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HIV & Aging Clinical Recommendations
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 (Sherman 2002; Soriano 2008).
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 (Shire 2004). By comparison, occult HBV infection has been reported in 0.1–2.4% of HIV-seronegative blood donors with isolated HBV core antibody positivity in Western countries (Hollinger 2008); the rate is increased more than twofold in those with chronic HCV (Cacciola 1999).
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 (Sherman 2002). 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 (Sulkowski 2003). Given the frequent overlap of HIV and viral hepatitis, baseline screening and repeat testing for those with ongoing risk are critical.
Hepatitis B and hepatitis C infections generally have a more virulent course in PLWH as compared to that in persons who do not have HIV; liver disease generally progresses faster in PLWH and liver-related complications are more frequent. These infections may affect HIV disease progression, though data is more mixed.
While most HIV-seronegative 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 (Soriano 2008; Konopnicki 2005; Puoti 2002).
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 (Thio 2002). 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 (Hadler 1991). Hepatocellular carcinoma (HCC) may develop at a younger age and be more aggressive in HBV-HIV coinfected individuals, as compared to individuals with HBV and without HIV (Brau 2007). The availability of anti-HBV medications has improved these outcomes to some degree.
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 (Daar 2001), that HCV seropositivity is associated with progression to a new AIDS-defining illness or death (Greub 2000), and that HCV seropositivity is associated with reduced CD4 cell recovery during antiretroviral therapy (Macias 2003).
With respect to HCV infection, HIV coinfection has been associated with faster progression to liver fibrosis and cirrhosis (Martinez-Sierra 2003; Soto 1997; Benhamou 1999), higher rates of morbidity and mortality (Bica 2001; Tedaldi 2003), more rapid progression to HCC, and more aggressive HCC (Brau 2007). Traditionally, HIV infection has correlated with poorer response to HCV treatment (Chung 2004; Perez-Olmeda 2003); 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-seronegative individuals, and HIV infection is no longer a marker for low cure rates with HCV therapy (Sulkowski 2014).
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 (Weber 2006).
In addition, age greater than 50 years has been associated with increased rates of hospitalization for liver-related disease among PLWH (Gebo 2005). Among those with HIV-HCV coinfection, an individual’s age at time of HCV-infection is independently associated with higher liver fibrosis progression rates (Benhamou 1999).
The Infectious Disease Society of America (IDSA) HIV primary care guidelines recommend that:
(i) Adults with HIV 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 (Aberg 2014a).
Some clinicians wait to vaccinate for hepatitis B until the patient is taking antiretroviral therapy with a suppressed HIV RNA and improved CD4 count given data for higher response rates to the vaccine (Landrum 2009; O’Bryan 2015).
Hepatitis B surface antibody (HBsAb) should be repeated one to two months after the final 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 (Aberg 2014a). 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 the standard dose (Chaiklang 2013; Launay 2011; Potsch 2012).
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) past hepatitis B 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 receive vaccination 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 (Aberg 2014a). 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.
There are now three hepatitis B vaccine choices that are acceptable. The US Food and Drug Administration (FDA) recently approved a new, adjuvanted hepatitis B vaccine, called Heplisav. An advantage of this new option, besides the adjuvant, is that only two doses are required (the second dose is given 1 month after the first dose). This vaccine has not been studied for PLWH; however, some practitioners offer it, especially if there will be benefit to reducing the dosing schedule to two doses or to completing the series within one month. Many practitioners still routinely offer the traditional hepatitis B vaccines, which are completed with 3 doses over 6 months (Recombivax or Engerix).
Guidelines agree that all PLWH should be screened for HCV at entry into care (Aberg 2014a; European 2011). The Infectious Disease Society of America (IDSA) HIV primary care guidelines recommend that:
(i) PLWH 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 (Aberg 2014a).
For repeat HCV screening among PLWH, guidelines suggest that those who remain at risk (due to ongoing injection drug use, high-risk sex, or other risk factors) 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 (European 2011).
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 (Aberg 2014a).
Some guidelines also suggest that, in addition to yearly antibody testing, all HIV-seropositive MSM be screened with liver function panel blood tests every six months (with a hepatitis C test added for any new transaminase elevation) (European 2011). In addition, some have suggested that all men who have sex with men (MSM) with HIV 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 MSM with HIV, particularly in association with other concurrent sexually transmitted infections (Luetkemeyer 2006; Browne 2004).
Persons 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.
In general, the HBV and HCV treatment principles and guidelines are the same for older individuals with HIV infection as for younger individuals with HIV.
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. Tenofovir alafenamide may be preferable for older individuals due to lower potential for renal toxicity or reductions in bone mineral density, as compared to TDF.
For HIV-HBV coinfection, monotherapy 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. If an individual does stop HBV therapy, transaminase levels should be monitored due to risk of HBV flare (in general, transaminases should be 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 treatment options have evolved dramatically in recent years. Treatment regimens no longer include interferon and, except in rare circumstances, no longer include ribavirin. Treatment now involves oral direct-acting antiviral drugs (DAA’s), which have drastically reduced toxicity as compared to the days of interferon-ribavirin therapy. Treatment courses in general are also much shorter (often two to three months), and probability of sustained virologic response (SVR) is very high (90-95%% or greater) for the majority of individuals. Additionally, in the modern era of DAA therapy for HCV, HIV coinfection and age no longer decrease the chance of SVR significantly. 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 successful 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 (Younossi 2016). 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 (Conti 2014).
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.
It is important to review a patient’s HBV serologies prior to starting HCV treatment because if active hepatitis B is present then it may flare with HCV therapy and HBV treatment should be started first. If the HBV surface antigen is negative but there is an isolated positive HBV core antibody, some practitioners would add checks of the hepatic transaminases during HCV therapy to monitor for signs of a flare.
For an individual with advanced fibrosis or cirrhosis prior to HCV treatment, regular screening for HCC should continue even after SVR is achieved because the risk for HCC may persist.