Viral Hepatitis in HIV and Aging (10/23/17)

  • Due to frequent overlap of risk factors for HIV and viral hepatitis, all HIV-seropositive individuals should be screened for hepatitis A, hepatitis B, and hepatitis C upon entry into care and receive appropriate vaccination if non-immune status to Hepatitis A and B is determined.
  • HIV infection accelerates the progression of liver disease in those who are co-infected with viral hepatitis; counseling about avoidance of alcohol is paramount because alcohol also hastens the progression to end-stage liver disease and liver-related complications.
  • Older age may be a risk factor for liver disease progression and complications in those individuals who are co-infected with HIV and viral hepatitis.
  • Persons with HIV who have ongoing risk for hepatitis C infection should undergo repeat screening at least annually; more frequent screening is indicated if risk is significant, such as ongoing injection drug use or diagnosis of a sexually transmitted infection (STI).
  • Individuals with risk for hepatitis C and elevated transaminases should be screened for hepatitis C with both an antibody and an RNA (viral load) test, given the possibility of seronegative hepatitis C infection.
  • In general, treatment of older individuals with HIV-HBV coinfection or HIV-HCV coinfection follows the same principles and treatment guidelines as for younger individuals.

Hepatitis B Virus (HBV) and Hepatitis C Virus (HCV) Rates and Clinical Course Among U.S.  Persons Living with HIV (PLWH)

The rate of HBV and HCV among PLWH in the United States and other Western countries is as much as tenfold higher than the rate among HIV-uninfected individuals [1, 2].

A prevalence study of active and occult HBV infection in a geographically representative US population of PLWH identified chronic HBV infection in 7.1% of the cohort overall and 10% of those with isolated HBV core antibody positivity [3]. By comparison, occult HBV infection has been reported in 0.1–2.4% of HIV-negative blood donors with isolated HBV core antibody  positivity in Western countries [4]; the rate is increased more than twofold in those with chronic HCV  [5].

In a representative cohort of PLWH from two large clinical studies of the AIDS Clinical Trials Group (ACTG), the overall estimate of HCV prevalence was 16.1%, with significant variability based on risk factors and HIV RNA levels [1]. In that study, among patients defined as “at risk” (e.g., parenteral exposure), a staggering 72.7% were HCV seropositive, whereas among low-risk individuals the seropositivity rate was 3.5%.

In some cohorts, as many as 85% of PLWH with high-risk behaviors like injection drug use are co-infected with HCV [6]. Given the frequent overlap of HIV and viral hepatitis, baseline screening and repeat testing for those with ongoing risk are critical.

Clinical Course of Viral Hepatitis Among PLWH

Hepatitis B and hepatitis C infections generally have a more virulent course in HIV-positive individuals as compared to that in HIV-negative individuals. These infections affect HIV disease progression and/or response to antiretroviral therapy (ART), while HIV infection appears to alter the clinical course of these chronic infections negatively, causing accelerated progression of liver disease and more frequent complications.

Hepatitis B

While most HIV-negative individuals spontaneously clear HBV infection, and most with chronic HBV do not progress to hepatic complications, the risk of developing chronic HBV infection, HBV-associated end-stage liver disease, and mortality are increased in the setting of HIV coinfection [2, 7, 8].

In the Multicenter AIDS Cohort Study (MACS) cohort, an eightfold increased risk of liver-related mortality was seen among HBV-HIV coinfected persons, as compared to HIV-monoinfected individuals [9]. Coinfection with HBV and HIV also increases the risk of progression to chronic HBV infection and reduces the rate of spontaneous HBsAg and HBeAg seroconversion [10]. Hepatocellular carcinoma (HCC) may develop at a younger age and be more aggressive in HBV-HIV coinfected individuals [11]. The availability of anti-HBV medications has improved these poor outcomes to some degree.

Hepatitis C

Some reports suggest that HCV infection has an effect on HIV disease. These studies indicate that increased HCV RNA levels are associated with clinical progression to AIDS [12], that HCV seropositivity is associated with progression to a new AIDS-defining illness or death [13], and that HCV seropositivity is associated with reduced CD4 cell recovery during antiretroviral therapy[14].

With respect to HCV infection, HIV coinfection has been associated with faster progression to liver fibrosis and cirrhosis [15-17], higher rates of morbidity and mortality [18, 19], more rapid progression to HCC, and more aggressive HCC [11]. Traditionally, HIV infection has correlated with poorer response to HCV treatment [20, 21]; however, in the era of directly acting antiviral (DAA) therapy for HCV infection, rates of sustained virologic response (SVR) in PLWH approach those of HIV-negative individuals, and HIV infection is no longer a marker for low cure rates with HCV therapy [22]. 

Hepatitis Among Older Adults Living with HIV

Older individuals co-infected with HIV and hepatitis B or C may be at higher risk for liver-related complications than younger co-infected individuals.

Older age is a predictor of liver-related complications in PLWH. In the D:A:D Study, predictors of liver-related death included latest CD4 cell count, older age, intravenous drug use, HCV infection, active HBV infection, HIV RNA level, and ART duration [23].

In addition, age greater than 50 years has been associated with increased rates of hospitalization for liver-related disease among PLWH, [24]. Among those with HIV-HCV coinfection, an individual’s age at time of HCV-infection is independently associated with higher liver fibrosis progression rates [17].

Current Recommendations on Viral Hepatitis Screening for PLWH

Hepatitis B

The Infectious Disease Society of America (IDSA) HIV primary care guidelines recommend that:

(i) HIV-positive adults should be screened for evidence of HBV infection upon initiation of care by detection of hepatitis B surface antigen (HBsAg), antibody to hepatitis B surface antigen (HBsAb) and antibody to hepatitis B total core antigen (HBcAb or anti-HBc);

(ii) those who are susceptible to infection should be vaccinated against HBV; and

(iii) sexual partners of persons who are positive for HBsAg should also be offered vaccination [25].

Some clinicians wait to vaccinate for hepatitis B until the patient is on antiretroviral therapy with a suppressed HIV RNA and improved CD4 count given data for higher response rates to the vaccine [26, 27].

Hepatitis B surface antibody (HBsAb) should be repeated one to two months after the third dose of the Hepatitis B vaccine to assess for immunogenic response, and those without an adequate response should be considered for a repeat series of vaccination [25]. Some data suggest benefit from using double-dose vaccine, and some clinicians use double-dose (40 mcg instead of 20 mcg) for either initial vaccine series or for repeat vaccine series in those who did not respond to a series with the standard dose [28-30].

Isolated hepatitis B core antibody positivity (positive anti-HBc antibody, negative HBsAg and negative HBsAb) is a common clinical scenario among PLWH. Possible reasons for this pattern of results include:

(i) remote past infection with subsequent loss of HbsAb;

(ii) occult hepatitis B infection with loss or low level of HbsAg; or

(iii) a false-positive anti-HBc antibody result.

Most guidelines agree that individuals with isolated HBV core antibody positivity should be vaccinated for hepatitis B, because of low rates of anamnestic response and data that these individuals remain susceptible to infection.

Some guidelines suggest that those patients who are negative for HBsAg and antibody to HBsAg but positive for hepatitis B total core antigen antibody should be screened for chronic occult HBV infection by determination of HBV load by HBV DNA PCR [25]. Certainly, in the setting of isolated HBcAb positivity clinicians should have a low threshold to screen for occult hepatitis B infection, especially if there are specific risk factors or if transaminitis is present.

Hepatitis C

For initial screening in HIV-infected individuals, guidelines agree that all should be screened for HCV at entry into care [25, 32]. The Infectious Disease Society of America (IDSA) HIV primary care guidelines recommend that:

(i) HIV-infected patients should be screened for HCV infection upon initiation of care by a test for HCV antibody;

(ii) positive HCV antibody test results should be confirmed by measurement of HCV RNA levels by PCR; and

(iii) infants born to HCV- positive women should be tested for HCV transmission [25].

For repeat HCV screening among HIV-infected individuals, guidelines suggest that those who remain at risk should undergo repeat screening at least yearly (sooner if there are clinical reasons to suspect hepatitis C infection, such as elevation of AST or ALT levels). Some guidelines additionally suggest that those individuals with ongoing injection drug use or those diagnosed with a sexually transmitted infection (STI) should be screened three months after last use or diagnosis, respectively [32].

Furthermore, because around 6% of PLWH may have seronegative HCV infection (chronic infection with detectable HCV RNA but negative HCV antibody), all those with risk factors and elevated transaminases should be screened with HCV RNA (viral load) testing in conjunction with HCV antibody testing [25].

Some guidelines also suggest that, in addition to yearly antibody testing, all HIV-positive MSM be screened with liver function panel every six months (with a hepatitis C test checked for any new transaminase elevation) [32]. In addition, some have suggested that all HIV- positive men who have sex with men (MSM) who have unexplained elevated transaminase values should be evaluated for acute HCV infection. This recommendation is based on the increasing detection of sexually transmitted acute HCV infection in HIV-infected MSM, particularly in association with other concurrent sexually transmitted infections [33, 34].

Patients with HBV and/or HCV should receive HAV vaccination unless they have documented immunity (and patients with HCV should also receive HBV vaccination, if susceptible).  All persons with chronic viral hepatitis should be instructed on the importance of avoiding alcohol and of limiting acetaminophen use.

Treatment of HBV and HCV for Older PLWH

In general, the HBV and HCV treatment principles and guidelines are the same for older individuals with HIV infection as for younger individuals.

Hepatitis B

Per the Centers for Disease Control and Prevention (CDC) Opportunistic Infections Treatment Guidelines and the Department of Health and Human Services (HHS) Adult and Adolescent HIV Treatment Guidelines, all individuals with HIV-HBV coinfection should be treated for both viral infections; the key for treating HIV-HBV coinfection is that the HIV ART regimen should include at least two ARV’s that are active against HBV. In general, the favored combination that fulfills this parameter is tenofovir (either tenofovir disoproxil fumarate or tenofovir alafenamide) plus emtricitabine. This treatment principle is the same for older individuals as for younger individuals. Tenofovir alafenamide (TAF) is approved by the FDA for HBV treatment (as of November 2016) and may be used in the setting of HIV-HBV coinfection as one of the active HBV agents; it is ok to use TAF in the setting of mild to moderate renal insufficiency, but should not be used if the creatinine clearance is below 30 ml/min.

For HIV-HBV coinfection, montherapy with emtrictiabine or lamivudine is never used because HBV resistance develops rapidly. If a person cannot take tenofovir disoproxil fumarate (TDF) or tenofovir alafenamide (TAF) along with emtricitabine or lamivudine, the other option is to add an alternate agent, such as entecavir, to the suppressive ART regimen.

In general, most HIV-HBV coinfected individuals should continue anti-HBV therapy indefinitely due to high rates of reactivation if therapy is stopped.  Additionally, if an individual stops HBV therapy, transaminase levels should be monitored due to risk of HBV flare (in general, transaminases are checked every 6 weeks for 3 months then every 3 to 6 months in this setting).

Further details regarding treatment of HIV-HBV coinfection can be found in the CDC OI guidelines and the HHS Adult and Adolescent HIV Treatment Guidelines (both available at: https://aidsinfo.nih.gov/), and the AASLD-IDSA HBV treatment guidelines (available at: http://www.aasld.org/publications/practice-guidelines-0).

Hepatitis C

Hepatitis C treatment options have evolved dramatically in recent years. Treatment regimens no longer include interferon and, except in a small subset of circumstances, no longer include ribavirin. Treatment now involves oral direct-acting antiviral drugs (DAA) which have drastically reduced toxicity as compared to the days of interferon-ribavirin therapy. Treatment courses in general are also much shorter, and probability of sustained virologic response (SVR) is very high (90% or greater) for the majority of individuals. Additionally, in the modern era of DAA therapy for HCV, HIV coinfection and also age no longer decrease the chance of SVR significantly and, in general, HIV-HCV coinfection is treated similarly to HCV monoinfection and older individuals are treated similarly to younger individuals. HIV coinfection is a high priority scenario for HCV therapy because of the elevated risk of liver fibrosis progression, and it could be argued that older age also increases the priority, particularly if individuals have been infected for many years and thus have higher likelihood of advanced liver fibrosis.

Per the American Society of Liver Disease (AASLD)-Infectious Disease Society of America (IDSA) hepatitis C treatment guidelines, all individuals with hepatitis C infection should be treated, and HIV coinfection qualifies as a high priority condition. Per the guidelines, the only situation in which HCV treatment may not be indicated is if the life expectancy due to other comorbid conditions is so short that HCV treatment may not be beneficial (considered in the guidelines to be a life expectancy less than 12 months).

Studies that have examined patient-reported outcomes after hepatitis C therapy have documented significant improvement in factors such as physical functioning for individuals age 65 and older, with improvements similar to those reported by younger individuals [35]. Therefore, older individuals with HIV-HCV coinfection should be considered for HCV therapy, and the HCV DAA treatment options, which are based on HCV genotype and presence or absence of cirrhosis, are outlined in the AASLD/IDSA guidelines: http://www.hcvguidelines.org/. Modern HCV DAA regimens provide excellent options for HCV treatment for older individuals, and hopefully will increase the likelihood that older individuals can be treated [36].

In general, those individuals with more advanced fibrosis are considered to be higher priority for HCV therapy as compared to individuals with less liver fibrosis, and in the setting of HIV coinfection, it is always important to consider interactions between HCV DAA’s and HIV ARV’s, as interactions may dictate that one DAA regimen is favored or another, or sometimes an ARV regimen change needs to be considered before treating HCV with certain DAA’s.

Updated by Brian Wood, MD

February 2017

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