Update on HIV and Hepatitis C Virus Co-Infection

HCV/HIV Co-Infection

Hepatitis C is caused by the hepatitis C virus, which is a single-stranded RNA virus of the Flaviviridae family. Six unique HCV genotypes with 50 subtypes have been identified to date. Infection with HCV genotype 1 accounts for an estimated 75% of HCV-infected individuals in the U.S., and of all the genotypes, genotype 1 has the poorest treatment response.<⁸

Transmission

HCV transmission occurs mainly through infected blood or blood products. Currently, the primary route of acquisition in the U.S. is through injection drug use. Prior to 1992, the predominant mode of transmission was transfusion-related. Other transmission routes include vertical, sexual, and needle stick injuries. HCV transmission from mother to child accounts for an estimated 5% of HCV spread, but this estimate increases to 17% if the mother is infected with HIV.8 Sexual transmission rates in monogamous couples are low (<1%); however, these rates are thought to be higher (5%-10%) in men who have sex with men.^10-11

Pathogenesis and Natural History

HIV appears to hasten the natural history of HCV infection. Patients with HIV/HCV co-infection have higher blood levels of HCV RNA, an accelerated progression of liver disease, and a greater rate of hepatitis-related deaths than patients who have HCV infection alone.^12-13 The pathogenesis of accelerated progression is poorly understood. HIV may have a direct cytopathic effect on liver cells and may also aid in infecting extrahepatic cells.¹² The increased HCV viremia is attributed to the loss of CD4+ T lymphocytes in HIV-infected patients.¹² Spontaneous clearance of HCV occurs in 15%-30% of cases in mono-infected patients vs.5%-10% for coinfected patients.^7,14

The risk for progressive liver disease is estimated to be 2.9 times higher among HIV/HCV co-infected individuals compared to HCV mono-infected patients.⁸ Progression to cirrhosis occurs in 15%-25% of co-infected patients as compared to 3%-6% of HCV mono-infected patients.^14-15 This progression generally takes 20 to 30 years in HCV mono-infected patients and is accelerated to 6 to 10 years in co-infected individuals.¹⁶ Hepatocellular carcinoma (HCC) occurs at a younger age and after a shorter duration of HCV infection, and once cirrhosis is established, the rate of progression to HCC is 1%-4% per year.^14,17 The time from infection to HCC has been demonstrated to occur 10 years earlier in co-infected patients (from 28 to 18 years).¹⁸ Factors such as alcohol use and older age also increase the rate of liver fibrosis progression.¹⁹

Whether HCV impacts the rate of progression of HIV infection is uncertain. Limited studies have found that HCV may increase morbidity and mortality in HIV infected patients on HAART.^20-21 In the Swiss HIV cohort study, it was shown that the clinical progression to AIDS at 2 years was 6.6% in HIV mono-infected individuals as compared to 9.7% in co-infected patients.²⁰ A meta-analysis study by Miller and colleagues found that co-infected patients had a diminished rise in the CD4 cell count when they begin HAART as compared to HIV mono-infected patients.²² However, further follow-up studies of patients on HAART suggest that there may not be a difference in HIV-related mortality between patients coinfected with HCV and patients infected with HIV alone.¹²

Clinical Manifestations

HCV infection is responsible for approximately 15% of acute viral hepatitis, 60-70% of chronic hepatitis, 50% of cirrhosis, endstage liver disease, and liver cancer, and for 10,000 to 12,000 deaths annually in the U.S.²³ Because its presentation is often asymptomatic or mildly symptomatic, acute hepatitis is often not diagnosed. Symptoms of acute infection include low-grade fever, mild right-upper-quadrant pain, nausea, vomiting, anorexia, dark urine, and jaundice.⁸

Symptoms of chronic hepatitis C range from no symptoms at all to mild, nonspecific symptoms, which include fatigue, mild right-upper- quadrant tenderness, nausea, poor appetite, and muscle and joint pain.²³ As the disease progresses into cirrhosis, patients may present with muscle weakness, weight loss, itching, dark urine, fluid retention, and abdominal swelling.²³ Signs of portal hypertension such as spider angiomata, temporal wasting, splenomegaly, caput medusa, and encephalopathy may also be present.⁸ Occasionally, some patients experience cutaneous manifestations such as leukocytoclastic vasculitis and porphyria cutanea tarda.⁸

Physical examination of patients with chronic hepatitis C may reveal mild hepatomegaly. Patients who have cirrhosis may have hepatomegaly, splenomegaly, jaundice, muscle wasting, excoriations, ascites, and ankle edema on examination.²³ Other hepatic manifestations of HCV include fulminant hepatitis and hepatocellular carcinoma (often asymptomatic). Extrahepatic manifestations of HCV occur in 1-2% of patients and commonly include mixed cryoglobulinemia, glomerulonephritis, Sjogren syndrome, and hypothyroidism especially in women.²⁴

Who Should Be Tested?

Current guidelines supported by the American Association for the Study of Liver Diseases (AASLD) and the Infectious Diseases Society of America (IDSA) recommend that the detection of HCV infection is best accomplished by screening populations for risk factors and then testing identified, high-risk individuals (see Table 1).²⁵ Through careful questioning, an HCV risk factor can be found in more than 90% of cases.²⁵ Because of the high prevalence of HCV in HIV-infected patients, all patients with HIV should be tested for anti-HCV antibody.³

Laboratory Evaluation

The 2004 guidelines from the CDC, the NIH, and the HIV Medicine Association/IDSA on the treatment of opportunistic infections among HIV-infected adults and adolescents recommend that HIV patients be tested first for antibody to HCV using the most sensitive enzyme immunoassay (EIA) licensed for the detection of HCV antibody, and if positive confirmed utilizing a qualitative HCV ribonucleic acid (RNA) assay with a lower detection limit of ≤50 IU/mL. Additional, more specific testing for HCV antibody by recombinant immunoblot assay can be used as a subsequent confirmatory method if the HCV RNA is negative and the EIA is positive (See Figure 1).⁸ Such findings occur occasionally in patients who have recovered from acute hepatitis C and are no longer viremic and occasionally among patients whose HCV RNA levels transiently decline below the detection level of the assay.

Enzyme Immunoassay

Enzyme immunoassays were originally developed as an alternative to radioisotopes. EIAs achieve their signal through the catalytic reaction of enzymes. There are many innovative formats in use. In the U.S., a third generation EIA is in use but because of sensitivity/specificity issues, a confirmatory test is needed to ensure appropriate specificity of a positive fi nding.¹⁰ A negative HCV antibody result generally excludes the diagnosis of HCV with the following exceptions: acute HCV infection in the antibody ‘window’ or immunosuppressed states. In 30%-40% of patients, anti-HCV is not detected until 2 to 8 weeks after the onset of symptoms.23,25 Patients with acute hepatitis and patients who are co-infected with HIV with suspected liver disease and who test negative for anti-HCV antibody should be re-tested using the HCV RNA assay, primarily because it reduces the window of viral detection.^23,25

Qualitative and Quantitative Assays for HCV RNA

HCV RNA levels can be detected within 1 to 2 weeks of infection.²⁵ Both qualitative and quantitative HCV RNA assays can be utilized. Many clinicians prefer a quantitative assay rather than qualitative test, because the test measures the amount of HCV RNA, which is useful for initiating and monitoring treatment. Qualitative assays are designed to be more sensitive than the quantitative assays, so some experts recommend that the qualitative HCV RNA test be used as the initial test or to confirm a positive HCV antibody test when there is a negative quantitative HCV RNA assay.²⁵

Qualitative nucleic amplification assays for HCV RNA utilize either a polymerase chain reaction (PCR) or transcription mediated amplification (TMA) technique. The PCR-based tests are able to detect HCV RNA in serum down to a lower limit of 50 IU/ml, and the TMA-based assays are able to identify HCV RNA in serum down to a lower limit of 9.6 IU/mL.²⁵

Quantitative assays for HCV RNA utilize either a target amplification technique (PCR, TMA) or a signal amplification technique (branched DNA) to measure the concentration of the virus. The measure of HCV RNA viral levels do not correlate with the severity of hepatitis as is the case when assessing HIV viral load. Rather, the quantification of HCV RNA in blood helps in predicting the likelihood of a response to antiviral therapy.²³ The amount of HCV RNA in the blood should therefore be assessed prior to the initiation of antiviral therapy in order to monitor treatment response. Since serial values are needed to monitor the antiviral therapy, it is recommended that the same quantitative assay be utilized for all assessments to reduce test variability.⁸

Recombinant Immunoblot

The strip immunoblot assay, also known as RIBA™, is a supplemental anti-HCV test manufactured by the Chiron Corporation (Emeryville, CA) with high specificity for four HCV-encoded antigens and synthetic HCV-encoded peptides immobilized as individual bands onto test strips. The two recombinant antigens (c33c and NS5) and two of the synthetic peptides (c100p and 5-1-1p) are derived from putative nonstructural regions of the virus, while the third peptide (c22p) corresponds to the putative nucleocapsid (core) viral protein.²⁶

The recombinant immunoblot assay (RIBA) is useful in confirming the presence of HCV antibody when the EIA result is positive in the face of an undetectable HCV RNA.27 A negative immunoblot result suggests that the positive HCV antibody test was a false positive result, whereas a positive immunoblot with two or more negative qualitative HCV RNA tests indicate that HCV infection has likely resolved. In both instances, no more further confirmatory HCV testing is needed.

HCV Genotyping

Since 80% of patients with HCV genotype 2 or 3 respond favorably to treatment, specialists do recommend that genotype testing be obtained in order to help make recommendations regarding therapy duration and likelihood of treatment response.8 Genotypespecific antibodies can be assessed for the 6 genotypes by direct sequence analysis utilizing a technique of reverse hybridization to genotype-specific oligonucleotide probes or by the use of restriction fragment length polymorphism. These tests will not identify the genotype in less than 3% of HCV-infected individuals, and approximately 1%-4% of individuals may be identified to have a mixed genotype.²⁵

Liver biopsy

The liver biopsy remains the only definitive test for the evaluation of liver fibrosis in HCV infected patients.²⁸ The CDC recommends that all co-infected patients who are candidates for antiviral therapy receive a liver biopsy unless contraindications are present.⁸ The liver biopsy provides information regarding the degrees of fibrosis and hepatic inflammation. The Metavir scoring system and the Ishak grading system are scoring systems that characterize the amount of fibrosis (staging) and inflammation (grading). If the liver biopsy results demonstrate a Metavir score of ≥2 or an Ishak score of ≥3, treatment is recommended.²⁵ Studies have suggested that the degree of liver fibrosis is an independent predictor of treatment response.²⁵ Individuals with mild fibrosis generally have a better response to treatment than do patients with more severe fibrosis (bridging fibrosis or cirrhosis). The need for treatment, however, is stronger in the group with the more severe fibrosis.

In clinical practice, most specialists will obtain a liver biopsy for patients with HCV genotype-1 infection to help determine the need for treatment. It is argued that those with treatment responsive genotypes (2 or 3) should be treated regardless of the severity of liver disease and that a liver biopsy is not necessary to start treatment.²⁸ In patients who have been found to have little or no fibrosis on biopsy with a Metavir score <2 or Ishak score <3, liver biopsies can be obtained in intervals of 4 to 5 years to monitor the progression of liver disease.²⁵

Generally, the extent of liver fibrosis correlates with elevated blood levels of aminotransferases. However, 14% to 24% of patients have normal aminotransferase levels despite having more-than portal fibrosis on biopsy.²⁵ Cases such as these demonstrate the need for liver biopsy to facilitate treatment recommendations. The AASLD Practice Guidelines recommend that a liver biopsy be done regardless of aminotransferase blood levels, but a biopsy is not mandatory for the initiation of therapy.²⁵

The problem with the liver biopsy is that it is invasive, expensive, and has complications. Complications include puncture of another organ, infection, bleeding (1/100 to 1/1,000 cases), and deaths (1/5,000 to 1/10,000 cases).²³ Higher rates of complications have been reported in HIV-co-infected patients with thrombocytopenia, coagulation defects, or liver lesions with high vascularity.⁸ In these patients, it may be preferred to obtain a transjugular liver biopsy.⁸

Current investigations are looking at non-invasive markers of inflammation and fibrosis (such as serum fibrosis markers and tissue elastography), but their utility in HIV/HCV co-infected patients requires further validation studies.^8,25,28 These markers demonstrate utility in differentiating between low, intermediate, and advance grades of liver fibrosis but not between different levels of intermediate fibrosis scores.²⁹

Further Evaluation

Biochemical markers are important components of initial and ongoing monitoring of HCV in HIV-infected persons. Increases in alanine (ALT) and aspartate (AST) aminotransferases range from 0 to 20 times (usually <5 times) the upper limit of normal with HCV infection.²³ In general, ALT is higher than AST in hepatitis C infection (approximately 10-fold elevation in acute hepatitis C infection), but may be reversed with cirrhosis. In approximately 5%-10% of cases, elevations in aminotransferases will occur with the initiation of antiretroviral therapy, which makes it more difficult to clearly delineate the etiology of the hepatotoxicity.³⁰ Certain subgroups will not demonstrate a rise in liver enzymes despite a persistent HCV RNA viremia.¹⁹

Further evaluation should include a complete blood count (CBC), hepatic panel, prothrombin time (PT), ferritin, thyroid stimulating hormone (TSH), and anti-nuclear antibody.31 Alkaline phosphatase and gamma glutamyl transpeptidase levels are often normal; if elevated, they may be indicators of cirrhosis. Also with severe fibrosis or cirrhosis, rheumatoid factor may be present, and low platelet or white blood cell counts may occur. The prothrombin time and albumin levels are usually normal until advanced disease occurs. The LDH and creatine kinase are generally normal, while iron and ferritin levels may be slightly elevated. In 60% of cases, serum cryoglubulins are present but will rarely (<5%) present symptomatic disease.8 Further evaluation includes tests to screen for HCC using alfa-fetoprotein (AFP) and performing an ultrasound of the liver at 6-month intervals for co-infected patients with cirrhosis.⁸