Hepatitis B virus coinfection in human immunodeficiency virus-infected patients: A review

Table 1 Characteristics of antiviral drugs for chronic hepatitis B in human immunodeficiency virus-infected patients

Characteristics	Interferon alfa-2b1	Pegylated interferon alfa-2a1	Lamivudine	Emtricitabine	Adefovir	Entecavir	Telbivudine	Tenofovir disoproxil fumarate
Antiviral effect	Immune modulation	Immune modulation	Interference of HBV DNA synthesis	Interference of HBV DNA synthesis	Interference of HBV DNA synthesis	Interference of HBV DNA synthesis	Interference of HBV DNA synthesis	Interference of HBV DNA synthesis
HIV-1activity	No	No	Yes	Yes	No, at low dose2	Yes	No7	Yes
Dosage and administration	10 million IU SC or IM 3 times a week	180 mg SC once a week	300 mg/d oral	200 mg/d oral	10 mg/d oral	0.5 mg/d oral5	600 mg/d oral	300 mg/d oral
Defined treatment duration	48 wk	48 wk	Indefinite	Indefinite	Indefinite	Indefinite	Indefinite	Indefinite
Undetectable HBV DNA	-	-	40%-84% at 1 yr	53% at 2 yr	8.6% and 5.7% at 36 wk 36 and 48, respectively8	38% by the end of study (mean follow-up, 74 wk)9	-	Up to 91% at 5 yr
HBeAg seroconversion	0%-20%	0%-20%	22%-35% at 1 yr	14% at 48 wk	9% at 144 wk	-	-	50% of TDF use; 57% of TDF plus FTC use at 5 yr
Tolerability	Poor	Poor	Excellent	Excellent	Good	Excellent	Good	Good
Major adverse events	Leukopenia, depression	Leukopenia, depression	-	-	Nephrotoxicity (3%)	-	-	Nephrotoxicity (1%-3%)
Viral resistance barrier	No	No	Low (50% at 2 yr and 90% at 4 yr)	Intermediate (18% at 2 yr)	High	High	-	High
HBV resistancemutations	No	No	M204I/VL180MA181T/VV173L	M204I/VL180MA181T/V	N236TA181T/V	M204I/V4L180MT184I/A/G/LS202I/GI169T	M204IA181T/V	A194T3A181T/VN236T
Cross-resistance to LAM	No	No	-	Yes	No	No	Yes	No
Interaction with other antiretrovirals	No	No	No	No	No	No	Zidovudine; stavudine6	Didanosine; atazanavir6

¹HBeAg positive subjects with CD4 cell counts of > 350 cells/μL and aminotransferase levels elevated to at least twice the upper limit of normal would probably achieve the greatest benefit from IFN-alfa therapy[70,71];

²While ADV (20 mg/d) does have minimal HIV-1 activity, the development of HIV-1 resistance mutations has not been demonstrated at low dose adefovir (10 mg/d)[72,80];

³TDF mutations have not been clearly associated with decreased anti-HBV efficacy[73];

⁴Presence of several mutations is necessary to decrease efficacy for ETV at a dose of 1 mg/d;

⁵1 mg/d for LAM-resistant HBV infection;

⁶LdT is a thymidine analogue that might interact with zidovudine or stavudine[74]. TDF can interact with didanosine by increasing the concentration of didanosine and impairing immunologic response[75]. It also decreases the concentration of atazanavir sulfate[76];

⁷LdT showed a potent anti-HBV activity in HIV-1-positive, hepatitis B e antigen-positive patients with high HBV viremia in a case report. However, a transient reduction in HIV-1 RNA between 2 and 3 log₁₀ copies/mL after 24 wk of telbivudine therapy was found in 2 of 3 patients although no genotypic resistance mutations to anti-HIV-1 were found[81]. In another study, no significant decline in HIV-1 RNA load or in the selection of genotypic or phenotypic resistance in HIV-1 RT was observed in 2 patients who received LdT treatment[77]. In vitro virologic analyses demonstrated that LdT had no activity against wild-type HIV and drug-resistant variants;

⁸In a prospective randomized, double-blind, placebo-controlled trial of 10 mg/d ADV vs 300 mg/d of TDF in subjects with HBV and HIV coinfection on stable ART, with serum HBV DNA > 100000 copies/mL, and plasma HIV-1 RNA < 10000 copies/mL, the mean time-weighted average change in serum HBV DNA from baseline to week 48 was -4.44log₁₀ copies/mL for TDF and -3.21log₁₀ copies/mL for ADV[78];

⁹In a small cohort of 13 patients with positive HBeAg and detectable HBV DNA who had received > 6 mo of TDF/FTC therapy, add-on ETV to TDF/FTC-experienced patients achieved undetectable HBV DNA load in 38% and normal ALT levels in 8 (62%)[79]. ADV: Adefovir dipivoxil; ETV: Entecavir; FTC: Emtricitabine; HBV: Hepatitis B virus; HBeAg: HBV envelope antigen; IM: Intramuscularly; LAM: Lamivudine; LdT: Telbivudine; SC: Subcutaneously; TDF: Tenofovir disoproxil fumarate.

Table 2 Comparisons regarding the use of anti-hepatitis B virus agents in human immunodeficiency virus-infected patients among the different guidelines

	Agents for HBV treatment only	Agents for HBV/HIV treatment	Timing of cART initiation	Comments
DHHS 2013[82]	ADV, ETV, or LdT	TDF can safely be used: TDF/LAM-containing cART or TDF/FTC-containing cART TDF cannot safely be used: ETV plus LAM-cART, or ETV plus LAM-cART	HBV: NA HIV: prioritized; regardless of CD4 count	CART may attenuate liver disease progression by preserving or restoring immune function and reducing HIV-related immune activation and inflammation
EACS 2013[83]	ADV and LdT	LAM-naïve cART including TDF/LAM or FTC LAM-experienced Add or substitute 1 NRTI with TDF as part of cART HBV treatment indicated Early ART including TDF/FTC or LAM PEF-IFN (if genotype A, high ALT, low HBV DNA)	HBV: HBV DNA > 2000 IU/mL; significant liver fibrosis (F2-F4) even when HBV-DNA is below 2000 IU/mL and liver enzymes are not elevated HIV: CD4 < 500 cells/μL or symptomatic HIV, cirrhosis, or HBV treatment indicated	The optimal treatment duration for nucleos(t)ide analogues with anti-HBV activity has not yet been determined and experts recommend life-long therapy if anti-HBV nucleos(t)ides are given as part of ART In persons with HBV genotype A, high ALT and low HBV DNA, Peg-IFN might be used for a total treatment period of 48 wk. The addition of an NRTI-based anti-HBV regimen has not been proved to increase Peg-IFN efficacy In persons with liver cirrhosis, stopping effective anti-HBV treatment is not recommended in order to avoid liver decompensation due to flares of liver enzymes Anti-HBV therapy may be stopped cautiously in HBeAg-positive persons who have achieved HBe seroconversion for at least 6 mo or after confirmed HBs seroconversion in those who are HBeAg-positive The addition of ETV to TDF in persons with low persistent HB -replication has not been statistically proved to be efficient and should therefore be avoided Caution is warranted when switching from a TDF-based regimen to drugs with a lower genetic barrier, e.g., FTC or LAM, in particular in LAM-pretreated cirrhotic persons as viral breakthrough due to archived YMDD mutations is likely to occur
BHIVA 2013[84]	NA	CD4 count > 500 cells/μL: TDF/FTC-cART Unwilling or unable to receive TDF/FTC: ADV or 48 wk of PEG-IFN plus cART CD4 count < 500 cells/μL: Wild-type HBV: TDF/FTC-cART or TDF/LAM-cART LAM/FTC-resistant HBV or HIV: TDF as the sole anti-HBV active agent TDF is contraindicated: ETV plus cART	HBV: HBV DNA > 2000 IU/mL; more than minimal fibrosis on liver biopsy (Metavir > F2 or Ishak > S2) or indicative of > F2 by TE (FibroScan > 9.0 kPa) regardless of HBV DNA HIV: CD4 < 500 cells/μL or patients requiring HBV therapy	At least 2 baseline HBV DNA measurements 3 to 6 mo apart to guide initiation of therapy 6-mo HBV DNA measurements for routine monitoring of therapy An ALT level below the upper limit of normal (30 IU/L for men; 19 IU/L for women) should not be used to exclude fibrosis or as a reason to defer HBV therapy

ADV: Adefovir dipivoxil; ALT: Alanine aminotransferase; cART: Combination antiretroviral therapy; ETV: Entacavir; FTC: Emtricitabine; HBV: Hepatitis B virus; LAM: Lamivudine; LdT: Telbivudine; NA: Not available; Peg-IFN: Pegylated interferon; TDF: Tenofovir disoproxil fumarate; TE: Transient elastography.

Table 3 Hepatitis B vaccine in adults with human immunodeficiency virus: Standard and alternative strategies

Ref.	Year	Study design	n	Dose (μg)	Schedules/ administration	Age, median, yr	CART	HIV-1 VL, RNA copies/mL < 10000	CD4, median, cells/μL	Response rate	Predictors
Standard-dose vaccination
Rey et al[141]	2000	Prospective	20	3 × 20	0, 1, 2 mo, IM	30.5	85%	NA	470	55%	CD4 > 500 cells/μL
Tedaldi et al[143]	2004	Retrospective, cross-sectional	198	52.5% ≥ 3 × 20	NA	41	70.7%	> 75%	406	37.2%	Higher CD4; HIV-1 VL < level of detection
Overton et al[142]	2005	Retrospective	194	3 × 10 (97%-99%)	0, 1 to 3, 6-9 mo, IM	34.1	82.0%	38.1% (< 400)	290	17.5%	HIV-1 VL < level of detection
Ungulkraiwit et al[148]	2007	Prospective	65	3 × 20	0, 1, 6 mo, IM	39	88%	> 75%	345	46%	Higher CD4; young age
Paitoonpong et al[137]	2008	Prospective	28	3 × 20	0, 1, 6 mo, IM	35	100%	100% (< 50)	324	71.4%	Higher CD4; use of efavirenz
Kim et al[144]	2008	Retrospective	97	3 × 20	0, 1, 6 mo, IM	39	31%	24% (< 400)	325	44%	Nadir CD4 > 200 cells/μL; young age ( < 40 yr); HIV-1 VL < level of detection
Irungu et al[139]	2013	Prospective	293	3 × 20	0, 1 to 3, 6 mo, IM	31	HIV-1 uninfected			85.7%	CD4 > 500 cells/μL; female
			310				0%	65.7%	557	64.2%
Alternative strategies
Fonseca et al[140]	2005	RCT	94	3 × 20	0, 1, 6 mo, IM	37	85.1%	80.9%	≥ 350, 59.6%	34%	CD4 > 350 cells/μL; HIV-1 VL < 10000 copies/mL
			98	3 × 40			87.8%	75.5%	≥ 350, 57.1%	47% (P = 0.07)
Cornejo-Juárez et al[147]	2006	RCT	39	3 × 10	0, 1, 6 mo, IM	35.6	56.4%	≤ 20000, 56.6%	≥ 200, 48.8%	61.5%	CD4 ≥ 200 cells/μL
			40	3 × 40		34.1	72.5%	≤ 20000, 55.6%	≥ 350, 47.5%	60% (P = 0.89)
Potsch et al[145]	2010	Prospective	47	3 × 40	0, 1, 2, 6 mo, IM	36	79%	< 80, 70%	402	89%	HIV-1 VL < 80 copies/mL
Launay et al[146]	2011	RCT	145	3 × 20	0, 1, 6 mo, IM	43	86%	< 50, 79%	516	65% (95%CI: 56-72)	Young age; four-dose
			148	4 × 40	0, 1, 2, 6 mo, IM	42	80%	< 50, 77%	509	82% (95%CI: 77-88)
			144	4 × 4	0, 1, 2, 6 mo, ID	43	86%	< 50, 78%	482	77% (95%CI: 56-72)

ID: Intradermal injections; IM Intramuscular injections; RCT: Randomized clinical trial; VL: Viral load; cART: Combination antiretroviral therapy.