Guidelines for the Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents
Hepatitis C Virus Infection
(Last updated:5/7/2013; last reviewed:5/7/2013)
Hepatitis C virus (HCV) is a single-stranded RNA virus; the estimated worldwide prevalence of HCV infection is 2% to 3%, which translates to an estimated 170 million infected individuals of whom approximately 3.2 million live in the United States.1
Seven distinct HCV genotypes have been described.2
Genotype 1 infection accounts for approximately 75% of infections in the United States and approximately 90% of infections among blacks.3,4
Both HIV and HCV can be transmitted by percutaneous exposure to blood or blood products, through sexual intercourse, and from a mother to her infant; however, the relative efficiency of transmission by these routes varies substantially. Approximately, 20% to 30% of HIV-infected patients in the United States are co-infected with HCV.5,6
HCV is approximately 10 times more infectious than HIV through percutaneous blood exposures and has been shown to survive for weeks in syringes.7-9
Transmission via injection drug use remains the most common mode of acquisition in the United States while transmission through contaminated blood products is now rare. Health care-associated transmission of HCV also can occur as a result of improper reuse of parenteral medications and equipment.10-12
Other factors that have been associated with HCV infection include accidental occupation-related needle-stick injuries, intranasal cocaine use, chronic hemodialysis, and tattoo placement.
Heterosexual transmission of HCV is uncommon but more likely in those whose partners are co-infected with HIV and HCV.13,14
Existing data also suggest that sexual contact is a relatively inefficient mode of transmission between HIV seronegative men who have sex with men (MSM).15
However, in HIV-infected MSM, multiple outbreaks of acute HCV infection demonstrate that sexual transmission is an important mode of acquisition in this population.16
Risk factors include unprotected receptive anal intercourse, use of sex toys, non-injection recreational drug use, and concurrent sexually transmitted diseases.15,17-19,20,21
Temporally, the increase in the incidence of sexual transmission of HCV among HIV-infected MSMs coincides with an increase in high-risk sexual behaviors following the introduction of antiretroviral therapy (ART).22,23
Mother-to-child transmission of HCV infection occurs in approximately 1% to 3% of infants born to HCV-seropositive mothers without and 4% to 7% of infants born to HCV-seropositive mothers with detectable plasma HCV RNA levels.24-27
Incidence of mother-to-child HCV transmission is increased when mothers are HIV-co-infected, reaching rates of 10% to 20%.28,29
Both acute and chronic HCV infections are usually minimally symptomatic or asymptomatic. Fewer than 20% of patients with acute infection have characteristic symptoms, including low-grade fever, mild right upper quadrant pain, nausea, vomiting, anorexia, dark urine, and jaundice. Unexplained elevations in serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels may be the only laboratory finding during acute and chronic infection. Recognition of acute HCV infection in patients with new-onset liver enzyme elevations is clinically important since HCV treatment during the early phases of infection is more efficacious than treatment during the chronic phase.30,31
Cirrhosis develops in approximately 20% of patients with chronic HCV infection within 20 years after infection, although the risk for an individual is highly variable.32,33
Risk factors for development of significant liver disease include older age at the time of infection, male sex, obesity, and concomitant alcohol use.33,34
HIV co-infection adversely affects the course of HCV infection, resulting in significantly accelerated progression of liver disease to cirrhosis, particularly in those with advanced immunodeficiency (CD4 t-lymphocyte [CD4] count <200 cells/mm3
Further, co-infected patients with cirrhosis progress more rapidly to life-limiting outcomes such as end-stage liver disease and hepatocellular carcinoma (HCC) than do those who are HCV-mono-infected.37,38
Because of its high prevalence and accelerated progression, death due to HCV disease is a leading non-AIDS cause of death in HIV-infected persons.39-41
In addition to liver disease, HCV may be associated with symptomatic vasculitis due to cryoglobulinemia (largely affecting the skin), renal disease (membranoproliferative glomerulonephritis), and porphyria cutanea tarda.
On entry into HIV care, all HIV-infected patients should undergo routine HCV screening. Initial testing for HCV should be performed using the most sensitive immunoassays licensed for detection of antibody to HCV (anti-HCV) in blood.42
For at risk HCV-seronegative persons, HCV antibody testing is recommended annually or as indicated by risk exposure.
False-negative anti-HCV antibody results are possible but are uncommon (<1%) in HIV-infected patients with advanced immunosuppression.43,44
In addition, negative anti-HCV antibody results can occur during acute infection. Following acute HCV infection, the duration of the window period prior to seroconversion is highly variable, ranging from 2 weeks to 12 weeks. Serum ALT levels are frequently elevated early in the course of acute infection and high ALT levels should prompt testing for HCV RNA if serologic test results are negative or indeterminate in persons at risk for HCV infection.45
Persons who test positive for HCV antibody should undergo confirmatory testing by using a sensitive quantitative assay to measure plasma HCV RNA level. Importantly, plasma HCV RNA viral load does not correlate with HCV disease severity, and therefore, should not be monitored serially in patients not taking HCV treatment. Plasma HCV RNA levels do provide important prognostic information about the likelihood of response to HCV treatment.
The primary route of HCV transmission is drug injection via a syringe or other injection paraphernalia (i.e., “cookers,” filters, or water) previously used by an infected person. HCV-seronegative injection drug users should be encouraged to stop using injection drugs by entering a substance abuse treatment program or, if they are unwilling or unable to stop, to reduce the risk of transmission by never sharing needles or injection equipment.46-48
HCV also can be transmitted sexually, especially between HIV-infected MSM. HCV-seronegative patients must be counseled regarding the risk of sexual acquisition. The effectiveness of male condoms in reducing HCV transmission is unknown, nonetheless, barrier precautions are strongly recommended to reduce the risk of sexually transmitted diseases, including HCV (BIII
There is no vaccine or recommended post-exposure prophylaxis to prevent HCV infection. Following acute HCV infection, chronic infection may be prevented within the first 6 to 12 months after infection through treatment with peginterferon with or without ribavirin. Relatively high rates of viral clearance have been observed with HCV treatment during the acute phase of infection;50,51
thus, in the absence of contraindications, acutely infected patients with HIV co-infection should be offered HCV treatment (AII
). However, based on the potential for spontaneous clearance after acute infection, some experts recommend observation of acutely infected patients, particularly those who are more likely to resolve their infection (e.g., those with C/C IL28B genotype), for approximately 3 to 6 months before initiating HCV treatment.52
HCV-infected persons should be counseled about methods to prevent liver damage by avoiding any alcohol consumption (as alcohol accelerates progression of liver disease), limiting ingestion of potentially hepatotoxic medications (e.g., acetaminophen should be limited to <2 g/day), and avoiding iron supplementation in the absence of documented iron deficiency.53
HCV-infected patients should be tested for previous or concurrent hepatitis B virus (HBV) infection because co-infection with HBV is associated with increased morbidity. Those without evidence of immunity to HBV should be vaccinated (see Hepatitis B Virus Infection
section). Likewise, because acute hepatitis A virus (HAV) infection is more likely to be fulminant in HCV-infected individuals, these patients should be screened for immunity (HAV IgG or antibody total) and those susceptible should be vaccinated (BIII
Co-infected patients with cirrhosis are at risk for life-threatening complications and should be managed in consultation with a gastroenterologist or hepatologist. In particular, individuals with cirrhosis should undergo serial screening for HCC;54
some experts recommend performing ultrasonography at 6- to 12-month intervals, although the optimal screening strategy is unknown. Because of its relatively poor specificity and sensitivity, alfa-fetoprotein should not be the sole screening method. HIV infection is not an absolute contraindication to liver transplantation; accordingly, co-infected patients with decompensated liver disease and/or early HCC may be considered for transplantation at specialized transplant centers.
Although earlier studies focused on the potential for antiretroviral (ARV)-associated liver injury with certain agents, more recent studies have found that effective HIV treatment is associated with reduced risk of liver disease progression. Co-infected patients should be treated with ART in accordance with the Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents
developed by the Department of Health and Human Services Panel.55
Dose adjustment of certain ARV agents may be needed in patients with decompensated cirrhosis.
The goal of HCV therapy is to achieve a sustained virologic response (SVR). SVR is defined as the absence of detectable viremia ≥6 months after discontinuation of HCV treatment. SVR is durable in persons with and without HIV disease and is consistent with HCV cure.56
Importantly, SVR is associated with decreased likelihood of end-stage liver disease, HCC, death and may decrease the risk of ARV-related liver injury.57-59
Assessments Prior to HCV Treatment:
All HIV/HCV co-infected patients should be considered for HCV treatment. Treatment specific clinical, laboratory, and/or histologic evaluation should be performed to determine the type of treatment and the potential risks and benefits of the therapy.
- HCV genotype. HCV treatment recommendations are genotype specific as HCV genotype is an important determinant of the likelihood of response to interferon (IFN)-based HCV treatment regimens (genotype 2 > 3 > 1 and 4). Further, the HCV NS3A/4 protease inhibitors (PIs) are only approved for the treatment of HCV genotype 1 infection. Thus, HCV genotyping should be done before the initiation of HCV treatment. In patients with HCV genotype 1 infection, the viral subtype (A or B) also may influence the treatment response and should be determined before treatment.
- IL28B genotype. Host genetic polymorphisms near the interleukin-28B gene (IL28B encoding an interferon lambda) are strongly linked to spontaneous clearance of acute HCV infection and to response to IFN-based therapy for chronic HCV infection.60,61 Specifically, the C/C genotype on nucleotide rs12979860 of chromosome 19q13 is associated with markedly better outcomes, compared with either the C/T or T/T genotypes. The relationship of IL-28B genotype and HCV outcomes is similar in persons with and without HIV co-infection.62 IL28B genotyping assays using blood specimens are commercially available; however, its utility and cost-effectiveness in clinical practice is uncertain. IL28B genotype testing is not required before the initiation of HCV treatment.
- Liver disease stage. Baseline and serial monitoring of serum ALT and AST levels should be performed. Although higher serum ALT and AST levels are predictive of more rapid liver disease progression, cirrhosis can be present despite persistently normal ALT levels.63 Liver biopsy is the preferred test to evaluate liver disease stage, exclude other causes of liver disease, and guide treatment decisions. However, liver biopsy is expensive, subject to sampling error, and may result in complications, including pain, bleeding (<0.5%), bile peritonitis (0.09%), and rarely, internal organ injury.64,65 Liver biopsy is not required before the initiation of HCV therapy.
The combination of peginterferon alfa (PegIFN) plus ribavirin is the recommended backbone of therapy for HIV/HCV-co-infected patients regardless of HCV genotype (AI)
. For HCV-genotype-1-infected patients who are not co-infected with HIV, a HCV NS3/4A PI, either boceprevir or telaprevir, in combination with PegIFN/ribavirin is recommended on the basis of large clinical trials demonstrating significantly higher SVR rates with an acceptable safety/tolerability profile compared to PegIFN/ribavirin alone.66-68
For HIV/HCV co-infected patients, preliminary data from two, small ongoing phase 2 clinical trials of boceprevir or telaprevir plus PegIFN/ribavirin for the treatment of HCV genotype 1 infection in HIV/HCV co-infected patients also demonstrate greater efficacy than PegIFN/ribavirin alone, with a safety and tolerability profile similar to that observed in HCV monoinfected patients treated with boceprevir or telaprevir plus PegIFN/ribavirin.69,70
Preliminary recommendations regarding their use for the treatment of patients with chronic HCV genotype 1 infection are provided below. However, given the paucity of data and incomplete risk-benefit assessment of HCV PIs in this population, consideration should be given to enrollment of such HIV/HCV co-infected patients into clinical trials investigating novel direct acting antiviral agents (DAAs) whenever feasible (BIII
- Pegylated IFN. Two formulations of PegIFN are available (alfa-2a and alfa-2b) for weekly subcutaneous injection. These agents are used for all HCV genotypes.
- Ribavirin. Ribavirin is recommended for use with PegIFN for all HCV genotypes. The ribavirin dose varies by HCV genotype. However, the optimal dose of ribavirin for HIV-infected patients with HCV genotype 1 is uncertain since 1 randomized controlled trial failed to demonstrate greater efficacy with higher dose ribavirin compared to 400 mg twice daily in HIV/HCV co-infected patients.71 Nonetheless, on the basis of data from HCV monoinfected patients, the recommended ribavirin dose for HCV genotype 1 infection is weight-based according to the FDA-approved regimens for HCV monoinfected patients.
- Boceprevir. Boceprevir is approved for use in combination with PegIFN/ribavirin in HCV-genotype-1-monoinfected-patients. The approved regimen for HCV monoinfected treatment naive patients is PegIFN/ribavirin administered for 4 weeks (lead-in phase) followed by boceprevir 800 mg orally every 7 to 9 hours (with a light snack) added to PegIFN/ribavirin for an additional 24, 32, or 44 weeks. Using the response guided therapy strategy, the duration of boceprevir and PegIFN/ribavirin are determined by presence or absence of cirrhosis and the observed HCV response at the end of the 4 week lead-in phase (< 0.5 to 1 log10 decline in HCV RNA level from the baseline level) and at the end of HCV treatment week 8 (HCV RNA detected or not detected). For treatment naive HCV monoinfected patients, SVR was achieved in 41% to 68% of those treated with boceprevir plus PegIFN/ribavirin versus 23% to 40% of those treated with PegIFN/ribavirin alone.
For HIV/HCV-co-infected patients, the regimen being evaluated is PegIFN/ribavirin administered for 4 weeks (lead-in phase) followed by boceprevir 800 mg orally every 7 to 9 hours (with a light snack) added to PegIFN/ribavirin for an additional 44 weeks. This clinical trial enrolled co-infected patients receiving ART with an undetectable HIV RNA. Due to pharmacokinetic interactions with boceprevir, patients taking NNRTIs were not enrolled. ART regimens of enrolled patients included ritonavir-boosted HIV-1 PIs or raltegravir in most patients in combination with tenofovir/emtricitabine or abacavir/lamivudine. In an interim analysis, HCV RNA was undetectable at 12 weeks post-treatment (SVR-12) in 62.5% (40 of 64 patients) of those treated with boceprevir plus PegIFN/ribavirin versus 26.5% (9 of 34) of those treated with PegIFN/ribavirin alone.69
- Telaprevir. Telaprevir is approved for use in combination with PegIFN/ribavirin in HCV-genotype-1-monoinfected-patients. The approved regimen for HCV monoinfected patients is telaprevir 750 mg orally (with at least 20 grams of fat) every 7 to 9 hours plus PegIFN/ribavirin for the initial 12 weeks of treatment followed by the discontinuation of telaprevir and the continuation of PegIFN/ribavirin for an additional 12 or 36 weeks, according to the observed HCV response at the end of treatment week 4 (response guided therapy). For treatment-naive, HCV-monoinfected patients, SVR was achieved in 72% to 79% of those treated with telaprevir plus PegIFN/ribavirin versus 44% of those treated with PegIFN/ribavirin alone.
An ongoing clinical trial enrolled HIV/HCV genotype 1 co-infected patients not taking ART (CD4 >500/mm3) and patients taking tenofovir/emtricitabine plus either ritonavir-boosted atazanavir or efavirenz. Due to pharmacokinetic interactions between telaprevir and certain ARV drugs, patients taking other HIV-1 PIs were not enrolled and those taking efavirenz received the higher telaprevir dose (1125 mg). The regimen being evaluated is telaprevir 750 mg (if not on ART or receiving ritonavir-boosted atazanavir) or 1125 mg (if receiving efavirenz) orally every 7 to 9 hours plus PegIFN/ribavirin for the initial 12 weeks of treatment followed by the discontinuation of telaprevir and the continuation of PegIFN/ribavirin for an additional 36 weeks. In the final analysis, HCV RNA was undetectable at 24 weeks post treatment (SVR-24) in 74% (28 of 38) of those treated with telaprevir plus PegIFN/ribavirin versus 45% (10 of 22) of those treated with PegIFN/ribavirin alone.72
Treatment of Acute HCV Infection
Because of the high likelihood of SVR with therapy, HIV-infected patients with acute HCV infection should be offered treatment (AII
). The optimal regimen and duration are unknown; recent studies suggest that HIV-infected patients should receive standard doses of PegIFN/ribavirin for 24 or 48 weeks (AII
In multiple, uncontrolled trials of PegIFN/ribavirin therapy, SVR was achieved in approximately 75% of HIV-infected patients with acute HCV infection. Due to high SVR rates achieved with PegIFN/ribavirin and the lack of any data for HCV PIs use during acute infections, HCV PIs should not be routinely used
in HIV-infected patients with acute HCV infection (AIII
Treatment of Chronic HCV Infection
HCV treatment should be considered in all chronically HCV-infected patients with HIV infection. The decision to initiate HCV therapy requires careful assessment of the individual’s potential risks and the benefits of current therapy (see Who to Treat below). For most patients, the medical urgency for HCV treatment is based on the degree of hepatic fibrosis observed on liver histology or other non-invasive markers of fibrosis. For patients with minimal HCV disease (i.e., no or mild portal fibrosis), HCV treatment may be deferred for some patients in the context of rapidly evolving HCV drug development.74,75
Similarly, antiviral treatment with PegIFN is not recommended
in patients with decompensated liver disease.
PegIFN/ribavirin for 48 weeks is recommended for HIV/HCV co-infected patients infected with HCV genotype 1 who are unable to access approved HCV PIs or experimental DAA regimens and for whom HCV treatment cannot be deferred (e.g., those with more than minimal hepatic fibrosis), and those infected with non-1 HCV genotypes (2, 3, 4, 5, or 6) (AI
). For those with HCV genotype 2 or 3 infection, since the approved treatment duration is 24 weeks in HCV monoinfected patients, some experts recommend the use of response guided therapy with 24 weeks of therapy for patients who achieve an undetectable HCV RNA level at treatment week 4, particularly if they are experiencing significant side effects (CIII
). HCV PIs should not be used
in patients with HCV genotype 2 or 3, or 4 infection (AIII
For patients with HCV genotype 1 and stable HIV disease not requiring ART, or those who are on specific ART regimens for which significant drug-drug interactions between ARV drugs and telaprevir or boceprevir are not anticipated, the addition of boceprevir or telaprevir to the PegIFN/ribavirin backbone is recommended (BIII
For patients with HIV disease that requires treatment with an ART regimen that cannot be confidently administered with telaprevir or boceprevir, the following management strategies may be considered:
- If HCV disease is minimal (i.e., no or mild portal fibrosis), consider deferring HCV treatment in the context of rapidly evolving HCV drug development (BIII).
- If good prognostic factors for HCV treatment response are present (e.g., IL28B C/C genotype or low HCV RNA level <400,000 IU/mL) consider PegIFN/ribavirin for 48 weeks without a HCV NS3/4A PI.
- If possible, based on ART history and HIV genotype testing results, consider switching to the ART regimens listed above to permit the use of telaprevir or boceprevir.
- For patients with complex ART history or resistance to multiple classes of ART, consultation with experts regarding the optimal strategy to minimize the risk of HIV breakthrough may be needed (AIII); in such patients, telaprevir may be the preferred HCV NS3/4A PI due to the shorter duration of use (12 weeks) compared to boceprevir (24 to 44 weeks).
For patients with contraindications to the use of ribavirin that cannot be modified, the recommended regimen is PegIFN monotherapy (BII
). Patients should be counseled that the likelihood of SVR is markedly lower in the absence of ribavirin. HCV PIs should not be administered
without ribavirin because of the high likelihood of virologic failure (AI
Who to Treat
Pre-treatment predictors of SVR include both viral and patient factors: HCV genotype, HCV RNA level, stage of liver disease, patient race, and patient IL28B genotype. Although clinical stabilization of HIV disease (with or without ART) is strongly recommended prior to HCV treatment, CD4 count and HIV suppression have not been strongly associated with HCV treatment outcomes.77
Factors favoring initiation of treatment for chronic HCV infection, given the high likelihood of SVR or because of medical necessity, include the following:
- HCV genotype 2 or 3 infection
- HCV genotype 1 infection and low-level viremia (HCV RNA level <400,000 IU/mL)
- HCV genotype 1 infection and favorable IL-28B genotype (i.e., C/C)
- Significant hepatic fibrosis (bridging fibrosis or cirrhosis)
- Vasculitis (due to HCV)
- Membranoproliferative glomerulonephritis (due to HCV)
- High motivation for treatment on the part of the patient
Factors favoring deferral of HCV treatment because of the potential for serious adverse effects include the following:
- Untreated HIV infection with advanced immunosuppression (e.g., CD4 cell count <200/mm3)
- Hepatic decompensation with coagulopathy, encephalopathy, ascites, or variceal hemorrhage
- Severe, concurrent medical conditions, such as cancer or cardiopulmonary disease
- Severe, uncontrolled psychiatric illness
- Current alcohol and/or substance abuse
- Significant, uncontrolled hematologic abnormality, such as hemoglobin <10.0 g/dL, absolute neutrophil count <1000/µL, platelet count <50,000/µL
- In women, pregnancy or breastfeeding; in those of child-bearing potential, unwillingness to practice contraception during treatment and for 6 months after treatment ends
- In men with pregnant partners or partners of child-bearing potential: unwillingness to practice contraception during treatment and for 6 months after treatment ends due to the potential for teratogenic effects of ribavirin transmitted via semen.
- Sarcoidosis (due to the risk of flare with IFN)
- Active, uncontrolled autoimmune disease (due to the risk of flare with IFN)
- Hemoglobinopathies such as thalassemia major and sickle cell anemia (ribavirin is contraindicated)
Special Considerations with Regard to Starting ART
The optimal timing of initiation of ART relative to treatment for HCV infection has not been established. Before initiating HCV therapy, a patient’s HIV disease should be clinically stable with or without ART. Although a specific CD4 threshold has not been defined, HCV treatment trials have largely enrolled patients with CD4 counts >200 cells/mm3
and in one study, HCV RNA suppression was greater in co-infected patients with CD4 count ≥450 cells/mm3
Accordingly, most HIV/HCV co-infected patients with CD4 counts <350 cells/mm3
who are receiving ART should receive at least 6 months of ART before starting HCV treatment; HCV treatment is not routinely recommended in patients with CD4 counts <200 cells/mm3
). However, there may be a role for the treatment of HCV in co-infected patients who are unable to tolerate ART due to recurrent ARV associated liver injury (CIII
Concurrent use of ART and HCV treatment generally is acceptable; however, these combined interventions may lead to complex medical regimens with respect to pill burden, potential drug-drug interactions, and increased toxicities. Severe anemia due to PegIFN/ribavirin is more common in HIV-infected patients taking zidovudine; concomitant use of the drug should be avoided
). Ribavirin also inhibits inosine-5-monophosphate dehydrogenase, an effect that potentiates didanosine toxicity. Because symptomatic, and sometimes fatal, lactic acidosis has been reported with ribavirin and didanosine, the use of these medications together is strictly contraindicated
). In some studies, abacavir use has been associated with a lower likelihood of SVR, compared with other ARV regimens;79,80
however, other studies have failed to confirm this finding.81,82
The routine discontinuation of abacavir prior to HCV treatment is not recommended
The potential drug-drug interactions when ARVs are combined with the HCV PIs (telaprevir or boceprevir) is substantial (see Table 5
). Accordingly, some experts recommend completion of the HCV PI phase of HCV treatment prior to ART initiation in co-infected patients with CD4 count >500/mm3
. Pharmacokinetic interaction and/or clinical studies have been conducted for some but not all ARVs and the HCV PIs. Based on these data, telaprevir can be administered in combination with efavirenz (with telaprevir dose increase from 750 mg to 1125 mg), ritonavir-boosted atazanavir, and raltegravir. Boceprevir was administered in combinations with ritonavir-boosted darunavir, ritonavir-boosted atazanavir, ritonavir-boosted lopinavir, or raltegravir in the ongoing Phase 2 trial. Subsequent drug interaction studies performed in healthy volunteers with these agents indicated bi-directional effects on the concentration of boceprevir and the HIV-1 PI, but not with raltegravir. In patients not yet started on HCV therapy, boceprevir should be prescribed only for patients who are not on ART, or on a raltegravir-based regimen. Before taking telaprevir or boceprevir, HIV-infected patients who require ART, and are taking a regimen known or suspected to interact with the HCV PI, should be assessed for switching to an acceptable ART regimen, if medically feasible (i.e., based on ARV history and HIV genotype testing, if available). If ART is modified to accommodate telaprevir or boceprevir use, patients should be monitored for tolerability and effectiveness of the new ART regimen for at least 4 weeks before starting HCV therapy. Both HIV RNA and HCV RNA should be monitored while these therapies are used in combination. After the discontinuation of the HCV PI, the ART regimen may be switched back to the original regimen at the discretion of the patient and HIV clinician.
Monitoring of Response to Therapy and Adverse Events (Including Immune Reconstitution Inflammatory Syndrome [IRIS])
. As the primary measure of response, HCV RNA monitoring is required before, during, and after treatment. Determination of treatment response and futility is based on the absolute HCV RNA level or the change in HCV RNA levels from baseline at specific treatment time points.83
- Treatment Week 4. The change in HCV RNA at week 4 provides an early assessment of the likelihood of SVR. With PegIFN/ribavirin alone, HIV-infected patients who experience <1 log10 reduction at treatment week 4 are unlikely to achieve an SVR (<5%), whereas those who achieve a rapid virologic response (rapid virological response [RVR]/undetectable HCV RNA level) have the highest probability of SVR (~80%). With telaprevir/PegIFN/ribavirin, all 3 medications should be stopped if the HCV RNA is >1000 IU/mL at week 4 (BIII).
- Treatment Week 8. With boceprevir/PegIFN/ribavirin, this represents the fourth week of HCV PI treatment. Patients with undetectable HCV RNA level at this time are significantly more likely to achieve SVR than those with detectable HCV RNA levels.
- Treatment Week 12. With PegIFN/ribavirin, the virologic response at treatment week 12 is classified according to the log10 change from baseline:
- Null virologic response: <2 log10 reduction; PegIFN/ribavirin alone should be discontinued for futility in patients with null virologic response (AI).
- Partial early virologic response: ≥2 log10 reduction but detectable
- Complete early virologic response: undetectable HCV RNA level; patients who achieve complete early virologic response have a high probability of SVR (~60%–65%).
With telaprevir/PegIFN/ribavirin, all three medications should be stopped if the HCV RNA is >1,000 IU/mL (BII).84 With boceprevir/PegIFN/ribavirin, all three medications should be stopped if the HCV RNA is ≥100 IU/mL (BII).85
- Treatment Week 24. With PegIFN/ribavirin, patients who had a partial early virologic response at week 12 should be retested at week 24; if the HCV RNA is undetectable, the probability of SVR is ~20%. For all treatment regimens, including those that contain telaprevir or boceprevir, all medications should be discontinued in patients who have detectable HCV RNA levels at week 24 (BI).
- End of Treatment (Treatment Week 24 or 48). The plasma HCV RNA level should be measured to exclude viral breakthrough during treatment and determine end-of-treatment response.
- Post Treatment. Patients with undetectable HCV RNA levels at the end of treatment should be monitored for virologic relapse at 24 weeks after therapy. SVR is defined as undetectable HCV RNA at 24 weeks after treatment cessation.
Side effects due to PegIFN/ribavirin occur in most patients; however, their severity and frequency are highly variable. Frequent adverse events of PegIFN include influenza-like symptoms (e.g., fever, headache, myalgia) that occur early in treatment, as well as fatigue, rash, alopecia, neuropsychiatric effects (i.e., depression, irritability, insomnia, and cognitive dysfunction), cough, dyspnea, nausea, vomiting (less common), and weight loss. Ophthalmologic complications, including cotton wool spots and retinitis, may be observed. Cytopenias are common in HIV-infected patients taking PegIFN (e.g., neutropenia, lymphopenia, thrombocytopenia, and anemia) and ribavirin (e.g., hemolytic anemia). PegIFN-induced lymphopenia typically includes a reduction in absolute CD4 count with the preservation of the percentage of lymphocytes that are CD4-positive (CD4%). However, an adverse impact on HIV disease has not been observed. PegIFN can induce autoimmune thyroid disease, resulting in hypo- or hyperthyroidism. HIV disease does not appear to alter the frequency or severity of any of these adverse effects except weight loss and cytopenias.
Telaprevir is used in combination with PegIFN/ribavirin and is associated with additional side effects. The most common side effects observed with telaprevir are rash (mild rashes occur in up to 56% of patients, with severe eczematous rashes occurring in 5% of patients), pruritus, anemia, and gastrointestinal effects (e.g., nausea, vomiting, and diarrhea). Anal discomfort or burning was reported in 29% of telaprevir-treated patients but discontinuation of the drug due to this was uncommon. While most observed rashes were mild to moderate, serious skin reactions such as drug rash with eosinophilia and systemic symptoms (DRESS) and Stevens-Johnson Syndrome have been observed in some patients; further, fatal serious skin reaction have been reported. During telaprevir/PegIFN/ribavirin therapy, patients with mild to moderate rashes should be followed for progression of rash or development of systemic symptoms. If rash progresses and becomes severe or if systemic symptoms develop, telaprevir should be discontinued; PegIFN/ribavirin can be continued. If improvement is not observed within 7 days of telaprevir discontinuation, PegIFN/ribavirin should be discontinued. Telaprevir must not be restarted if it is discontinued due to rash. Treatment of rash with oral antihistamines or topical corticosteroids may provide symptomatic relief but systemic corticosteroids are not recommended
. In patients with serious skin reactions (DRESS or Stevens-Johnson Syndrome), all medications should be stopped and the patient referred for urgent medical care. In the small group of HIV/HCV co-infected patients treated with telaprevir/PegIFN/ribavirin (n = 38), adverse events were similar in frequency and severity to those seen in HCV-monoinfected patients with the exception of hyperbilirubinemia. Bilirubin adverse events occurred in 27% of co-infected patients taking ritonavir-boosted atazanavir and telaprevir/PegIFN/ribavirin compared to none of those taking ritonavir-boosted atazanavir and PegIFN/ribavirin; one patient discontinued therapy due to hyperbilirubinemia.
Boceprevir is used in combination with PegIFN/ribavirin and is associated with additional side effects. The most common side effects observed with boceprevir are anemia, neutropenia, and dysgeusia. In the registration trials of boceprevir/PegIFN/ribavirin in HCV monoinfected patients, anemia (hemoglobin <10 g/dL) occurred in 45% to 49% of patients treated with boceprevir/PegIFN/ribavirin compared to 20% to 29% treated with PegIFN/ribavirin.66,86
Erythropoietin alfa was used in 43% of patients treated with boceprevir/PegIFN/ribavirin. Neutropenia (grade 3—absolute neutrophil count 500–750/mm3
) was seen in 19% to 24% of boceprevir-treated patients compared to 9% to 14% of those treated with PegIFN/ribavirin. Dysgeusia was also more common with boceprevir/PegIFN/ribavirin (~44%) but rarely treatment limiting. In the small group of HIV/HCV co-infected patients treated with boceprevir/PegIFN/ribavirin (n = 64), adverse events were similar in frequency and severity to those seen in HCV-monoinfected patients.69
Patients should undergo clinical and laboratory monitoring before treatment and at least monthly during treatment; however, more frequent monitoring may be required during the initial 12 weeks of HCV PI therapy. Pre-treatment evaluations should include a complete blood count; comprehensive metabolic panel (that is, a chemistry panel that includes serum creatinine, ALT, AST, albumin, and total bilirubin); measurement of thyroid stimulating hormone, HIV RNA level, CD4 cell count and percentage; and pregnancy testing in women of child-bearing potential. Screening for depression before therapy is recommended; some specialists recommend using standardized depression screening tools, such as the Center for Epidemiologic Studies Depression Scale (CES-D). During treatment, monthly clinical visits and laboratory assessments (i.e., complete blood count, comprehensive metabolic panel, and pregnancy tests) are recommended to monitor patient status, screen for depression (CES-D), and manage ongoing adverse effects of therapy. Other laboratory tests should be monitored every 3 months, including HIV RNA level, CD4 count, and thyrotropin. Treatment-emergent cytopenias, including anemia, neutropenia and thrombocytopenia, should be managed with dose reduction of PegIFN (neutropenia, thrombocytopenia) and/or ribavirin (anemia). While some experts advocate for the use of adjuvant drugs to increase neutrophils (filgrastim) or red blood cells (erythropoietin alfa or darbepoetin alfa), the initial strategy for management treatment related cytopenia is dose reduction of PegIFN and/or ribavirin; the use of growth factors should be reserved for those patients in whom dose reduction is not sufficient (BIII
). Adverse neuropsychiatric effects of PegIFN can be managed with adjunctive agents such as antidepressants or other mood stabilizers.
Managing Treatment Failure
Data are limited regarding retreatment of HIV/HCV-co-infected patients who fail to respond to HCV therapy.87-90
In general, the SVR rates for retreatment of non-responders are markedly lower than for treatment-naive patients.90-92
Boceprevir and telaprevir are approved in combination with PegIFN/ribavirin for retreatment of HCV genotype 1 in monoinfected patients who failed prior HCV treatment regimens. In this population, the likelihood of SVR with HCV PI/PegIFN/ribavirin was dependent on the prior virologic response pattern; the highest SVR rates were observed in patients with prior virologic relapse (75% to 88%) and those with partial virologic response (50% to 59%); in contrast, only ~30% of patient with prior null virologic response achieved SVR. There are no data on the efficacy of boceprevir or telaprevir plus PegIFN/ribavirin in HIV/HCV-co-infected patients who have failed prior HCV treatment. Because SVR rates are anticipated to be low in this population, HIV/HCV co-infected treatment failure patients should be carefully evaluated for the medical necessity of re-treatment. Patients with minimal liver disease may elect to forgo treatment with HCV PI/PegIFN/ribavirin whereas such regimens may be considered for HIV/HCV co-infected treatment failure patients with significant liver disease in the absence of other treatment options (CIII
). However, given the paucity of data and incomplete risk-benefit assessment of HCV PIs in this population, consideration should be given to enrollment of such HIV/HCV co-infected patients into clinical trials investigating novel DAAs whenever feasible (CIII
Treatment-induced SVR is durable in HIV/HCV co-infected patients and is consistent with virologic cure.56
To prevent re-infection, HIV/HCV co-infected patients who achieve an SVR should be counseled to avoid re-infection since protective immunity is not present and re-infection has been demonstrated in patients who engage in high-risk behaviors (e.g., injection drug use and/or unprotected intercourse). Use of barrier precautions and other methods to prevent sexual transmission of HIV should be adequate to prevent reinfection with HCV via sexual practices.
Special Considerations During Pregnancy
Pregnant HIV-infected women should be tested for HCV infection to allow appropriate management for the mother during pregnancy and after delivery, and also for their infants.93
HCV treatment with PegIFN and ribavirin is contraindicated
during pregnancy (AII
). IFNs are abortifacient at high doses in monkeys and should not be used
in pregnant women because of their direct antigrowth and antiproliferative effects.94
Ribavirin is an FDA category X drug because of its teratogenicity at low doses in multiple animal species. Defects noted in animals include limb abnormalities, craniofacial defects, exencephaly, and anophthalmia. Ribavirin should not be used
during pregnancy (AII
). Women of childbearing potential and men receiving ribavirin should be counseled about the risks and need for consistent contraceptive use during and for 6 months after completion of ribavirin therapy (AIII
). Inadvertent pregnancy during paternal exposure was not associated with adverse events in two newborns.95
Pregnancies that occur in women taking ribavirin or those in women whose male partner is taking the drug should be reported to the Ribavirin Pregnancy Registry (800-593-2214 or http://www.ribavirinpregnancyregistry.com
). Telaprevir and boceprevir are Pregnancy Category B; however, these agents must be used in combination with PegIFN/ribavirin, which are not recommended
Evaluation of HCV-infected pregnant women, including liver biopsy, can be delayed until >3 months after delivery to allow potential pregnancy-related changes in disease activity to resolve. HAV and HBV vaccines can be administered during pregnancy and women who have not previously been vaccinated should receive them. Several studies have reported that perinatal transmission of HCV occurs more frequently in women with HIV/HCV-co-infection than in those with HCV monoinfection. However, data are limited regarding the role of medical or surgical interventions to reduce the risk of perinatal HCV transmission. Nearly all studies, including those in HIV-uninfected and HIV-infected women, have found that elective cesarean delivery does not reduce the risk of perinatal HCV transmission.26,96-98
Moreover, there is an increased risk of maternal morbidity associated with cesarean compared with vaginal delivery, particularly in the setting of maternal HIV infection.99-102
Thus, while elective cesarean delivery in HIV/HCV-co-infected women can be considered based on HIV-related indications, data are insufficient to support its routine use for prevention of HCV transmission.
Recommendations for Treatment of Hepatitis C Virus (HCV) Infection
|Treating Acute HCV Infection
Treatment should be offered to HIV-infected patients with acute HCV infection (AII). Because of the high rate of spontaneous clearance, some experts recommend observation for 3 to 6 months (especially for patients with C/C IL28B genotype) before initiation of therapy.
Treating Chronic HCV Infection
- (PegIFN-2a 180 µg or PegIFN-2b 1.5 µg/kg) SQ weekly + RBV (dosed according to HCV genotype as for chronic HCV infection) for 24 to 48 weeks
Please refer to the Who to Treat section in the text for factors favoring initiation or deferral of HCV treatment.
(PegIFN-2a 180 µg or PegIFN-2b 1.5 µg/kg) SQ weekly for 48 weeks (AI) + RBV PO for 48 weeks (AI) +/- An HCV PI (based on ART use as indicated below) (BIII)
Weight-based dosing for:
PegIFN + RBV for 48 weeks (without an HCV PI) is recommended for HCV genotype 1 patients who are unable to access an HCV PI or experimental directly acting agent regimen, and for whom HCV treatment cannot be deferred (e.g., those with more than minimal hepatic fibrosis) (AI)
- <75 kg: 600 mg qAM and 400 mg qPM;
- ≥75 kg: 600 mg qAM and 600 mg qPM
If an HCV PI is to be used, the following table provides dosage guidelines based on concomitant ARV regimens used:
|No ART or
RAL + 2 NRTI
- BOC 800 mg PO TID (q 7–9 h) with food, beginning after 4 weeks of PegIFN/RBV and continue for 44 weeks (based on response guided therapy), or
- TVR 750 mg PO TID (q 7–9 h) with at least 20 g of fat for 12 weeks (with PegIFN/RBV), then continue PegIFN/RBV (without TVR) for a total of 48 weeks
|ATV/r + 2 NRTI
|TVR 750 mg PO TID (q 7–9 h) with at least 20 g of fat for 12 weeks (PegIFN/RBV to be continued for 48 weeks)
|EFV + 2 NRTI
|TVR 1125 mg PO TID (q 7–9 h) with at least 20 g of fat for 12 weeks (PegIFN/RBV to be continued for 48 weeks)
|On other ART regimen
- Defer HCV treatment (especially in patients with no or minimal fibrosis) (BIII); or
- Use PegIFN/RBV without HCV PI in patients with good prognosis (e.g., IL28B C/C genotype or low HCV RNA level [<400,000 IU/mL]), or
- If feasible based on ARV history and HIV genotype testing, modify ART to one of the above regimens, and monitor for at least 4 weeks for tolerability and efficacy before starting HCV therapy, or
- For patients with complex ART history or resistance to multiple classes of ART, consultation with experts regarding the optimal strategy to minimize the risk of HIV breakthrough may be needed (AIII); in such patients, TVR may be the preferred HCV NS3/4A PI due to the shorter duration of use (12 weeks) compared to BOC (44 weeks).
Genotype 2, 3, 4, 5, or 6 (AI)
Duration of therapy: 48 weeks (AI)
Some experts recommend the use of response-guided therapy, shortening duration to 24 weeks for patients with HCV genotype 2 or 3 infection who achieve an undetectable HCV RNA at treatment week 4, particularly if they experience significant side effects (CIII).
- (PegIFN-2a 180µg or PegIFN-2b 1.5 µg/kg) SQ weekly + RBV 400 mg PO BID
In Patients for Whom RBV Is Contraindicated
Patients must be counseled that the likelihood of SVR without RBV is markedly lower.
- PegIFN-2a 180 µg or PegIFN-2b 1.5 µg/kg SQ weekly (AII)
HCV PI should not be given with peginterferon without RBV, because of the high likelihood of virologic failure (AI).
In Patients with Decompensated Liver Disease
- Liver transplantation if feasible (CIII); treatment with PegIFN is contraindicated
- ddI + RBV may lead to increased mitochondrial toxicities; concomitant use is contraindicated (AII).
- ZDV + RBV +/- HCV PI may lead to increased anemia; concomitant use should be avoided. (AII).
- IFN is an abortifacient in high doses and RBV is teratogenic. HCV treatment is not recommended in pregnant women or women who are not willing to use birth control (AII).
- BOC and TVR are not recommended for non-genotype 1 HCV infection (AIII).
- HCV treatment is generally not recommended in patients with CD4 count <200 cells/µL (CIII).
- Alter MJ. Epidemiology of hepatitis C virus infection. World J Gastroenterol. May 7 2007;13(17):2436-2441. Available at http://www.ncbi.nlm.nih.gov/pubmed/17552026.
- Scott JD, Gretch DR. Molecular diagnostics of hepatitis C virus infection: a systematic review. JAMA. Feb 21 2007;297(7):724-732. Available at http://www.ncbi.nlm.nih.gov/pubmed/17312292.
- Armstrong GL, Wasley A, Simard EP, McQuillan GM, Kuhnert WL, Alter MJ. The prevalence of hepatitis C virus infection in the United States, 1999 through 2002. Ann Intern Med. May 16 2006;144(10):705-714. Available at http://www.ncbi.nlm.nih.gov/pubmed/16702586.
- Blatt LM, Mutchnick MG, Tong MJ, et al. Assessment of hepatitis C virus RNA and genotype from 6807 patients with chronic hepatitis C in the United States. J Viral Hepat. May 2000;7(3):196-202. Available at http://www.ncbi.nlm.nih.gov/pubmed/10849261.
- Staples CT, Jr., Rimland D, Dudas D. Hepatitis C in the HIV (human immunodeficiency virus) Atlanta V.A. (Veterans Affairs Medical Center) Cohort Study (HAVACS): the effect of coinfection on survival. Clin Infect Dis. Jul 1999;29(1):150-154. Available at http://www.ncbi.nlm.nih.gov/pubmed/10433578.
- Sherman KE, Rouster SD, Chung RT, Rajicic N. Hepatitis C Virus prevalence among patients infected with Human Immunodeficiency Virus: a cross-sectional analysis of the US adult AIDS Clinical Trials Group. Clin Infect Dis. Mar 15 2002;34(6):831-837. Available at http://www.ncbi.nlm.nih.gov/pubmed/11833007.
- Sulkowski MS, Moore RD, Mehta SH, Chaisson RE, Thomas DL. Hepatitis C and progression of HIV disease. JAMA. Jul 10 2002;288(2):199-206. Available at http://www.ncbi.nlm.nih.gov/pubmed/12095384.
- Ciesek S, Friesland M, Steinmann J, et al. How stable is the hepatitis C virus (HCV)? Environmental stability of HCV and its susceptibility to chemical biocides. J Infect Dis. Jun 15 2010;201(12):1859-1866. Available at http://www.ncbi.nlm.nih.gov/pubmed/20441517.
- Paintsil E, He H, Peters C, Lindenbach BD, Heimer R. Survival of hepatitis C virus in syringes: implication for transmission among injection drug users. J Infect Dis. Oct 1 2010;202(7):984-990. Available at http://www.ncbi.nlm.nih.gov/pubmed/20726768.
- Prati D. Transmission of hepatitis C virus by blood transfusions and other medical procedures: a global review. J Hepatol. Oct 2006;45(4):607-616. Available at http://www.ncbi.nlm.nih.gov/pubmed/16901579.
- Alter MJ. Healthcare should not be a vehicle for transmission of hepatitis C virus. J Hepatol. Jan 2008;48(1):2-4. Available at http://www.ncbi.nlm.nih.gov/pubmed/18023493.
- Centers for Disease C, Prevention. Acute hepatitis C virus infections attributed to unsafe injection practices at an endoscopy clinic--Nevada, 2007. MMWR Morb Mortal Wkly Rep. May 16 2008;57(19):513-517. Available at http://www.ncbi.nlm.nih.gov/pubmed/18480743.
- Eyster ME, Alter HJ, Aledort LM, Quan S, Hatzakis A, Goedert JJ. Heterosexual co-transmission of hepatitis C virus (HCV) and human immunodeficiency virus (HIV). Ann Intern Med. Nov 15 1991;115(10):764-768. Available at http://www.ncbi.nlm.nih.gov/pubmed/1656825.
- Lissen E, Alter HJ, Abad MA, et al. Hepatitis C virus infection among sexually promiscuous groups and the heterosexual partners of hepatitis C virus infected index cases. Eur J Clin Microbiol Infect Dis. Nov 1993;12(11):827-831. Available at http://www.ncbi.nlm.nih.gov/pubmed/7509282.
- van de Laar TJ, van der Bij AK, Prins M, et al. Increase in HCV incidence among men who have sex with men in Amsterdam most likely caused by sexual transmission. J Infect Dis. Jul 15 2007;196(2):230-238. Available at http://www.ncbi.nlm.nih.gov/pubmed/17570110.
- van de Laar TJ, Matthews GV, Prins M, Danta M. Acute hepatitis C in HIV-infected men who have sex with men: an emerging sexually transmitted infection. AIDS. Jul 31 2010;24(12):1799-1812. Available at http://www.ncbi.nlm.nih.gov/pubmed/20601854.
- Rauch A, Rickenbach M, Weber R, et al. Unsafe sex and increased incidence of hepatitis C virus infection among HIV-infected men who have sex with men: the Swiss HIV Cohort Study. Clin Infect Dis. Aug 1 2005;41(3):395-402. Available at http://www.ncbi.nlm.nih.gov/pubmed/16007539.
- Danta M, Brown D, Bhagani S, et al. Recent epidemic of acute hepatitis C virus in HIV-positive men who have sex with men linked to high-risk sexual behaviours. AIDS. May 11 2007;21(8):983-991. Available at http://www.ncbi.nlm.nih.gov/pubmed/17457092.
- van de Laar T, Pybus O, Bruisten S, et al. Evidence of a large, international network of HCV transmission in HIV-positive men who have sex with men. Gastroenterology. May 2009;136(5):1609-1617. Available at http://www.ncbi.nlm.nih.gov/pubmed/19422083.
- Fierer DS, Uriel AJ, Carriero DC, et al. Liver fibrosis during an outbreak of acute hepatitis C virus infection in HIV-infected men: a prospective cohort study. J Infect Dis. Sep 1 2008;198(5):683-686. Available at http://www.ncbi.nlm.nih.gov/pubmed/18627270.
- Taylor LE, Holubar M, Wu K, et al. Incident hepatitis C virus infection among US HIV-infected men enrolled in clinical trials. Clin Infect Dis. Mar 15 2011;52(6):812-818. Available at http://www.ncbi.nlm.nih.gov/pubmed/21282184.
- Crepaz N, Hart TA, Marks G. Highly active antiretroviral therapy and sexual risk behavior: a meta-analytic review. JAMA. Jul 14 2004;292(2):224-236. Available at http://www.ncbi.nlm.nih.gov/pubmed/15249572.
- Stolte IG, Dukers NH, Geskus RB, Coutinho RA, de Wit JB. Homosexual men change to risky sex when perceiving less threat of HIV/AIDS since availability of highly active antiretroviral therapy: a longitudinal study. AIDS. Jan 23 2004;18(2):303-309. Available at http://www.ncbi.nlm.nih.gov/pubmed/15075549.
- Ohto H, Terazawa S, Sasaki N, et al. Transmission of hepatitis C virus from mothers to infants. The Vertical Transmission of Hepatitis C Virus Collaborative Study Group. N Engl J Med. Mar 17 1994;330(11):744-750. Available at http://www.ncbi.nlm.nih.gov/pubmed/8107740.
- Roberts EA, Yeung L. Maternal-infant transmission of hepatitis C virus infection. Hepatology. Nov 2002;36(5 Suppl 1):S106-113. Available at http://www.ncbi.nlm.nih.gov/pubmed/12407583.
- McMenamin MB, Jackson AD, Lambert J, et al. Obstetric management of hepatitis C-positive mothers: analysis of vertical transmission in 559 mother-infant pairs. Am J Obstet Gynecol. Sep 2008;199(3):315 e311-315. Available at http://www.ncbi.nlm.nih.gov/pubmed/18771997.
- Valladares G, Chacaltana A, Sjogren MH. The management of HCV-infected pregnant women. Ann Hepatol. 2010;9 Suppl:92-97. Available at http://www.ncbi.nlm.nih.gov/pubmed/20714003.
- Mast EE, Hwang LY, Seto DS, et al. Risk factors for perinatal transmission of hepatitis C virus (HCV) and the natural history of HCV infection acquired in infancy. J Infect Dis. Dec 1 2005;192(11):1880-1889. Available at http://www.ncbi.nlm.nih.gov/pubmed/16267758.
- Alter MJ. Epidemiology of viral hepatitis and HIV co-infection. J Hepatol. 2006;44(1 Suppl):S6-9. Available at http://www.ncbi.nlm.nih.gov/pubmed/16352363.
- Jaeckel E, Cornberg M, Wedemeyer H, et al. Treatment of acute hepatitis C with interferon alfa-2b. N Engl J Med. Nov 15 2001;345(20):1452-1457. Available at http://www.ncbi.nlm.nih.gov/pubmed/11794193.
- Kamal SM, Fouly AE, Kamel RR, et al. Peginterferon alfa-2b therapy in acute hepatitis C: impact of onset of therapy on sustained virologic response. Gastroenterology. Mar 2006;130(3):632-638. Available at http://www.ncbi.nlm.nih.gov/pubmed/16530503.
- Tong MJ, el-Farra NS, Reikes AR, Co RL. Clinical outcomes after transfusion-associated hepatitis C. N Engl J Med. Jun 1 1995;332(22):1463-1466. Available at http://www.ncbi.nlm.nih.gov/pubmed/7739682.
- Poynard T, Bedossa P, Opolon P. Natural history of liver fibrosis progression in patients with chronic hepatitis C. The OBSVIRC, METAVIR, CLINIVIR, and DOSVIRC groups. Lancet. Mar 22 1997;349(9055):825-832. Available at http://www.ncbi.nlm.nih.gov/pubmed/9121257.
- Sulkowski MS, Thomas DL, Chaisson RE, Moore RD. Elevated liver enzymes following initiation of antiretroviral therapy. JAMA. May 17 2000;283(19):2526-2527. Available at http://www.ncbi.nlm.nih.gov/pubmed/10815113.
- Benhamou Y, Bochet M, Di Martino V, et al. Liver fibrosis progression in human immunodeficiency virus and hepatitis C virus coinfected patients. The Multivirc Group. Hepatology. Oct 1999;30(4):1054-1058. Available at http://www.ncbi.nlm.nih.gov/pubmed/10498659.
- Di Martino V, Rufat P, Boyer N, et al. The influence of human immunodeficiency virus coinfection on chronic hepatitis C in injection drug users: a long-term retrospective cohort study. Hepatology. Dec 2001;34(6):1193-1199. Available at http://www.ncbi.nlm.nih.gov/pubmed/11732009.
- Pineda JA, Romero-Gomez M, Diaz-Garcia F, et al. HIV coinfection shortens the survival of patients with hepatitis C virus-related decompensated cirrhosis. Hepatology. Apr 2005;41(4):779-789. Available at http://www.ncbi.nlm.nih.gov/pubmed/15800956.
- Ragni MV, Eghtesad B, Schlesinger KW, Dvorchik I, Fung JJ. Pretransplant survival is shorter in HIV-positive than HIV-negative subjects with end-stage liver disease. Liver Transpl. Nov 2005;11(11):1425-1430. Available at http://www.ncbi.nlm.nih.gov/pubmed/16237709.
- Salmon-Ceron D, Lewden C, Morlat P, et al. Liver disease as a major cause of death among HIV infected patients: role of hepatitis C and B viruses and alcohol. J Hepatol. Jun 2005;42(6):799-805. Available at http://www.ncbi.nlm.nih.gov/pubmed/15973779.
- Weber R, Sabin CA, Friis-Moller N, et al. Liver-related deaths in persons infected with the human immunodeficiency virus: the D:A:D study. Arch Intern Med. Aug 14-28 2006;166(15):1632-1641. Available at http://www.ncbi.nlm.nih.gov/pubmed/16908797.
- Smith JA, Aberle JH, Fleming VM, et al. Dynamic coinfection with multiple viral subtypes in acute hepatitis C. J Infect Dis. Dec 15 2010;202(12):1770-1779. Available at http://www.ncbi.nlm.nih.gov/pubmed/21067369.
- National Institutes of H. National Institutes of Health Consensus Development Conference Statement: Management of hepatitis C: 2002--June 10-12, 2002. Hepatology. Nov 2002;36(5 Suppl 1):S3-20. Available at http://www.ncbi.nlm.nih.gov/pubmed/12407572.
- Chamot E, Hirschel B, Wintsch J, et al. Loss of antibodies against hepatitis C virus in HIV-seropositive intravenous drug users. AIDS. Dec 1990;4(12):1275-1277. Available at http://www.ncbi.nlm.nih.gov/pubmed/1965126.
- Thio CL, Nolt KR, Astemborski J, Vlahov D, Nelson KE, Thomas DL. Screening for hepatitis C virus in human immunodeficiency virus-infected individuals. J Clin Microbiol. Feb 2000;38(2):575-577. Available at http://www.ncbi.nlm.nih.gov/pubmed/10655348.
- Sulkowski MS, Thomas DL. Hepatitis C in the HIV-infected patient. Clinics in liver disease. Feb 2003;7(1):179-194. Available at http://www.ncbi.nlm.nih.gov/pubmed/12691466.
- Hagan H, Jarlais DC, Friedman SR, Purchase D, Alter MJ. Reduced risk of hepatitis B and hepatitis C among injection drug users in the Tacoma syringe exchange program. Am J Public Health. Nov 1995;85(11):1531-1537. Available at http://www.ncbi.nlm.nih.gov/pubmed/7485666.
- Hagan H, McGough JP, Thiede H, Weiss NS, Hopkins S, Alexander ER. Syringe exchange and risk of infection with hepatitis B and C viruses. American journal of epidemiology. Feb 1 1999;149(3):203-213. Available at http://www.ncbi.nlm.nih.gov/pubmed/9927214.
- Vlahov D, Junge B, Brookmeyer R, et al. Reductions in high-risk drug use behaviors among participants in the Baltimore needle exchange program. J Acquir Immune Defic Syndr Hum Retrovirol. Dec 15 1997;16(5):400-406. Available at http://www.ncbi.nlm.nih.gov/pubmed/9420320.
- Centers for Disease C, Prevention. Sexual transmission of hepatitis C virus among HIV-infected men who have sex with men--New York City, 2005-2010. MMWR Morb Mortal Wkly Rep. Jul 22 2011;60(28):945-950. Available at http://www.ncbi.nlm.nih.gov/pubmed/21775948.
- Lambers FA, Brinkman K, Schinkel J, et al. Treatment of acute hepatitis C virus infection in HIV-infected MSM: the effect of treatment duration. AIDS. Jun 19 2011;25(10):1333-1336. Available at http://www.ncbi.nlm.nih.gov/pubmed/21516025.
- Piroth L, Larsen C, Binquet C, et al. Treatment of acute hepatitis C in human immunodeficiency virus-infected patients: the HEPAIG study. Hepatology. Dec 2010;52(6):1915-1921. Available at http://www.ncbi.nlm.nih.gov/pubmed/21064156.
- Grebely J, Petoumenos K, Hellard M, et al. Potential role for interleukin-28B genotype in treatment decision-making in recent hepatitis C virus infection. Hepatology. Oct 2010;52(4):1216-1224. Available at http://www.ncbi.nlm.nih.gov/pubmed/20803561.
- Wiley TE, McCarthy M, Breidi L, McCarthy M, Layden TJ. Impact of alcohol on the histological and clinical progression of hepatitis C infection. Hepatology. Sep 1998;28(3):805-809. Available at http://www.ncbi.nlm.nih.gov/pubmed/9731576.
- Forns X, Bruix J. Treating hepatitis C in patients with cirrhosis: the effort is worth it. J Hepatol. May 2010;52(5):624-626. Available at http://www.ncbi.nlm.nih.gov/pubmed/20334945.
- Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. Available at /ContentFiles/lvguidelines/AdultandAdolescentGL.pdf. Accessed June 1, 2012
- Swain MG, Lai MY, Shiffman ML, et al. A sustained virologic response is durable in patients with chronic hepatitis C treated with peginterferon alfa-2a and ribavirin. Gastroenterology. Nov 2010;139(5):1593-1601. Available at http://www.ncbi.nlm.nih.gov/pubmed/20637202.
- Berenguer J, Alvarez-Pellicer J, Martin PM, et al. Sustained virological response to interferon plus ribavirin reduces liver-related complications and mortality in patients coinfected with human immunodeficiency virus and hepatitis C virus. Hepatology. Aug 2009;50(2):407-413. Available at http://www.ncbi.nlm.nih.gov/pubmed/19575364.
- Morgan TR, Ghany MG, Kim HY, et al. Outcome of sustained virological responders with histologically advanced chronic hepatitis C. Hepatology. Sep 2010;52(3):833-844. Available at http://www.ncbi.nlm.nih.gov/pubmed/20564351.
- Labarga P, Soriano V, Vispo ME, et al. Hepatotoxicity of antiretroviral drugs is reduced after successful treatment of chronic hepatitis C in HIV-infected patients. J Infect Dis. Sep 1 2007;196(5):670-676. Available at http://www.ncbi.nlm.nih.gov/pubmed/17674307.
- Ge D, Fellay J, Thompson AJ, et al. Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance. Nature. Sep 17 2009;461(7262):399-401. Available at http://www.ncbi.nlm.nih.gov/pubmed/19684573.
- Thomas DL, Thio CL, Martin MP, et al. Genetic variation in IL28B and spontaneous clearance of hepatitis C virus. Nature. Oct 8 2009;461(7265):798-801. Available at http://www.ncbi.nlm.nih.gov/pubmed/19759533.
- Rauch A, Kutalik Z, Descombes P, et al. Genetic variation in IL28B is associated with chronic hepatitis C and treatment failure: a genome-wide association study. Gastroenterology. Apr 2010;138(4):1338-1345, 1345 e1331-1337. Available at http://www.ncbi.nlm.nih.gov/pubmed/20060832.
- Ghany MG, Kleiner DE, Alter H, et al. Progression of fibrosis in chronic hepatitis C. Gastroenterology. Jan 2003;124(1):97-104. Available at http://www.ncbi.nlm.nih.gov/pubmed/12512034.
- Van Thiel DH, Gavaler JS, Wright H, Tzakis A. Liver biopsy. Its safety and complications as seen at a liver transplant center. Transplantation. May 1993;55(5):1087-1090. Available at http://www.ncbi.nlm.nih.gov/pubmed/8497887.
- Bravo AA, Sheth SG, Chopra S. Liver biopsy. N Engl J Med. Feb 15 2001;344(7):495-500. Available at http://www.ncbi.nlm.nih.gov/pubmed/11172192.
- Bacon BR, Gordon SC, Lawitz E, et al. Boceprevir for previously treated chronic HCV genotype 1 infection. N Engl J Med. Mar 31 2011;364(13):1207-1217. Available at http://www.ncbi.nlm.nih.gov/pubmed/21449784.
- Jacobson IM, McHutchison JG, Dusheiko G, et al. Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med. Jun 23 2011;364(25):2405-2416. Available at http://www.ncbi.nlm.nih.gov/pubmed/21696307.
- Ghany MG, Nelson DR, Strader DB, Thomas DL, Seeff LB, American Association for Study of Liver D. An update on treatment of genotype 1 chronic hepatitis C virus infection: 2011 practice guideline by the American Association for the Study of Liver Diseases. Hepatology. Oct 2011;54(4):1433-1444. Available at http://www.ncbi.nlm.nih.gov/pubmed/21898493.
- Sulkowski MP, S.; et al. . Boceprevir + pegylated interferon + ribavirin for the treatment of HCV/HIV co-infected patients: End of treatment (Week 48) interim results. 18th Conference on Retroviruses and Opportunistic Infections. Seattle, WA, Abs 472012.
- Sulkowski M, Sherman K, Soriano V, et al. . Telaprevir in Combination with Peginterferon Alfa-2a/Ribavirin in HCV/HIV Co-infected Patients: SVR24 Final Study Results. 63rd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2012). Boston, November 9-13, 2012. Abstract 54.
- Rodriguez-Torres M, Slim J, Bhatti L, et al. Peginterferon alfa-2a Plus Ribavirin for HIV-HCV Genotype 1 Coinfected Patients: A Randomized International Trial. HIV Clin Trials. May-Jun 2012;13(3):142-152. Available at http://www.ncbi.nlm.nih.gov/pubmed/22592094.
- Dieterich DS, V; et al. . Telaprevir in combination with peginterferion alpha-2a + ribavirin in HCV/HIV-co-infected patients: a 24-week treatment interim analysis. 18th Conference on Retroviruses and Opportunistic Infections. Seattle, WA, Abs 46.2012.
- Dore GJ, Hellard M, Matthews GV, et al. Effective treatment of injecting drug users with recently acquired hepatitis C virus infection. Gastroenterology. Jan 2010;138(1):123-135 e121-122. Available at http://www.ncbi.nlm.nih.gov/pubmed/19782085.
- Gane EJ, Stedman CA, Hyland RH, et al. Nucleotide polymerase inhibitor sofosbuvir plus ribavirin for hepatitis C. N Engl J Med. Jan 3 2013;368(1):34-44. Available at http://www.ncbi.nlm.nih.gov/pubmed/23281974.
- Poordad F, Lawitz E, Kowdley KV, et al. Exploratory study of oral combination antiviral therapy for hepatitis C. N Engl J Med. Jan 3 2013;368(1):45-53. Available at http://www.ncbi.nlm.nih.gov/pubmed/23281975.
- Hezode C, Forestier N, Dusheiko G, et al. Telaprevir and peginterferon with or without ribavirin for chronic HCV infection. N Engl J Med. Apr 30 2009;360(18):1839-1850. Available at http://www.ncbi.nlm.nih.gov/pubmed/19403903.
- Mira JA, Gutierrez-Valencia A, Gil Ide L, et al. Efficacy and safety of pegylated interferon plus ribavirin in HIV and hepatitis C virus-coinfected patients with advanced immunosuppression. Clin Infect Dis. Oct 15 2009;49(8):e84-91. Available at http://www.ncbi.nlm.nih.gov/pubmed/19772388.
- Avidan NU, Goldstein D, Rozenberg L, et al. Hepatitis C viral kinetics during treatment with peg IFN-alpha-2b in HIV/HCV coinfected patients as a function of baseline CD4+ T-cell counts. J Acquir Immune Defic Syndr. Dec 1 2009;52(4):452-458. Available at http://www.ncbi.nlm.nih.gov/pubmed/19797971.
- Vispo E, Barreiro P, Rodriguez-Novoa S, et al. Distinct hepatitis C virus kinetics in HIV-infected patients treated with ribavirin plus either pegylated interferon alpha2a or alpha2b. Antivir Ther. 2008;13(4):511-517. Available at http://www.ncbi.nlm.nih.gov/pubmed/18672529.
- Mira JA, Lopez-Cortes LF, Barreiro P, et al. Efficacy of pegylated interferon plus ribavirin treatment in HIV/hepatitis C virus co-infected patients receiving abacavir plus lamivudine or tenofovir plus either lamivudine or emtricitabine as nucleoside analogue backbone. J Antimicrob Chemother. Dec 2008;62(6):1365-1373. Available at http://www.ncbi.nlm.nih.gov/pubmed/18854330.
- Laufer N, Laguno M, Perez I, et al. Abacavir does not influence the rate of virological response in HIV-HCV-coinfected patients treated with pegylated interferon and weight-adjusted ribavirin. Antivir Ther. 2008;13(7):953-957. Available at http://www.ncbi.nlm.nih.gov/pubmed/19043930.
- Amorosa VK, Slim J, Mounzer K, et al. The influence of abacavir and other antiretroviral agents on virological response to HCV therapy among antiretroviral-treated HIV-infected patients. Antivir Ther. 2010;15(1):91-99. Available at http://www.ncbi.nlm.nih.gov/pubmed/20167995.
- Ghany MG, Strader DB, Thomas DL, Seeff LB, American Association for the Study of Liver D. Diagnosis, management, and treatment of hepatitis C: an update. Hepatology. Apr 2009;49(4):1335-1374. Available at http://www.ncbi.nlm.nih.gov/pubmed/19330875.
- Adda N, Bartels DJ, Gritz L, et al. Futility rules for telaprevir combination treatment for patients with hepatitis C virus infection. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association. Feb 2013;11(2):193-195. Available at http://www.ncbi.nlm.nih.gov/pubmed/23159528.
- Jacobson IM, Marcellin P, Zeuzem S, et al. Refinement of stopping rules during treatment of hepatitis C genotype 1 infection with boceprevir and peginterferon/ribavirin. Hepatology. Aug 2012;56(2):567-575. Available at http://www.ncbi.nlm.nih.gov/pubmed/22619063.
- Poordad F, McCone J, Jr., Bacon BR, et al. Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med. Mar 31 2011;364(13):1195-1206. Available at http://www.ncbi.nlm.nih.gov/pubmed/21449783.
- Rodriguez-Torres M, Rodriguez-Orengo JF, Rios-Bedoya CF, et al. Effect of hepatitis C virus treatment in fibrosis progression rate (FPR) and time to cirrhosis (TTC) in patients co-infected with human immunodeficiency virus: a paired liver biopsy study. J Hepatol. Apr 2007;46(4):613-619. Available at http://www.ncbi.nlm.nih.gov/pubmed/17316873.
- Esteban JI, Sauleda S, Quer J. The changing epidemiology of hepatitis C virus infection in Europe. J Hepatol. Jan 2008;48(1):148-162. Available at http://www.ncbi.nlm.nih.gov/pubmed/18022726.
- Soriano V, Vispo E, Labarga P, Medrano J, Barreiro P. Viral hepatitis and HIV co-infection. Antiviral research. Jan 2010;85(1):303-315. Available at http://www.ncbi.nlm.nih.gov/pubmed/19887087.
- Myers RP, Benhamou Y, Bochet M, Thibault V, Mehri D, Poynard T. Pegylated interferon alpha 2b and ribavirin in HIV/hepatitis C virus-co-infected non-responders and relapsers to IFN-based therapy. AIDS. Jan 2 2004;18(1):75-79. Available at http://www.ncbi.nlm.nih.gov/pubmed/15090832.
- Crespo M, Mira JA, Pineda JA, et al. Efficacy of pegylated interferon and ribavirin for retreatment of chronic HCV infection in HIV co-infected patients failing a previous standard interferon-based regimen. J Antimicrob Chemother. Oct 2008;62(4):793-796. Available at http://www.ncbi.nlm.nih.gov/pubmed/18567911.
- Labarga P, Vispo E, Barreiro P, et al. Rate and predictors of success in the retreatment of chronic hepatitis C virus in HIV/hepatitis C Virus coinfected patients with prior nonresponse or relapse. J Acquir Immune Defic Syndr. Mar 2010;53(3):364-368. Available at http://www.ncbi.nlm.nih.gov/pubmed/20101191.
- ACOG educational bulletin. Viral hepatitis in pregnancy. Number 248, July 1998 (replaces No. 174, November 1992). American College of Obstetricians and Gynecologists. Int J Gynaecol Obstet. Nov 1998;63(2):195-202. Available at http://www.ncbi.nlm.nih.gov/pubmed/9856330.
- Boskovic R, Wide R, Wolpin J, Bauer DJ, Koren G. The reproductive effects of beta interferon therapy in pregnancy: a longitudinal cohort. Neurology. Sep 27 2005;65(6):807-811. Available at http://www.ncbi.nlm.nih.gov/pubmed/16186517.
- Hegenbarth K, Maurer U, Kroisel PM, Fickert P, Trauner M, Stauber RE. No evidence for mutagenic effects of ribavirin: report of two normal pregnancies. Am J Gastroenterol. Jul 2001;96(7):2286-2287. Available at http://www.ncbi.nlm.nih.gov/pubmed/11467687.
- Ghamar Chehreh ME, Tabatabaei SV, Khazanehdari S, Alavian SM. Effect of cesarean section on the risk of perinatal transmission of hepatitis C virus from HCV-RNA+/HIV- mothers: a meta-analysis. Archives of gynecology and obstetrics. Feb 2011;283(2):255-260. Available at http://www.ncbi.nlm.nih.gov/pubmed/20652289.
- Marine-Barjoan E, Berrebi A, Giordanengo V, et al. HCV/HIV co-infection, HCV viral load and mode of delivery: risk factors for mother-to-child transmission of hepatitis C virus? AIDS. Aug 20 2007;21(13):1811-1815. Available at http://www.ncbi.nlm.nih.gov/pubmed/17690581.
- European Paediatric Hepatitis CVN. A significant sex--but not elective cesarean section--effect on mother-to-child transmission of hepatitis C virus infection. J Infect Dis. Dec 1 2005;192(11):1872-1879. Available at http://www.ncbi.nlm.nih.gov/pubmed/16267757.
- Read JS, Tuomala R, Kpamegan E, et al. Mode of delivery and postpartum morbidity among HIV-infected women: the women and infants transmission study. J Acquir Immune Defic Syndr. Mar 1 2001;26(3):236-245. Available at http://www.ncbi.nlm.nih.gov/pubmed/11242196.
- Grubert TA, Reindell D, Kastner R, et al. Rates of postoperative complications among human immunodeficiency virus-infected women who have undergone obstetric and gynecologic surgical procedures. Clin Infect Dis. Mar 15 2002;34(6):822-830. Available at http://www.ncbi.nlm.nih.gov/pubmed/11850864.
- Grubert TA, Reindell D, Kastner R, Lutz-Friedrich R, Belohradsky BH, Dathe O. Complications after caesarean section in HIV-1-infected women not taking antiretroviral treatment. Lancet. Nov 6 1999;354(9190):1612-1613. Available at http://www.ncbi.nlm.nih.gov/pubmed/10560681.
- Fiore S, Newell ML, Thorne C, European HIViOG. Higher rates of post-partum complications in HIV-infected than in uninfected women irrespective of mode of delivery. AIDS. Apr 9 2004;18(6):933-938. Available at http://www.ncbi.nlm.nih.gov/pubmed/15060441.