Focus on Hepatitis

• Introduction
• HIV/HCV Coinfection
• HCV Evaluation in HIV/HCV-Coinfected Patients
• HIV and HCV Treatment
• Preferred Therapies for HCV
• Management of HCV Therapy Side Effects and Toxicities
• Conclusion
• References

Introduction

Hepatitis C virus (HCV) was initially identified in 1989 when it was found to be the primary causative agent of non-A, non-B hepatitis, a condition associated with high rates of progressive liver disease, cirrhosis, end-stage liver disease, and hepatocellular carcinoma.

Since being identified, appreciation of the significant worldwide health impact of chronic HCV infection has grown. Approximately 170 million people, or 3 percent of the world's population, are infected with HCV, and the annual toll in lives and lost productivity due to HCV is staggering. In the United States alone, approximately 4 million people, or 1.8 percent of the population, are infected, and 10,000 people die each year due to HCV-related complications.

HCV is an enveloped RNA virus in the flaviviridae family, which has 10 variants, referred to as genotypes. The HCV genotype with which the person is infected is important, since it is somewhat predictive of the likelihood of HCV disease progression¹ and highly predictive of the likelihood of treatment success. It is now well established that genotypes 1 and 4 have the lowest rates of treatment success, while genotypes 2 and 3 have the highest.

The prevalence of HCV infection and of various HCV genotypes has significant geographic variability. HCV infection rates are approximately 1 percent to 2 percent in the United States and Europe, while some countries in South America, Africa, and Asia have rates from 2.5 percent to 10 percent. Further, while in many areas of the world -- for example, Europe -- genotypes other than 1 may predominate, in the United States genotype 1 is the most common, with genotypes 1, 2, 3 and 4 infecting approximately 71 percent, 14 percent, 12 percent, and 2 percent, respectively, of HCV-infected patients, while cumulatively genotypes 5 to 10 infect <1 percent of those patients.² Due to the high prevalence of HCV genotype 1 in the United States, achieving high rates of treatment success, especially in HIV/HCV-coinfected patients, can be challenging.

Patients infected with HCV have an 80 percent to 85 percent chance that the HCV infection will persist and that they will go on to have a chronic HCV infection. Chronic HCV infection has multiple manifestations, the most common of which is chronic, progressive liver disease associated with inflammation and fibrosis that in some patients may progress to cirrhosis. Cirrhosis, or end-stage liver disease, is associated with multiple complications including variceal bleeding, ascites, encephalopathy, and hepatocellular carcinoma. These conditions are common causes of morbidity and mortality in HCV-infected patients. In addition to liver disease, HCV-infected patients are also at risk for other "extrahepatic" medical conditions, including essential mixed cryoglobulinemia, Sjögren's syndrome, lichen planus, renal disease, arthritis, and porphyria cutanea tarda.

The evaluation and treatment of HCV infection are complex. An algorithm from the 2002 NIH Consensus Development Conference on the management of HCV provides a useful and simple algorithm for the diagnosis and treatment of HCV in HCV-mono-infected patients. (Figure 1)

As discussed below, the NIH consensus algorithm is not necessarily applicable in all respects to HIV/HCV-coinfected patients.

HIV/HCV Coinfection

Due to shared risk factors, HCV infection is present in a higher percentage of HIV-infected patients than the population as a whole. It is estimated that 300,000 people in the United States are HIV/HCV-coinfected, and, in some studies of HIV-infected, urban populations, HCV coinfection was found in 40 percent of all patients and 90 percent of persons who had hemophilia or a history of intravenous drug use (IDU). (Figure 2)

While most HIV/HCV-coinfected patients have intravenous drug use as a risk factor for HCV, other risk factors, including bloody fights, tattoos, body piercing, and unprotected anal or vaginal sex, also may have been the cause of HCV infection.^5-7 There is even some evidence for salivary shedding of HCV, which allows for the possibility that oral contact is another method for non-parenteral transmission of HCV.⁸

Since highly active antiretroviral therapy (HAART) became widely available in 1996, morbidity and mortality related to HIV infection have remarkably declined.⁹ In the meantime, however, the proportion of patients suffering morbidity or mortality related to liver disease, much of it related to chronic HCV, has risen significantly.¹⁰ The cause of this increased morbidity and mortality is likely to be multifactorial. Studies have demonstrated that HIV/HCV-coinfected patients may be at particularly high risk for cirrhosis and end-stage liver disease, hepatocellular carcinoma, and extrahepatic manifestations of HCV.^{11, 12} Factors that may contribute to these higher rates of HCV-related complications in HIV/HCV-coinfected patients include:

• Higher baseline HCV viral loads;

• Continued alcohol use/abuse;

• Immunocompromising conditions, especially a CD4 count <200 cells/mm³; and

• Liver toxicity from certain antiretroviral therapies (e.g., high-dose ritonavir [RTV] and nevirapine [NVP]).

Further, while controversial, some studies have also shown that HIV/HCV-coinfected patients may experience more rapid progression of their HIV infection and have compromised immune reconstitution with HAART compared to HIV-mono-infected patients.^13-16

HCV Evaluation in HIV/HCV-Coinfected Patients

The first step in providing appropriate monitoring and therapy for HIV/HCV-coinfected patients is to identify them. The recommendations of 1999 USPHS/IDSA Guidelines for the Prevention of Opportunistic Infections provide that all patients infected with HIV should be tested for HCV, and that HCV-positive patients should be counseled regarding their need for evaluation and, if appropriate, treatment of HCV.

Like HCV-mono-infected patients, the evaluation of an HIV-infected patient should include HCV serology; however, given the possibility of a false negative HCV serology in HIV-infected patients,¹⁷ consideration should be given to confirming a negative HCV serology by checking a qualitative HCV RNA PCR for the presence of HCV. In addition, HIV/HCV-coinfected patients should be counseled to avoid alcohol use and, if not immune, should be vaccinated against infection with hepatitis A or B virus.¹⁸

Since transaminitis, HCV viral load or genotype, and liver imaging -- for example, liver ultrasound or computerized tomography -- do not always correlate with the degree of HCV-related liver inflammation or fibrosis, a liver biopsy is indicated in most HIV/HCV-coinfected patients. A liver biopsy is associated with some risk -- complication rates, mainly bleeding, are generally in the 1 percent to 3 percent range and the risk of mortality is <.01 percent -- but the biopsy is important not only to establish the patient's current level of liver disease but also to predict the patient's risk of progression to cirrhosis, which is one indicator of the need for prompt treatment, and to rule out other liver diseases that may impact the patient's HCV treatment (e.g., non-alcoholic steatohepatitis).

There are a number of methods for assessing the histologic findings of the liver biopsy. Under one commonly used system, the METAVIR histologic scoring system, inflammation is graded from 0 (none) to 3 (severe) and fibrosis is staged from 0 (no fibrosis) to 4 (cirrhosis).

HCV-mono-infected patients with mild fibrosis (portal fibrosis without septa; stage 1) have a low risk of progression to cirrhosis over 15 years, while patients with more advanced fibrosis, indicated by stages 2 (portal fibrosis with few septa) and 3 (portal fibrosis with many septa), are at increased risk with a median time to progression to cirrhosis of 10 years and 18 months, respectively.

While a biopsy is generally desirable, treatment without biopsy may be reasonable in patients who are newly or recently infected with HCV or are infected with HCV geno-types 2 or 3 and those patients without stigmata of advanced HCV who refuse biopsy but are willing to accept HCV therapy.

HIV and HCV Treatment

Decisions regarding if and when to treat HIV/HCV-coinfected patients for their HCV disease requires close collaboration between the physician and the patient. This decision should include an assessment of the risks to the patient of HIV or HCV disease progression, the patient's risk of adverse consequences of HIV or HCV treatment, the likelihood that the patient will be able to take and tolerate HCV therapy -- for example, issues surrounding continuing psychiatric disease, intravenous drug use or alcohol abuse should be addressed, if at all possible, prior to therapy being started -- and the chance for a positive effect from the treatment, including slowing or reversion of fibrosis, prevention of HCV-related complications, and/or a sustained virologic response (SVR).

It is extremely important that clinicians keep in mind that while for some patients -- for example, those with early HCV disease, HCV genotypes 2 or 3, and a CD4 count >200 cells/mm³ -- the goal of HCV treatment is usually viral eradication, in other patients -- for example, those with more advanced HCV disease, HCV genotypes 1 or 4, and a CD4 count <200 cells/mm³ -- the goal may be to decrease ALT and HCV RNA, decrease fibrosis progression, decrease the risk of hepatoma and decrease the risk of death, all of which HCV treatment can achieve, even in the absence of achieving a virologic cure.

Balancing all the factors involved in making the decision to immediately treat HCV or defer therapy is often complex and requires a case-by-case approach. In making these decisions, clinicians and patients should be guided by information regarding the predictors of successful HCV therapy, which include:

• non-1 HCV genotype;

• no or low levels of fibrosis on liver biopsy;

• higher baseline CD4 count;

• lower HCV viral load (<2 million copies/mL);

• younger age (<40 years); and

• female gender.

The clinician and patient should also consider the absolute or relative contraindications to HCV treatment:

• decompensated liver disease;

• active alcohol or drug use (controversial);

• severe depression or other psychiatric disease;

• significant blood count abnormalities;

• autoimmune disorders;

• pregnancy;

• cardiovascular disease;

• diabetes mellitus; and

• renal failure.

While deferral of therapy is not unusual in clinically stable patients with stage 0-1 fibrosis, especially those with HCV genotype 1 (due to lower chance of SVR), clinicians and patients who opt to defer therapy should keep in mind that progression to cirrhosis in HIV/HCV-coinfected patients may be significantly more rapid than in HCV-mono-infected patients. Therefore, if treatment is deferred, a follow-up biopsy should be performed approximately every three years (the exact timing is controversial) to reassess and monitor the patient's status. Further, clinicians and patients should be mindful of data that indicate that early treatment in patients with mild fibrosis is cost effective and resulted in improved outcomes.^{19, 20}

Prior to deciding to defer HCV treatment, however, clinicians and patients should consider whether the best opportunity for HCV treatment may be missed. Unlike HCV-mono-infected patients, who generally experience slow progression of HCV-related liver disease and maintain a relatively intact immune system throughout their lifetime, the window of opportunity to treat HCV infection in HIV/HCV-coinfected patient's may be significantly smaller.

First, it is clear that the more intact the patient's immune system -- in particular, having a CD4 count >200 cells/mm³ -- the higher the likelihood of significant response or sustained virologic response to the HCV therapy. Therefore, if the HCV therapy is delayed too long, the chance for successful therapy may be compromised.

Second, since adherence to HCV therapy is critical for success, having the patient on as few medications as possible -- and only the HCV therapy, if possible -- is obviously desirable in order to minimize the chance of treatment fatigue, additive side effects, or drug interactions. This line of logic would support starting therapy at an early juncture, preferably prior to the need for HAART, but to this point studies have not definitively established this approach. An AIDS Clinical Trial Group (ACTG) study will shed some light on this issue by evaluating in HIV/HCV-coinfected patients with CD4 counts >350 cells/mm³ whether it is better to start HAART (for six months) and then add HCV therapy or treat HCV first, and add HAART later.

Of course, it should be noted that if HAART is used in combination with HCV therapy, and ribavirin in particular, caution should be exercised regarding the use of didanosine (ddI) (increased intracellular levels increase risk of toxicity), zidovudine (ZDV) (risk of additive anemia due to bone marrow suppression and decreased ZDV efficacy due to decreased phosphorylation), and stavudine (d4T) (risk of decreased efficacy due to decreased phosphorylation).

Finally, the decision about whether to treat HIV or HCV first, or treat both simultaneously, is a complex one. This decision involves many factors that must be weighed by the clinician and the patient, including:

• the risk for HIV progression in the absence of HAART -- especially since the patient's CD4 counts may be lowered by HCV therapy;

• the risk of HCV progression in the absence of treatment;

• the possibility that HIV therapy -- by boosting the patient's CD4 count and other potential immune benefits -- can improve the chance for successful HCV therapy or the patient's degree of liver fibrosis;²¹ and

• the possibility or reality of patient intolerability of HIV therapy due to hepatotoxicity.^{22, 23}

Needless to say, consulting a clinician experienced in making these decisions can be of great help in arriving at the appropriate treatment decision.

Preferred Therapies for HCV

In the past few years, significant advances have been made in the treatment of HCV. These advances include the use of ribavirin in combination with interferon and the development of two pegylated interferons: pegylated interferon alfa-2b and pegylated interferon alfa-2a. These developments have revolutionized the treatment of HCV and are rapidly becoming the standard of care.

The combination of pegylated interferon plus ribavirin has significantly increased the percentage of patients achieving an SVR -- that is, an undetectable HCV RNA level six months following the completion of therapy. These improved success rates are reflected in several studies involving HCV mono-infected patients in which treatment with pegylated interferon plus ribavirin was compared to treatment with standard interferon plus ribavirin.

In a large study by Manns et al., high-dose pegylated interferon alfa-2b (1.5 µg/kg/week) plus ribavirin (800 mg/day) achieved an overall SVR of 54 percent, with 42 percent of genotype 1 and 82 percent of genotypes 2/3 achieving SVR. In patients overall and with genotype 1, but not with genotypes 2/3, the SVR rates achieved with high-dose pegylated interferon alfa-2b plus ribavirin were significantly better than those achieved with lower doses of pegylated interferon alfa-2b (0.5 µg/kg/week) plus ribavirin (1,000-1,200 mg/day) or interferon alfa-2b (3 MU subcutaneously three times per week) plus ribavirin (1,000-1,200 mg/day).²⁴ (Figure 3)

In a major study by Fried et al., the investigators compared pegylated interferon alfa-2a (180 µg/week) alone to pegylated interferon alfa-2a (180 µg/week) plus ribavirin (1,000-1,200 mg/day) to standard interferon alfa-2b (3 MIU subcutaneously three times per week) plus ribavirin (1,000-1,200 mg/day). Overall, SVR was achieved in 30 percent, 56 percent, and 45 percent of subjects, respectively. Further, unlike the Manns study which involved pegylated interferon alfa-2b, in this trial SVR in the pegylated interferon alfa-2a plus ribavirin arm was not only significantly higher overall and in the genotype 1-infected subjects, but also was significantly higher in those subjects infected with genotypes 2/3.²⁵

Preliminary results from the largest two studies conducted to date evaluating pegylated interferon and ribavirin treatment in HIV/HCV-coinfected patients -- ACTG 5071 and RIBAVIC -- indicate it also leads to higher rates of success in that population, especially in patients with the more difficult-to-treat HCV genotype 1. It should be noted, however, that the rates of success seen in those trials were lower than those seen in the HCV-mono-infected patients, indicating that the presence of HIV infection compromises the efficacy of HCV treatment even in patients with relatively high CD4 counts.

ACTG 5071 enrolled HIV/HCV-coinfected patients, the majority of whom were on HAART, and randomized them to pegylated interferon alfa-2a (180 µg/week) plus ribavirin (600-1,000 mg/day) or interferon alfa-2a (6 MIU thrice weekly for 12 weeks followed by 3 MIU thrice weekly) plus ribavirin (600-1,000 mg/day). At 24 weeks of therapy, the pegylated interferon arm achieved higher rates of virologic response overall (44 percent versus 15 percent, p=0.0003) and in genotype 1 patients (33 percent versus 7 percent, p=0.0014), and there was also a strong trend toward higher response rates in genotype 2/3 patients (80 percent versus 40 percent, p=0.06). (Figure 4) Predictors of virologic success included use of pegylated interferon, white race, a Karnofsky performance status of 100, and a fibrosis score of 0-2 (out of 6). Toxicities were somewhat higher in the pegylated interferon arm, in particular those patients experienced more grade 4 toxicities (11 percent versus 6 percent, p=0.0012) and a greater loss of CD4 cells (194 versus 112 cells/mm³, p=0.01).

The RIBAVIC trial also enrolled HIV/HCV-coinfected patients, 80 percent of whom were on HAART and who had a mean CD4 count of 515 cells/mm³, and randomized them to receive either pegylated interferon alfa-2b (1.5 µg/kg/week) plus ribavirin (800 mg/day) or interferon alfa-2b (3 MIU thrice weekly) plus ribavirin (800 mg/day). At 48 weeks of therapy, using either an intent-to-treat or as-treated analysis, the pegylated interferon arm achieved higher rates of virologic success overall (38 percent versus 24 percent, p=0.01; and 51 percent versus 31 percent, p<0.01, respectively). (Figure 5) While rates of success were higher in patients with HCV genotypes 1 and 4, they were similar in HCV genotypes 2 and 3. Due to high rates of toxicity, over 50 percent of the patients had discontinued therapy by week 48. The side effects and toxicities leading to these discontinuations included generalized flu-like symptoms, and gastrointestinal, psychiatric, respiratory, and dermatologic problems.

The ACTG 5071 and RIBAVIC studies indicate that response rates in HIV/HCV-coinfected patients are improved by but remain suboptimal with the use of pegylated interferon and ribavirin combination therapy. This therapy presents many unique challenges in HIV/HCV-coinfected patients, including problems with tolerance and potential non-adherence. Guidance regarding the chance of therapy success may help to encourage patient tolerance of some side effects, improve adherence and, in patients who are experiencing problems with the therapy, provide an additional basis for considering continuation of therapy.

In a recent study, HCV-mono-infected patients who failed to achieve a 2 log 10 copies/mL decline or undetectable HCV RNA by week 12 had only a 3 percent chance of achieving SVR, while patients who did achieve that level of HCV RNA suppression had a 65 percent chance of SVR.²⁶ This finding has been tentatively confirmed in HIV/HCV-coinfected patients, but more data are needed before a decision is made based upon this criterion in co-infected patients.²⁸ Further, prior to using this criterion to discontinue HCV therapy, clinicians should consider other benefits that may accrue with that therapy (e.g., a reversion of fibrosis), and whether that should also be considered an independent treatment goal.

Finally, clinicians should note that in addition to the benefits of pegylated interferon in the treatment of HCV infection, this therapy has also been shown to be effective at decreasing HIV viral loads, in some studies by as much as 0.5 log 10 copies/mL.²⁹

Management of HCV Therapy Side Effects and Toxicities

The side effects and potential toxicities of interferon and ribavirin therapy are legion. (Figure 6)

Since these discourage and prevent many patients from even starting HCV therapy, appropriate pre-therapy counseling and preparation are essential components of HCV treatment. In addition, patients should be carefully monitored while on therapy for side effects or complications that may challenge adherence to HCV treatment or place the patient at risk for morbidity or mortality. Notable considerations in this regard include:

• preparing the patient for the flu-like symptoms and local site reactions that commonly occur with interferon therapy;

• screening patients for psychiatric disease, in particular depression, prior to starting interferon and considering the use of an antidepressant prior to the initiation of HCV therapy;

• avoiding the use of medications that may increase the risk of side effects or toxicities (e.g., ddI due to its established interaction with ribavirin); and

• screening patients before starting medications that may be absolutely or relatively contraindicated (e.g., pregnancy and cardiovascular disease, respectively, with ribavirin).

Further, the appropriate use of medications to manage side effects (e.g., acetaminophen for flu-like symptoms, and antidepressants for depression) and toxicities (e.g., granulocyte-colony stimulating factor [G-CSF] for neutropenia, and erythropoietin for anemia) is likely to lead to improved adherence to and persistence with therapy.^31-35

Conclusion

While HCV treatment is difficult for clinicians and patients, it may result in a significant improvement in the health of HIV/HCV-coinfected patients. Clinicians treating HIV-infected patients should test their patients for HCV and should aggressively pursue the evaluation and, if appropriate, the treatment of that condition. Improved outcomes and responses to therapy are likely to result from providing patients with the medical, educational, and psychosocial support needed to get them on, and keep them on, HCV therapy.

Brian Boyle is Associate Professor of Medicine at Cornell University Medical College, and Attending Physician at New York-Presbyterian Hospital.

Editor's Note: Reprinted with permission from HIV and Hepatitis.com (www.HIVandHepatitis.com).

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