Joel E. Gallant, MD, MPH and Christopher Hoffmann, MD, MPH
- Chronic HBV (HBsAg+ >6 mos) is present in 5-15% of Zambians with HIV (probably higher in rural than urban areas). 25% of individuals with chronic HBV are HBeAg+.
- Most acute infections occur in early childhood with <10% of adults with chronic HBV first becoming infected during adulthood ( uncertain whether acute HBV more common among HIV+ individuals in Zambia).
- Individuals with active chronic HBV (high HBV DNA levels) more likely to have elevated ALT. Thus targeted screening for HBsAg among individuals with elevated pre-ART ALT should be considered.
- Cost-benefit of HBV vaccination of HIV+ adults unclear in Zambia.
- Among HIV/HBV co-infected patients, consider regimen that includes TDF and either 3TC or FTC as first-line and consider continuing HBV active agent (3TC) if 1st line is switched to a 2nd line regimen that does not include HBV active agents. This may also reduce perinatal transmission of HBV, as risk of transmission associated with serum HBV DNA level.
Zambia Information Author: Christopher Hoffmann MD, MPH
- Hepatitis B virus (HBV): enveloped DNA virus with surface antigen surrounding nucleocapsid made up of core protein, viral genome, and polymerase protein. Maintains persistence in hepatocytes with covalently closed circular (ccc) DNA
Acute Hepatitis B:
- Acute infection rare in U.S. (3/100,000 p-yr). Risk factors: unprotected sex, sharing IDU needles, maternal to fetal, piercing, & tattoo with unsterile equipment, & lack of vaccination
- After exposure, average incubation period 45-160 days before Sx. Subclinical in most pts. In patients with Sx: malaise, anorexia, loss of taste for food & cigarettes, aches, arthralgias, and low grade fever followed by jaundice. Fulminant and fatal <1%.
- Extrahepatic manifestations: PAN, membranous GN, aplastic anemia, erythema multiforme, and serum sickness.
Chronic Hepatitis B:
- Chronic hepatitis B (CHB; defined by persistence of HBsAg > 6 mos) common among HIV+ pts because of shared modes of transmission & increased progression from acute to CHB with HIV coinfection. Approx. 10% of HIV+ pts co-infected with HBV in US, Europe, and Australia.
- Approx. 5% of HIV-negative adults progress from acute to chronic infection vs. 25% of HIV+ adults.
- HIV alters natural Hx of CHB, leading to higher HBV DNA levels, higher likelihood of HBeAg persistence, lower rates of treatment response & more rapid emergence of resistance to therapy
- With CHB mono-infection, 25% develop chronic active hepatitis, with progression to cirrhosis in 15-30%. Hepatocellular carcinoma (HCC) usually occurs after cirrhosis but can also occur without cirrhosis. Among HIV-HBV co-infected, progression to liver disease occurs more frequently than in CHB mono-infected pts.
- Patients with CHB have 4-fold increased risk of non-AIDS death (mostly from liver disease)
- ALT flares during ART can occur for multiple reasons 1) ART related hepatotoxicity: usually asymptomatic & spontaneously resolving elevation occurring in 1st 6 mos of ART, but can be life threatening. 2) immune reconstitution inflammatory syndrome (IRIS): immune response to HBV antigens in liver. May lead to severe hepatitis. Usually occurs in 1st 6 mos 3) ALT flares as part of natural Hx of CHB, may herald seroconversion from HBeAg to anti-HBe. Occurs at any time, usually among HBeAg+ 4) HBV reactivation after suppression with an anti-HBV agent when agent is withdrawn or with development of resistance (2-3 months after stopping therapy) 5) Reactivation of HBV with waning immunity
- CHB does not affect HIV progression (CD4 decline, etc) or HAART response (HIV suppression or CD4 increase)
- Occult hepatitis B defined by presence of HBV DNA (usually <105 c/mL) in absence of HBsAg. It is more common in HIV+ pts and is associated with lower CD4 count. Occult HBV can be transmitted but clinical impact unclear.
- Acute hepatitis: Detection of anti-HBc IgM with or without HBsAg with appropriate clinical picture. (Both anti-HBc IgM & HBsAg may also be present during chronic infection; clinical picture important.) HBV DNA and HBeAg also present.
- Recovery from acute HBV infection: disappearance of HBV DNA, seroconverion of HBeAg to anti-HBe and HBsAg to anti-HBs.
- Resolved HBV infection: presence of anti-HBs and anti-HBc. However, anti-HBs detectability wanes with time, anti-HBc persists. Immunity to HBV infection after vaccination indicated by presence of anti-HBs only.
- Chronic HBV infection: Carrier state defined as persistence of HBsAg >6 mos. If positive, check for high-level HBV replication with HBeAg and HBV DNA.
- Occult HBV: HBV DNA present, no detectable HBsAg, HBeAg, or anti-HBs. Anti-HBc may be present.
- Check HBV DNA if (1) HBsAg+, (2) HBsAg- with unexplained elevation in ALT, (3) anti-HBc+ with negative HBsAb and HBsAg with unexplained elevation in ALT.
- HBsAg: marker of viral replication and infectiousness. HBeAg: marker of high-level replication and enhanced infectiousness. Absence of both and presence of anti-HBs and anti-HBe, suggests immunologic control (but may still have HBV cccDNA in hepatocytes).
- Liver Bx for evaluation of HBV not usually necessary, though Bx may support decision to delay therapy in coinfected patients
- Test for HAV, HCV, and HDV to rule out superinfection with other hepatitis viruses
- Prevent progression of fibrosis and development of cirrhosis or HCC by suppressing HBV replication.
- Seroconversion from HBeAg+ to anti-HBe & establishment of effective immune control.
- Suppression of HBV DNA; however, therapy does not eradicate cccHBV in hepatocytes.
- HBsAg+ & HBeAg+ & liver disease (ALT > 2x ULN or necroinflammation on liver Bx)
- HBsAg+ & HBeAg- & either HBV DNA > 104 c/mL or evidence of liver inflammation
- Use HBV -active ART if ART indicated
- ART using HBV-active agents (e.g. TDF/FTC + 3rd agent) now indicated in all coinfected patients when HBV therapy required
- No consensus guidelines of HIV/HBV coinfection
- Routinely assess HBV DNA, ALT, and HBeAg (if + at start of Rx)
- HBV DNA level should decline gradually on effective therapy, without development of resistance. Usually HBV DNA rapidly declines several logs, becoming undetectable within 6-12 mos.
- Consider adding entecavir for pt on TDF + either FTC or 3TC with persistently detectable HBV DNA. However, no RCTs have evaluated this approach.
- PEG-IFN: HBeAg+ x16 wks (goal of HBe seroconversion); HBeAg- x12 mos.
- All therapy: after seroconversion from HBeAg+ to anti-HBe if anti-HBe persists >6 mos
- NRTIs: Indefinite therapy may be needed if no seroconversion, risk of HBV flare if HBV therapy stopped. Monitor closely if Rx stopped with ALT, HBV DNA levels.
Tenofovir DF (TDF): (active against HIV & HBV) 300 mg once-daily: Potent (avg. decrease in HBV DNA 5 log), including those with 3TC resistance. Low rates of resistance reported.
Lamivudine (3TC): (active against HIV & HBV) 100 mg once-daily for HBV, 300 mg once-daily for HIV. At 12 mos, most have decreased ALT and negative HBV DNA. Resistance develops rapidly w/ monotherapy: 50% in 2 yrs, 90% at 4 yrs. Cross-resistance with entecavir , telbivudine, FTC
Emtricitabine (FTC) : (active against HIV & HBV) 200 mg/d: limited clinical experience but activity appears similar to 3TC. Also coformulated with TDF.
- Entecavir: (HBV active, partial HIV RT inhibitor, may select for M184V HIV mutation) 0.5 mg PO once-daily (for 3TC-naive pts) or 1 mg PO once-daily (for 3TC-refractory pts) on empty stomach. Potent agent. Cross-resistance with FTC, 3TC, telbivudine.
- Adefovir (ADF): (active only against HBV at 10mg/d) 10 mg once-daily (with or without 3TC). Less potent than TDF or etravirine
- Telbivudine: (active only against HBV). Less potent than TDF or entecavir.
- PEG-IFN: 180 mcg/wk: minimal experience with HBV, but probably equally effective as IFN-alfa and better tolerated. Good option for HBV genotype A, low HBV DNA, elevated ALT, & when HIV Rx not needed.
- HBV & HIV Rx in 3TC naïve: include TDF+FTC (Truvada) in ART regimen. Adding FTC to TDF for Rx of HBV may increase potency & delay TDF resistance, but no data yet on TDF/FTC for HBV
- HBV & HIV Rx in 3TC-experienced with possible HBV resistance to 3TC: continue 3TC or FTC & add TDF
- HIV Rx only: ideally use Rx effective for both HIV & HBV (consider Truvada backbone)
- HBV Rx only: Treatment of both HIV & HBV generally preferred because of simplicity of treating both infections. If treating only HBV, consider PEG-IFN (esp if genotype A, low HBV DNA, & high ALT). ADF is option but limited potency. Resistance develops rapidly with telbivudine. Others have HIV activity and select for HIV resistance if non-suppressive of HIV (TDF, FTC, 3TC, possibly entecavir)
- Increased survival among HIV+ pts with ART has led to increased benefit of treatment of HBV; however, goal of HBV treatment is avoidance of cirrhosis rather than viral eradication
- Reactivation of HBV following immune reconstitution with HAART also described, monitor ALT in coinfected patients early after initiating HAART.
- Initiate ART with drugs active against HIV & HBV (TDF + either FTC or 3TC + 3rd agent) if HBV therapy required, regardless of CD4 count (DHHS 2008 recommendation).
- Advise abstinence from alcohol
- Vaccinate against HAV
- Monitor ALT regularly (q 3 mos) & HBV DNA if not current Rx candidate
- HCC screening q 6-12 mos with AFP and U/S. Most important if pt in high-risk group (age >45 yrs, cirrhosis, or family history of HCC). Note that unlike HCV, HBV can cause HCC in the absence of cirrhosis. Optimal HCC screening in HIV unknown. For now, follow HIV-negative guidelines.
- Transplantation an option for ESLD. HBV infection rate high in transplanted liver but risk of cirrhosis reduced with HBV immune globulin and antivirals
- Vaccination indicated for all HIV+ individuals negative for anti-HBs and HBsAg. Unclear whether HIV+ pts with only positive anti-HBc benefit from immunization; however, there is evidence of lack of amnestic response among these individuals, suggesting that vaccination necessary to achieve HBV immunity.
- Vaccination response best with HIV RNA < 50 & CD4 > 200. Defer vaccination until CD4>200 or check titers after vaccination at lower CD4 count.
- Dose schedule: 0 mos, 1 mo (1 - 2 mos), and 6 mos (6 - 12 mos). If vaccination schedule interrupted, complete 3 doses as if no interruption occured (unnecessary to restart).
- Alternative dosing schedules have been studied in other populations to achieve higher rates of completing series (0, 7 d, 21 d, and 12 mo; 0, 1 mo, 2 mos, & 12 mos). However, rates of completion similar to standard schedule and limited data available for accelerated schedules among HIV+ populations.
- For highest risk transmission groups, check anti-HBs titer soon after completing series (within 6 mos). If titer < 10 IU/L, repeat 3 dose series with double-dose vaccine.
||Probably best option in HIV/HBV co-infection, combined with FTC or 3TC and 3rd anti-HIV agent.
|| Effective in both HBeAg+ and HBeAg- patients. Lower rate of resistance than 3TC. Higher doses not more effective, and more nephrotoxic. No activity against HIV at standard dose, so TDF generally preferred in pts who require HAART. Hypothetical concern that adefovir could select for TDF-resistant HIV.
||Given widespread use of 3TC as component of HAART and 25% annual incidence of resistance among HBV isolates, majority of previously treated HIV-HBV pts already have 3TC-resistant HBV. Good option for treatment-naive pts (with TDF) in combinations with 3rd anti-HIV agent.
||Approved for Rx of HBV and HIV, and coformulated with TDF, but 3TC-resistant HBV will be cross-resistant to FTC. TDF/FTC (Truvada) good option for treatment-naive pts in combination with 3rd anti-HIV agent.
||First medication approved for treatment of HBV. Not well-studied in HIV-HBV coinfection; efficacy appears to be low, and use largely replaced by oral agents.
||Appears to be more effective than IFN, but no published data in HBV-HIV coinfection
||Viral load suppression greater than with 3TC or adefovir. Useful for patients not on HAART. No published data on combination therapy for HIV/HBV co-infected patients, but may be useful for pts with 3TC resistance. May have some anti-HIV activity; may select for M184V
||HBV-specific, but limited potency, and cross-resistance with entecavir, 3TC, FTC. Lower threshold for resistance than TDF or entecavir.