Management Guidelines for the HCV/HIV Co- Infected Adult
Recommendations of a Multidisciplinary Expert Panel

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Introduction

Epidemiology, Natural History and Treatment of HIV

More than 45,000 Canadians have been reported to be infected with HIV, the virus that leads to AIDS [2]. Although men who have sex with men (MSM) remains the predominant risk group for HIV infection overall in this country, an increasing proportion of patients have been infected through intravenous drug use (IDU) and needle sharing with contaminated blood [2]. Injection drug use as a risk factor for HIV is found disproportionately in certain urban cities, and in Vancouver has now become the predominant risk factor for new cases of HIV. The HIV prevalence rates in Canadian IDU [3] is estimated as 25% in Vancouver,18% in Montreal, 20.5% in Ottawa-Hull, 8% in Toronto, and 14% in Winnipeg [4]. Also, injection drug use as a risk factor for HIV infection is increasing in proportion in certain sub-groups such as women, prisoners and aboriginals. In 1999 46.1% of all new cases of HIV in women in Canada, reported injection drug use as the primary risk factor [2]. A survey of federal prison inmates in 1998 determined that 33% were hepatitis C infected, 2% HIV infected and 24% reported a history of injection drug use [5]. Of the cumulative AIDS cases in Canada, 14.4% were reported in Aboriginals in 1999, compared to <1% in this ethnic group prior to 1990 [2].

Prior to the use of highly active antiviral therapy (HAART), the mean life expectancy of persons with HIV infection was 8-10 years [6]. Since the introduction of HAART, the incidence of opportunistic infections, hospitalizations and HIV associated mortality have decreased dramatically although the mean survival for patients in the HAART era is currently unknown [7-11].

Although no cure is yet realized, combination antiretroviral therapy has been the key to this success. The improvements in outcome were initially attributed to antiretroviral combination therapy with two nucleoside reverse transcriptase inhibitors (NRTI) together with 1-2 protease inhibitors (PI) [12,13]. However, more recent evidence has suggested that equivalent virologic (HIV RNA levels) and immunologic (CD4 cell) responses have been achieved with non-nucleoside reverse transcriptase (NNRTI) in combination with NRTI or triple NRTI based regimens, at least over the short term [14-16]. Treatment is costly, and difficult to adhere to because of the large number of pills, frequent dosing schedules with specific food and water requirements and frequent short term and long term toxicities ( i.e. peripheral neuropathy, diarrhea, renal colic, lipodystrophy etc.) which may be dose limiting [17].

The appropriate time to initiate antiretroviral therapy remains controversial and represents a balance in a given patient between prevention of immune damage and virologic failure resulting from non-adherence or antiviral resistance and quality of life issues related to drug adverse events [18]. No clinical trial data are available to dictate the best time to initiate therapy, although many guidelines based on expert opinion are available [19-22]. The most recent guidelines recommend the initiation of therapy if the CD4 count decreases below 350/mm³ or if the HIV RNA increases above 5000-30,000 copies/ml [19,20]. The goal of treatment is to suppress viral replication as completely as possible and for as long as possible, enabling stabilization or improvement in immune function and decrease probability of infectious complications. Although optimal responses (viral load suppression to <50 copies/ml) are observed in approximately 60-80% of patients previously naïve to therapy, the proportion responding to and the durability of response to subsequent or salvage combinations is less due to problems with resistance and cross resistance [23,24].

Epidemiology, Natural History and Treatment of Hepatitis C

Hepatitis C, an RNA virus, is transmitted from person to person by contaminated blood. Therefore, persons at risk include those who have been exposed to blood or blood products prior to the introduction of testing for anti HCV, (i.e.: 1990), and those who have been exposed to contaminated needles used for injection, either of illegal drugs, tattooing, body piercing or whenever reusable needles are used. Sexual transmission of hepatitis C occurs but at a significantly lower rate than either hepatitis B or HIV (e.g. <10%) [25]. Sexual transmission may be increased in the setting of mucosal damage related to trauma or sexually transmitted diseases. Maternal transmission of hepatitis C is <7% unless there is coinfection, where the figure rises to almost 20% [26]. Using antibody screening the prevalence of HCV in Canadians is estimated to be approximately 0,8% [27] Fewer will test HCV RNA positive. In certain populations, e.g. IDU, >80% are infected, typically within the first year of drug use. Long-term follow-up studies suggest that when children and young adults are infected with hepatitis C, persistent infection occurs in approximately 50% [28,29]. In those patients infected at an older age, it is probable that more than 80% become chronically infected [30] Persistent infection is associated with a chronic hepatitis which may range from mild to severe with varying amounts of fibrosis, from none to cirrhosis. Progression of this disease is generally slow, taking place over several decades. However, chronic hepatitis C infection is now the most common indication for orthotopic liver transplantation, as the infection is common and decompensated cirrhosis develops in about 20-30% of patients infected. Cirrhosis is complicated by hepatic decompensation and/or the development of hepatocellular carcinoma. Once cirrhosis is established, the rate of hepatic decompensation ranges from 25% at 10 years (Italy) to 25% at 5 years (United States) [31,32] In the Western world hepatocellular carcinoma is known to complicate cirrhosis secondary to hepatitis C in 1 - 4% per year [31]. Risk factors for rapidly progressive disease include: male gender, age >40yrs at the time of acquisition of HCV, daily alcohol consumption of >50 grams per day (3-4 drinks), obesity and immunosuppression particularly co-infection with HIV [33,34]

The current standard of care for chronic hepatitis C [35] is treatment with a combination of Interferon alpha 2b, 3 million units, 3 times a week, SC and oral ribavirin 1000 - 1200 mg daily given to patients who on an adequate liver biopsy have any inflammation > grade 2/4 and/or fibrosis ? stage 2/4 (METAVIR score [36] i.e.: more than minimal disease. If the Knodell score is being used this would be equivalent to an activity score of >6 and a fibrosis score of 0-1. The duration of therapy ranges from 6 months to 1 year depending on the pre-treatment and viral genotype. This therapy is expensive and is associated with many side effects. In those patients who require treatment for six months, cessation of treatment due to adverse events occurs in 12% and in those who require treatment for a year, in 21%. Sustained virologic response rates are less than 50% [37,38]. Long-term follow-up of patients treated for hepatitis C with IFN?2b plus ribavirin who have a sustained virological response at 6 months following cessation of therapy have a 97% chance of remaining with undetectable HCV RNA in serum (by qualitative Amplicor) for up to two years - longer follow-up data is not available [39]. Long-term follow-up studies following successful treatment of HCV with IFN monotherapy for up to 6 yrs indicate that lack of detectable HCV RNA in serum is associated with no progression of liver disease as judged by resolution of inflammation and no increase in fibrosis on liver histology [40,41,42]. Sustained virological response is also associated with a decreased risk of hepatocellular carcinoma [43]. Subjectively non-specific symptoms reported in subjects infected with HCV improve with a sustained virological response to therapy [44,45].

Impact of Coinfection with HIV and HCV

As both HIV and HCV share the same transmission routes, co-infection with these two viruses is common [46]. Hepatitis C co-infection is especially prevalent in persons who acquired HIV through the transfusion of contaminated blood or blood products (e.g. hemophilic patients and IDU). The immunodeficiency associated with HIV infection appears to accelerate the course of HCV [47-54]. The impact of treatment of either virus on the natural history of the co-infected patient remains speculative. Chronic liver disease and hepatocellular carcinoma related to HCV are emerging as increasingly common causes of death in persons with HIV, as their overall mortality and life expectancy from HAART therapy increase [55]. Consequently, recent attention has focused on the management of these two viruses in the co-infected patient. It has been recommended that patients with stable HIV be considered for treatment of the Hepatitis C. However, it needs to be recognized that the potential hepatotoxic effects of antiretroviral therapy may be enhanced in the co-infected patient and could have a negative impact on the liver disease due to HCV [56,57]. Further, as the pathogenesis of hepatitis C depends on the host immune response, improvements in immunity following the introduction of HAART could cause a flare-up in hepatitis C related liver disease as has been reported [58,59]. The optimal duration of treatment for HCV in the co-infected patient is unknown.

Special Issues for the Management of the Patient with Co-infection

Management of the patient with HCV/HIV co-infection frequently requires consideration of the treatment of 3 diseases - not only the HIV and HCV but also addiction and related problems. Without adequate functional control of the addiction issues, it is unlikely that treatment for either the HIV or HCV will be optimal. Not only are there treatment related concerns, such as a decreased ability to adhere to or tolerate the adverse effects of the antiviral therapy, but also there is a risk of progressive liver disease from continued alcohol use or re-infection with hepatitis C following treatment through continued unsafe needle use [60-63]. There is also concern that the subcutaneous use of nterferon could serve as a conditioned cue for relapse of needle use and addictive behaviors. There are also special issues related to the importance of education specifically targeted to this group, as well as access to care and treatment. In addition, issues of confidentiality related to the HIV infection may require particular sensitivity when working with certain subgroups, such as prison inmates and Aboriginals.

Identification of the Coinfected Patient (see algorithm)

Because of the overlapping risk categories (IDU, hemophiliac, blood transfusion recipients) co-infection should be considered in all patients diagnosed with either HIV or HCV infection. Counseling guidelines and patient information about the significance of
the test results are required. Upon diagnosis of HCV and/or HIV, in addition to referral to the appropriate physician(s) for care, the patient should be made aware of community organizations that can provide support and further information.

Recommendations:

• All HIV infected patients should have an HCV antibody test (Hepatitis C serology)(IIIA)
• Some HIV infected individuals may have a negative Hepatitis C antibody test despite co-infection although this is now rare with current assays [64]. Those with unexplained abnormal alanine aminotransferase levels (ALT/SGPT) or high risk (e.g. hemophilia, IDU) should have a PCR Amplicor qualitative test for HCV RNA if Hepatitis C serology is negative. (IIIB)
• Hepatitis C infected patients should have HIV testing (ELISA screening and Western Blot if positive) as appropriate for risk: (e.g. all those who have acquired HCV through IDU, hemophilia, contaminated needles, or blood transfusion and those with other risk factors for HIV - i.e. men who have sex with men, unprotected sexual intercourse with an individual from an endemic country, multiple sexual partners, previous STD, known HIV positive partner etc). This needs to be performed before the initiation of therapy for HCV. (IIIA)
• HIV testing must be performed within the context of appropriate pre and post test counseling [65] (IIIA).
• If the patient is HIV or HCV negative and appropriate risk reduction strategies are not adhered to - repeat testing at intervals is recommended (IIIA).

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