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Diagnosis and Management of the HCV/HIV-Coinfected Patient

Diagnosis and management of HCV in the patient without comorbidities are under constant evaluation and evolution; management of the HIV-coinfected patient takes on additional complexity due to issues of immunologic dysfunction, drug interactions, and medication adherence. This article addresses the 10 most common questions that HIV caregivers ask with regard to the HIV/HCV-coinfected patient.

Since its introduction in 1996, potent combination antiretroviral therapy has significantly altered the course and spectrum of disease in HIV-infected patients. Although overall morbidity and mortality have declined with the steep drop in occurrence of opportunistic infections, other processes -- including hepatic injury, cardiovascular disease, and metabolic disorders -- have emerged as serious problems in this population. In many cohorts, end-stage liver disease has been identified as the leading cause of morbidity and mortality in HIV-infected patients.¹ The reasons for the increase in liver disease incidence are multifactorial and include a high prevalence of coinfection with hepatotropic viruses (hepatitis B and C), direct toxicity associated with antiretroviral agents, and the central role of the liver in the metabolism of drugs, toxins, and lipids. The longer life expectancy in this era of potent antiretroviral therapy has permitted full development of these complex and chronic injury processes.²

Among the etiologies of liver disease in HIV-infected patients, chronic coinfection with hepatitis C virus (HCV) appears to be the most important. HCV is highly prevalent in the general population; data from the NHANES III survey estimate an overall prevalence of 1.8% in the non-incarcerated U.S. population, with significantly higher rates in specific, identifiable risk groups.³ The disease is chronic and indolent, leading to slowly progressive fibrosis in a high proportion of infected patients. Progression of the fibrotic process ultimately leads to cirrhosis and an increased risk for development of hepatocellular carcinoma. Since 1994, HCV has been the leading indication for orthotopic liver transplant in the U.S. Diagnosis and management of HCV in the patient without comorbidities are under constant evaluation and evolution; management of the HIV-coinfected patient takes on additional complexity due to issues of immunologic dysfunction, drug interactions, and medication adherence. This article addresses the 10 most common questions that HIV caregivers ask with regard to the HIV/HCV-coinfected patient.

WHEN SHOULD I SCREEN HIV-INFECTED PATIENTS FOR HCV?

The prevalence of HCV in HIV-infected patients is highly dependent on their risk factors for these viruses, each of which can be transmitted parenterally, through use of contaminated factor concentrates, or through sexual contact. Results from studies of high-risk cohorts, such as IV drug users and hemophiliacs who received factor concentrates prior to 1987, show HCV-antibody reactivity in 80% to 100% of HIV-infected individuals.⁴, ⁵, ⁶ In contrast, significantly lower HCV prevalence is seen in HIV-infected patients whose risk factors include heterosexual or homosexual contact, random needle stick, or other risk factors with lower rates of disease transmission.⁷, ⁸, ⁹ Overall estimates of HCV prevalence in HIV-infected individuals are difficult to determine. However, in a recent study of a large ACTG cohort (in which specimens were derived from patients with multiple risk factors who were enrolled from across the U.S.), investigators estimated an overall weighted HCV prevalence of 16.1% in HIV-infected individuals. A regression model showed that risk for HCV infection is related to the patient's HIV risk factor and, interestingly, HIV viral load.¹⁰ The advisory panel to the U.S. Public Health Service for prevention of hepatitis C in HIV-infected patients determined that all HIV-infected patients should be screened for HCV, because discovery of HCV may alter disease management. Implementation of this policy eliminates reliance on taking detailed HCV-risk-based histories when evaluating HIV-infected patients.

CAN SEROLOGIC ASSAYS BE USED FOR DIAGNOSIS, OR SHOULD I RELY ON HCV RNA ASSAYS EXCLUSIVELY?

The CDC-developed algorithm for hepatitis C screening involves use of the HCV enzyme-linked immunosorbent assay (ELISA) as the initial screening modality. This relatively inexpensive assay is very sensitive, but it yields a high rate of false-positive results due to nonspecific immunoglobulin binding. Therefore, the CDC algorithm recommends confirmatory testing with either the recombinant immunoblot assay (RIBA) or an HCV RNA assay. In several studies, researchers have compared the utility of serologic and virologic HCV assays in HIV-infected patients. Although false-negative serologic test results have been reported in HIV-infected patients with compromised immunologic status, this is relatively uncommon. Several series report false-negative occurrences ranging from 1.8% to <5.0% of all tested samples.¹⁰ In addition, reversion to HCV seronegative has been reported in patients with worsening immune status.⁴ Use of the RIBA as a confirmatory test is somewhat limited because of the differential response to the antigen bands, which are embedded on the nitrocellulose strips; it therefore is not recommended in coinfected patients.¹¹ HCV RNA testing now represents the gold standard for diagnosing active infection. However, both false positives and false negatives have been found by blinded panels of virologic test facilities.¹² Therefore, virologic assays should not be used independently of serologic assays for determining or confirming active (acute or chronic) HCV infection. If suspicion of HCV infection is high (e.g., abnormal serum transaminases or clear history of high risk behavior) and the ELISA is nonreactive, HCV RNA testing can be used; however, the test should be repeated before initiating therapy.

DOES MY PATIENT NEED A LIVER BIOPSY?

Fibrosis progresses through stages ranging from mild expansion of the portal and periportal areas, to bridging fibrosis (fibrous bands between portal, central areas, or both), and, finally, to cirrhosis (defined as a liver lobule completely surrounded by a band of scar tissue). Bridging fibrosis and cirrhosis lead to inhibition of blood flow through the hepatic sinusoids causing an increase in portal pressure commonly referred to as portal hypertension. The body's physiologic responses to portal hypertension include the signs and symptoms of end-stage liver disease: splenomegaly with associated thrombocytopenia, development of ascites and encephalopathy, and variceal enlargement with eventual variceal bleeding. Imaging modalities, including liver/spleen scan, ultrasound, CT, and MRI, can detect signs of portal hypertension associated with significant hepatic fibrosis or cirrhosis. However, until significant portal hypertension has developed, imaging studies do not differentiate mild-to-moderate from severe fibrotic lesions. Imaging modalities, therefore, fail to provide prognostic information that would aid in making decisions about therapeutic intervention. Although predictive test panels -- developed by analyzing the sensitivity and specificity of a compilation of multiple laboratory parameters -- have been described, these also failed to clearly distinguish gradations outside of the extremes.¹³ For this reason, a liver biopsy with proper histologic evaluation remains the only method for staging the fibrotic process. It is also a useful adjunct in evaluating comorbid etiologies of liver disease.

A liver biopsy may be performed via either a percutaneous or transjugular route. The percutaneous route is most often employed and can be used with or without ultrasound marking or guidance by clinicians experienced in this procedure. In patients with early evidence of decompensated disease or in those with bleeding disorders, risk for bleeding complications may be reduced by use of the transjugular route in an angiography suite and use of factor correction, platelet transfusion, or both. Risk for serious bleeding from liver biopsy in a patient without malignancy or significant coagulopathy is less than 1 in 1000. Sedation before the procedure significantly reduces patient anxiety. Following the procedure, approximately 1 in 4 patients will have local site tenderness or referred pain in the right shoulder; these symptoms are transient and can be treated with pain medications.

Interpretation of the biopsy specimens is critical. Results from recent studies suggest that correct liver-biopsy interpretation may require a pathologist with specific training and experience in this area.¹⁴ The treating clinician should become familiar with hepatic pathology and, when possible, review the histologic material before discussing therapy with the patient, rather than relying on written reports.

WHAT OTHER TESTS SHOULD BE PERFORMED BEFORE INITIATING HCV TREATMENT?

It is important to evaluate potentially treatable comorbid conditions that could play a role in chronic hepatitis, liver injury, and the ability to treat advanced HCV infection. Patients younger than 30 who have abnormal liver enzymes should always be tested for elevated ceruloplasmin levels. Elevated ceruloplasmin suggests the possibility of Wilson's disease, a disorder of copper overload that results in copper deposition in the liver and other organs. Although this disease is rare, it is treatable if it's identified early. Much more common is genetic hemochromatosis. This disease -- which is due to a defect in regulation of iron absorption from the small intestine -- results in iron accumulation in the liver and other organs. Screening for hemochromatosis involves determination of the iron saturation. Saturation levels >50% should lead to further evaluation, including specific genetic testing for HFE gene defects and for qualitative and quantitative evaluation of iron in liver tissue. Alpha-1-antitrypsin deficiency also may be observed in a significant subset of the population and may be associated with more rapidly progressive liver disease, which may increase the urgency of treating HCV. Finally, patients should be screened for hepatitis B surface antigenemia, which is quite common in HIV-infected patients. Testing for anti-hepatitis B surface antigen and anti-hepatitis A IgG antibody also is required. It is appropriate to vaccinate patients who lack these antibodies to reduce risk for secondary acute infection, which can lead to hepatic failure in patients with chronic liver disease.

Liver enzymes (e.g., alanine aminotransferase [ALT] and aspartate aminotransferase [AST]) may or may not be elevated in HCV-infected patients. Although high levels of serum transaminases seem to be associated with increased levels of histologic activity, lower levels do not rule out the presence of significant fibrosis and do not significantly affect treatment decisions.

WHAT IS THE OPTIMAL TREATMENT FOR HCV IN HIV-INFECTED PATIENTS?

Since 1998, the standard therapy for HCV monoinfection has been interferon alfa + ribavirin.¹⁵ In recent studies, pegylated forms of interferon -- in which 1 or more polyethylene glycol molecules are attached to the interferon, resulting in delayed degradation and excretion -- have led to demonstrable increased areas under the curve (AUC). Clinical trials of 2 different pegylated interferon products (Peg Intron^TM and Pegasys^TM) suggest that these agents are superior to standard interferon + ribavirin therapies in treating monoinfected patients.¹⁶, ¹⁷

Reports of combination therapy in HCV/HIV-coinfection are limited. Small, uncontrolled trials from Europe and the U.S. suggest that rates of response to interferon + ribavirin are lower in coinfected patients than in patients with HCV alone.¹⁸, ¹⁹ Several studies have demonstrated a relation between CD4-cell count and likelihood of sustained HCV treatment response, which is defined as eradication of detectable HCV RNA by PCR or similar technique 24 weeks following the completion of therapy.²⁰ An exact CD4-cell count threshold has not been identified, but the treatment response likely is directly related to the CD4 count. CD4 levels of <500 cells/mm³ appear to reduce the likelihood of an adequate response. The use of pegylated interferon + ribavirin in coinfected patients is being investigated in several ongoing clinical trials. In preliminary data presented at the 9th Conference on Retrovirus and Opportunistic Infections, 44% of coinfected patients who were randomized to pegylated interferon + ribavirin responded to therapy, compared with 15% of those randomized to standard interferon + ribavirin.²¹ However, this response rate still is much lower than the 60% to 70% on-treatment response observed in patients with HCV monoinfection. No published long-term data are available on response rates in coinfected patients treated with pegylated interferon + ribavirin. However, this intervention currently represents the best line of therapy in coinfected patients who need HCV treatment, and such therapy should be recommended for patients with active HCV infection and fibrosis who are unwilling or unable to enter clinical trials.

View this table: [in a new window]   Table 1. Medications Commonly Used for HCV Treatment

 

SHOULD I TREAT HCV BEFORE INITIATING ANTIRETROVIRAL THERAPY?

This decision is highly dependent upon the immune status of the patient at the time of evaluation. As noted above, HCV-treatment trials suggest a relation between CD4-cell count and likelihood of treatment response. Many clinicians choose to withhold antiretroviral therapy until CD4 counts have dropped to lower than 300 cells/mm³. This practice may be detrimental to the goal of achieving a sustained virologic response to HCV treatment. Similarly, structured treatment interruptions may lead to reduced CD4-cell counts before or during HCV therapy, which may adversely affect treatment outcome. For these reasons, I generally recommend that antiretroviral therapy be initiated before HCV therapy. HCV therapy should not be initiated in patients with evidence of decompensated liver disease, including presence of ascites, encephalopathy, variceal bleeding, or coagulopathy (PT >3 seconds above normal). Such patients should be treated only by clinicians experienced in the management of end-stage liver disease; referral to a center where hepatic transplantation is performed in HIV-infected patients, rather than initiation of HCV antiviral therapy, may be indicated.

HOW FREQUENTLY, AND WITH WHAT TESTS, SHOULD MY PATIENTS UNDERGOING HCV TREATMENT BE FOLLOWED?

Although there is no mandatory interval for following patients who receive HCV therapy, the following guidelines have been employed successfully in many patients who've had good adherence to, and have completed, interferon + ribavirin treatment. On the day of treatment initiation, patients undergo a teaching session with a nurse who is trained and experienced in the dosing administration of the drugs and who can competently discuss potential side effects. Patients are then seen 1 to 2 weeks after drug initiation so that the provider can discuss problems related to dosing, as well as reinforce concepts such as premedication with analgesic/antipyretic agents and the need for adequate fluid intake. At this visit, samples for safety labs, including liver enzyme levels and complete blood counts (CBC) with differential, are obtained. Patients are asked to return 4 weeks later for brief physical examination, review of labs, and further discussion of any adverse events. Patients tolerating therapy and comfortable with the regimen should then be followed approximately every 6 months, while those with significant anxiety, increased irritability, or particularly severe side-effect profiles should be seen at least monthly. Although probably not cost-effective, evaluation of HCV RNA at week 12 is useful, particularly if a decrease in HCV viral load is detected, because such decreases provides encouragement for patients to continue the regimen.

An HCV RNA test is clearly indicated at week 24, at which time a determination is made on whether to continue therapy. In addition to liver enzyme levels and CBC with differential, it is reasonable to evaluate thyroid-stimulating hormone (TSH) levels at this time, because development of thyroid abnormalities is common. Abnormal TSH should be further evaluated with a full thyroid profile. Development of hypo- or hyperthyroidism does not necessarily mandate discontinuation of drugs, but it may require use of beta-blockers, thyroid replacement, or other agents. If the patient is tolerating therapy well, and HCV RNA is undetectable by 24 weeks, efforts are aimed at continuing patients through the next 24 weeks without adherence lapses or discontinuation. At this stage, most patients are quite familiar with the treatment process, and it is reasonable to follow patients at 8-week intervals. At the completion of therapy at 48 weeks, the patient will be classified as a responder or nonresponder. In classifying patients, it is imperative to use the most sensitive assay available and to test no later than 1 week after therapy completion. The current tests of choice include either a transcription-mediated amplification (TMA) assay or a sensitive and reproducible, qualitative, PCR-based assay. The TMA assay has been demonstrated to be more effective than the PCR-based assay in identifying nonresponders at the completion of therapy.

Although not mandatory, patients are generally seen 4 to 6 weeks following treatment completion. A bump in serum transaminases at this time often indicates recurrence of HCV-associated disease. It is not necessary to obtain an HCV viral load at this visit, although some patients are quite anxious to know their HCV RNA status. The definitive outcome of HCV treatment is sustained virologic response, defined as the absence of detectable virus by a sensitive PCR or TMA technique 24 weeks following completion of therapy. Detection of virus at this time in a patient who was HCV RNA-negative at therapy completion classifies the patient as a responder who has relapsed. This follow-up is not indicated in a patient who was classified as a nonresponder at the completion of therapy.

WILL THE SIDE EFFECTS OF INTERFERON BE MANAGEABLE?

Interferon alfa is a potent cytokine with many well-documented side effects. Following subcutaneous administration, most patients will develop an influenza-like syndrome characterized by muscle aches, increased fatigue, low-grade fevers, and chills. These effects are observed with both standard interferon and the pegylated formulations. Although many patients will experience these symptoms initially, they are both manageable and tolerable in most circumstances. Premedication with NSAIDs (e.g., 400 to 800 mg of ibuprofen) significantly reduces side effects. Cytopenias, including thrombocytopenia and neutropenia, occur frequently and are related to direct marrow suppression. These adverse effects may be exacerbated in patients with underlying portal hypertension who already have splenomegaly with splenic sequestration of platelets and white blood cells. Pretreatment platelet counts <100,000 cells/mm³ generally indicate pre-existing portal hypertension; treatment of these patients should proceed cautiously because antiretroviral agents may also cause marrow suppression. Neutropenia should be evaluated by regular CBCs in all patients, but with increased frequency in patients with low white-blood-cell counts at the start of therapy. When absolute neutrophil counts fall to between 500 and 750 cells/mm³, patients require addition of GCSF (300 mg, once or twice weekly).

Neuropsychiatric abnormalities, including depression and cognitive dysfunction, are common in HIV-infected patients and may be exacerbated by use of interferon. Patients should be evaluated at each visit for signs of worsening depression, with or without suicidal ideation. Development of suicidal ideation generally requires discontinuation of therapy and intervention by mental health professionals. Milder depression may be treated by the clinician, who should become familiar with the use of a sedating tricyclic antidepressants and SSRIs. (See also Feature, November 2001 ACC.)

Patients with other underlying autoimmune diseases also must be treated with great caution because interferon can exacerbate autoimmune processes, including autoimmune thyroiditis, inflammatory bowel disease, and rheumatoid arthritis. In addition, retinopathy may be associated with long-term use of high-dose interferon. Baseline dilated eye examination, particularly in patients with diabetes or hypertension, may be desirable.

DOES RIBAVIRIN ALSO CAUSE SIGNIFICANT SIDE EFFECTS?

Ribavirin causes a dose-dependent hemolytic anemia in 70% to 80% of treated patients. The optimal dosing for ribavirin has not been established, and studies are underway to determine whether weight-based dosing might be associated with increased efficacy, as has been suggested in post hoc analysis of pegylated interferon alfa 2b + ribavirin in HCV-monoinfected patients. Hemolytic anemia can be controlled by dose modification in most cases. Target hemoglobin levels are individually determined based on tolerability of anemia. Most patients with hemolytic anemia have significantly increased fatigue and dyspnea upon exertion when their hemoglobin levels are less than 10g/dl. Studies to determine the efficacy and cost benefits of erythropoietin are in progress. Results from in vitro studies have demonstrated antagonism between ribavirin and some antiretroviral agents, including the pyrimidine analogues, such as AZT, ddI, and d4T. The clinical significance of these interactions has not been determined. Case reports suggest that an interaction between ribavirin and ddI may result in inhibition of mitochondrial DNA polymerase-gamma, leading to severe lactic acidosis in some patients.²² Therefore, the combination of ribavirin and ddI should be used with caution until additional data become available. Ribavirin is also a potent teratogen, and it is important that heterosexual men and women use appropriate birth control (or practice abstinence) during, and for 6 months after, ribavirin use.

View this table: [in a new window]   Table 2. Common Side Effects of Interferons and Ribavirin

 

HOW LONG SHOULD PATIENTS WITH HCV/HIV-COINFECTION BE TREATED?

In the U.S., pegylated interferon alfa 2b + ribavirin is approved for treatment periods of 48 weeks. The studies that led to licensure of this intervention did not differentiate between HCV viral genotypes in relation to treatment duration. In contrast, in studies on standard interferon + ribavirin therapy, McHutchison and colleagues clearly demonstrated that patients with non-1 HCV genotypes had similar sustained viral clearance rates, regardless of whether they were treated for 24 or 48 weeks.¹⁵ Therefore, pretreatment HCV genotyping permitted tailored decision making about treatment duration. Because data are not yet available regarding patients treated with pegylated interferon, a full 48 weeks of therapy is currently recommended. However, extrapolating from the older data, one may choose to treat non-1 genotypes with pegylated interferon for a shorter period. Data from recently completed trials evaluating length of treatment with pegylated interferon + ribavirin in patients monoinfected with HCV genotypes 2 and 3 will be available soon.

Considerable efforts have been expended to determine an appropriate stopping point for patients unlikely to respond to therapy. In HCV monoinfection, it is generally accepted that patients who do not clear virus by 24 weeks of therapy are unlikely to achieve sustained viral clearance with additional therapy and drug discontinuation is recommended. Earlier stopping points also have been examined, and statistical associations between probability of nonresponse and earlier stopping times have been described. Sustained viral response rates are lower in HCV/HIV-coinfected patients than in HCV-monoinfected patients; thus, the clinician and coinfected patient must consider the potential benefits of longer treatment regimens, which may reduce inflammation, fibrosis, and risk for hepatocellular carcinoma. The role of HCV maintenance therapy is under investigation in monoinfected patients and likely will be the subject of future studies in the coinfected population. At this time, no specific recommendations can be made regarding maintenance therapy in coinfected patients.

CONCLUSION

Patients with HCV/HIV coinfection present complex diagnostic and treatment challenges. Acceleration of liver fibrosis in coinfected patients mandates HCV screening, histologic evaluation, and determination of candidacy for treatment. Optimization of response to current therapeutic regimens requires attention to the patient's immunologic status, interest in and ability to adhere to treatment, and use of monitoring and management techniques that permit the patient to continue therapy for the appropriate period of time. This field is rapidly evolving, and it is incumbent upon the healthcare provider to follow these changes and adapt treatment as new knowledge becomes available.

— Kenneth E. Sherman, MD, PhD

Dr. Sherman is Director of the Hepatology and Liver Transplantation Section at the University of Cincinnati College of Medicine.

Published in AIDS Clinical Care May 1, 2002

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