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By Sharon Stancliff, M.D. 8/18/02
Hepatitis C is the most common blood borne infection in the United States and injection drug use represents the most common mode of transmission. However until recently the NIH and some other policy-making bodies advocated against treatment of active drug users, and many liver transplant programs have denied transplants even to otherwise abstinent patients maintained on methadone (Koch). At the same time injection drug users (IDUs) and clinicians have been subjected to media and pharmaceutical company reports asserting that the majority of hepatitis patients will progress to severe liver disease (Heyman, Cowley), while an objective examination of the literature suggests otherwise.
Thus the clinician caring for the current or former injection drug user may be faced with the task of advocating for the patient's right to treatment while simultaneously assuaging unrealistic fears of disability and death.
Those providing care to drug users should be familiar with:
HCV is primarily a blood borne infection. Injection drug use (IDU) is currently the most common mode of transmission.
It is estimated that over 60% of HCV infections in the U.S. were transmitted through injection drug use. HCV appears to be much more easily transmitted than HIV, as is illustrated by a study in which after one year of injecting 65% of IDUs were found to be HCV positive while only 14% were positive for HIV (Garfein). The ease with which HCV is transmitted may have important implications for how best to construct prevention strategies.
It is possible for HCV to be transmitted sexually, but the frequency with which this actually occurs remains subject to significant debate as the data are not straightforward. Infection is associated with a history of multiple sex partners (Mele, Alter 1999) however transmission is low among monogamous heterosexual couples in which one partner is infected (Dienstag). Furthermore, the prevalence is not particularly higher among men who have sex with men who are being treated for sexually transmitted diseases (MMWR, 1998). The CDC estimates that 15-20% of currently acquired infections are sexually transmitted, but does not currently recommend condom use among monogamous couples for prevention of HCV in which one partner is infected.
HCV is transmitted perinatally to about 5% of infants born to infected mothers, with higher rates among mothers co-infected with HIV. The prognosis of perinatally infected children is unknown (American Academy of Pediatrics), however it is generally believed to be good. HCV is not considered by the CDC to be a contraindication to pregnancy.
Recipients of blood transfusions and/or organ transplants prior to 1992, clotting factors prior to 1987, and/or hemodialysis at anytime are considered at risk for HCV infection.
Body piercing, and shared items such as cocaine straws, razors, or toothbrushes have been suspected to be transmission vectors. In the late 1990's the CDC suggested that sharing cocaine straws was a mode of transmission, however further studies found few cocaine sniffers without another well-demonstrated risk factor. Tattooing under incarceration has been a documented mode of transmission (Thompson).
Occupational exposure is also a risk (Sulkowski 2002). The CDC estimates a 1.8% risk of infection when an needlestick injury source is HCV antibody positive.
The mode of transmission remains unknown for about 10% of patients. However it seems likely that the stigma surrounding injection drug use will continue to obscure our understanding of the epidemiology of HCV. A study of HCV infected blood donors who had initially denied drug injection found with in-depth interviews that 40% had a remote history of IDU (Conry-Cantilena). It is possible that more candid histories would reveal that injection drug use was in fact responsible for many infections currently classified as of sexual or unknown origin.
Most prevention efforts should be focused on IDUs, as this is the primary group at risk. Unfortunately it appears to be far more difficult to prevent the transmission of HCV than HIV. The CDC has reported that transmission of HCV among IDUs has been decreasing since about 1989 — coinciding with the beginning of HCV prevention efforts and provision of equipment for safer injection (Alter MJ 1997). However the validity of this report is subject to debate, particularly in light of data from syringe exchanges and in comparing the United States to Australia. An early study on the impact of syringe exchange found decreased prevalence of Hepatitis C among participants but no difference was found in a later study (Hagan 1997, 1999). Australia has a far more extensive network of syringe exchange programs and a very low prevalence of HIV yet continues to document high rates of HCV transmission, suggesting that these interventions are not sufficient (Crofts). Yet it would be inappropriate to give up all hope of abating the epidemic through syringe access. An Australian study found that prevalence at Australian syringe exchange programs has been decreasing (MacDonald), and decreases in prevalence in younger cohorts in Glasgow and Geneva are also suggestive of the success of harm reduction (Broers, Goldberg), as is the lower prevalence found in younger users in Chicago (Thorpe).
There are several reasons why syringe exchange and methadone maintenance treatment (Crofts 1997) do not seem to have a major impact on Hepatitis C. Users do not usually access these services early in their injecting careers when they are at high risk of HCV. Furthermore, while sharing syringes has been significantly reduced among drug users, the sharing of cookers and cotton has been implicated as a vehicle of transmission of HCV (Hagan2001). The actions of users assisting one another in injection have also been suggested as a possible means of transmission (Kral). Further research on the transmission and prevention of HCV among injection drug users is urgently needed.
The enzyme immunoassay (ELISA) is 99% sensitive and specific for HCV exposure but active infection must be confirmed by a qualitative viral load. A negative viral load should be repeated at least once to rule out infection. Regardless of the results of liver function tests, the NIH Consensus Statement recommends a liver biopsy in most cases to determine the extent of liver disease when considering treatment. A variety of circumstances including severe liver disease may obviate the need for a biopsy.
10-25% of patients have symptoms about 2 weeks to 6 months after infection, though these are usually mild. Between 70 and 85% of those exposed will become chronically infected.
The majority of these will develop some degree of hepatic inflammation, and it is now estimated that between 3-20% of chronic HCV patients will develop cirrhosis over the course of 20-40 years. Of these about 1% will progress to hepatocellular carcinoma each year. In the past it has been suggested that as many as 50% of HCV positive people would progress to severe liver disease but these estimates were based on patients recruited in hepatology clinics in which one finds patients who are already ill and therefore most likely to progress (Dore, Seeff, Thomas, Vogt, Kenny-Walsh).
Those infected through injection drug use may be less likely to progress (Gordon, Thomas, Rai).
Women and those infected at younger ages are less likely to progress.
Heavy use of alcohol is associated with more rapid progression (Poynard).
HIV infection is associated with more rapid progression however it is unclear if this is due to the virus, toxicity of HIV related medications, or the reconstitution of the immune system due to therapy (Soriano). The effect of HCV on the progression of HIV remains unclear but it probably does not have a major impact (Sulkowski 2002).
Level of hepatitis C viral load is not predictive.
Methadone has not been found to have an impact on progression, and HCV infected patients are not likely to need to decrease their methadone dose (Novick), in fact it has been suggested that HCV activity may cause an increase in the metabolism of methadone leading to higher doses requirements (Shinderman)
Given that the natural history of HCV remains unclear, deciding whom to treat is often complicated. Patients with HCV RNA, abnormal liver tests, and evidence of chronic HCV on liver biopsy may be considered for treatment. Those with persistently normal liver function tests are currently not recommended for treatment as one study showed no benefit and possible harm (Marcellin, NIH Consensus 2002). Patients with controlled HIV can respond to treatment (Soriano).
Those with a history of serious depression may require close follow up, as it is a major side effect of Interferon treatment, even in those with no history of depression. There is debate over treatment of those with advanced liver disease- full response is unlikely however it may slow the virus and reduce life-threatening complications (Wright).
The initial NIH Consensus Panel statement on Management of Hepatitis C suggested that drug users not be treated until abstinence had been achieved for 2 years - a time frame later modified to 6 months by the NIDDK. Following extensive debate and new studies on the issue (Edlin, Stephenson) the 2002 consensus reversed this and suggested that drug users be targeted for testing and treatment.
Treatment adherence by active drug users has been cited as a concern. While some studies have found somewhat lower rates of adherence to AZT treatment (Samet, Webster), others have found that drug users are able to comply with that regimen at rates comparable to those of nonusers (Samuels, Broers). Since then it has been shown that even active drug users can adhere to and benefit from the more complicated HAART therapy for HIV (Lucas). Furthermore, studies have found that drug users can complete and benefit from treatment for HCV (Backmund, Sylvestre. The NYS AIDS Advisory Council convened a workgroup on "Ethical Issues in Access to HIV Treatment" which concluded that it is unethical to deny HIV treatment on the basis of current or past risk group membership (NYS Lerner). Following the initial NIH consensus statement, the council referred to conclusion in protesting the HCV guidelines barring active users from treatment (Stephenson).
While more study would be useful, it is fairly clear that cocaine (Lefkowitz) and opiates (Novick) such as heroin are not hepatotoxic and there is no evidence that use of either presents any pharmacological contraindication to HCV treatment. While some have expressed concern that the similarities between the side effects of Interferon treatment and the symptoms of opioid withdrawal might induce relapse in patients with opioid abuse histories, there is no evidence supporting such a connection.
Alcohol is a more complicated issue. Alcohol consumption during treatment reduces the likelihood of response in a dose-related manner (Ohnishi). However the length of the period of abstinence prior to treatment to restore the response remains unclear. It is also unknown if drinkers who do not achieve a virologic response may still have a reduction in the risk of progression.
A comprehensive guide to HCV treatment is beyond the scope of this discussion, however it should be pointed out all injection drug users should be offered screening for immunity against Hepatitis A and B and offered vaccination if not immune. The risk factors for hepatitis B are similar to those for HCV. This is also indicated in persons with Hepatitis C as Hepatitis A may cause fulminant liver failure in HCV positive patients. Patients should also be informed that decreasing or stopping alcohol use is very important in preventing progression. Of the risk factors for progression this is the most modifiable.
Treatment has improved considerably, in clinical trials over 40% of those with the most common genotype clear the virus and may be considered cured. However the side effects — which may include a flu-like syndrome, severe anemia, and depression — can be disabling.
The barriers to follow up of a positive antibody test are significant. Although treatment has improved and the NIH Consensus no longer advises against treating drug users, significant barriers to HCV treatment remain.
A positive antibody test must be followed by a confirmatory viral load for a patient to learn if they are currently infected. This may be out of the reach of uninsured patients. There is also a federal cap on Medicare and Medicaid payments for the test of about $50 while the test costs $75-400 depending on the lab. Thus patients may be left knowing that they might be infected but without the tools to confirm it.
Actually obtaining treatment post diagnosis poses an even larger problem for the uninsured and under-insured. The expense of the medical evaluation necessary for treatment is significant and the medications cost at least $1500 a month; many patients may be unable to afford it.
For those able to access treatment it is important to understand that the regimen is extremely difficult for all patients — not just drug users. Two recent studies evaluating treatment outcomes outside clinical trials (Cawthorne) (Falck-Ytter) were quite discouraging. Many potential patients were eliminated because they did not adhere to the pretreatment testing (57 and 37% did not complete testing), others were excluded based on relative and absolute medical and psychiatric contraindications (27 and 34%). Of the few patients finally treated the sustained viral response was only 13%.
Given the high rates of Hepatitis C among injection drug users and the changes in the eligibility for treatment of IDUs, it may seem logical that routine screening should be promoted in drug treatment settings.
Depending on the available resources Hepatitis C positive individuals can be offered:
However in view of the lack of clarity regarding the outcomes of Hepatitis C, and the potential barriers to follow up confirmatory testing and HCV care, the treatment provider has an obligation to give education and information on available resources to individuals wishing to be tested. It is a very different test than the RPR for example, in which the diagnosis is relatively straightforward and the treatment is available and effective. The CDC guidelines recommend that counseling and consent accompany testing (MMWR); this counseling should include information on what follow up options will be available, if any.
Injection drug users remain at high risk for Hepatitis C. Harm reduction measures may be helping to reduce the risk, however the impact of such interventions appears moderate at best and more interventions are urgently needed. The natural history of Hepatitis C remains unclear, however there is evidence that progression in the injection drug using population is less assured than was previously thought. It is no longer recommended that drug users be actively excluded from treatment, however significant barriers to follow-up testing and treatment are still pervasive. These issues as well as local resources should be considered in designing educational and screening programs for drug users at risk of Hepatitis C infection.
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