegylated interferon plus ribavirin produced SVR rates between 20% and 37%. The authors noted that “a recent systematic review of predominantly therapeutic intervention studies also confirms that 30.2% of patients treated with pegylated interferon plus ribavirin will attain an SVR.”
Liver Transplantation Costs2
- Estimated first-year charge: 314,600
- Estimated yearly follow-up charge: 21,900
The predictors of treatment response are more useful in this setting. The best predictors of treatment response in the general HCV population are early virological response (EVR) which is defined as either elimination of HCV RNA or a 2 log10 drop of HCV RNA by week 12 of treatment. Breaking it down by type of EVR appears to be even more important – in a treatment-naïve population a log drop ≥ 2 log10 produced a positive predictive value (PPV = the proportion of patients who are correctly predicted to achieve an SVR) of 21% compared to a PPV of 83% in the patients who were HCV RNA undetectable at week 12. EVR and PPV have not been thoroughly studied in the post-transplant treatment population, but data from recent studies have found a PPV range of 49% to 69.2% that suggests the use of EVR is also useful in this setting.
The authors noted that identifying which patients are suitable for treatment at the pre-transplant stage, immediately following transplant stage (prophylactic) or after evidence of re-infection (established ) stage will be important to improve the SVR rates. Two new studies – PHOENIX (Pegasys plus Copegus Administered After Liver Transplantation for Hepatitis C) and PROTECT (Pegylated Interferon Alfa-2b and Ribavirin After Orthotopic Liver Transplantation: Efficacy and Safety in Hepatitis C Recurrence Therapy) will provide much needed information about the best strategies to improve HCV treatment outcomes in patients with post-transplant hepatitis C infection.
1 Liver Transplantation 15:126-136, 2009
2 Financial Matters: Liver Transplant Cost, www.cpmc.org
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HCV Cirrhosis is a Life Threatening Disease,
by Bennet Cecil, MD
Hepatitis C in Children,
by Philip Rosenthal, MD
- Hepatitis B in Children
- Hepatitis C and Telemedicine
- Hepatitis C in the Hispanic Population
- Overview of Treament of Hepatitis B
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