Tenofovir-Emtricitabine Therapy for the Prevention of

Hepatitis B Recurrence in Four Patients After Liver

Transplantation

Katrina H. McGonigal,1 Iman E. Bajjoka,2,* and Marwan S. Abouljoud,2

1Creighton School of Pharmacy and Health Professions, Creighton University, Omaha, Nebraska;2Henry Ford Transplant Institute, Henry Ford Hospital, Detroit, Michigan

In patients infected with chronic hepatitis B virus (HBV) that goes untreated, therapeutic options are lim-ited once the disease decompensates, and orthotopic liver transplantation is often the only treatmentavailable to save the patient’s life. After liver transplantation, combined therapy with hepatitis B immuneglobulin (HBIG) and a nucleos(t)ide analog is the standard of practice for the prevention of HBV recur-rence. Historically, nucleos(t)ide analogs such as lamivudine and adefovir have been used with low-doseHBIG for the prevention of HBV recurrence after liver transplantation. However, these analogs are ineffec-tive when used alone due the emergence of resistance mutations. Newer nucleos(t)ide analogs such astenofovir disoproxil fumarate have demonstrated higher resistance thresholds and effective viral suppres-sion when paired with low-dose HBIG. In this case series, we evaluated the safety and efficacy of switch-ing four patients from low-dose HBIG plus nucleos(t)ide analog therapy for the prevention of HBVrecurrence to a combination tenofovir-emtricitabine regimen. At the end of follow-up, all patientsremained hepatitis B surface antigen negative and had HBV DNA levels of less than 10 IU/ml. Addition-ally, no tenofovir-associated nephrotoxicity was observed among the four patients. Tenofovir-emtricita-bine monotherapy in lieu of HBIG plus nucleos(t)ide analog therapy demonstrated prevention of HBVrecurrence without tenofovir-associated nephrotoxicity after 9 months of follow-up in all four patientsand up to 15 months in one patient.KEY WORDS hepatitis B, liver transplantation, hepatitis B immune globulin, nucleos(t)ide analog, ten-ofovir-emtricitabine, antiviral therapy.(Pharmacotherapy 2013;33(9):e170–e176) doi: 10.1002/phar.1306

Chronic infection with hepatitis B virus(HBV) affects an estimated 400 million peopleworldwide and results in substantial morbidityand mortality across the world.1, 2 An estimated1 million people die annually from thecomplications of HBV, and chronic hepatitis Bcan be a silent disease for decades; however,cirrhosis, hepatocellular carcinoma, and liverfailure can result from infection that goes

untreated.1 Therapeutic options have beenlimited once the disease decompensates, and5-year survival rates decline to well below 20%in these patients.3 At this stage of decompensa-tion, orthotopic liver transplantation (OLT) isoften the only treatment available to save thepatient’s life. In the past, the initial results ofOLT in HBV-infected patients were disappoint-ing, with high rates of allograft reinfection, lead-ing to rapidly progressive liver disease andcirrhosis of the new graft.4, 5 Historically, theoutcomes of hepatitis B surface antigen (HBsAg)-positive patients have been worse than those ofpatients transplanted for other chronic liverdiseases. At highest risk for reinfection are those

*Address for correspondence: Iman E. Bajjoka, HenryFord Transplant Institute (CFP #235), Henry Ford Hospi-tal, 2799 West Grand Boulevard, Detroit, MI 48202; e-mail:ibajjok1@hfhs.org.� 2013 Pharmacotherapy Publications, Inc.

C A S E R E P O R T

with high HBV levels and high HBV replicationrates prior to OLT, and there is a decreasedsurvival rate after transplantation in patientswho are hepatitis B envelope antigen (HBeAg)positive prior to OLT.6, 7 The initial 5-year sur-vival rate for patients undergoing liver trans-plantation for HBV was only 50%.8 Hepatitis Bimmune globulin (HBIG) was the first therapyto have a significant positive impact on thecourse of posttransplantation HBV disease andhas long been used to prevent reinfection.8 Theprotective effect of HBIG is not clear, but it hasbeen attributed to several different mechanismsincluding binding of circulating virions, blockingthe HBV receptor on hepatocytes, and promo-tion of antibody-independent, cell-mediatedcytotoxicity leading to lysis of infected cells.9, 10

In previous studies, recurrent disease wasfrequent at the time HBIG was stopped; thussubsequent protocols used high-dose antibodytherapy for longer or indefinite periods, whichproved to be more efficacious but at a highcost.8, 11 More recently, the use of an oral antiv-iral nucleos(t)ide analog has been combinedwith HBIG to provide highly effective HBVprophylaxis in liver transplant recipients andhas been suggested as the standard of ther-apy.10, 12, 13 Antiviral agents such as lamuvidine(LAM) and adefovir dipivoxil (ADV) have beenused along with HBIG to prevent recurrent HBVin the liver allograft, and it has been shown thatrecurrence of HBV can be prevented in allpatients through the use of a low-dose HBIGregimen combined with an oral antiviral agent.13

Antivirals such as LAM and ADV are ineffectiveas monotherapy to prevent HBV recurrence afterOLT due to the emergence of resistance muta-

tions; however, newer antivirals such as tenofo-vir disoproxil fumarate have higher resistancethresholds, even in patients with LAM- and/orADV-resistant strains.14, 15 A combination prod-uct containing tenofovir and emtricitabine([TDF-FTC] Truvada; Gilead Sciences, Inc.,Foster City, CA) has been approved for use inthe treatment of human immunodeficiency virus(HIV) infection; however, both components haveshown to inhibit HBV replication, even inpatients with strains resistant to other nucleos-(t)ide analogs.16 In this case series, we reportthe findings after 15 months of conversion toTDF-FTC therapy. Prevention of HBV recur-rence without tenofovir-associated nephrotoxi-city after 9 months of follow-up wasdemonstrated in all four patients and up to15 months in one patient.

Case Reports

Clinical Characteristics of Patients at the Timeof Liver Transplantation

Table 1 shows the clinical characteristics ofthe four patients evaluated in this case series atthe time of their liver transplantation. Themean � SD age of the patients was49 � 9.27 years, with 75% of the patients male,50% African-American, and 50% Asian. Half thepatients underwent liver transplantation due toHBV-related liver disease alone, whereas theother half underwent transplantation due to bothHBV and hepatocellular carcinoma. All patientsreceived immunosuppression consisting ofmycophenolate mofetil, tacrolimus, and methyl-prednisolone at the time of transplantation,

Table 1. Clinical Characteristics of the Four Patients at the Time of Orthotopic Liver Transplantation

Characteristic Patient 1 Patient 2 Patient 3 Patient 4

Age at transplantation, yrs 63 47 48 41Race African-American African-American Asian AsianSex Male Male Female MaleReason for orthotopic livertransplantation

HBV infection HBV infection HBV infection andhepatocellularcarcinoma

HBV infectionandhepatocellularcarcinoma

HBsAg status Positive Positive Negative NegativeHBeAg status Negative Positive Negative NegativeHBV DNA level, IU/ml <300 330 <300 <29Antiviral therapy from time oftransplantation to conversionto tenofovir-emtricitabinemonotherapy

Entecavir 0.5 mgq.o.d.,a increasedto 1 mg q.d. onPOD 57

Lamivudine 150 mgq.d. + adefovir 10 mg q.d.;changed to tenofovir300 mg q.d. on POD 61

Entecavir 0.5 mgq.d.; increased to1 mg q.d. onPOD 872

Tenofovir300 mg q.d.

HBV = hepatitis B virus; HBsAg = hepatitis B surface antigen; HBeAg = hepatitis B envelope antigen; POD = postoperative day.aThe dosage was adjusted for renal failure while the patient underwent liver transplantation (the patient was also receiving dialysis).

TENOFOVIR-EMTRICITABINE TO PREVENT HBV RECURRENCE AFTER LIVER TRANSPLANTATION McGonigal et al e171

except for one patient who received cyclosporineinstead of tacrolimus. Details of immunosup-pressant drug regimens for each patient at thetime of transplantation, conversion to TDF-FTCtherapy, and the 12 to 15 months afterconversion are shown in Table 2.

HBIG Use

According to our institutional protocol, all fourpatients received intravenous HBIG 10,000 IUduring the anhepatic phase of the transplant.After this phase, all patients received 10,000 IUdaily for the first 7 days after transplantation,then weekly for the first 2 months after dischargefollowing transplantation. After the initial2 months after discharge, the patients wouldreceive intramuscular administration of HBIG,dosed at 3120 IU (10 ml) if their hepatitis Bsurface antibody (HBsAb) signal-to-noise (S:N)ratio fell below 10. The HBsAb was measuredonce a month, and the goal levels for HBsAb wereless than 150. Following conversion to TDF-FTC,two of the four patients did not require furtherintramuscular HBIG injections within the15 months of follow-up. One patient requiredthree further injections at 1, 3, and 6 monthsfollowing conversion to TDF-FTC. Anotherpatient required one further intramuscular HBIGinjection 1 month after conversion.

Liver Function at the Time of TDF-FTCConversion and at End of Follow-up

The mean � SD time from transplantation tothe conversion of antiviral therapy to TDF-FTC

was 3.5 � 0.8 years (range 2.5–4.2 years). Thefour patients considered in this analysis were allconverted to TDF-FTC therapy with amean � SD alanine aminotransferase (ALT)level of 19.25 � 5.6 units/L at the start of ther-apy. At the end of follow-up, the ALT level was19.75 � 5.4 units/L. Figure 1 shows the trendsin ALT level up to 15 months for each of thefour patients. Patient 1 demonstrated somemarked elevation in liver function tests at12 months after conversion; however, thisresolved at 15 months. Other liver functiontests, including alkaline phosphatase, aspartateaminotransferase (AST), and both total anddirect bilirubin levels, remained stable through-out the evaluation. All patients were HBsAgnegative at the time of TDF-FTC initiation andremained negative up to evaluation at15 months. All patients had HBV DNA levels ofless than 20 IU/ml at the time of starting TDF-FTC therapy, and all had levels of < 10 IU/ml atthe time of assessment at 15 months.

Renal Function at the Time of TDV-FTCConversion and at End of Follow-up

One patient (patient 1) was in renal failureand receiving dialysis during liver transplanta-tion; however, renal function parametersreturned to the desirable ranges. Another patienthad an increase in serum creatinine concentra-tion of 0.34 from baseline (start of TDF-FTCtherapy), and the mean creatinine clearance forall four patients increased from a mean � SD of0.9 � 0.22 to 0.97 � 0.31 mg/dl. Glomerularfiltration rate (GFR) was calculated for each

Table 2. Immunosuppressant Drug Regimens and Levels at the Time of Transplantation, Conversion to Tenofovir-Emtricit-abine Monotherapy, and 12 to 15 Months after Conversion

Time

Immunosuppressant Drug Regimen (Drug Level)

Patient 1 Patient 2 Patient 3 Patient 4

Transplantation MMF 500 mg b.i.d.,CsA 175 mg b.i.d.(203 ng/ml),methylprednisolone10 mg q.d.

MMF 500 mg b.i.d.,tacrolimus 2 mg b.i.d.(8.3 ng/ml),methylprednisolone10 mg q.d.

MMF 500 mg b.i.d.,tacrolimus 2 mg b.i.d.(9.8 ng/ml),methylprednisolone10 mg q.d.

MMF 500 mg b.i.d.,tacrolimus 1 mg b.i.d.(8.9 ng/ml),methylprednisolone10 mg q.d.

Conversion totenofovir-emtricitabine

MMF 250 b.i.d., CsA50 mg b.i.d. (104 ng/ml)

MMF 500 mg b.i.d.,tacrolimus 2 mg everyA.M. and 1 mg every P.M.(5.0 ng/ml)

MMF 250 mg b.i.d.,tacrolimus 3 mg everyA.M. and 2 mg everyP.M. (4.0 ng/ml)

MMF 500 mg b.i.d.,tacrolimus 1 mg everyA.M. and 0.5 mg everyP.M. (6.2 ng/ml)

12–15 mo afterconversion totenofovir-emtricitabine

MMF 250 mg b.i.d.,CsA 50 mg every A.M.and 25 mg every P.M.(114 ng/ml)

MMF 500 mg b.i.d.,tacrolimus 1 mg b.i.d.(3.4 ng/ml)

MMF 250 mg b.i.d.,tacrolimus 3 mg everyA.M. and 2 mg everyP.M. (6.4 ng/ml)

MMF 500 mg b.i.d.,tacrolimus 1 mg everyA.M. and 0.5 mg everyP.M. (4.5 ng/ml)

MMF = mycophenolate mofetil; CsA = cyclosporine.Therapeutic ranges are as follows: CsA 200 to 300 ng/ml and tacrolimus 5.0 to 19.9 ng/ml.

e172 PHARMACOTHERAPY Volume 33, Number 9, 2013

patient by using the modification of diet in renaldisease formula.

Discussion

Practices of administering HBIG vary consid-erably in the United States. Based on a multicen-ter analysis, high-dose intravenous HBIG(10,000 IU/month) was administered in 26% ofOLT programs, low-dose intravenous HBIG(3000 to 6000 IU/month) in 22% of programs,low-dose intramuscular HBIG (1000 to 1500 IU/month) in 40%, and finite-duration HBIG in12% of patients.17 Earlier studies have shownthat high-dose protocols of 10,000 IU intravenousmonthly to maintain anti-HBsAb titers higherthan 500 IU/L prevented recurrence more effec-tively than low-dose protocols.12, 18 However,more recent studies have strongly suggested thatlow-dose HBIG delivered intramuscular (gener-ally 800 to 2000 IU/month with a goal HBsAb of100 IU/L) is not associated with an increasedrisk of HBV recurrence.17 Studies evaluatingthe combination of HBIG and a nucleos(t)ideanalog demonstrated that the combination ofHBIG and LAM as prophylaxis in the transplantsetting was superior in preventing HBV recur-rence than prophylaxis with either treatmentused as monotherapy.6 Most HBIG-LAM combi-nation regimens begin in the pre-OLT setting,with LAM and HBIG added on in the anhepaticphase.6 The optimal duration and dosage ofHBIG in this setting is not well defined and is ofinterest due to the high costs of HBIG and theadditional cost of the nucleos(t)ide analog. Thelength of pre-OLT LAM treatment, and hencethe rate of development of LAM-resistant viralstrains, may play a role in the individual HBIGdosage requirements.4 Additionally, by switching

from the intravenous to intramuscular route ofadministration, HBIG doses and costs could bereduced significantly, with good results.19 In atrial consisting of 29 low-risk patients, it wasreported that HBIG was successfully discontin-ued after 1 month in combination with LAM forprophylaxis after careful monitoring of the HBVDNA level.20 Nonetheless, long-term treatmentor prophylaxis with LAM evolves rapidly resis-tant mutants, and patients with LAM resistanceprior to OLT were at the highest risk for earlyHBV recurrence.6 Treatment with ADV, asmonotherapy and in combination with LAM,was found to benefit both pre- and posttrans-plantation patients with LAM-resistant chronichepatitis B including decompensated cirrhoticpatients in terms of HBV DNA suppression.21

However, the use of ADV also has several draw-backs such as nephrotoxicity in those at risk forrenal dysfunction, less potency toward HBVDNA suppression compared with that of TDF,and an increase in emergence of HBV resistanceto ADV.14 In patients with chronic hepatitis B,TDF has been shown to have potent activityagainst HBV DNA polymerase and acts througha similar mechanism of action to ADV. Morerecently, TDF was shown to be superior to ADVin both HBeAg-negative and -positive patients.22

Additionally, for LAM-resistant HBV, TDF aloneor combined with LAM exerts greater viralreduction than ADV.14, 23 A more recent studyevaluating several of the newer nucleos(t)idetherapies—ADV, TDF, and entecavir—afterHBIG withdrawal found that of 47 patients, 3developed detectable HBsAg. However, allpatients had undetectable HBV DNA levels andhad no clinical manifestations of viral recurrenceat a median of 24 months of follow-up,24 alonger follow-up than that in our case series.FTC, a nucleoside reverse transcriptase

inhibitor, with a mechanism of action similar tothat of LAM, has also been shown to havepotent antiviral activity against HBV, and datahave indicated that FTC has synergistic activitywith TDF in the treatment of HBV.25 Over a2-year trial period, 55% of patients with HBVtaking a daily dose of emtricitabine 200 mg hadHBV DNA4700 copies/ml or less, and 19% sero-converted to anti-HBe.26 In a study evaluatingthe effect of switching to TDF-FTC for chronicHBV treatment after failure to respond to anADV-containing regimen, it was found that theTDF-FTC combination resulted in undetectableHBV DNA levels without any renal toxicity.27

In the post-OLT setting, a study that substituted

0

5

10

15

20

25

30

0 5 10 15 20

ALT

(U

/L)

Months From Conversion to TDF/FTC

Trend in ALT Levels

Patient 1

Patient 2

Patient 3

Patient 4

Figure 1. Trends in alanine aminotransferase (ALT) levelsat 12 to 15 months after conversion to tenofovir-emtricitabine (TDF/FTC).

TENOFOVIR-EMTRICITABINE TO PREVENT HBV RECURRENCE AFTER LIVER TRANSPLANTATION McGonigal et al e173

TDF-FTC for intramuscular HBIG plus LAM in21 patients showed effective prevention of HBVDNA recurrence in all compliant OLT recipi-ents.28 This study evaluated patients whoreceived transplants from 1985 to 2009, com-pared with the present case series that analyzedpatients receiving transplants from 2007 to2009. It is worthwhile to consider the changesin surgical techniques and immunosuppressionand HBV treatment regimens from the 1980s tothe present, highlighting the importance of eval-uating patients who received the more recentliver transplants. In the liver transplant popula-tion, where HBV viral replication is often higherthan in nontransplanted patients leading toselection for resistant mutants, therapy withTDF-FTC may provide an additional safety bar-rier over TDF therapy alone.28 In this case ser-ies, we evaluated the efficacy and safety ofcombination TDF-FTC over a 15-month periodin four patients after liver transplantation, fol-lowing complete discontinuation of low-doseintramuscular HBIG in two patients. Two otherpatients received HBIG following conversion toTDF-FTC according to protocol.In the present case series, our HBIG protocol

prior to TDF-FTC conversion was intramuscularHBIG 3120 IU/month depending on the levels ofHBsAb present. If the S:N ratio fell below 10,then the patient would be scheduled to receivethe HBIG dose. Following the conversion toTDF-FTC, two patients did not demonstrate aneed for further HBIG administration. Accordingto records, the patient who received an addi-tional dose of HBIG 1 month following the con-version to TDF-FTC may have had a severalweek delay in starting TDF-FTC due to initialreimbursement issues. The patient who receivedthree additional doses of HBIG up until6 months after the conversion was the patientwho was both HBsAg and HBeAg positive at thetime of transplantation, both strong indicatorsfor HBV recurrence in patients after liver trans-plantation; however, it is not known at this timewhether these factors affect the benefit of TDF-FTC in this population.26, 28 This patient didnot receive further HBIG doses in the last9 months of this study and will be of interest toacknowledge in later follow-up. Additionally, thetwo patients who did not require further HBIGadministration following conversion to TDF-FTC only received one 3120 IU intramuscularHBIG treatment each from the time of transplan-tation, whereas the two patients who requiredfurther HBIG following conversion had received

five and six 3120 IU intramuscular HBIG treat-ments, respectively, from the time of transplan-tation until conversion to TDF-FTC. All patientsin this cases series received initial high-dose(10,000 IU) HBIG following transplantation andwere evaluated for further intramuscular HBIGtreatments (3120 IU) in the same manner aspatients not converted to TDF-FTC.Based on the pharmacy drug prices available

at our institution and assuming standard dosing,the yearly cost for TDF-FTC (available asTruvada) is approximately $20,400. Generally,the yearly cost of HBIG varies based on thefrequency and route of administration. Currentpractice at our institution involves up tomonthly injections of intramuscular HBIG com-bined with a nucleos(t)ide inhibitor with theleast expensive maintenance regimen consistingof intramuscular HBIG plus LAM, which cancost up to $23,253/year. This would provide acost savings of at least $2853/year based on ourinstitution’s pricing. However, it is important tonote that these do not take into account severalother cost- and compliance-related issues associ-ated with the use of HBIG. According to ourinstitution’s protocols, the first year after trans-plant includes treatment with high-dose HBIGfor 8 weeks following discharge. Thus the costof HBIG plus LAM therapy for the first year fol-lowing transplant can be up to $66,801. Costssuch as additional nucleos(t)ide therapy otherthan LAM, medications to pretreat against infu-sion-related reactions, health care professionals’time to administer HBIG and monitor for reac-tions, and reimbursement-related costs due tothe Food and Drug Administration indication forprevention of HBV infection recurrence follow-ing transplantation belonging to HepaGam B([HBIG] Cangene Corp., Winnipeg, MB, Can-ada) are all important to note. Also, manyinstitutions continue to use high- or low-doseintravenous HBIG after the initial 8 weeks fol-lowing discharge from transplantation, addingfurther to the costs associated with HBIG ther-apy.10 Additionally, compliance in terms ofHBIG administration must be acknowledgedbecause it requires the patient to visit an outpa-tient setting for its administration, and pain anddiscomfort can be associated with the injections.In terms of liver function, the data in our case

series indicate that liver function remainedrelatively preserved. In the one patient whodemonstrated an upward trend in ALT and ASTlevels at 12 months, it was discovered on liverbiopsy that the patient had a biliary obstruction,

e174 PHARMACOTHERAPY Volume 33, Number 9, 2013

which was found to be due to a stricture in asurgical anastomosis requiring stenting. At15 months, this patient’s ALT and AST levelsreturned to baseline. In one patient there was anotable decline in ALT level following conver-sion, and in the remaining two patients, changesin ALT levels were unremarkable. Anotherpatient did not have liver function tests availablefor review at 15 months postconversion; how-ever, a computed tomography scan of the livershowed no significant findings. All patientsremained HBsAg negative and had HBV DNAlevels less than 10 IU/ml at follow-up, indicatingadequate viral suppression.With regard to renal function after up to

15 months of therapy with TDF-FTC, the risk ofTDF-induced renal toxicity appears to be verylow in this cohort of patients. Documented casesof TDF-related nephrotoxicity have been demon-strated in the HIV-positive population receivingTDF therapy.26 These cases of nephrotoxicitygenerally take two forms: one is a modestdecrease in overall renal function associated withFanconi syndrome, and the other is acute renalfailure, which can be potentiated by the use ofother antiretrovirals.26 We did not see these typesof nephrotoxicity demonstrated in this case series.One patient demonstrated an upward trend inserum creatinine concentration and GFR duringthe 15 months of conversion therapy. It wasnoted that in the 24 months prior to convertingto TDF-FTC therapy, this patient’s serumcreatinine levels were consistently higher than thevalues at the time of conversion to TDF-FTC andwere more in agreement with his level at15 months postconversion. It was also importantto acknowledge that the patient who was in renalfailure at the time of transplantation did notexperience any renal impairment during the15 months of TDF-FTC therapy.

Conclusion

Substitution of TDF-FTC for intramuscularHBIG plus nucleos(t)ide therapy demonstratedprevention of recurrence of HBV withoutnephrotoxicity after 9 months of follow-up in allfour patients and up to 15 months in onepatient. Considering cost and compliance issuesrelated to HBIG administration, safety andefficacy of the TDF-FTC regimen, as well as thegoal of less resistance with this regimen, thisstudy suggests the importance of further pro-spective evaluation of TDF-FTC in the post-OLTpopulation.

References

1. Heathcote EJ, Marcellin P, Buti M, Gane E, et al. Three-year efficacy and safety of tenofovir disoproxil fumaratetreatment for chronic hepatitis B. Gastroenterology 2011;140:132–43.

2. Berg T, Marcellin P, Zoulim F, et al. Tenofovir is effectivealone or with emtricitabine in adefovir-treated patients withchronic-hepatitis B virus infection. Gastroenterology2010;139:1207–17.

3. DeJongh FE, Janssen HL, DeMan RA, Hop WC, Schalm SW,van Blankenstein M. Survival and prognostic indicators inhepatitis B surface antigen-positive cirrhosis of the liver. Gas-troenterology 1992;103:1630–5.

4. Eisenbach C, Sauer P, Mehrabi A, Stremmel W, Encke J.Prevention of hepatitis B virus recurrence after liver transplan-tation. Clin Transplant 2006;20:111–6.

5. Shouval D, Samuel D. Hepatitis B immune globulin toprevent hepatitis B virus graft reinfection following livertransplantation: a concise review. Hepatology 2000;32:1189–95.

6. Riediger C, Berberat PO, Sauer P, et al. Prophylaxis and treat-ment of recurrent viral hepatitis after liver transplantation.Nephrol Dial Transplant 2007;22:37–46.

7. Berenguer M, Wright TL. Treatment of recurrence of hepatitisB in transplant patients. J Hepatol 2003;39:190–3.

8. Terrault NA, Vyas G. Hepatitis B immune globulin prepara-tions and use in liver transplantation. Clin Liver Dis2003;3:537–50.

9. Coffin CS, Terrault NA. Management of hepatitis B in livertransplant recipients. J Viral Hepat 2007;14:37–44.

10. Mehrabi A, Esmaeilzadeh M, Fonouni H, et al. The role ofHBIg as hepatitis B reinfection prophylaxis following livertransplantation. Lagenbecks Ach Surg 2012;397:697–710.

11. Muller R, Gubernatis G, Farle M, et al. Liver transplantationin HBs antigen (HBSAg) carriers: prevention of hepatitis Bvirus (HBV) recurrence by passive immunization. J Hepatol1991;13:90–6.

12. Adler R, Safadi R, Caraco Y, et al. Comparison of immunereactivity and pharmacokinetics of two hepatitis B immuneglobulins in patients after liver transplantation. Hepatology1999;29:1299–305.

13. Yilmaz N, Shiffman ML, Stravitz RT, et al. Prophylaxisagainst recurrence of hepatitis B virus after liver transplanta-tion: a retrospective analysis spanning 20 years. Liver Int2008;1:72–8.

14. Hann HW, Chae HB, Dunn SR. Tenofovir (TDF) has strongerantiviral effect than adefovir (ADV) against lamivudine(LAM)-resistant hepatitis B virus (HBV). Hepat Int 2008;2:244–9.

15. Patterson SJ, George J, Strasser SI, et al. Tenofovir disoproxilfumarate rescue therapy following failure of both lamuvidineand adefovir dipivoxil in chronic hepatitis B. Gut 2011;60:247–54.

16. Santos SA, Uriel AJ, Park JS, et al. Effect of switching to ten-ofovir with emtricitabine in patients with chronic hepatitis Bfailing to respond to an adefovir-containing regimen. Eur JGastroenterol Hepatol 2006;18:1247–53.

17. Degertekin B, Han SH, Keefe EB, et al. Impact of virologicbreakthrough and HBIG regimen on hepatitis B recurrenceafter liver transplantation. Am J Transplant 2010;10:1823–33.

18. McGory R, Ishitani M, Oliveira W, et al. Improved outcomesof orthotopic liver transplantation for chronic hepatitis Bcirrhosis with aggressive passive immunization. Transplanta-tion 1996;61:1358–64.

19. Faust D, Rabenau HF, Allwinn R, Caspary WF, Zeuzem S.Cost-effective and safe ambulatory long-term immunoprophy-laxis with intramuscular instead of intravenous hepatitis Bimmunoglobulin to prevent reinfection after orthotopic livertransplantation. Clin Transplant 2003;17:254–8.

20. Buti M, Mas A, Prieto M, et al. A randomized study compar-ing lamivudine monotherapy after a short course of hepatitis B

TENOFOVIR-EMTRICITABINE TO PREVENT HBV RECURRENCE AFTER LIVER TRANSPLANTATION McGonigal et al e175

immune (HBIg) and lamivudine with long-term lamuvidineplus HBIg in the prevention of hepatitis B virus recurrenceafter liver transplantation. J Hepatol 2003;38:811–7.

21. Schiff ER, Lai CL, Hadziyannis S, et al. Adefovir dipivoxiltherapy for lamivudine-resistant hepatitis B in pre-and post-liver transplantation patients. Hepatology 2003;38:1419–27.

22. Marcellin P, Heathcote EJ, Buti M, et al. Tenofovir disoproxilfumarate versus adefovir dipivoxil for chronic hepatitis B. NEngl J Med 2008;359:2442–55.

23. Gish RG, McCashland T. Hepatitis B in liver transplantrecipients. Liver Transpl 2006;12:54–64.

24. Cholongitas E, Vasiliadis T, Antoniadis N, Goulis I, Papani-kolaou V, Akriviadis E. Hepatitis B prophylaxis post-livertransplantation with newer nucelos(t)ide analogues after hepa-titis B immunoglobulin discontinuation. Transplant Infect Dis2012;14:479–87.

25. Lim SG, Ng TM, Kung N, et al. A double-blind placebo-con-trolled study of emtricitabine in chronic hepatitis B. ArchIntern Med 2006;166:49–56.

26. Gish RG, Trinh H, Leung N, et al. Safety and antiviral activityof emtricitabine (FTC) for the treatment of chronic hepatitis Binfection: a two-year study. J Hepatol 2005;43:60–6.

27. Liaw YF, Sheen IS, Lee CM, et al. Tenofovir disoproxilfumarate (TDF), emtricitabine/TDF, and entecavir in patientswith decompensated chronic hepatitis B liver disease. Hepatol-ogy 2011;53:62–72.

28. Stravitz RT, Shiffman ML, Kimmel M, et al. Substitution oftenofovir/emtricitabine for Hepatitis B immune globulinprevents recurrence of Hepatitis B after liver transplantation.Liver Int 2012;32:1138–45.

e176 PHARMACOTHERAPY Volume 33, Number 9, 2013