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Guidelines for the Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents
Hepatitis B Virus Infection
(Last updated: May 7, 2013; last reviewed: May 7, 2013)
Hepatitis B virus (HBV) is the leading cause of chronic liver disease worldwide.1,2 Globally and in North America, approximately 10% of HIV-infected patients have evidence of chronic HBV infection.3-5
In countries with a low prevalence of endemic chronic HBV infection, the virus is transmitted primarily through sexual contact and injection drug use, whereas perinatal and early childhood exposures are responsible for most HBV transmission in higher prevalence regions. Although the general modes of transmission are similar to HIV, HBV is transmitted more efficiently than HIV.1,2,6 HBV has an average incubation period of 90 days (range 60–150 days) from exposure to onset of jaundice and 60 days (range 40–90 days) from exposure to onset of abnormal liver enzymes. Genotypes of HBV (A–H) have been identified with different geographic distributions. Genotype A is most common among patients in North America and Western Europe.
Acute infection may be asymptomatic. Symptoms may include right upper quadrant abdominal pain, nausea, vomiting, fever, and arthralgias with or without jaundice. Most patients with chronic HBV infection are asymptomatic or have non-specific symptoms, such as fatigue, until they develop cirrhosis and signs of portal hypertension (i.e., ascites, variceal bleeding, coagulopathy, jaundice, or hepatic encephalopathy). Hepatocellular carcinoma (HCC) is asymptomatic in its early stages and usually, but not always, occurs in the setting of hepatitis-B- or hepatitis-C-related cirrhosis.
All HIV-infected patients should be tested for HBV infection. Initial testing should include serologic testing for surface antigen (HBsAg), hepatitis B core antibody (anti-HBc total), and hepatitis B surface antibody (anti-HBs). In acute infection, HBsAg can be detected 4 weeks (range 1–9 weeks) after exposure and anti-HBc immunoglobulin M is usually detectable at the onset of symptoms.
Chronic HBV infection is defined as persistent HBsAg detected on 2 occasions at least 6 months apart. Patients with chronic HBV infection should be further tested for HBV e-antigen (HBeAg), antibody to HBeAg (anti-HBe), and HBV DNA. Active disease, which can be HBeAg negative or positive, can be distinguished from inactive disease by the presence of serum HBV DNA and persistent or fluctuating alanine transaminase (ALT) elevation. Patients with past infection that has cleared are HBsAg negative with positive anti-HBs and anti-HBc.
A patient who is seropositive for anti-HBc and anti-HBs has resolved infection. Some patients test positive for anti-HBc alone, which usually signifies infection with HBV in the past with subsequent loss of anti-HBs or, in a low prevalence country such as the United States, it may be a false-positive result.7,8 The clinical significance of isolated anti-HBc is unknown7-10 but may indicate chronic infection in HIV-infected persons, so requires testing for HBV DNA.7,8,11 HIV-infected patients have a higher frequency of isolated anti-HBc, particularly those with underlying hepatitis C virus (HCV) infection.12 Some specialists recommend that HIV-infected individuals with anti-HBc alone be tested for HBV DNA. If positive for HBV DNA they should be treated as chronically infected; if negative they should be considered still susceptible to HBV and vaccinated accordingly (see below).
Diagnosis of Disease Progression and the Role of Liver Biopsy
HIV infection is associated with higher levels of hepatitis B viremia and lower viral clearance rates following acute HBV infection. In HBV monoinfection, HBV DNA suppression, anti-HBe seroconversion, HBsAg loss, and acquisition of anti-HBs are all associated with a decreased incidence of cirrhosis, HCC,13-16 and improved survival.17-20 Data characterizing the predictive value of these parameters in individuals with HIV/HBV co-infection indicate that HIV-infected patients with chronic HBV infection in the United States usually have acquired HBV infection as adults; they are more likely to have detectable HBeAg,21,22 lower rates of seroconversion to anti-HBe, and an increased risk of liver-related mortality and morbidity.23
HBV infection can result in a dynamic disease with a number of phases that are associated with either active or inactive chronic hepatitis. Disease phases are different in those who acquire infection as neonates and young children compared with those who acquire infection as adults. Clinicians should be knowledgeable about these phases for monoinfected patients to determine who needs treatment and who should be monitored. In HIV/HBV co-infection, monitoring and treatment are generally focused on both viruses.
HBV-monoinfected patients who are HBeAg seropositive usually have high HBV DNA levels (>20,000 international units/mL) and abnormal ALT levels. However, with perinatal infection or infection acquired in early childhood, patients initially have an immune tolerance phase, with the presence of HBeAg, normal ALT levels, and high levels of HBV DNA but minimal or no liver disease. These patients may develop HBeAg-positive chronic hepatitis B with elevated ALT levels and remain at risk for HCC, cirrhosis, and flares of hepatitis B.24
In some instances, increased levels of ALT may precede a decline in HBV DNA that is accompanied by anti-HBe seroconversion; that is, loss of HBeAg and development of anti-HBe. Anti-HBe seroconversion usually implies a transition from active disease to an inactive carrier state.24 This transition can be spontaneous or associated with effective HBV treatment. Spontaneous HBeAg conversion rates in HIV-infected patients appear to be lower than in monoinfected patients. The inactive chronic hepatitis B state is characterized by a negative HBeAg, normal ALT levels, and an HBV DNA level <2,000 international units/mL. Patients in the inactive state remain at risk for reactivation of HBV and development of HCC, but the risk is lower than for those with active HBV replication. However, the re-emergence of abnormal liver enzyme tests may reflect HBeAg-negative chronic hepatitis B disease, a result of mutations in the basal core and precore promoter regions. Although levels of HBV DNA are usually lower, HBeAg-negative patients experience an unrelenting but fluctuating course of disease progression, with fluctuating HBV DNA levels.24 Thus, in a patient without HBeAg, serum ALT and HBV DNA levels still should be monitored.
Patients diagnosed with chronic HBV infection should have a complete blood count, ALT, aspartate aminotransferase (AST), albumin and bilirubin levels, and prothrombin time monitored at baseline and every 6 months thereafter to assess severity and progression of liver disease. Patients with chronic hepatitis B are at increased risk for HCC and imaging studies every 6 months are recommended in those who are cirrhotic; Asian male and older than age 40; Asian female and older than age 50; and male older than age 20 and from sub-Saharan Africa, as these individuals are at increased risk of disease progression.24
Persistent low-level serum ALT abnormalities may be associated with significant liver disease, although normal ALT levels also may be seen in the setting of cirrhosis. Transient or persistent elevations in serum ALT levels can occur before loss of HBeAg, on discontinuation of anti-HBV therapy, and in association with emergence of HBV drug resistance.
Liver biopsy with histologic examination remains a valuable tool for characterizing the activity and severity of chronic hepatitis B and may provide important information in monitoring disease progression, guiding treatment, and excluding other diseases. However, the decision to perform a liver biopsy should be individualized, especially given Department of Health and Human Services recommendations to initiate antiretroviral therapy (ART)-containing anti-HBV drugs regardless of CD4 T lymphocyte (CD4) cell count in HIV/HBV co-infected patients.25 The availability of non-invasive methods (i.e., elastometry and serum biochemical indices) to evaluate liver fibrosis is promising but not yet validated in HIV/HBV co-infection.26-28
HBV is primarily transmitted by percutaneous or mucosal exposure to infectious blood or body fluids. Therefore, HIV-infected patients should be counseled about transmission risks for HBV and avoidance of behaviors associated with such transmission (AIII). Such counseling should emphasize the transmission risks associated with sharing needles and syringes, tattooing or body-piercing, and sexual transmission.
All household members and sexual contacts of patients with HBV should be screened and all susceptible contacts should receive both hepatitis A and B vaccines regardless of whether they are HIV infected (AII). Hepatitis B immunization is the most effective way to prevent HBV infection and its consequences. All HIV-infected patients without chronic hepatitis B or immunity to HBV should be vaccinated with hepatitis B vaccine (AII) or with the combined hepatitis A and B vaccine (AII). All non-immune patients with high-risk behaviors associated with hepatitis B should be tested annually for both immunity to HBV and for infection, as is recommended for dialysis patients.29-32
Pre-vaccination screening should include HBsAg, anti-HBs, and anti-HBc. A patient who is seropositive for anti-HBc and anti-HBs has resolved infection and does not need vaccination. Similarly, the presence of anti-HBs alone at levels of >10 international units/mL is consistent with seroprotection, usually from vaccination,30 and no further vaccinations are required. The interpretation of persons with isolated anti-HBc is less clear. Aside from false-positive results, this pattern may signify infection in the distant past with subsequent loss of anti-HBs.33 Most HIV-infected patients with isolated anti-HBc are HBV DNA negative and not immune to HBV infection. They should be vaccinated with a complete series of hepatitis B vaccine followed by anti-HBs testing (BII).34,35
The magnitude and duration of immunogenicity to hepatitis B vaccination in HIV-infected adults36 is significantly lower than in HIV-seronegative healthy adults.37-40 Factors associated with poor response to vaccine include low CD4 cell counts,38,41-46 presence of detectable HIV RNA,42,46,47 co-infection with HCV, occult HBV infection (a rare situation of unclear clinical significance), and the general health status of the host.34,48-53 Based on these data, early vaccination is recommended in HIV-infected patients before CD4 cell counts decline to <350 cells/mm3 (AII). However, in patients who present to care at a lower CD4 cell count, vaccination should not be deferred until CD4 counts increase to >350 cells/mm3 because some HIV-infected patients with CD4 counts <200 cells/mm3 do respond to vaccination (AII). Given decreased vaccine responses among HIV-infected patients compared to HIV uninfected persons, anti-HBs titers should be obtained 1 month after completion of the vaccine series. For patients with anti-HBs levels <10 international units/mL, a second vaccine series is recommended (BIII), although some specialists might delay re-vaccination until after a sustained increase in CD4 cell count is achieved on ART (CIII). Some experts recommend a double dose (40 mcg) of vaccine because one study suggested that HIV-infected patients with CD4 counts >350 cells/mm3 had improved responses when vaccinated with this dose on a 0-, 1-, and 6-month schedule (CIII).41 Although other approaches have been investigated to improve responses, such as increasing the number of doses,38 the use of combined hepatitis A and B vaccine,54,55 or the use of adjuvants,56 these data are insufficient to support a broad recommendation for these approaches at this time. Additional studies are needed to determine optimal vaccination strategies in patients with advanced immunosuppression. In general, the vaccination series should be initiated at first visit regardless of CD4 cell count.
Hepatitis A vaccination is recommended for all hepatitis A antibody-negative patients who have chronic liver disease, are men who have sex with men, or who are injection drug users (AIII). Responses to the hepatitis A vaccine are reduced in HIV-infected patients with CD4 counts <200 cells/mm3.57,58 Antibody response should be assessed 1 month after vaccination. If hepatitis A virus Ab immunoglobulin G is negative, patients should be revaccinated when the CD4 cell count is >200 cells/mm3 (BIII).
Patients with chronic hepatitis B disease should be advised to avoid alcohol consumption (AIII).
The ultimate treatment goals in HIV/HBV co-infection are the same as for HBV monoinfection: to prevent disease progression and to reduce HBV-related morbidity and mortality. To this end, treatment for HBV is intertwined with that for HIV.
In general, HBV treatment is indicated in patients who have active HBV disease.24 Anti-HBV therapy is indicated for elevated ALT and elevated HBV DNA >2,000 international units/mL or significant fibrosis (AI).24 All patients with advanced liver disease or cirrhosis should also be treated. Additional information on HBV treatment indications is found in the American Association for the Study of Liver Diseases guidelines.24 ART including agents with activity against both HIV and HBV is recommended for all patients co-infected with HIV and HBV, regardless of CD4 cell count or HBV treatment status (AII).
For HIV/HBV co-infected individuals, ART must include two drugs active against HBV, preferably tenofovir and emtricitabine, regardless of the level of HBV DNA (AIII). Such a regimen will reduce the likelihood of immune reconstitution inflammatory syndrome (IRIS) against HBV. The reasons behind this latter recommendation include prevention of IRIS (see next section) and the lack of preferred ART regimens without HBV activity.
If the patient refuses ART there are few options that can be used for treatment of HBV alone. Directly acting HBV drugs must not be given in the absence of a fully suppressive ART regimen. This is because most drugs active against HBV also are active against HIV (anti-HBV drugs such as tenofovir, entecavir, emtricitabine, lamivudine, adefovir, and likely telbivudine) but when given without more potent anti-HIV agents can produce drug-resistant HIV in the recipient (AI). Alternative HBV therapy for patients who refuse initiation of ART would be 48 weeks of pegylated interferon (IFN) (see below).
The Department of Health and Human Services guidelines for treatment of HIV infection recommend the fixed-dose coformulation of tenofovir/emtricitabine as the preferred nucleoside reverse transcriptase inhibitor (NRTI) backbone for ART-naive patients.25 Because both of those NRTIs have anti-HBV activity, it is also the treatment of choice for HIV/HBV co-infected patients (AIII). Tenofovir is active against wild-type and lamivudine-resistant HBV strains. Studies in HBV/HIV-co-infected patients (most of them carrying lamivudine-resistant HBV) have shown, on average, 4 log10 declines in HBV DNA levels.59-64 Tenofovir has a high genetic barrier for development of resistance mutations. However, the nephrotoxicity associated with tenofovir may limit its use in some patients. In patients who have renal dysfunction or are at high risk for developing renal dysfunction, entecavir can be added to a fully suppressive ART regimen (BIII). Chronic administration of lamivudine or emtricitabine as the only active drug against HBV should be avoided because of the high rate of selection of HBV drug-resistance mutations (AI).
Alternative Treatment of HBV in HIV-Infected Patients Who Are Not Receiving ART
For HIV/HBV-co-infected patients not receiving ART who meet criteria for HBV therapy, pegylated interferon-alfa-2a alone or adefovir alone are the only options that will not predispose to antiretroviral drug resistance (CIII). However, data are scarce on these agents alone in the HIV/HBV-co-infected population. Patients who are HBeAg positive, infected with HBV genotype A, in the early stages of liver disease, and have high ALT levels are the most likely to benefit from a 48-week course of pegylated interferon alfa (CIII). Adefovir alone is of limited value because it is less potent and has a higher risk of selecting for resistance mutations than the preferred HBV nucleos(t)ides.24 Tenofovir, entecavir, lamivudine, emtricitabine, and telbivudine should not be used in the absence of ART because of the development of HIV-resistance mutations.65,66 If there is no indication for HBV treatment, continued monitoring and reassessment of risk of liver-related morbidity and mortality is required because HBV is a dynamic disease that can change with time.
Most patients receiving ART should continue HBV therapy indefinitely (CIII) because relapses after response occur, particularly in those with lower CD4 cell counts, and because reports of hepatitis flares after discontinuation of lamivudine in those who have not reached treatment endpoints can be extrapolated to other HBV-active drugs.38,67-69 Pegylated interferon alfa requires a defined course of 48 weeks.
Some HIV/HBV-co-infected patients also have chronic HCV infection. There is scant information on the treatment of HBV/HCV/HIV co-infection. Because patients with HBV, HCV, and HIV appear to have accelerated progression of liver fibrosis, higher risk of HCC, and increased mortality,70-72 attempts should be made to treat both hepatitis viruses, if feasible. If ART is administered, then anti-HBV therapy must be included as part of the regimen (as above) and anti-HCV therapy can be introduced as needed (see Hepatitis C Infection) (CIII). If ART is not desired, interferon alfa-based therapy, which has activity against both HCV and HBV, should be considered (CIII).
Special Considerations with Regard to Starting ART
Regardless of CD4 count, initiation of ART is strongly recommended for all individuals with HIV and HBV co-infection (AII). As noted above, ART including agents with activity against both viruses is recommended (AII).
Monitoring of Response to Therapy and Adverse Events (Including IRIS)
In order to prevent emergence of drug-resistant variants and evaluate response for patients on nucleos(t)ide analogues, treatment response should be monitored by testing for HBV DNA at 12-week intervals. HBeAg also should be tested every 6 months in patients who are HBeAg positive. Treatment responses are defined as follows:
Primary non-response is an HBV DNA <1 log10 decline at 12 weeks.73
A complete virological response is an undetectable HBV DNA by real-time polymerase chain reaction at 24 to 48 weeks.73
An undetectable HBV DNA at Week 24 strongly predicts a lower risk of development of drug resistance.74
A partial virologic response is ≥1 log10 decline but still detectable HBV DNA at Week 24.73
A maintained virological response is a response that continues while on therapy, and a sustained virological response is one that is still present 6 months after stopping therapy.
For patients who are HBeAg positive, loss of HBeAg is also a measure of virological response. Other markers that indicate treatment success include improvement in liver histology based on biopsy or non-invasive markers; normalization of serum aminotransferases; and, in those with loss of HBeAg, the development of anti-HBe. Sustained loss of HBsAg is considered by some to be a complete response; however, this desirable serologic response is uncommon.24
Major toxicities of IFN-alfa (pegylated or standard) are detailed in the HCV section.
Nucleos(t)ide analogs: Renal toxicity with tenofovir, including increased serum creatinine or renal tubular dysfunction, has been observed; both are more frequent in HIV-infected patients with underlying renal insufficiency or those treated for prolonged periods. Electrolytes and serum creatinine levels should be evaluated at baseline and every 3 to 6 months, and urinalysis every 6 months. Because renal toxicity may be reversible, alternative anti-HBV therapy should be used if renal toxicity occurs (AI). If tenofovir is used in patients with baseline renal insufficiency, dose adjustment as noted in the package insert is required.
Entecavir-associated lactic acidosis is uncommon but has been reported in HBV-monoinfected patients with advanced cirrhosis.75 Telbivudine can cause creatine phosphokinase (CPK) elevations >7 times the upper limit of normal, with some reports of myopathy.76 Thus, CPK should be measured at baseline, every 3 to 6 months, and if musculoskeletal symptoms develop. If CPK levels are elevated, telbivudine should be discontinued and replaced with another anti-HBV agent (AI).
Adefovir causes renal tubular disease at doses of 30 mg/day or higher, but this toxicity is uncommon at the recommended 10 mg/day dose. In HBV-monoinfected patients, incidence of increased creatinine levels with 5 years of adefovir therapy ranges from 3% to 8%.77,78
Discontinuation of nucleos(t)ide analogue therapy before reaching treatment endpoints is associated with a hepatitis B flare in approximately 30% of cases,79,80 with loss of the benefit accrued from previous anti-HBV treatment and possible decompensation of liver disease. If anti-HBV therapy is discontinued, transaminase levels should be monitored every 6 weeks for 3 months and every 3 months thereafter. If a flare occurs, anti-HBV therapy should be reinstituted and can be potentially lifesaving (AIII).
Return of immune competence after ART (or after steroid withdrawal or chemotherapy) can lead to reactivation of HBV-associated liver disease. Any immune reconstitution can lead to a rise in serum aminotransferases, so called “hepatitis flare”,81 which constitutes IRIS in HIV/HBV-co-infected persons. IRIS may be manifested by dramatic increases in serum aminotransferase levels as CD4 cell counts rise within the first 6 to 12 weeks after starting ART, with signs and symptoms characteristic of acute hepatitis. After introduction of ART, serum aminotransferase levels should be monitored closely; some experts recommend monthly for the first 3 to 6 months and then every 3 months thereafter. Any association between abnormal aminotransferases and clinical jaundice or synthetic dysfunction (elevated International Normalized Ratio and low serum albumin) should prompt consultation with a hepatologist.
Patients with HBV and HIV should receive concomitant anti-HBV therapy when ART is used because these flares can be life threatening (AIII). Flares are worse in patients with more severe liver disease, especially cirrhosis.82 Distinguishing between hepatotoxicity or other causes of hepatitis (acute hepatitis a virus or acute HCV) and IRIS is difficult. When changing antiretroviral (ARV) regimens, continuing agents with anti-HBV activity is important because of the risk of IRIS (AIII).
All classes of ARVs have been associated with hepatotoxicity, as evidenced by substantial elevations in serum aminotransferases.83 ARV-associated hepatotoxicity may be dose dependent or idiosyncratic. The risk of hepatotoxicity has been consistently associated with elevated pre-ART aminotransferases (ALT, aspartate aminotransferase) and the presence of HBV or HCV co-infection before initiation of ART.84-92 However, despite this increased risk of hepatotoxicity in the setting of HCV or HBV co-infection, most (80%–90%) co-infected patients do not have hepatotoxicity,87 and clinically significant hepatotoxicity is rare; aminotransferase levels return to baseline in most cases, even if the offending medication is continued.85,93 Therefore, discontinuing ART usually is not necessary in the presence of hepatotoxicity unless patients have symptoms of hypersensitivity (e.g., fever, lymphadenopathy, rash), symptomatic hepatitis (i.e., nausea, vomiting, abdominal pain, or jaundice), or elevations in serum aminotransferase levels >10 times the upper limit of normal. However, the development of jaundice is associated with severe morbidity and mortality and the offending drug(s) should be discontinued (AIII).94
The major problem in managing ALT flares is distinguishing between drug-induced liver injury and hepatitis B reactivation, IRIS, emergence of drug resistance, and HBeAg seroconversion. In drug-induced liver toxicity, determining the offending medication also can be challenging. A review of the medication history and testing for serum HBV DNA, HBeAg, HIV RNA levels, and CD4 cell count can help distinguish between these possibilities. Liver histology also may help to differentiate drug toxicity (e.g., increased eosinophils) from viral hepatitis (e.g., portal inflammation). If the flare is severe or HBV drug resistance is suspected, then consultation with a hepatologist is recommended. Other causes of abnormal liver tests should be sought, including use of drugs or alcohol, other viral hepatitis infections (hepatitis A, C, D, and E), and nonalcoholic fatty liver disease.
Managing Treatment Failure
HBV treatment failure on nucleos(t)ide analogues is defined as primary nonresponse after 12 weeks of therapy in patients who consistently adhere to HBV therapy or an increase in HBV DNA levels greater than 1 log10 above nadir. In either situation, treatment failure is generally due to drug-resistant HBV and a change in treatment needs to be made (AII). Many experts will obtain HBV-resistance testing. Distinct resistance patterns exist with the different groups of anti-HBV drugs: the L-nucleosides (telbivudine, lamivudine, emtricitabine); acyclic phosphonates/nucleotides (adefovir and tenofovir); and the third class, which only has entecavir and shares some resistance mutations with the L-nucleosides. Resistance testing has value in distinguishing between noncompliance and resistance, evaluating patients with unclear prior drug history, assessing different adefovir-resistance pathways, and predicting the level of resistance to entecavir.
HBV monotherapy should not be used in HIV-infected patients because of the risk of development of resistance mutations to both HIV and HBV (AII). Lamivudine (or emtricitabine) monotherapy for HBV leads to resistant HBV increasingly with time on treatment. The rate of development of lamivudine resistance is approximately 20% per year in HIV/HBV-co-infected patients treated with lamivudine alone.95 If lamivudine resistance is suspected or documented, tenofovir should be added (BIII).96-98 Because patients with lamivudine-resistant HBV will have cross-resistance to the other L-nucleosides (telbivudine, emtricitabine), those agents should not be used in patients found to have lamivudine-resistant HBV (AI). All nucleoside analogs must be dose adjusted for renal insufficiency per package insert guidelines and Table 8.
If treatment failure occurs on entecavir, then the only rational choice is replacement with tenofovir (+/- emtricitabine) because of the cross resistance that occurs with L-nucleosides (telbivudine, lamivudine, emtricitabine) (AI).
If treatment failure with tenofovir occurs, particularly in lamivudine- or emtricitabine-experienced patients, then entecavir may be an active alternative, especially if higher doses of entecavir can be used (CIII). However, documented in vivo resistance to tenofovir has not yet been reported.
Patients whose HBV initially fails to respond to pegylated IFN-alfa can be given nucleos(t)ide analogue therapy following the recommendations previously described (CIII).
Declines in HBV DNA levels can be slow, especially when pretherapy HBV DNA levels are very high. HBV DNA levels usually drop quickly in patients who are receiving an HBV drug, such as tenofovir, with high potency and a high genetic barrier to resistance, but they may still be detectable for some years and the drug should be continued with monitoring of HBV DNA levels (BII). Intensification with addition of entecavir has been reported, but whether it is required is unclear because clinical resistance to tenofovir has not yet been reported. However, patients on adefovir or L-nucleosides who have partial virologic responses (<2 log10 drop in HBV DNA levels from baseline) should be switched to a more potent regimen such as tenofovir with emtricitabine or entecavir because of the risk of resistance (BII).
Treatment of end-stage liver disease in HIV/HBV-co-infected patients should be managed as it is in HIV-seronegative patients. These patients should be referred to a hepatologist. As with monoinfected patients, IFN-alfa is contraindicated in end-stage liver disease (AI), but nucleoside analogs are safe and efficacious (AI).95,99,100 All patients with ascites should undergo paracentesis to exclude spontaneous bacterial peritonitis (SBP).101 Management of ascites includes sodium restriction (<2 g/day) and the recommended diuretic regimen is spironolactone combined with furosemide (ratio of 40 mg furosemide: 100 mg spironolactone) (AI). All patients who have had SBP and those with ascites total protein <1 g/dL should receive prophylaxis against SBP with administration of oral antibiotics such as norfloxacin (400 mg/day) or trimethoprim-sulfamethoxazole (one double-strength tablet/day) (AI).102
Esophagogastroduodenoscopy (EGD or upper endoscopy) should be performed on all patients with cirrhosis at the time of diagnosis and then every 1 to 2 years to identify substantial gastroesophageal varices. Individuals with varices require non-selective beta blockers, such as nadolol or propranolol, which are the mainstay of both primary and secondary prevention of variceal hemorrhage. Esophageal variceal banding is another preventive option, particularly for those who cannot tolerate beta blockers. Hepatic encephalopathy is treated with a 40-g protein diet and the use of non-absorbable disaccharides such as lactulose and/or antibiotics such as rifaximin.
Patients with HBV-related cirrhosis are at increased risk of HCC103 and should be screened every 6 to 12 months with imaging studies, as recommended in HBV monoinfection. Choice of imaging (ultrasound, computed tomography, or magnetic resonance imaging) depends upon the expertise of the imaging center and whether the patient has cirrhosis. Usually ultrasound is the initial preferred imaging modality. HIV co-infection appears to increase the risk of HCC in HBV,104 but more frequent screening in HIV/HBV co-infection has not been studied, and so is not recommended. HIV/HBV-co-infected patients with decompensated liver disease and/or early HCC are candidates for orthotopic liver transplantation. HIV infection is not a contraindication to organ transplantation with the use of effective ART.105 Because transplantation does not cure HBV infection, post-transplant HBV treatment is required (AII).
As previously indicated, most patients should continue HBV therapy (with the exception of pegylated IFN) indefinitely (CIII) because relapses after response occur, particularly in those with lower CD4 cell counts, and because reports of hepatitis flares after discontinuation of lamivudine in those who have not reached treatment endpoints can be extrapolated to other HBV-active drugs.38,67-69
Special Considerations During Pregnancy
Pregnant women, including HIV-infected women, should be screened for HBsAg, anti-HBc, and anti-HBs. Those who are HBsAg and anti-HBs negative should be offered vaccination against hepatitis B. Treatment of symptomatic acute HBV infection during pregnancy should be supportive, with special attention given to maintaining blood glucose levels and normal clotting status. Risk of pre-term labor and delivery may be increased with acute HBV infection.
High maternal HBV DNA levels correlate strongly with perinatal HBV transmission, including failures of HBV passive-active immunoprophylaxis.106-108 Although a high viral load is clearly important, it is not the only factor predisposing to prophylaxis failure, as demonstrated by a case report in which perinatal HBV transmission occurred despite suppression of HBV DNA to undetectable levels in the mother with antepartum lamivudine and appropriate immunoprophylaxis of the infant.109
ART including drugs active against both HIV and HBV is recommended for all individuals with HIV/HBV co-infection, including pregnant women, who require HBV treatment or who are initiating ART for their own health. Because combination ART is recommended for all HIV-infected women during pregnancy to prevent mother-to-child transmission of HIV, even if it is not required for their own health, all HIV/HBV-co-infected pregnant women should receive an ART regimen containing HBV-active drugs. This is because of concern about potential IRIS-related flare of HBV activity after initiation of ART, even in women with relatively high CD4 cell counts, if drugs without anti-HBV activity are used. In addition, using drugs with anti-HBV activity during pregnancy will lower HBV levels and potentially decrease the risk that hepatitis B immune globulin and hepatitis B vaccine will fail to prevent perinatal transmission of HBV. Following delivery, considerations regarding the continuation of ARV drugs in mothers are the same as in other adults who are not pregnant. Therefore, once HBV therapy with nucleos(t)ide analogs is initiated, treatment is recommended to be continued indefinitely. However, if ARV drugs are discontinued postpartum, frequent monitoring of liver function tests for potential HBV flare is recommended, with prompt reinitiation of treatment for both HIV and HBV, should a flare occur.
Because emtricitabine, lamivudine, and tenofovir have activity against both HIV and HBV, the recommended dual-NRTI backbone for HIV/HBV-co-infected individuals who are not pregnant is tenofovir/emtricitabine or tenofovir/lamivudine (AI). Of the ARV agents with activity against hepatitis B, the one used most often in pregnancy is lamivudine. As of January 2012, more than 4,000 cases of pregnancy outcomes after first-trimester exposure to lamivudine have been reported to the Antiretroviral Pregnancy Registry, with no indication of an increased risk of birth defects after exposure.110 Lamivudine has been well tolerated by pregnant women and is a recommended NRTI for use in pregnancy (AII).111 Similarly, no increase in birth defects has been noted in almost 900 cases of first-trimester exposure to emtricitabine, which is an alternative NRTI for use in pregnancy (http://www.apregistry.com) (BII).111 Tenofovir was not teratogenic in animals, but at high doses, reversible bone changes were seen in multiple animal species. A total of 1,370 cases of first-trimester exposure to tenofovir have been reported to the Antiretroviral Pregnancy Registry with no increase in birth defects noted.110 Although tenofovir is recommended as an alternative NRTI during pregnancy for ARV-naive women, given in combination with lamivudine or emtricitabine, it is the preferred dual-NRTI backbone for pregnant women with chronic HBV infection (AIII), as it is in nonpregnant HIV/HBV-co-infected individuals.111
Several other ARV agents with activity against HBV, including entecavir, adefovir, and telbivudine, have been evaluated and found not to be teratogenic in animals, but experience with these agents in human pregnancy is limited. These drugs could be included in a regimen during pregnancy if other options are inappropriate. Each of these agents should be administered only in combination with a fully suppressive ARV regimen because of the risk of development of ARV drug resistance. Entecavir was associated with skeletal anomalies in rats and rabbits, but only at high, maternally toxic doses. Data on use of entecavir and adefovir in human pregnancy are not available. Telbivudine was given to 95 HBV-seropositive, HIV-seronegative women during the third trimester in 1 study, and it was well tolerated with no birth defects observed.112 Cases of exposure during pregnancy to any of the ARV and HBV drugs listed should be reported to the Antiretroviral Pregnancy Registry (800-258-4263; http://www.apregistry.com).
Interferon alfa formulations are not recommended for use in pregnancy. Although these agents are not teratogenic, they are abortifacient at high doses in monkeys and should not be used in pregnant women because of their direct antigrowth and antiproliferative effects (AII).113
Infants born to HBsAg-positive women should receive hepatitis B immune globulin and hepatitis B vaccine within 12 hours of delivery (AI). The second and third doses of vaccine should be administered at 1 and 6 months of age, respectively.
Recommendations for Preventing and Treating Hepatitis B Virus (HBV) Infection
Preventing HBV Infection
Indications for HBV Vaccination:
Patients without chronic hepatitis B or without immunity to HBV (anti-HBs <10 IU/mL) (AII)
Patients with isolated anti-HBc and with negative HBV DNA (BII).
Early vaccination is recommended before CD4 count falls below 350 cells/mm3 (AII), as low CD4 count at time of vaccination has been associated with poor response to the vaccine.
However, in a patient with low baseline CD4 cell count, vaccination should not be deferred until CD4 reaches >350 cells/mm3, as some patients with CD4 <200 cells/mm3 do respond to vaccination (AII).
Hepatitis B vaccine IM (Engerix-B® 20 µg/mL or Recombivax HB® 10 µg/mL) at 0, 1, and 6 months (AII), or
Combined Hepatitis A and Hepatitis B vaccine (Twinrix®) 1 mL IM as a 3-dose series (at 0, 1, and 6 months) or as a 4-dose series (at days 0, 7, 21 to 30, and 12 months) (AII)
Anti-HBs should be obtained 1 month after completion of the vaccine series, anti-HBs <10 IU/mL will be considered as non-responders. (BIII)
For Vaccine Non-Responders:
Revaccinate with a second vaccine series (BIII)
For patients with low CD4 count at the time of first vaccination series, some experts might delay revaccination until after a sustained increase in CD4 count with ART (CIII).
Alternative Vaccine Dose for Non-Responders:
Some experts recommend revaccinating with 40 µg doses of either vaccine (CIII)
Treating HBV Infection:
Indication for Therapy:
All HIV/HBV co-infected patients, regardless of CD4 count or HBV treatment status (AII). Treatment should be used for both HIV and HBV infections (AIII).
The ART regimen should include 2 drugs active against HBV, such as (tenofovir 300 mg + [emtricitabine 200 mg or lamivudine 300 mg]) PO once daily (AIII).
Duration of Therapy:
Patients on treatment for HBV and HIV will receive therapy indefinitely (CIII).
Alternative Therapy If patients do not want to or are unable to take ART, or are HIV long term non-progressors:
Assess HBV disease stage to evaluate for treatment. In general anti-HBV therapy is indicated when there is presence of active liver disease, elevated transaminases, and elevated HBV DNA >2,000 international units/mL, or significant liver fibrosis (AI).
Peginterferon alfa 2a 180 mcg SQ once weekly for 48 weeks (CIII), or
Peginterferon alfa 2b 1.5 mcg/kg SQ once weekly for 48 weeks (CIII)
If tenofovir cannot be used as part of the ART regimen because of current or high risk of renal dysfunction:
A fully suppressive ART regimen without tenofovir should be used, with the addition of entecavir to the regimen (BIII)
Note: Chronic administration of emtricitabine or lamivudine as the only HBV active drug should be avoided due to high rate of selection of HBV drug resistance mutation (AI).
Adefovir, emtricitabine, entecavir, lamivudine, telbuvidine, or tenofovir should not be used for the treatment of HBV infection in patients who are not also receiving combination ART (AII),
As patients with HBV/HCV/HIV co-infection appear to have accelerated liver fibrosis progression, high risk of hepatocellular carcinoma, and increased mortality, treatment for both HBV and HCV infection should be initiated, if feasible.
When changing ART regimens, it is crucial to continue agents with anti-HBV activity because of the risk of IRIS (BIII).
If anti-HBV therapy is discontinued and a flare occurs, therapy should be re-instituted, as it can be potentially life saving (AIII).
Key to Acronyms: anti-HBs = hepatitis B surface antibody; ART = antiretroviral therapy; CD4 = CD4 T-lymphocyte cell; HBV = hepatitis B virus; HCV = hepatitis C virus; IM = intramuscular; IRIS = immune reconsitituion inflammatory syndrome; PO = orally; SQ = subcutaneous
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