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Report 3, June 11
Reported by Jules Levin
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Therapy in Special Situations is the first section at this morning's session beginning at 8:30am. HIV/HCV coinfection will be reviewed later this morning by David Thomas, MD, from Johns Hopkins University Medical School. Side effects and tolerability of HCV therapy will be reviewed today. Today's conference ends at 12:30 and then the panel convenes. They are scheduled to present the consensus statement at 9am tomorrow morning. The statement will be made available on the NIH website:
Maureen Jonas, MD, from the Division of GI & Nutrition at Boston Children's Hospital, is reviewing Children & HCV. About 240,000 children in the US are HCV+ but this doesn't include special populations such as homeless women. She said that despite the report yesterday that new infections are decreasing she believes new infections in children is increasing in part due to transmission due to mother-fetal transmission. Pediatricians do not consider HCV infection but GI doctors & hepatologists do. Often this is because a mother heard about HCV and had testing performed. The disease is the same in kids as in adults. There appears that there is an association with age or time & progression, as in adults. It appears to be benign for 25 years. The interferon studies in children have been small and not controlled. The results show better results in children than adults. The average SVR was 35%. There is a difference between genotype 1 & 2 responses, as in adults. The suggestion is that because children are younger, have less advanced disease & better immune systems their responses may be better.
Two multi-national studies of 160 children have been conducted. She presents a study in 61 children aged 11 and received a dose equivalent to 5 MU in adults (I think 3 times per week). Mostly, they were genotype 1. RBV dose varied. 40-45% was the SVR. 31% with genotype 1 had SVR. Children with higher RBV dose had best response (45%). Height & weight improved in children after therapy. These children continue to be followed. Safety and adverse events was similar as in adults. Dropout rate was low.
In the next study of 100 children, results will be presented at AASLD. In a study of Pegasys, there were PK differences from adults. By week 12 82% (9/11) had 2 log drop in HCV RNA. These results are very promising. She recommended children less than 2 should not be treated and treatment should be conducted in clinical trials. Perhaps should be treated early because they appear to respond well.
Bruce Bacon, MD, from the Division of GI & Hepatology at St Louis University, reviewed patents with normal ALT. About 1/3 of patients have normal ALT. About 40% have slight elevations in ALT. Most patients with normal ALT have mild disease but 25% have advanced histology, and the only way to know about this is to do a biopsy. Some studies suggest progression is slower when ALT is normal. But some studies show these patients can have advanced disease. He reviewed an interferon study in patients with normal ALT, and the SVR was 19%. Over half of patients in this study had elevated ALT during the study. These response rates were equivalent to patients with abnormal ALT. The concern raised that ALT elevations during therapy may reflect harm. Bacon said that the rate of progression is about half for patients with normal ALT. Bacon commented that 6 months of following ALT should not dictate whether or not patient should have biopsy. I heard the tail end of the discussion on biopsy yesterday. My impression was that although there was some controversy on the need for biopsy but most doctors feel compelled that biopsy is required and important in patient evaluation. The results from biopsy yield important information in understanding the patient's liver status not just in understanding whether or not therapy should be started.
Bacon reviewed several studies. 6% (105) had ALT < 1.3 ULN in a registration trial of IFN/RBV HAI & fibrosis scores were lower in these patients. In patients receiving IFN/RBV with high or low ALT, SVRs were the same. In 19 patients in a second study SVR was 45%. In 124 patient study, 24 with normal ALT, ALT stayed normal and 25% achieved SVR. He reviewed Ira Jacobson's study presented at the recent DDW conference in 56 patients with normal ALT. Details available on NATAP website. Overall SVR was 33%, 24% for geno 1 and 80% for geno 2. There were in general no ALT elevations during study. In a PegIFN/RBV study patients responded well, particularly in patients with mild disease. Bacon recommended treatment should not be precluded for patients with normal ALT. They respond as well and there does not appear to safety issue. As well, they have early disease in general. Bacon commented that we see patients for 6 months evaluation period & measure ALT 2-3 times during that period while they may have had HCV for numerous years.
Teresa Wright, MD, Chief of GI at VA Medical Center in SF, reviewed managing patients with advanced disease. Once patients with cirrhosis develop the first severe decompensated complication the risk for severe complication is 50% over 10 years. The overall risk is 30%. The goal of therapy in these patients is first eradication but clear needs is to reduce risk for progression, HCC, improve histology, need for transplant, & to improve quality of life. Clinical endpoints have not been subject of study in patients with compensated cirrhosis. The studies have not been conducted for long enough to see clinical outcome. She reviewed several studies. The response rate in study using Pegasys was 30% and 7% using standard IFN. Patients with stage 4 was 32% and 22% for stage 3.
28% in the PegIntron/RBV Manns study had advanced disease (stage 3/4) but I think she said only 3% had cirrhosis. Patients with Peg/RBV achieved same response as patients with IFN/RBV. The study subgroup was perhaps too small to detect real differences. In the Fried DDW Pegasys/RBV study IFN/RBV was less effective than Pegasys/RBV 1000/1200 mg. The SVR was 43% vs 33%, favoring Peg/RBV, but again the numbers of patients were too small to draw conclusions. She reported on a study of pre and post treatment biopsies. The results found that patients receiving PegIntron had more improved histology than patients receiving IFN. She discussed study which reported that cirrhosis was partially reversible. I think she was referring to study reported by French recently. PegIFNs are associated with more toxicities and may affect ability to take medications. She concluded that therapy is safe and effective. But we need studies proving lon-term clinical benefit in these patients. She reviewed treatment of patients with decompensated cirrhosis and commented on extensive toxicities. She briefly mentioned the need for optimal therapy in transplant patients.
Alfredo Alberti, MD, from the University of Padova, discussed treatment during acute infection. He recommends treatment in acute infection but said we are not yet sure how to treat these patients. These cases are hard to recognize, as is acute HIV infection. The eventual clinical outcome may be difficult to assess in treating acute infection so long-term studies are needed. The available studies are 6 randomized studies using IFN monotherapy only. The studies were small. The most recent had the most of 44 patients published recently in NEJM. The SVR in patients treated in acute infection, outcomes are significantly better. In the NEJM study 98% had SVR using 5 MU units I think daily for 4 weeks then 5 MU 3 times per week. He reported on 2 studies treating within 20 weeks of infection achieving 90%+ SVR. In 9 studies looking at safety & tolerability, there was no deterioration in liver function although studies were not well done. In conclusion, studies provide evidence that chronic outcome is beneficial & should be recommended, although we're not sure how to treat. Available studies suggest you can wait 2-3 months before starting treatment. Daily high dose may be more effective & PegIFN should be more effective. He said we need studies in Peg monotherapy vs Peg/RBV and we need studies examining long-term clinical outcome studies. Alberti commented that patients with SVR were able to maintain response & achieve cure.
Dave Thomas, MD, from Johns Hopkins University Medical School, reviewed HCV/HIV coinfection. He reviewd ACTG 5071 study preliminary week 24 results. About 110 patients were randomized to Pegasys/RBV or IFN/RBV. Patients receiving Pegasys/RBV achieved better response (44% vs 15%). Coinfected patients can respond to therapy. Thomas said there was slight increase in grade 4 adverse events for patients receiving Pegasys but rate of discontinuation similar to that seen in IFN studies. Evidence is that SVR and improved histology can be achieved. Coinfection is understudied. Almost every area of coinfection has not received any adequate research. We are unsure how HIV affects HCV, how long should treatment last, benefits of maintenance therapy, and treating patients in hard to reach HIV+ populations. Thomas commented that so far in 5071 study there does not appear to be negative interaction between HCV medication & HIV medications. We await final study results. Thomas said there is no lower threshold of CD4 count that excludes HCV treatment unless there is some special situation, perhaps if CD4s are <50. Treating patient with low CD4s do have special considerations. But the concern for patient's ability to live is important consideration, and patients with low CD4s may die if they don't receive HCV therapy. Thomas suggested repeating biopsy closer to 3 years rsather thsan 5 in coinfected patients not receiving HCV therapy. In coinfected patients with grade 0 disease perhaps re-biopsy in 3 years is not needed. We need more data on this question, and I think he said an ongoing study is looking at this. Thomas commented that preliminary research shows that coinfected patients appear to respond as well to liver transplantation as HIV negative patients. The improved disease situation with HIV followed a huge government commitment & we need the same for HCV.
Brian Edlin reviewed IVDU and HCV. IVDUs are the largest group of infected patients. They are the group most infected by HCV & in whom most new infections occur. This needs much attention. The natural history of HCV in these group is not understood & has not been well studied. Who should be treated should be based on the individual situation. These patients need an interdisciplinary approach to address their HCV and drug use. Patients need support & monitoring before & during therapy. He said we need to teach safe injection & access to safe syringes. We need research into finding effective strategies on how to best treat these patients. Risk/benefit considerations should be used in deciding who to treat. Drug users should receive same consideration for treatment. Edlin said that there is abundant evidence that drug users can be adherent to HCV therapy, particularly when programs to support them are designed. It is difficult to screen out in advance who can adhere to treatment. Mental or psychiatric side effects of therapy can be managed in these patients. HCV & drug use can be treated in patients. Reinfection is a concern if patient continues IVDU. He said there is data supporting that reinfection can be prevented if patient uses IVDUs. He reported a German study showing recovering IVDUs taught clean & safe needle use could respond well to HCV therapy. In this study 80% of patients relapsed to IVDU. Keeping weekly clinical appointments was associated with success with therapy showing doctor/patient relationships & support programs is key to success. In this German study patients with IVDU relapse responded well to HCV therapy. Edlin referred to study reported at DDW recently of Methadone Maintenance therapy and the SVR was 29%. 33% of patients who intermittently used IVDs during HCV therapy achieved SVR. Patients who used moderate alcohol also responded successfully. Support groups are integral to success in this study. Details of this study are on NATAP website in DDW Reports.
These patients should receive discussion from doctors about treatment for drug recovery. He recommends this be in the new consensus statement. These patients need special support for adherence & mental health, and if these are not in statement this will not receive support. In addition, these patients need education emphasis for safe needle use. Edlin reported that evidence shows HCV spread can be decreased in IVDUs when safe needle & IVDU equipment is practiced. HCV can be transmitted by IVDU equipment: cookers, cottons, torniquets, etc. Doctors should be referred to needle exchange programs and patients should receive prescriptions for clean needles. And pharmacists should practice this as well. HCV in prisons needs attention, and prisoners also deserve access to treatment & care gor HCV. Patients on methadone maintenance should receive HCV treatment. With proper support programs IVDUs can succeed with HCV therapy. This includes treatment for substance abuse, street outreach & counseling. These programs can prevent HCV spread. Several observers commented that more of these types of programs in IVDUs with HCV are crucial for curbing the spread of HCV in these populations. One person commented from the audience that IVDUs and persons with psychiatric issues comprise the greatest proportion of persons with HCV. And these populations need the most attention.
Marion Peters, MD, Chief of Hepatology Research at UCSF, reviewed the use of alcohol use & HCV. She reviewed studies. French study showed 34% increase in progression in heavy drinkers compared to nondrinkers. From Japanese study cirrhosis rate increases in heavy alcohol use. She reported 2 additional studies showing heavy alcohol use increases fibrosis progression. Risk increases in these studies 2-3 fold. In another study, patients drinking >30 grams of alcohol death & progression worsened. In Italian study, as you drink more alcohol fibrosis rate progression increases. Alcohol increases fibrosis, heavy alcohol increases HCC and cirrhosis. There haven't been adequate studies in using low levels of alcohol. Response to therapy decreases as alcohol use increases during HCV therapy. Alcohol can increase HCV RNA and HCV diversity. Is there a threshold of alcohol amount that is harmful? We don't know. Since heavy drinkers don't respond well to therapy we don't know if they are abstaining during HCV therapy. She said that the data for low amounts of alcohol (1-2 drinks per day) are not available to state that all patients with HCV should abstain.
Doris Strader, MD, GI & Hepatology with the VA Medical Center in Washington DC, suggested that patients with minimal to moderate alcohol use (couple of drinks per day) may not be harmed & can respond well to therapy. If that's true she said they should not be excluded from HCV therapy. Patients need education about treatment and prevention. Patients not receiving treatment need close monitoring.
Anne De Groot commented that prisoners ought to be treated. She also suggested inmates should be tested for HCV. Treatment should be considered in correctional settings and adherence may be better in prison.
HCV+ persons need to be considered for hep A and B vaccinations. An audience participant commented that patients who are severely mentally ill can respond well to therapy & their side effects can be managed.
Michael Fried, MD, from the University of North Carolina, discussed side effects. He said the side effects can be managed. There have not been any new classes of side effects in PegIFN studies compared to that seen in IFN studies. Some side effects were lower incidence in Pegasys/RBV study, Fried was the investigator for this study. Dose reduction can be greater in Peg compared to IFN use. Many side effects are similar in terms of incidence comparing Peg vs IFN studies. Dose reduction can be used to manage side effects, but we need to evaluate through study the impact of dose reduction on SVR. Early preliminary retrospective study of Pegasys/RBV found dose reduction had less negative effects on therapy outcome than discontinuation. This needs further evaluation in prospective studies. Increasing adherence is important. Patient education before therapy on what side effects to expect and other issues can help adherence and encouraging success with therapy. Support groups can be very helpful. Anemia from RBV can be managed. Fatigue can result & a reduction in quality of life. Once therapy is discontinued hemoglobin should return to normal. Neutrophil count (neutropenia) can drop early after starting therapy and can be managed. A study of EPO found anemia may be manageable & RBV dose reduction addressed through use of RBV, but confirmatory studies are needed. Neuropsychiatric side effects are also a key concerning side effect. These side effects occur more often & can reduce adherence. These side effects can also be managed. Depressive side effects may occur more often in the first 12-24 weeks of therapy. Patients should be monitored early for depression & other side effects. You may have to communicate with a patient's family to evaluate depression in the patient. Suicidal ideation can occur, although infrequently. Anti-depressive medications can be used. HCV therapy dose reduction can be considered. We need further studies in evaluating managing side effects to optimize response to therapy.
John McHutchison, MD, from Scripps Clinic, reviewed future therapies for HCV. Disposal injection pumps may be developed to deliver interferon. Second generation RBVs may be safer having less side effects than the current RBV, and these drugs are in early research development. He mentioned histamine which is in phase 2 studies. Studies suggest perhaps there is benefit when combined with IFN or IFN/RBV. Further results from studies are needed to assess this therapy. Antiviral approaches include a number of potential targets including helicase and polymerase inhibitors but potential drug resistance should be considered. Numerous potential agents including antivirals are in early clinical & pre-clinical research. Several polymerase & helicase inhibitors are in early development stages. Antisense drugs are in research. One study of an antisense drug in patients saw ALT flares and HCV RNA reduction when high doses were used. Prevention of fibrosis progression is another approach to therapy. These drugs may reduce progression without an antiviral response. Gamma interferon is currently being studied in patients with advanced disease. Early research of this drug showed promise. McHutchison said he thinks IFN/RBV will remain the mainstay of therapy for the next 5 years. It can take 5 years to usher a new drug through the drug development process. We will however need studies to evaluate combinations of therapies with new drugs, as they become available.
There were 3 added unscheduled speakers at the end of the program. Here are their comments. They recommended stop smoking (I think there is some data showing smoking cigarettes can be harmful to disease), increased testing for HCV. Many patients don't know they are HCV-infected. The risk of infection from tattooing may be underestimated. IVDUs may be stigmatized and this may prevent adequate reporting of this as a source for transmission. HCV awareness needs to be increased among the public and medical community. Messages must be crafted to target specific populations. For example, messages to IVDUs must be designed for them. We must unduely alarm the public as we deliver these urgent messages. Screening & diagnosis must be available to all at risk. Information about treatment options, treatment education, must be effectively delivered. Access to treatment must be available for all. We need an NIH funded HCV trials research group. This group can fund other research groups and conduct its own research. This group can research vaccines, epidemiology, natural history, treatment outcomes, and other questions. The 1997 Consensus Statement was used all over the world and so this new document will be relied upon in countries all over the world. Most countries don't have the health infrastructure to issue such a document. Implications of the worldwide epidemic of HCV needs to be appreciated.
Editorial note from Jules Levin: NATAP provides HCV treatment education througout the USA. In my travels, including in big cities, I am stunned at the lack of knowledge and education about HCV/HIV coinfection in the HIV community among patients and service providers. There appears to me to be little communication about coinfection between HIV doctors and patients.
African-African and Hispanic communities are disproportionately affected by HCV but receive the least attention in terms of awareness, testing, and treatment education for patients and service providers. In addition, there is little support from local, state and federal governments to address these problems. Local government officials oftentimes would like to educate the community but are not adequately financially supported to do this. It appears the governments are examining the problems but not proactively addressing these problems. It appears that the state and federal governments do not want to spend the monies necessary to address these issues. Service providers and patients need special attention for treatment & testing education. Specialized support programs are necessary, but there is little appreciation on the part of the patient and service provider community of what is needed. And there is little willingness to fund these types of programs. At this point in time there appears to be major gaps in access & reimbursement for HCV therapy. For HCV/HIV coinfected patients receiving HIV medications through ADAP, currently there is virtually no access to HCV therapy from ADAP. I have visited numerous Congressional offices and found even less knowledge about HCV and HCV/HIV coinfection. In the end it's the patient stupid. And society. If we don't address the needs now the problem will worsen in our socirt. So it's cost effective to address these needs.
Tomorrow morning the panel will present a consensus statement for public scrutiny.
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