COMMENTARY

HIV and Hepatitis C Co-infection: Guideline and Commentary

Douglas G. Fish, MD

Disclosures

January 05, 2011

In This Article

Baseline Assessments and Counseling at Initiation of Therapy

Laboratory Assessments

Recommendations. Clinicians should obtain the following baseline assessments when the decision to initiate anti-HCV therapy has been made (AII):

  • Serum liver enzymes

  • Complete blood count

  • Thyroid-stimulating hormone

  • Antinuclear antibody

  • Glucose

  • Quantitative HCV RNA in serum

  • HCV genotype

  • α-Fetoprotein (only if cirrhotic)

  • Pregnancy testing for female patients of childbearing potential, as well as female partners of male patients, immediately prior to initiation of therapy

Anti-HCV Treatment and Antiretroviral Therapy

Recommendations. Clinicians should initiate or continue antiretroviral therapy (ART) in HIV/HCV co-infected patients according to current ART guidelines (AIII), except for the following caveats:

  • The combined use of didanosine and ribavirin is contraindicated (AIII)

  • The combination of zidovudine with interferon and ribavirin should be used with caution due to synergistic bone marrow suppressive effects (AIII)

  • The combination of abacavir and ribavirin should be used with caution due to possible competitive inhibition between these agents (BIII)

Growing evidence suggests that ART may improve clinical outcomes in HIV/HCV co-infected patients. Findings of the Swiss HIV Cohort Study and the Women’s Interagency HIV Study have shown that patients with HIV/HCV co-infection have an increased risk for progression to a new AIDS-defining event or death.[53,54] Other reports have demonstrated an increased risk for opportunistic infections[55] and liver disease[56,57,58] among HIV/HCV co-infected patients not receiving ARV treatment.

ART is not contraindicated in HIV/HCV co-infected patients. Co-infected patients should initiate or continue ART as indicated by current HIV treatment guidelines. However, the hepatotoxic effects of ARV agents or a hyperactive immune response precipitated by ART may accelerate HCV-induced liver damage, suggesting the possible benefit of treating HCV infection before initiating ART. In some settings, it may also be necessary to treat HCV before the patient is able to tolerate HIV therapy.[59]

The adverse events associated with anti-HCV treatment in HIV/HCV co-infected patients are comparable with those seen in patients with HCV alone. However, the combination of anti-HCV treatment and ART in co-infected patients may lead to an increased incidence of metabolic complications and/or adverse drug interactions due to synergistic toxicity profiles.

Didanosine. The combination of didanosine and ribavirin is contraindicated. Several ongoing clinical trials have identified an increased risk for pancreatitis, lactic acidosis, hepatic decompensation, and death associated with the combination of ribavirin and didanosine in patients with cirrhosis. The combination of ribavirin and didanosine is known to raise intracellular levels of didanosine metabolites, which may be caused by the increased phosphorylation of didanosine by ribavirin and/or additive mitochondrial toxicity of these nucleoside analogs.[60]

Zidovudine. Zidovudine can cause significant anemia and sometimes leukopenia, and the addition of interferon with ribavirin may exacerbate these complications. Hematopoietic growth factors may be required earlier in these patients, and, in general, this combination of drugs can be difficult for patients to tolerate and should be avoided if possible.[61]

Abacavir. Both abacavir and ribavirin are guanosine analogs and, theoretically, could competitively inhibit one another.[62,63] One study involving 426 HIV/HCV co-infected patients receiving treatment for HCV infection found a 2-fold increased risk for HCV treatment failure by logistic regression analysis in patients also receiving abacavir.[62] In another retrospective study, the use of abacavir with lamivudine as the nucleoside reverse transcriptase inhibitor (NRTI) backbone in HIV/HCV co-infected patients treated with pegylated interferon plus ribavirin was associated with a lower rate of SVR (29%) compared to a backbone of tenofovir plus lamivudine or emtricitabine (45%).[64] Additional studies are required to confirm these findings.

Contraception Counseling During Anti-HCV Therapy

Recommendation. Clinicians should counsel female HIV/HCV co-infected patients and HIV/HCV co-infected male patients with female partners to use 2 effective methods of contraception to avoid pregnancy during ribavirin treatment and for 6 months afterward.

In addition to the regular use of condoms in the presence of HIV/HCV co-infection, patients receiving ribavirin and their partners should use a second effective method of contraception.

Prescribing Anti-HCV Therapy for Patients With a History of Mental Health Disorders

Recommendation. Clinicians should prescribe interferon alfa in consultation with a psychiatrist when treating HIV/HCV co-infected patients with a history of mental health disorders, including depression.

Patients receiving effective treatment for mental health disorders may safely complete a course of anti-HCV therapy. However, the mental health disorder should be in remission, prescription of anti-HCV therapy should be in consultation with a psychiatrist, and sufficient interdisciplinary support should be available.[44] (See Section 5: Evaluation and Initial Management of Confirmed Hepatitis C Infection.)

Counseling Regarding Alcohol Use

Recommendation. Clinicians should advise patients to abstain from alcohol and substance use during HCV antiviral therapy.(AII)

Patients who consume light or moderate amounts of alcohol should be advised to abstain from alcohol during antiviral therapy. A pretreatment period of abstinence for these individuals is not necessary.[65]

Although active substance use may diminish the efficacy of treatment, few studies address ongoing substance use during antiviral treatment among patients. The data that are available indicate that active and recent injection drug users can be treated successfully for HCV,[66,67] and methadone and buprenorphine are not contraindications to treatment of HCV. Methamphetamine use has been shown to compromise the anti-HCV activity of interferon alfa.[43] (See Section 5: Evaluation and Initial Management of Confirmed Hepatitis C Infection.)

Treatment Regimens for Hepatitis C Virus in HIV-Infected Patients

Recommendations. Pegylated interferon with ribavirin for 48 weeks is the standard recommended therapy for HIV/HCV co-infected patients with chronic HCV. (AI)

Weight-based ribavirin dosing is recommended in HIV/HCV co-infected patients with genotypes 1, 4, 5, and 6. (AI)

The primary goal of anti-HCV therapy for chronic HCV is eradication of HCV from the serum, as determined by undetectable HCV RNA. A secondary goal is reduction of hepatic inflammation/fibrosis with the expectation of decreased disease progression and subsequent reduction in HCC risk.

The most effective treatment for HCV infection is pegylated interferon with ribavirin. This form of interferon has covalently bound molecules of polyethylene glycol that slow the metabolism of interferon, thereby permitting a weekly dosing schedule, increased serum levels of interferon, and improved anti-HCV activity. Two approved forms of pegylated interferon are now available: alfa-2a and alfa-2b. Although the manner in which they are pegylated differs, clinical outcomes are similar. See Table 5 for dosing recommendations.

Table 5. Comparison Dosing With Interferon Alfa-2a and -2b

  Pegylated interferon alfa-2b
(Peg-Intron)
Pegylated interferon alfa-2a (Pegasys)
Interferon dosing 1.5 µg/kg SC weekly 180 µg SC weekly
Ribavirin dosing Genotype 1 or 4:
<75 kg: 400 mg + 600 mg PO bid (total daily dose of 1000 mg)
≥75 kg: 600 mg PO bid

Genotype 2 or 3:
400 mg PO bid or same as above[68]


Data from clinical trials have shown efficacy of pegylated interferon alone and as part of combination therapy with ribavirin 800 to 1000 mg/day in HIV/HCV co-infected patients.

Three trials using the 2 different forms of pegylated interferon with ribavirin have confirmed that pegylated interferon plus ribavirin is superior compared with standard interferon plus ribavirin.[69,70,71] Appendix A provides a summary of data from clinical trials on anti-HCV therapy.

Treatment of Acute HCV Infection

SVR rates of 60% to 70% have been achieved in most studies when combination pegylated interferon and ribavirin were used for 24 weeks in patients with acute HCV mono-infection.[12] These data are from noncomparative studies, with the predominant risk group for HCV infection being men who have sex with men. The necessity of using ribavirin in addition to interferon has not been established for acute infection.

Duration of Treatment

Recommendation. Clinicians should consider discontinuation of treatment in patients whose ALT levels increase after 12 weeks of treatment; rising ALT levels during treatment may be an indication of treatment failure. (AIII)

The standard duration of therapy for co-infected patients is 48 weeks, even for patients with genotypes 2 and 3, because relapse rates have been found to be higher if treatment is given for only 24 weeks.[72] However, after initiation of therapy, the decision to complete the full course of treatment is determined by the degree of change in HCV RNA at week 12 or 24 (see Figure 2). If serum ALT levels increase after initiation of treatment, then discontinuation of treatment may be warranted. Rising ALT levels during anti-HCV therapy may indicate treatment failure.

Although the optimal length of therapy has not yet been established for acute infection, the standard treatment duration for chronic infection may be a reasonable approach for acutely infected patients.

Figure 2.

Initial Anti-HCV Therapy for HIV/HCV Co-infected Patients * If ALTs have normalized or are continuing to improve, some experts would consider continuation of therapy, although this is not based on clinical trial evidence. A liver biopsy could be repeated to assess for histologic improvement.
† Forty-eight weeks is the standard recommended duration of therapy for all genotypes. According to HCV-HIV International Panel guidelines, discontinuation of treatment could be advised at 24 weeks in patients with HCV genotypes 2 or 3 who experience rapid virologic response under certain conditions (see Section 8: Hepatitis C Treatment and Treatment Monitoring). Otherwise, 48 weeks of therapy remains advisable.[40] Patients with genotypes 1 and 4 may demonstrate a better clinical outcome with a longer course of treatment (see Section 8: Hepatitis C Treatment and Treatment Monitoring).

Shorter Courses of Therapy

Shorter courses of therapy have been studied in HCV mono-infected patients and, to a lesser extent, in HIV/HCV co-infected patients. These studies examined 4-week viral load responses; those who experienced rapid virologic response (RVR) by 4 weeks were candidates for a shorter treatment course, such as 24 weeks. Among the 389 HIV/HCV co-infected patients in the PRESCO trial (discussed in Appendix A), a 4-week RVR was the best predictor of an SVR. Among patients who received treatment for 24 to 48 weeks, an RVR had a 90% positive predictive value for SVR in patients with genotype 3, whereas the positive predictive value for SVR in patients with genotype 1 was 69%.[73] Similar findings were subsequently reproduced in a smaller study.[74]

According to HCV-HIV International Panel guidelines, discontinuation of treatment could be advised at 24 weeks in the following patients with HCV genotypes 2 or 3 who experience rapid virologic response in the presence of all of the following conditions:

  • HCV RNA is undetectable

  • Weight-based ribavirin dosing has been prescribed

  • The patient has adhered to treatment

  • No advanced hepatic fibrosis is present

Longer Courses of Therapy

A subset of HCV-infected patients may benefit from longer therapy. However, the data demonstrating this possible benefit derive from studies involving HCV mono-infected patients with genotype 1 or 4 who did not have an RVR but who had the expected treatment response by week 24 of therapy. Among these patients, a benefit from longer courses of treatment was demonstrated. The greater rate of SVR occurred after 72 weeks of therapy instead of 48 weeks.[75,76]

For HIV/HCV co-infected patients with genotype 1, the per-protocol analysis of the PRESCO trial did not demonstrate a significant difference in SVR rates among those with genotype 1 who were treated for either 48 or 72 weeks.[73] More studies are needed in HIV/HCV co-infected populations before current recommendations are likely to change. Potential obstacles to longer therapy include tolerability and adherence.

Identification and Management of Side Effects of Anti-HCV Treatment

Recommendations. Clinicians should assess for possible side effects of anti-HCV treatment in HIV-infected patients (see Table 6).

Clinicians should educate HIV/HCV co-infected patients about strategies for managing side effects of anti-HCV therapy (see Table 7).

Mood Alterations With Anti-HCV Therapy

For patients who develop mood alterations, including depression, during interferon alfa therapy, most symptoms emerge by 8 weeks of treatment and appear to be dose-dependent. The side effects include fatigue, hypersomnia, irritability, emotional lability, social withdrawal, and impaired concentration (see Section 5: Evaluation and Initial Management of Confirmed Hepatitis C Infection).

Key Point

The significant association between interferon alfa and depression underscores the importance of screening for depression at least every 4 weeks during anti-HCV therapy.[77] Simple screening techniques are provided in the Mental Health Guidelines Depression and Mania in Patients With HIV/AIDS .

Other Side Effects of Anti-HCV Treatment

Interferon alfa has significant potential side effects, including flu-like symptoms, fatigue, alopecia, bone marrow suppression, and neuropsychiatric effects, such as apathy, cognitive changes, irritability, depression, and suicide (see Table 6). In some patients, side effects are severe enough to require dose reductions or even discontinuation of treatment; however, some of these adverse effects may be treated with hematopoietic growth factors for bone marrow toxicity and with antidepressants for depression. Patients treated with interferon may also develop a paradoxical worsening of liver disease, possibly attributable to autoimmune processes, and fatal liver failure has occurred; however, this is a rare event and primarily occurs in patients with already decompensated liver disease or those who have undergone transplantation.[78]

Table 6. Possible Side Effects of Treatment for Hepatitis C

Interferon Ribavirin
  • Flu-like symptoms

    • Fatigue, myalgia, headache, low-grade fever (99-101.5°F)

  • Alopecia

  • Bone marrow suppression

    • Thrombocytopenia

    • Neutropenia

    • Anemia

  • Fatigue

  • Emotional lability

  • Depression/suicide

  • Insomnia

  • Anorexia/weight loss

  • Thyroid dysfunction

    • Hypothyroid

    • Hyperthyroid

  • Neuropathy

  • Injection site reactions

  • Paradoxical worsening of liver disease

  • Hemolytic anemia (dose-dependent)

  • Nausea

  • Cough, shortness of breath

  • Teratogenic effects

  • Rash, dry skin

  • Pruritus

  • Lactic acidosis

  • Pancreatitis


Table 7 provides strategies for managing side effects of anti-HCV therapy.

Table 7. Strategies for Managing Side Effects of Anti-HCV Therapy

  • Treatment of preexisting depressive symptoms before and during interferon therapy, as well as 6 to 12 months after interferon therapy, to avoid post-interferon therapy relapse*

  • Treatment of depressive symptoms that occur during interferon therapy, as well as continued treatment 6 to 12 months after interferon therapy completion, to avoid post-interferon therapy relapse*

  • Treatment of insomnia and anxiety as needed

  • Use of hematopoietic growth factors to manage bone marrow suppression as needed

  • Dose reduction of ribavirin and/or the use of recombinant erythropoietin to manage ribavirin-induced hemolytic anemia

  • Administration of the weekly injection of pegylated interferon at a time when side effects would cause the least disruption (eg, on Friday night to mitigate side effects that could cause disruption during the work week)

  • Administration of acetaminophen or ibuprofen to alleviate symptoms, or for prophylactic use at the time of the injection and the following morning

  • Small, light meals and/or antiemetics

  • Regular light exercise

  • Adequate hydration

*Treatment of depression in patients receiving interferon with selective serotonin reuptake inhibitors is generally safe and often effective (see Section 5: Evaluation and Initial Management of Confirmed Hepatitis C Infection).


When side effects are intolerable and cannot be managed effectively, dose reduction or discontinuation of therapy may be necessary. Use of red blood cell or white blood cell hematopoietic growth factors, such as erythropoietin or granulocyte colony-stimulating factor, respectively, are commonly used to avoid dose reductions of anti-HCV therapy, because maintenance of therapeutic doses has demonstrated more favorable treatment responses.[79]

Treatment Monitoring of HIV/HCV Co-Infected Patients

Recommendations. Clinicians should monitor anti-HCV treatment in HIV/HCV co-infected patients according to the assessments and schedules listed in Table 8.

A liver biopsy after eradication of HCV infection is not routinely indicated.(AIII)

HCV treatment should be monitored in HIV/HCV co-infected patients not only to determine whether the patient is responding to treatment but also to ensure that any complications associated with anti-HCV therapy are identified and addressed appropriately. Table 8 provides monitoring schedules for patients receiving anti-HCV therapy.

Table 8. Monitoring of HIV/HCV Co-Infected Patients Receiving Anti-HCV Therapy

Time Point Recommended Laboratory Tests and Assessments
Baseline (at initiation of treatment)
  • Obtain HIV viral load, CD4 count, CBC, chemistry panel, and quantitative HCV viral load, TSH

  • Perform pregnancy testing in female patients of childbearing potential, as well as female partners of male patients

  • Screen for comorbid disease/medications, alcohol and drug use, and depression

  • For patients with a history of depression, consider consultation with a psychiatrist for prophylactic antidepressant (see Section 5: Evaluation and Initial Management of Confirmed Hepatitis C Infection)

Week 1-2
  • Obtain CBC with differential and LFTs

Week 4
  • Obtain HCV quantitative viral load

Week 4 and every 4 weeks thereafter
  • Obtain CBC and chemistry panel

  • Perform pregnancy testing in female patients of childbearing potential, as well as female partners of male patients, as long as ribavirin is administered and until 6 months after discontinuation

  • Evaluate for drug-drug interactions, mood alteration, and side effects

Week 12 and every 12 weeks thereafter
  • Obtain HIV viral load, CD4 cell count, and quantitative HCV viral load

  • Screen for interferon-induced thyroid disease with TSH

Week 24 following therapy

  • HCV quantitative viral load

CBC, complete blood count; HCV, hepatitis C virus; LFT, liver function test; TSH, thyroid-stimulating hormone.

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