Diagnosis>Opportunistic Infections>

PATHOGENS

• Hepatitis C virus (HCV): small, enveloped, single-stranded RNA virus of the family Flaviviridae spread primarily by contact with blood and blood products

CLINICAL

• HIV/HCV coinfection common in US & Europe due to shared routes of transmission. In U.S. 30% of HIV+ pts are coinfected, with highest rates among IDUs. HCV is 10x more infectious from needlestick than HIV. Co-infection uncommon in most of Africa.
• After exposure, HIV+ pts more likely to progress to chronic HCV infection (>80%) especially pts with low CD4 counts. They also ave higher HCV RNA levels and are more likely to progress to liver disease fibrosis (7-26 vs 23-38 yrs) & cirrhosis than with HCV alone. Lower CD4 count associated with increased fibrosis.
• ESLD is common cause of mortality in HIV+ pts, especially HCV co-infected. Sustained virologic response (SVR) to HCV therapy lower than with HCV infection alone.
• Effect of HCV on HIV progression unclear.
• Extra-hepatic manifestations of HCV: porphyria cutanea tarda, lichen planus, arthralgias, fatigue, mixed cryoglobulinemia (cutaneous & renal disease), & splenic lymphoma

DIAGNOSIS

• HCV EIA (Ab) for screening; sensitivity & specificity 99% with 3rd generation assay. All HIV+ pts should be tested in high HCV prevalence regions (such as U.S).
• False negatives (1-5% among all HIV+ pts, 15% among IDUs) justify RNA testing in high risk pts with negative EIA (IDU, low CD4, unexplained high ALT). False negatives also occur during acute infection before seroconversion.
• False positives common in Africa, where prevalence of HCV generally very low.
• Positive EIA should be followed with HCV RNA, which indicates current infection.
• If HCV RNA+, check  HCV genotype to predict treatment response.
• Liver Bx useful to determine stage of disease and to assess need for therapy. Serum tests (e.g. FibroSure) may be useful if they suggest either cirrhosis or no liver disease; intermediate results less informative. Imaging can help to assess for cirrhosis but has limited sensitivity. Pts not candidates for treatment because of minimal fibrosis should be re-evaluated q 2-3 yrs (with Bx or non-invasive means).
• ALT fluctuates during natural Hx & does not reflect disease activity or prognosis.

TREATMENT

• Reduce hepatic risks: vaccinate against HAV & HBV if non-immune, counsel on abstinence from alcohol and IDU, enroll in IDU treatment and/or methadone maintenance when appropriate, manage psychiatric co-morbidities, start ART if pt meets criteria for therapy. 
• Educate on HCV transmission modes: blood, shared IDU needles & 'works'; anal sex
• If HCV untreated, screen annually for HCC in high risk (men, age >45, cirrhotics, pts with HBV coinfection) with AFP & U/S or CT if high risk.
• Treatment indications: detectable HCV RNA, stable HIV infection, portal or bridging fibrosis or worse liver histology. Contraindications: decompensated liver disease, pregnancy (if on treatment, use contraceptives & 2 forms of birth control until 6 mos after completion of therapy due to risk of fetal loss and teratogenicity). Drug use and psychiatric disease not contraindications, but pts need to be carefully evaluated & may need extra support.
• Lower response with genotypes 1 & 4 (14-29% SVR) vs. 2 & 3 (44-73% SVR), HCV RNA > 800,000 (response with <800,000 similar to HIV-negative), & African-American & Latino vs. Caucasian. CD4 not predictive of outcome.
• Decompensated liver disease (portal hypertension, coagulopathy, ascites, encephalopathy) increase mortality with PEG-IFN. Consider evaluation for orthotopic liver transplantation.
• Liver fibrosis score improves with SVR.

• If acute HCV Dx'd, repeat HCV RNA assay at 8-12 wks post exposure. If HCV RNA persistently detectable, treat with PEG-IFN alfa for 24 wks (see below for dosing). Early treatment after acute infection increases probability of SVR

• PEG-IFN alfa-2a 180 mcg SQ q wk + RBV 800-1200* mg/d PO in divided doses.
• PEG-IFN alfa-2b 1.5 mcg/kgSQ q wk + RBV 800-1200 mg/d PO in divided doses. RBV dose based on HIV-negative studies for genotype 1: 1000 mg/d (<75 kg) or 1200 mg/d (>75 kg). For genotype 2 and 3 or weight <40kg: RBV 800 mg/d.
• PEG-IFN alfa-2a & alfa-2b have similar efficacy in HIV.
• Duration 48 wks for all genotypes in HIV+ pts, who may have slower response 
• If no evidence of response at 12 wks (HCV RNA decrease <2 log₁₀), discontinue treatment
• Clinical trials of HCV protease & polymerase inhibitors in combination with PEG-IFN are ongoing.

• Past failure of conventional (3x/wk) IFN (+/- RBV) does not preclude response to PEG-IFN + RBV (retreat with PEG-IFN + RBV)
• Among HIV-negative non-responders, prolonged low-dose IFN does not slow fibrosis.

• HAART- associated hepatotoxicity may be reduced by treating HCV first.
• NVP has high risk of hepatotoxicity, consider alternative
• RBV increases toxicity of ddI: avoid combination
• Anemia common with RBV + AZT: avoid AZT or use with careful monitoring and erythropoietin if necessary
• ABC may decrease SVR, especially with higher HCV RNA & lower RBV dose, consider another agent.

• HCV RNA testing: 1) 12 wks: if <2 log decline, low likelihood of SVR (<2%), D/C therapy. 2) 24 wks: if detectable, low likelihood of SVR; D/C therapy. 3) 48 wks: assess response. 4) 6 mos after completing therapy (if was neg at 48 wks): undetectable HCV RNA 24 wks after treatment = SVR.
• CBC, ALT at 2, 4 wks, & q month. TSH q3-6 mos. Neuropsych eval q month.
• HCG q month in women.
• CD4 q12 wks. Absolute CD4 usually declines approximately 60% or 100-200 cells while CD4% often rises 3%. Decline in CD4 count does not appear to affect OI risk & should not prompt change in therapy.

• Anemia (from RBV or PEG-IFN): if Hgb < 10 g/dL, decrease RBV (by 200 mg at a time); stop RBV if Hgb < 8.5 & support with epoeitin alfa (40K IU SQ qwk)
• Severe neutropenia (from PEG-IFN): support with G-CSF (5 mcg/d sq until ANC>1000)
• Depression: consider SSRI (optimally start before starting HCV therapy)

Drug Comments

Pathogen Specific Therapy

REFERENCES

REFERENCED WITHIN THIS GUIDE

• Baseline & routine testing
• Nephropathy, HIV-Associated (HIVAN)
• Post-exposure prophylaxis
• Toxicity & side effects: switching therapy (Zambia specific)