International Guidelines for Management of HIV-HCV Coinfection
international panel of experts issued updated guidelines for the management of
HIV-HCV coinfected patients in the May 31, 2007 issue
of AIDS. The new recommendations reflect an improved understanding of
concurrent infection and its treatment since the previous guidelines were issued
As background, the authors noted that an
estimated one-third of HIV positive individuals
also have hepatitis C virus (HCV). Coinfected
patients experience more rapid liver disease progression, though this may
be less likely if they have well preserved immune function and high CD4 cell counts.
In addition, coinfected patients typically do not respond as well as HCV
monoinfected individuals to treatment with pegylated
interferon plus ribavirin, but several recent studies
have explored ways to optimize treatment in this population.
panel issued recommendations in 11 areas:
with persistently normal ALT: About 7%-9% of coinfected patients have
persistently normal ALT, compared with about 25% of HCV monoinfected individuals.
Research also suggests that 25%-40% of coinfected patients with normal ALT have
significant liver fibrosis or cirrhosis, compared with 10%-30% of HCV monoinfected
patients. Given that the prevalence of and progression to advanced fibrosis is
higher among coinfected patients with normal ALT, the panel recommended that these
individuals should be considered for hepatitis C treatment regardless of ALT level.
of liver fibrosis: The panel reviewed non-invasive methods for assessing
fibrosis using serum biomarkers and imaging techniques. While these methods perform
well in diagnosing absent or mild fibrosis versus severe fibrosis or cirrhosis,
they are less able to distinguish between intermediate stages. Given the improved
rate of response to anti-HCV therapy, the faster rate of fibrosis progression
in HIV positive patients, and the ability to assess early virological response,
the panel stated that in most cases, liver biopsy is not mandatory for considering
the treatment of chronic HCV infection, adding that a combination of non-invasive
methods accurately predicts hepatic fibrosis in most cases.
of response to anti-HCV therapy: Many factors that predict response
to interferon-based therapy are the same in both coinfected and HCV monoinfected
individuals (age, sex, race, HCV viral load, HCV genotype, body mass index, minimal
liver fibrosis or steatosis), but there are some additional factors associated
with poor response in coinfected patients, including lower CD4 cell count. Insulin
resistance is also a concern, given its association with protease inhibitors.
Rapid virological response (RVR) at week 4 predicts sustained virological response
(SVR) in coinfected patients as it does in those with HCV monoinfection. Coinfected
patients who do not achieve early virological response (EVR) by week 12, or who
still have detectable HCV RNA at week 24, are unlikely to achieve SVR, and should
be advised to stop treatment early.
dosing of pegylated interferon and ribavirin: Adequate doses and duration
of therapy are especially necessary for coinfected patients to obtain optimal
treatment outcomes. Studies have shown that weight-based ribavirin (1000 mg/day
if < 75 kg and 1200 mg/day if > 75 kg) is superior to an 800 mg fixed dose.
While some studies have tested higher doses of pegylated interferon, the benefits
have not been established in coinfected patients, and the panel recommended the
standard dose: 180 mcg/week of pegylated interferon alfa-2a (Pegasys) or 1.5 mcg/kg/week
of pegylated interferon alfa-2b (PegIntron).
duration of therapy: The panel recommended 48 weeks of pegylated interferon
plus ribavirin for coinfected patients with all HCV genotypes. However, they said
that 24 weeks may be adequate for those with genotypes 2 or 3, while slow-responding
individuals with genotypes 1 or 4 (those who achieve EVR but not RVR) might
benefit from extended (60-72 weeks) courses of therapy.
of coinfected non-responders and relapsers: A growing number of coinfected
patients have already been treated with interferon-based therapy without achieving
SVR. Based on available data, the panel stated that, coinfected non-responders
and relapsers are a heterogeneous population and therapeutic interventions
in them should be individualized. Those who previously received suboptimal
therapy (e.g., conventional interferon, interferon monotherapy, low ribavirin
doses) may be retreated with the best current standard therapy. While SVR is uncommon
in true prior non-responders and relapsers to optimal treatment, even failed therapy
or long-term interferon maintenance monotherapy may help slow liver disease progression.
The panel suggested that investigational drugs¾including new types of interferon
and HCV protease and polymerase inhibitors¾offer the prospect of improved
outcomes, recommending that, Trials exploring the efficacy and safety of
these drugs in coinfected patients should be prioritized, without waiting for
the final results of Phase III trials conducted in HCV-monoinfected.
with end-stage liver disease: The panel noted that management of coinfected
persons with advanced liver cirrhosis is complex. Antiretroviral therapy may
significantly improve short- and mid-term outcomes in HIV positive patients with
hepatic decompensation and, therefore, HAART should not be discouraged,
they wrote. The authors added that HIV infection should no longer be considered
a contraindication to liver transplantation, but said that the procedure should
be performed by a multidisciplinary team with experience in managing coinfected
of acute hepatitis C: The panel noted recent outbreaks of acute, apparently
sexually transmitted HCV infection among mostly HIV positive men who have sex
with men in Europe. Although 25%-30% of HIV negative individuals with acute HCV
infection experience spontaneous viral clearance, HIV positive individuals are
more likely to develop chronic hepatitis C. For this reason, the panel wrote,
early therapeutic intervention in acute HCV infection is particularly indicated
in patients with HIV disease. They recommended that HIV positive individuals
with acute HCV should be treated for 24 weeks with pegylated interferon plus weight-based
ribavirin, after waiting 12 weeks to allow for possible spontaneous clearance
with multiple hepatitis viruses: The prevalence of multiple hepatitis
viruses (HBV/HCV, HBV/HDV, HBV/HCV/HDV) is low in developed countries, but more
common in HIV-HCV coinfected patients than in HCV monoinfected individuals. People
with more than one hepatitis virus may experience accelerated liver disease progression
and are at higher risk for hepatocellular carcinoma. Whenever possible, the panel
recommended, treatment of all replicating viruses should be pursued.
between anti-HCV and antiretroviral therapy: The major interaction concerns relate
to concurrent use of ribavirin with ddI (Videx) or AZT (Retrovir). Both ddI and
ribavirin can cause mitochondrial damage (which can lead to lactic acidosis, pancreatitis,
and decompensated cirrhosis), and the panel said that this combination should
never be used. Similarly, both AZT and ribavirin can cause anemia, and the
authors recommended that AZT should also be avoided when possible.
of antiretroviral drugs: The panel noted that various antiretroviral
drugs affect the liver in different ways. Certain nucleoside reverse transcriptase
inhibitors -- especially ddI and d4T (Zerit) -- can cause mitochondrial toxicity
(which can lead to liver steatosis). Nevirapine (Viramune) can cause hypersensitivity
reactions that damage the liver, and some protease inhibitors -- such as full-dose
ritonavir (Norvir) -- can cause direct liver injury. Atazanavir (Reyataz) and
indinavir (Crixivan) can cause elevated bilirubin, but this does not reflect liver
damage. In addition, as HAART enables CD4 cell recovery, immune reconstitution
can worsen liver inflammation (a concern for patients with HBV).
the various complexities related to concurrent management of HIV
and HCV infection, the panel concluded that the benefits of antiretroviral therapy
outweigh the risks, noting that several studies have demonstrated lower rates
of liver-related mortality in coinfected patients taking
“Since severe immunosuppression
accelerates HCV-related liver fibrosis progression, it may be advisable to start
HAART without unnecessary delays in coinfected patients
and even consider earlier initiation of treatment,” the authors wrote.
Carlos III, Madrid, Spain; University Hospital, Brescia,
Italy; Johns Hopkins Medical Institutions, Baltimore, MD; Ospedale
Sacco, Milan, Italy; Hopital
Pitie-Salpetriere, Paris, France; University of California,
San Francisco, CA; Center for HIV and Hepatogastroenterology,
Duesseldorf, Germany; Mount Sinai Medical School, New
York, NY; Athens University Medical School, Athens, Greece; Necker-Cochin
Hospital, Paris, France; University Hospital, Bonn, Germany.
V Soriano, M Puoti,
M Sulkowski, and others. Care of patients coinfected with HIV and hepatitis C virus: 2007 updated recommendations from the HCV-HIV International Panel.
AIDS 21(9): 1073-1089. May 31, 2007.