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  --natural course of history of disease progression in HCV and HCV/HIV coinfection
--Transmission of HCV
--Testing: genotype, viral load, genotype, stopping therapy at week 12 or 24
--diagnostic tests: understanding the biopsy, ALT
--treatment for HCV in mono- and coinfected patients
--how does HAART affect the liver and what you can do about it
--management of side effects and adverse events, and tolerability of therapy
--who should be treated: HIV, IVDUs
--retreatment with pegylated interferon plus ribavirin for previously treated patients
--outcomes of therapy
--maintenance therapy
--new treatments in early development
--HCV/HIV coinfection policy and research direction and implications
The hepatitis C virus (HCV) is one of the most important causes of chronic liver disease in the United States. It accounts for about 15 percent of acute viral hepatitis, 60 to 70 percent of chronic hepatitis, and up to 50 percent of cirrhosis, end-stage liver disease, and liver cancer. About 4 million Americans, or 1.8 percent of the U.S. population, have antibody to HCV (anti-HCV), indicating ongoing or previous infection with the virus. 2.7 million have chronic Hep C. Hepatitis C causes an estimated 8,000 to 10,000 deaths annually in the United States. At the NIH HCV Consensus Conference in June 2002 HCV was called an epidemic.
African-Americans and Hispanics are disproportionately affected. The rate of HCV-infection among IVDUs is very high and IVDUs are the largest group of people infected with HCV. Among HIV-infected individuals 30% have HCV but among those infected with HIV by IVDU 60-90% are estimated to have HCV. Several studies suggest that HIV accelerates HCV progression at least 2-fold. HCV is the most prevalent blood-borne disease in the USA. 18% in an outpatient VA clinic had HCV in a study of 1000 persons. Among homeless vets the rate in a study was 40%. 39% had HCV in a prison study in California, and it was 55% among young women. The majority of people who die of HCV are 44-54 years of age.
A distinct and major characteristic of hepatitis C is its tendency to cause chronic liver disease. At least 75 percent of patients with acute hepatitis C ultimately develop chronic infection, and most of these patients have accompanying chronic liver disease.
Chronic hepatitis C varies greatly in its course and outcome. Chronic hepatitis C can cause cirrhosis, liver failure, and liver cancer. At one end of the spectrum are patients who have no signs or symptoms of liver disease and completely normal levels of serum liver enzymes. Liver biopsy usually shows some degree of chronic hepatitis, but the degree of injury is usually mild, and the overall prognosis may be good. At the other end of the spectrum are patients with severe hepatitis C who have symptoms, HCV RNA in serum, and elevated serum liver enzymes, and who ultimately develop cirrhosis and end-stage liver disease. In the middle of the spectrum are many patients who have few or no symptoms, mild to moderate elevations in liver enzymes, and an uncertain prognosis. These patients may go onto develop cirrhosis after 30, 40, or 50 years. Researchers estimate that at least 20 percent of patients with chronic hepatitis C develop cirrhosis, a process that takes 10 to 20 years or longer. After 20 to 40 years, a smaller percentage of patients with chronic disease develop liver cancer.
Some researchers estimate that about 20 percent of patients develop cirrhosis within 10 to 20 years of the onset of infection. 30-40% will never develop cirrhosis. About 40% may develop cirrhosis after 30, 40, or 60 years. Other researchers, including the NIH have reported that estimates of the proportion of chronically infected persons who develop cirrhosis 20 years after initial infection have been substantially higher from retrospective studies (17 to 55 percent) than from prospective studies (7-16 percent). The actual risk of progressive disease at 20 years is now considered to be closer to the estimates from prospective studies.
Cirrhosis can lead to liver cancer (hepatocellular carcinoma), HCC) and end stage liver disease or death. Liver failure from chronic hepatitis C is one of the most common reasons for liver transplants in the United States. Hepatitis C is the cause of about half of cases of primary liver cancer in the developed world. Men, alcoholics, patients with cirrhosis, people over age 40, and those infected for 20 to 40 years are more likely to develop HCV-related liver cancer.
HIV Coinfection
Results from a number of studies show that HIV accelerates HCV progression. The various results show an increased acceleration of 2-6 times. This suggests that HIV-infected patients may develop cirrhosis more quickly; and liver cancer and end stage liver disease more quickly. We have not had very many studies to clearly define if HCV progresses more quickly in HIV, nor have we had any studies to define the rate of progression oh HCV in HIV-infected patients. This makes it difficult to provide estimates of what percentage of patients will progress to cirrhosis, as we can do with HCV monoinfected patients, and how many years this will take. At this point most doctors appear to accept that HIV accelerates HCV progression and feel it's crucial to consider this in deciding when to begin HCV therapy. Doctors are very concerned about deferring HCV therapy in the HIV-infected patient who has fibrosis with say stage 2 disease. If a patient defers therapy close monitoring can be crucial.
There is a concern about how HAART medications may affect a patient's liver disease. The HIV antiretroviral drugs pass through the liver and liver enzymes (ALT) can be elevated mildly or more severely in a minority of cases. Having HCV or elevated ALT before starting HAART increases the risk that liver enzymes will be elevated. Although all the HIV drugs can be associated with ALT elevations, some may be more prone to cause this, such as d4T and ritonavir. All the HIV drugs have an affect on the liver. Double PI or PI boosted regimens may increase risk for elevated ALT. It may be helpful to select a regimen, if possible, that is less likely to cause ALT elevations.
The real question is what is the potential for harm to the liver from HAART medications for the person with HCV or HBV, or to the HIV+ person without hepatitis. Some patients are unwilling to start HIV therapy due to this concern, and some patients are nervous about staying on HIV therapy due to this concern and if they see ALT elevations while on HIV therapy. Some patients stop their HIV therapy due to this without telling their doctor. Some doctors are reluctant to start patients on HIV therapy if they have HCV.
There are some other factors affecting HCV+ patients associated with taking HIV medications. Some HAART medications, such as a PI or double or boosted PI regimen, may cause elevated fats in the blood. These fats can get deposited in the liver; this is called fatty liver. NRTIs may cause mitochondrial toxicity which can damage cells and occur in the liver cells. Such toxicity may not necessarily cause severe damage to the cells. But bear in mind, Ribavirin is an NRTI. A small number of patients from a study who were taking D4T/DDI and then added Ribaviron and Interferon developed pancreatitis. HCV and HIV infected patients can get increased glucose and diabetes. Patients with HIV experience higher rates of diabetes and it can be due to certain protease inhibitors. Patients with HCV are more likely to have diabetes then people without HCV. A damaged liver may be a factor in reduced or altered capacity to process fats and sugar. Patients with HIV are more likely to experience bone loss, reduce bone mineral density than people without HIV. Osteopenia and osteoporosis are more common in people with HIV than in people without HIV. A bone fracture can result from bone disease. HCV is associated with bone loss. This means people infected with HCV are more likely to have reduced bone mineral density than people without HCV. HCV/HIV coinfected patients may be more likely to develop lipodystrophy, and this may due to the factors mentioned immediately above.
So what can you do about this?
Not treating HIV can have severe consequences, since HIV can progress more quickly than HIV. Deferring HIV therapy when the timing is appropriate for a patient can be risky, HIV can seriously progress -- CD4 counts can go down, and infections can develop. If a patient has <200 CD4s it is important to try to raise the Cd4 count with HIV therapy. But if you haven't yet been treated for HIV it may be beneficial to consider HCV treatment first. This depends on your personal situation (CD4s, HIV viral load), but improving the condition of the liver may make HAART more tolerable.Select a HAART regimen that may be the least harmful to the liver If you are on HIV therapy you can talk to your doctor about the appropriateness of your regimen.
There has been little well done research on how HIV drugs affect the liver in the HCV+ patient. One French study found patients on HAART containing a PI did not see fast HCV progression. The same theory might apply to any HAART regimen that reduces viral load & increases CD4s. But this study was poorly conducted, has not been adequately confirmed with additional studies, and many doctors and researchers are skeptical of this theory. Other small studies have found that HAART drugs may affect the liver in a negative way. But all drugs affect the liver. The real question is do the HAART drugs have a significant negative clinical impact on HCV disease progression? We don't have an answer to this question yet. This is somewhat of a controversial issue. Doctors and researchers have different opinions. A number of researchers do not feel that HAART damages the liver in HCV-infected patients to a significant degree, while other doctors are unsure.
One way to address these concerns is to consider starting HCV therapy in the near term.
Transmission of HCV
Previous to 1991-1992 transfusion was a leading cause of HCV transmission. But at that time a blood screening test was instituted and the risk of transmission by transfusion has been very low since then. The main route of transmission for HCV today is by IVDU. HCV is transmitted by blood-to-blood contact, as is HIV. Most new HCV infections occur now from IVDU by sharing a contaminated needle or by sharing the paraphanalia used to prepare and use IV drugs. Sharing these even once can cause transmission. Drug paraphanalia includes the cooker (bottle cap or spoon used to mix the drug), the cotton used in the cooker through which the drug is drawn up into the needle, the torniquet used to tie up the arm, and the water used to mix with the drug. Transmission can occur by a needle stick in a health care setting to a health care worker.
The risk for sexual transmission is a controversial subject. There has been some research into this but not enough to well characterize the risk for sexual transmission. The risk of transmitting HCV from one person to another by sex is generally considered to be low, but itıs important to bear in mind the potential exceptions.. Among heterosexuals in a monogomous relationship studies have shown there is a risk but it is very low. Among heterosexuals who have been active sexually and have had multiple sex partners, the risk increases. It appears as though if an open sore from an STD such as herpes simplex is present this increases risk. If either sex partner has HIV the risk of HCV transmission increases. Anal sex may rupture membrane and may increase the risk for transmission. Sex during a womanıs period may increase risk. Sex that may draw blood could increase risk. So, for a monogomous or married heterosexual couple they should be informed that there is a potential risk but it is low. And they can discuss and decide upon the use of condoms. The CDC recommendations are that for such a couple a condom is not necessarily recommended. But for sexually active individuals condom use should be considered. Among men who have sex with men, one study found an increased risk associated with risky sex behaviors such as rimming and fisting. HCV can be transmitted from a pregnant woman to the newborn. But the risk of transmission of HCV was found to increase several times to about 18% when the woman has HIV. HCV has been found in semen and breastmilk but there is no evidence that itıs transmissible in this way. But I don't think there have been enough studies in semen and breastmilk to know for sure if it's transmissible that way.
There are other potential routes of transmission that most experts feel have a low risk but they have not been well studied. These include tattooing, household transmissions (such as by sharing toothbrushes or razors where blood can be present), the razor in a barbershop, utensils in a nail salon. Of course, if proper sterilization is practiced risk can be eliminated, but often sterilization is not used in certain of these circumstances. This discussion of potential routes of transmission is not exhaustive but I wanted to hit important points. Additional discussion can be found on the NATAP website. As you can see there are many unanswered questions about how HCV is transmitted. It is hard to conduct the studies required to answer these questions for several reasons including because if the rates are relatively low and there are so many potential routes of transmission you would need large studies. In addition, some people are reluctant to be honest about or donıt recall if they used an IVD one time.
Anti-HCV is detected by enzyme immunoassay (EIA). The third-generation test (EIA-3) used today is more sensitive and specific than previous ones. However, as with all enzyme immunoassays, false-positive results are occasionally a problem with the EIA-3. Additional or confirmatory testing is often helpful.
The best approach to confirm the diagnosis of hepatitis C is to test for HCV RNA (viral load) using a sensitive polymerase chain reaction (PCR) assay. The presence of HCV RNA in serum indicates an active infection. Testing for HCV RNA is also helpful in patients in whom EIA tests for anti-HCV are unreliable. For instance, immuno-compromised patients may test negative for anti-HCV despite having HCV infection because they may not produce enough antibodies for detection with EIA. Likewise, patients with acute hepatitis may test negative for anti-HCV when the physician first tests. Antibody is present in almost all patients by 1 month after onset of acute illness; thus, patients with acute hepatitis who initially test negative may need followup testing. In these situations, HCV RNA is usually present and confirms the diagnosis.
Recombinant Immunoblot Assay (RIA). Immunoblot assays are used to confirm anti-HCV reactivity, too. These tests are also called "Western blots". In some clinical situations, confirmatory testing by immunoblotting is helpful, such as for the person with anti-HCV detected by EIA who tests negative for HCV RNA. The EIA anti-HCV reactivity could represent a false-positive reaction, recovery from hepatitis C, or continued virus infection with levels of virus too low to be detected (the last occurs only rarely when sensitive PCR assays are used). If the immunoblot test for anti-HCV is positive, the patient has most likely recovered from hepatitis C and has persistent antibody virus. If the immunoblot test is negative, the EIA result was probably a false positive. Indeterminate RIA tests require further followup testing, including attempts to confirm the specificity by repeat testing for HCV RNA.
HCV RNA (PCR). Testing for HCV RNA is a reliable way of demonstrating that hepatitis C infection is present and is the most specific test for infection. Qualitative PCR amplification can detect low levels of HCV RNA in serum. Testing for HCV RNA is a reliable way of demonstrating that hepatitis C infection is present and is the most specific test for infection. Testing for HCV RNA by qualitative PCR is particularly useful when aminotransferases are normal or only slightly elevated, when anti-HCV is not present, or when several causes of liver disease are possible. This method also helps diagnose hepatitis C in people who are immunosuppressed, have recently had an organ transplant, or have chronic renal failure. A qualitative PCR assay made by Roche has now been approved by the Food and Drug Administration for general use. This assay will detect HCV RNA in serum down to a lower limit of 50 to 100 copies per milliliter which is equivalent to 25 to 50 international units. Almost all patients with chronic hepatitis C will test positive by this assay. The test result says a person is positive or negative, but does not tell the quantitative level of the viral load.
Several methods are available for measuring the titer or level of virus in serum (quantitative level), which is an indirect assessment of viral load. These methods include a quantitative PCR (Roche) and a branched DNA (bDNA) test (Chiron). Unfortunately, these assays are not well standardized, and different methods from different laboratories can provide different results on the same specimen. In addition, serum levels of HCV RNA can vary spontaneously by 3- to 10-fold over time. Nevertheless, when performed carefully, quantitative assays provide important insights into the nature of hepatitis C. Most patients with chronic hepatitis C have levels of HCV RNA (viral load) between 100,000 (105) and 10,000,000 (107) copies per milliliter. Expressed as international units (IU), these averages are 50,000 to 5 million IU. National Genetics Institute (NGI) offers the HCV Superquant test. NGI/LabCorp offer a very sensitive quantitative test measuring as low as 2-10 IU/ml and up to as high as 100 million IU/ml.
Viral levels as measured by HCV RNA do not correlate with the severity of the hepatitis or with a poor prognosis (as in HIV infection); but viral load does correlate with the likelihood of a response to antiviral therapy. Rates of response to a course of alpha interferon and ribavirin are higher in patients with low levels of HCV RNA. There are several definitions of a "low level" of HCV RNA, but the usual definition is below 1 million international units (2 million copies) per milliliter (mL).
In addition, monitoring HCV RNA levels during the early phases of treatment may provide early information on the likelihood of a response. If viral load has not been reduced by 2 log or more at week 12, there is a low likelihood that a patient will achieve a sustained viral response. Discontinuation of therapy at week 12 or 24 can be considered if a 2 log reduction has not been achieved. Although recent studies suggest evaluation at week 12 is sufficient there is concern that this may be too soon and a 24 week evaluation may be more reliable. Some patients, particularly those with HIV, may take lobger to achieve a 2 log response. Yet because of the shortcomings of the current assays for HCV RNA level, these tests are not always reliable guides to therapy. If a patient has advanced HCV, continuing therapy may be useful despite less than a 2 log reduction for the purpose of slowing HCV disease progression.
Genotype. There are 6 known genotypes, 1-6. Knowing the genotype of a patient's HCV is important in making recommendations and counseling regarding therapy. Patients with genotype 2 or 3 are 2-3 times more likely to achieve a sustained viral response to interferon/ribavirin. The duration of combination therapy may be 24 weeks or 48 weeks and that decision may be based on whether a patient is genotype 1 or 2/3.
All patients should be tested for their liver enzyme levels (ALT), HCV viral load, genotype, and a liver biopsy is recommended. The best way to evaluate a patient's disease is with a biopsy. Biopsy is helpful for grading the severity of disease and staging the degree of fibrosis and permanent architectural damage in a patient. Radiologic testing such as with ultrasound cannot tell what disease stage a person has except for cirrhosis. Patients with HCV monoinfection who have normal ALT year after year usually have early HCV disease but 12% can have more advanced disease. In HIV-infected patients a higher percentage of patients can have normal ALT but have moderate or greater liver disease. So, ALT is not completely reliable in assessing the stage of liver disease, particularly in HIV-infected patients.
In HIV, the viral load predicts outcome. If a patient has a low viral load they should have a good outcome, if CD4s are adequate. However in HCV, viral load does not predict outcome. A patient can have a low viral load and have cirrhosis. In HIV, a low viral load is 20,000. A high viral load is 100,000. In HCV, 500,000 is considered a low viral load. Viral load below 2 million is considered low.
HCV causes the following changes in liver tissue and biopsy can help in seeing these changes:
--Necrosis (death or injury to cells) and inflammation around the portal areas (port of entry to liver), so-called "piecemeal necrosis" or "interface hepatitis."
--Necrosis of hepatocytes and focal inflammation in the liver parenchyma (connective tissue framework as opposed to tissues performing special functions of the liver).
--Inflammatory cells in the portal areas ("portal inflammation").
--Fibrosis, with early stages being confined to the portal tracts, intermediate stages being expansion of the portal tracts and bridging between portal areas or to the central area, and late stages being frank cirrhosis characterized by architectural disruption of the liver with fibrosis and regeneration.
The degree of inflammation and necrosis can be assessed as none, minimal, mild, moderate, or severe. The degree of fibrosis can be similarly assessed. Scoring systems are particularly helpful in clinical studies on chronic hepatitis.
The therapy of chronic hepatitis C has evolved steadily since alpha interferon was first approved for use in this disease more than ten years ago. At the present time, the optimal regimen appears to be a 24- or 48-week course of the combination of pegylated alpha interferon and ribavirin.
Alpha interferon is a host protein that is made in response to viral infections and has natural antiviral activity. Recombinant (synthetically made in test tube) forms of alpha interferon have been produced, and several formulations (alfa-2a, alfa-2b, consensus interferon) are available as therapy of hepatitis C. These standard forms of interferon, however, are now being replaced by pegylated interferons (peginterferons). Peginterferon is alpha interferon that has been modified chemically by the addition of a large inert molecule of polyethylene glycol. Pegylation changes the uptake, distribution and excretion of interferon prolonging its half-life.
The development of pegylated interferon is an important advancement. Peginterferon can be given once weekly and provides a constant level of interferon in the blood, whereas standard interferon must be given several times weekly and provides intermittent and fluctuating levels. Interferon is administered by subcutaneous injection similar to how insulin is taken. More importantly, peginterferon is more active than standard interferon in inhibiting HCV and yields higher sustained response rates with similar side effects. Because of its ease of administration and better efficacy, peginterferon has been replacing standard interferon both as monotherapy as well as combination therapy for hepatitis C.
The accepted and preferred choice today for treatment is combination therapy with pegylated interferon plus ribavirin. Patients with HCV monoinfection and genotype non-1 can be treated for perhaps as little as 24 weeks. Patients with genotype 1 will need 48 weeks therapy. Although it has not yet been well researched, it is believed that patients coinfected with HIV will require 48 weeks therapy whether they have genotype 1 or 2. Preliminary response rates from studies of HIV-infected patients show these patients don't respond quite as well to therapy as HCV monoinfected patients. It's been suggested that a longer duration of therapy may improve their response rates. An 18 month therapy study is ongoing.
Ribavirin is an oral antiviral agent that has activity against a broad range of viruses. By itself, ribavirin has little effect on HCV, but adding it to interferon increases the sustained response rate by two- to three-fold. For these reasons, combination therapy is now recommended for hepatitis C and interferon monotherapy is applied only when there are specific reasons not to use ribavirin.
Two forms of peginterferon have been developed and studied in large clinical trials: peginterferon alfa-2a (Pegasys: Hoffman La Roche: Nutley, NJ) and peginterferon alfa-2b (Pegintron: Schering-Plough Corporation, Kenilworth, NJ). Peginterferon alfa-2a is given subcutaneously in a dose of 180 mcg per week. Peginterferon alfa-2b is given subcutaneously weekly in doses of 1.5 mcg per kilogram per week (thus in the range of 75 to 150 mcg per week). So, PegIntron is dosed by the patient weight. All patients receive the same dose of Pegasys. PegIntron is a powder and must be reconstituted by the patient by adding water. The water and powder come in 2 separate vials. Pegasys is provided in a liquid form in one vial. Pegasys is stored in a refrigeratoe and PegIntron is stored at room temperature, as long as its not abnormally hot such as in Florida in the Summer months.
Ribavirin is an oral medication, given twice a day in 200-mg capsules for a total daily dose of 800 to 1,200 mg based upon body weight and the form of peginterferon. When combined with peginterferon alfa-2b (PegIntron), the recommended dose of ribavirin is 800 mg per day. This is the current recommendation because Schering did not perform a study accepted by the FDA with dosing at other than 800 mg per day of Ribavirin. But they are conducting a study now examining Ribavirin dosed by the weight of the patient. When combined with peginterferon alfa-2a (Pegasys), the dose of ribavirin is 1,000 mg for patients who weigh less than 75 kilograms (165 pounds) and 1,200 mg for those who weight more than 75 kilograms. In all situations, ribavirin is given in two divided doses daily. Roche has completed a study examining 800 mg of Ribavirin vs 1000 or 1200 administered by weight (<165 lbs>). That is why these Ribavirin doses are recommended when in combination with Pegasys (peginterferon a-2a). At the present, peginterferon alfa-2a (Pegasys) has not been approved for use in chronic hepatitis C in the United States and is available only in clinical trials. Roche submitted their approval application to the FDA, review is ongoing, and approval is expected in October/November 2002. Thus, only peginterferon alfa-2b is available for general use. But, there has been a shortage of supply for PegIntron so there was a waiting list to get the drug.
Combination therapy leads to rapid improvements in serum ALT levels and disappearance of detectable HCV RNA in up to 70 percent of patients, depending on several factors including genotype, viral load, and stage of disease. Long-term improvement in hepatitis C disease occurs if HCV RNA disappears during therapy and stays undetectable once therapy is stopped (after 24 week follow-up period). Among patients who become HCV RNA negative during treatment, a proportion relapse when therapy is stopped. The relapse rate is lower in patients treated with combination therapy compared with monotherapy. Some studies have found that patients who are relapsers, nonresponders, and partial responders may achieve improvements in the condition of their liver, which in turn may slow disease progression. Nonresponders are patients who are unable to reduce viral load at all. Partial responders achieve a reduction in viral load while on therapy but viral load goes back up while still on therapy. However, these findings have not been firmly established so ongoing studies are examining this further. The NIH HALT-C study is exploring this question but we may not have results for another 4 years. This study is giving Pegasys + ribavirin to patients who were previous nonresponders. If they do not achieve a response on Pegasys/RBV patients will be offered a half dose of Pegasys for ongoing maintenance therapy to see if disease progression is slowed.
Long-Term Viral Outcomes & Cure: For patients who maintain negative HCV RNA for 24 weeks after stopping HCV therapy, results from several studies show 98% remain HCV RNA negative. Several small studies following patients for up to 11 years show well over 90% remain HCV RNA negative. One or two small studies show that they could not find HCV in the liver cells of these patients who were negative in the blood. In cancer when this type of response is achieved it is called a "cure" by doctors. So, HCV is considered "curable".
A 48-week course of combination therapy using peginterferon and ribavirin yields a sustained response rate of approximately 55 percent. A similar course of Pegasys monotherapy yielded in studies a sustained response rate as high as 35 percent. A response is considered "sustained" if HCV RNA remains undetectable for six months or more after stopping therapy.
The optimal duration of treatment varies depending on whether interferon monotherapy or combination therapy is used, as well as by HCV genotype. The patient's viral load before starting therapy also appears to be relevant to the response outcome. Patients with >2 million viral load have shown lower response rates than patients with <2 million viral load.
For patients treated with peginterferon monotherapy, a 48-week course is recommended, regardless of genotype. For patients treated with combination therapy, the optimal duration of treatment depends on viral genotype. Patients with genotypes 2 and 3 have a high rate of response to combination treatment (70 to 80 percent), and a study conducted with Pegasys and ribavirin found that a 24-week course of combination therapy yields results equivalent to those of a 48-week course. In contrast, patients with genotype 1 have a lower rate of response to combination therapy (40 to 45 percent), and a 48-week course yields a significantly better sustained response rate. Again, because of the variable responses to treatment, testing for HCV genotype is clinically useful when using combination therapy.
Three large studies have been conducted with pegylated interferon plus ribavirin in monoinfected patients. One study was conducted using PegIntron plus ribavirin. Two studies have been conducted using Pegasys plus ribavirin. These studies are used by the FDA for review of approval. The response rates in these studies were relatively similar for patients except for patients with genotype 1 and high viral load. In the PegIntron study (the Manns study) 29% of patients with genotype 1 and high viral load achieved a sustained viral response after 48 weeks treatment and a 24 week additional follow-up period. These patients received PegIntron 1.5 mcg/kg (weight-based dosed) once weekly by subcutaneous injection but only received 800 mg of ribavirin pills per day. This compared to 72% of patients (with genotype 1) who achieved a sustained viral response who had low viral load, and these patients received the same dosing regimen of PegIntron + RBV. So, this showed the difference in response between patients with low or high viral load.
There have been two large studies of Pegasys plus ribavirin in HCV monoinfected patients‹the Fried study presented at the 2001 DDW conference, and the EASL study presented this Spring at the European liver conference in Madrid. In the Fried study patients received either standard interferon plus ribavirin or Pegasys plus ribavirin for 48 weeks with a 24 week follow-up period. Unlike the Manns study all patients received 1000 or 1200 mg of ribavirin. Among patients with high viral load and genotype 1, patients receiving Pegasys plus ribavirin achieved a better sustained viral response than patients receiving standard interferon plus ribavirin (41% vs 33%). However, you should bear in mind that these patients received 1000 or 1200 mg ribavirin compared to the patients in the Manns study who received PegIntron with 800 mg of ribavirin. Since the dose of ribavirin is different this makes comparison of results difficult.
n the EASL study patients received either 800 mg of ribavirin or 1000 or 1200 mg of ribavirin plus Pegasys. There was no comparison arm in this study of patients receiving standard interferon plus ribavirin. Patients who received 800 mg ribavirin per day with Pegasys achieved a 35% sustained viral response rate. For patients receiving a higher dose of ribavirin (1000 or 1200 mg per day, based on patient weight) and genotype 1, those with a high viral load (>2 million) were able to achieve a 46% sustained viral response rate with 48 weeks of therapy compared to patients with a low viral load (<2 million) who achieved a 61% sustained viral response rate. This study found that patients with non-1 genotype, including genotype 2 and 3, patients responded the same whether they received 24 or 48 weeks therapy, or 800 or 1000/1200 mg per day of ribavirin, and regardless of their baseline viral load. The average sustained response rate was about 77%. In sum, this study found that these non-1 genotype patients could be treated for 24 weeks using 800 mg of ribavirin. This is important because 24 weeks of therapy is easier to tolerate than 48 weeks, and because 800 mg of ribavirin is easier to tolerate than 1000/1200 mg.
It is generally accepted that you should not compare results of one study to the results of another study. Although the baseline characteristics of the patients in these 3 studies are similar, there can be differences between the patient groups in the studies. As well, the study designs, implementation, and interpretation of results can be different. But, these two pegylated interferons are not being studied head to head. Therefore, the results of these studies are being compared by some doctors and patients.
Therapy in HIV Coinfection
Several studies were conducted a number of years ago finding coinfected patients responded as well to therapy as mono-infected patients. These studies were not well conducted and were small. More recently conducted studies, which are better designed, are showing preliminary data suggesting that coinfected patients may experience reduced rates of sustained viral response to HCV therapy compared to monoinfected patients. Coinfected patients may not respond as well to therapy as mono-infected patients, but coinfected patients can clearly respond well to therapy. This reduced response may be due to the impaired immune system caused by HIV. An additional concern is the ability of coinfected patients to maintain adherence to HCV therapy. Coinfected patients may experience more side effects and adverse events. These patients may be more likely to experience anemia and reduced white or red blood cells. As well, a high percentage of coinfected patients are African-Americans and studies find that greater than 90% have genotype 1. Patients with genotype 1 have a lower rate of response to therapy. One study showed that African-Americans with genotype 1 experienced lower response rates than Caucasians with genotype 1, so reduced response may not be due just to genotype.
Several large studies in coinfected patients are ongoing. ACTG 5071 is a moderately sized study in which patients are receiving either Pegasy s + ribavirin or standard interferon + ribavirin. After 24 weeks of therapy, patients receiving Pegasys/RBV had a much better response (44% undetectable viral load vs 15%). The 44% response rate was less than would be expected to be seen in HCV monoinfected patients. However, ribavirin was dose escalated starting with 600 mg per day. This was done to make therapy more tolerable and prevent study discontinuation of patients. But this may have affected the response rates. We await final study results. Roche is conducting 2 large coinfection studies using Pegasys + ribavirin in the US and internationally, but we don't have results yet. There are additional moderately sized ongoing studies in coinfected patients including the examination of PegIntron and ribavirin.
A French study of 400 coinfected individuals reported preliminary results in 2002. At the end of 48 weeks of therapy with PegIntron plus 800 mg of ribavirin/day 37% of patients had undetectable viral load (<100 copies/ml) compared to 24% of patients receiving interferon (standard dosing) plus 800 mg ribavirin/day. These rates are lower than observed in studies in monoinfected patients. In a small Spanish study of 68 coinfected patients, who received PegIntron plus 800 mg/ribavirin/day or stadard interferon plus 800 mg/ribavirin/day, the sustained response rate was 42% for patients receiving PegIntron regimen and 33% for the patients receiving stadard interferon regimen. These rates of response are lower than that seen in monoinfected patients.
Bear in mind that adherence to taking therapy is important in HCV just as it is in HIV therapy. The more adherent a patient is to taking the medications the better the response rates. Studies show that adherence of greater than 80% shows a better response rate than for patients with <80% adherence. 80% adherence means taking > 80% of the weekly interferon injections and ribavirin pills. Studies also show that patients taking >90% of the medications had a better response rate than patients taking 80% of the medications.
Side Effects, Adverse Events and Tolerability of HCV Therapy
Another important point for consideration is the tolerability of the drugs. These therapies for HCV can be difficult to tolerate. Patients may be discouraged from staying on therapy if they cannot tolerate the drugs. Obviously, if they don't stay on therapy they cannot achieve a positive outcome. Side effects and adverse events can be significant. Side effects can include fatigue, irritability, emotional distress, weight loss, and depression. Adverse events can include anemia, reduced red and white blood cell counts, and reduced platelet counts. Some of the side effects appeared at lower rates in the Pegasys/RBV patients (Fried study) than in the PegIntron/RBV patients (Manns study): depression, nausea, headache, myalgia, rigors. And other side effects and adverse events appeared to occur at similar rates in the two studies.
Most patients experience some of these side effects and have a varying degree of difficulty with tolerating the therapy. But some patients, a small percentage, do not have a problem with the side effects and some patients, a small percentage, will have more difficulty with them. The degree of difficulty in experiencing the side effects varies by individual. Many of these side effects are mild to moderate in severity and can be managed and tolerated. Side effects may diminish after the first few weeks of therapy. Acetaminophen (Tylenol) or Advil can be helpful for the muscle aches and low-grade fever. Clinically depressed patients may not be candidates for HCV therapy. This is an evaluation to be conducted by the doctor. However, less serious depression can be managed. Fatigue and depression are occasionally so troublesome that the dose of interferon may have to be decreased or therapy stopped early. But recently conducted preliminary research of drug therapy for this problem has found that EPO for anemia may avoid dose reduction or stopping therapy by improving hemoglobin. Similar therapy may be used for reduced white cell counts. Depression can be managed by using anti-depressants. Depression and personality changes can occur on interferon therapy and be quite subtle and not readily admitted by the patient. These side effects need careful monitoring. It is helpful for the patient's family or spouse to be called into a meeting with the doctor to apprise them of what side effects the patient may exhibit, particularly the irritability, emotional distress, fatigue, and depression. Support groups can be helpful in helping patients in their decision to accept therapy and during therapy.
Ribavirin causes a dose-related hemolysis of red cells; with combination therapy, hemoglobin usually decreases by 2 to 3 g/dL and the hematocrit by 5 to 10 percent. The amount of decrease in hemoglobin is highly variable. The decrease starts between weeks 1 and 4 of therapy and can be precipitous. Some patients develop symptoms of anemia, including fatigue, shortness of breath, palpitations, and headache.
The sudden drop in hemoglobin can precipitate angina pectoris in susceptible people, and fatalities from acute myocardial infarction and stroke have been reported in patients receiving combination therapy for hepatitis C. For these important reasons, ribavirin should not be used in patients with preexisting anemia or with significant coronary or cerebral vascular disease. If such patients require therapy for hepatitis C, they should receive interferon monotherapy.
Combination therapy with pegylated interferon plus ribavirin can uncommomly cause marked reduction in platelets (thrombocytopenia), neutropenia (neurtophils, a type of white blood cell). These adverse events including anemia may be slightly more common in HIV-infected patients. More uncommonly, therapy can cause autoimmune disease (particularly thyroid disease), and suicidal ideation or attempts. For these reasons patients are instructed to make weekly visits to their doctor upon initiation of therapy for 4 weeks. After the first month visits can lessen to every 2 and then every 4 weeks. It's important for the patient to inform the doctor of all experiences they are having.
A unique but rare side effect is paradoxical worsening of the disease. Because of this possibility, aminotransferases (liver enzymes) should be monitored. If ALT levels rise to greater than twice the baseline values, therapy should be stopped and the patient monitored. Some patients with this complication have required corticosteroid therapy to control the hepatitis.
Retreatment and Maintenance Therapy
What is the response to pegylated interferon for patients who were previously treated with interferon plus ribavirin but were not able to achieve a sustained response? Preliminary ongoing research suggest response rates of 11-15% for previous non-responders. Response to retreatment will be better for relapsers and partial responders than for non-responders. Non-responders to interferon monotherapy will respond better to retreatment with pegylated interferon plus ribavirin than nonresponders who received interferon plus ribavirin.
What is maintenance therapy? For patients who are unable to achieve a sustained viral response but have advanced disease "maintenance therapy" is a serious consideration. Patients can continue on a half dose of pegylated interferon in the hopes that interferon will slow disease progression until new drugs are developed. The results of a number of studies show that interferon slows disease progression, but these studies are not conclusive and doubts about the ability of interferon to do this linger. So it's expected that the ongoing HALT-C study, mentioned above, will answer the question. In the meantime results from this study are not expected for 4 years and doctors are using maintenance therapy for patients with no other options. The ability of the patient to tolerate interferon should be considered.
Achieving a sustained response for the person without cirrhosis should prevent progression of the disease. If a person has cirrhosis will achieving a sustained viral response prevent progression to cancer and decompensated liver disease? It should but we don't know for sure. Several studies already conducted provide evidence that interferon use in patients with cirrhosis and nonresponders can slow or reverse disease progression. A French study reported this finding at the AASLD liver conference in the Fall of 2002, and study results can be read on the NATAP website in the Conference Reports section. These results certainly support the notion that patients with cirrhosis who achieve a sustained viral response have a good chance of stopping and perhaps reversing disease progression. But some scientists are not convinced yet, so we need more studies to look at this question. The HALT-C study is examining this question. This study is exploring the possibility that half-dose Pegasys therapy can slow or reverse disease progression for previous nonresponders.
The recent NIH HCV Consensus conference panel of experts recommended that patients at risk for disease progression should be offered treatment. This 2002 conference however expanded their definitions of who should be recommended for treatment. The old 1997 conference panel recommended that all patients with fibrosis or moderate to severe degrees of inflammation and necrosis on liver biopsy should be treated and that patients with less severe histological disease be managed on an individual basis. Patient selection should not be based on the presence or absence of symptoms, the mode of acquisition, the genotype of HCV RNA, or serum HCV RNA levels. In the 1997 recommendations the panel were somewhat restrained or lukewarm in the strength of recommendations to treat patients with HIV. Regarding HIV, although they did not discourage treatment they said "the efficacy of combination therapy in HIV-infected people has been tested in only a small number of patients". The 1997 panel said therapy was contraindicated for active substance abuse, but the 2002 draft recommendations are clearly more supportive for treating these patient groups.
The 2002 draft recommendations said (they are available for reading on the NATAP website):
Injection Drug Users
Recent experience has demonstrated the feasibility and effectiveness of treating HCV in people who use illicit injection drugs (known as injection drug users or IDUs). This is important because IDUs comprise the largest group of hepatitis C patients in the United States, and successful treatment may reduce transmission. Management of HCV-infected IDUs is enhanced by linking IDUs to drug-treatment programs. Efforts should be made to promote collaboration between experts in HCV and substance-abuse providers. HCV therapy has been successful even when the patients have not been abstinent from continued drug use or are on daily methadone. Few data are available on HCV treatment in active IDUs who are not in drug treatment programs. We need support systems for these patients, and we need studies to explore the types of systems that may be more successful and to establish that they can work. A recent study reported at the 2002 DDW conference found patients on methadone maintenance who received group support could respond well to HCV therapy even if they experienced a brief relapse to IVDU. Timely intervention due to close monitoring through group support can stem the relapse and these patients could achieve a sustained viral response.
HIV Coinfection
F All HIV infected persons should be screened for HCV. Patients with chronic hepatitis C and concurrent HIV infection may have an accelerated course of HCV disease. Therefore, although there are no HCV therapies specifically approved for patients coinfected with HIV yet, these patients should be considered for treatment. Thus far, studies have enrolled only patients with stable HIV infection and well-compensated liver disease. In coinfected persons, an SVR can be achieved with HCV treatment. Some studies in coinfected patients are discussed below. Although treatment of HCV has not jeopardized control of the HIV infection, additional data are needed. In his report to the panel, David Thomas, MD, (Johns Hopkins University Medical School) strongly recommended that patients with HIV receive equal and adequate access to care and treatment for HCV. He made reference to that there are pockets of areas in the US where HIV-infected patients are not being tested for HCV.
New Treatments
Information from an early phase I study was reported at the AASLD liver conference in November 2002 on the first HCV protease inhibitor. The study was conducted in HCV+ patients. This study was preliminary and patients received the drug (BILN 2061) for 48 hours. The drug exhibited potency as HCV viral load decreased 2-3 logs by 48 hours and there did not appear to be safety concerns. Further studies are planned to begin in early 2003. As well, early studies are starting for a polymerase inhibitor in HCV-infected individuals this year. A second HCV protease inhibitor is expected to begin clinical study in 2003.
HCV/HIV Coinfection Policy and Research Direction
I've been following this field closely for several years, recognizing coinfection with HCV was emerging as a major concern. Many in the medical, patient, government, and service provider community still haven't fully realized the impact and potential impact HCV will or may have on HIV-infected patients. Several small and large studies show HCV is the leading cause of death in HIV increasing about 60% in recent years from about 5% to 8% of deaths in HIV. A number of studies show HIV accelerates HCV progression but we don't have clear characterization of nor do we understand well the natural history or course of progression of HCV in coinfected patients. In addition, there is little prevalence data on how many people have HCV and coinfection.
I have been advocating and speaking out for several years on the key issues our affected communities need to focus on improving, and these areas have not changed. areas of research and policy in coinfection where we need to step up attention include:
--HCV and lipodystrophy, metabolics, bone loss, and diabetes. A few small studies and an understanding of how HCV affects the liver and how HIV and HIV HAART affect the liver and these types of HIV-related complications (lipodystrophy) make it clear we need to do significantly more research into understanding this. HCV is asociated with bone loss and fatty liver and diabetes. As we know HIV is also associated with these complications. But, how is the coinfected patient affected (it's clear to me there is increased risk), and how can we address trying to manage or reduce the risks? This needs additional research attention. As David Thomas, MD, from Johns Hopkins Medical School, said in his talk on coinfection at the NIH HCV Consensus Conference, all areas of coinfection receive too little research attention.
--Should HCV or HIV therapy be started first? When should HIV-infected patient begin HCV therapy? It has been clear to me and others for 2 years that it appears important to consider HCV therapy first in the appropriate situation. But we need to research this.
--What is affect of HIV HAART medications and hepatotoxicity on liver disease progression? We don't have adequate answers to this question and this is an important area of resaerch needing attention. There is an ongoing initial study trying to examine this question. The best way to try to answer this question is pre- and post biopsy with HAART. Perform a biopsy before starting HAART and after being on HAART for a period of time.
--What do we do with special populations? A number of coinfected patients will be therapy nonresponders. African Americans respond less well to HCV therapy; but we don't understand why. An NIH study is examining this question. We have little data on response to therapy by Hispanics. What is the role of maintenance therapy in coinfection? We need research on these questions.
--How does HIV impair the immune response to HCV and what is the affect of HIV on response to HCV therapy? Some research into these areas have started. But we need to bolster and expand this research.
--There are potentially tremendous gaps in access to care & therapy for coinfected patients. Right now ADAP is mostly not covering HCV therapy. It remains uncertain what coverage Medicaid will offer. Studies show coinfected patients are not readily accessing the Hep A vaccine or perhaps the Hep B vaccine. There are gaps in access to proper diagnostic testing: HCV viral load, genotype testing, and liver biopsy are not readily available and reimburseable to all.
--Who will provide care to coinfected patients? The education level of HIV treating physicians in general about treating HCV is severely lacking right now. HCV treaters are not prepared to treat the the HIV-infected communities. The shear numbers of coinfected patients and the patient populations are not easily handled by HCV treaters. The HIV community of patients, educators, advocates, and service providers do not in general fully understand or recognize the problems related to coinfection. We have not begun to discuss a model for treating coinfected patients. A few hospital and clinic sites have implemented useful models, but on the whole few are discussing this.
--Most coinfected patients are African-Americans, IVDUs and Hispanics. This has tremendous implications for care, treatment, education, and reimbursement.
Management & tolerability of side effects and toxicities may be more difficult for some coinfected patients. We need to research better understanding of this for the goal of improving adherence and response to therapy.
--Coinfection is a different disease in a number of important ways from HCV. Support services needed for coinfected patients will be different but there has been virtually little discussion and committment about what the needs are & how to fund these programs. Special support groups, adherence programs, and services regarding self-injection for interferon are needed.
--A high proportion of IVDUs have HCV. It's estimated that 70% of patients on Methadone Maintenance have HCV, and 60-90% of those HIN-infected through IVDU have HCV. And we need programs to address these needs. HCV was recognized at the recent NIH Consensus Conference as an eidemic. It is more of an epidemic in HIV and among IVDUs. We need acceptance and recognition of this.
--In the end, we need new drugs to manage & treat HCV. We need to encourage and reinforce drug research.
This list on policy & care issues ir not meant to be exhaustive but highlights key concerns.
The recent NIH HCV Consensus Development Conference supported several important positions but as the Conference organizers said themselves their recommendations are not mandates but merely recommendations. Here are some key recommendations by the panel:
1. HIV positive patients should have access to care and receive treatment for HCV
2. IVDUs can respond well to HCV therapy in the right circumstances. The support this notion the panel recommended collaborations between the medical community and the community of service providers working with IVDUs would help promote creating & developing these circumstances.
3. Prisoners with HCV ought to receive attention in terms of receiving testing, care & treatment.
4. The panel recommended the establishment of an HCV Clinical Trials Group similar to the ACTG for HIV.
These are all good and supportable positions. The problem is that since these are only recommendations, not mandates, will these ideas be supported and instituted in the real world? At the moment there are no real-world mechanisms to institute these recommendations. This does not promote or encourage implementation of these recommendations.
Thanks to the National Institute of Diabetes & Digestive & Kidney Diseases of the NIH (NIDDK). Prepared by Jules Levin, NATAP
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