Chronic Hepatitis B Infection Among Preexposure Prophylaxis Users Enrolled in a Population-Based Program in British Columbia, Canada

Abstract

Initiation of human immunodeficiency virus preexposure prophylaxis (PrEP) medications will also treat hepatitis B infection (HBV). The prevalence of chronic HBV was 0.86% (n=41/4760) among enrollees in a provincial PrEP program in British Columbia, Canada. Overall, 46.3% lacked follow-up HBV DNA monitoring, underscoring the need for HBV-related education for PrEP prescribers.

Emtricitabine (FTC)/tenofovir disoproxil fumarate (TDF)–based preexposure prophylaxis (PrEP) is now recommended as standard of care for prevention in individuals at high risk for human immunodeficiency virus (HIV) infection [1–3]. Determination of hepatitis B virus (HBV) status for individuals initiating PrEP is essential as both FTC and TDF have HBV antiviral activity. As such, current clinical PrEP guidelines recommend baseline evaluation of HBV status [2, 3]. In individuals living with chronic HBV, both evaluation of baseline fibrosis stage to determine need for therapy and on-treatment monitoring for response are recommended [4]. Abrupt cessation of therapy may lead to risk for hepatitis flare, further necessitating expert management [5, 6]. There is limited clinical experience with the use of PrEP in those living with chronic HBV as this was an exclusion criterion for most of the original PrEP clinical trials [7, 8]. The iPrEx study included individuals living with HBV, but only 6/2499 (0.25%) received FTC/TDF [1, 9]. Given the relative paucity of clinical data, we sought to characterize baseline HBV status and monitoring among individuals receiving PrEP through a province-wide program in British Columbia (BC), Canada.

METHODS

The BC PrEP Program

The BC Centre for Excellence (BC-CfE) in HIV/AIDS offers a publicly-funded HIV PrEP program to all residents of BC deemed clinically at high risk for HIV infection according to provincial PrEP guidelines [10]. This program was launched in January 2018 to complement the existing HIV Treatment as Prevention Strategy (TasP) and provides FTC/TDF to eligible residents. Tenofovir alafenamide is not routinely covered in the provincial PrEP program. Eligibility criteria include an HIV Incidence Risk Index for Men Who Have Sex With Men (HIRI-MSM) score ≥10, condomless anal sex and prior history of infectious syphilis or rectal bacterial sexually transmitted infection (STI), recurrent use of HIV postexposure prophylaxis, or an ongoing sexual/injection drug use relationship with an HIV-positive partner who is not receiving stable and effective antiretroviral therapy (ART).

Study Population

The study population was made up of individuals enrolled in the BC-CfE HIV PrEP program from January 2018 to June 2019 and followed until 31 August 2019. To access PrEP, health care providers were required to document HBV status (HBV surface antigen [HBsAg] status as positive or negative) during the enrollment process. The BC-CfE PrEP program has ongoing linkage with data obtained from the St Paul’s Hospital/Providence Health Care laboratory interface in Vancouver, BC. Of note, the St Paul’s Virology Laboratory performs all HBV DNA monitoring for the province.

We evaluated the prevalence of HBV defined based on physician report as indicated on a PrEP Enrollment and Prescription Request Form or documented baseline HBsAg in the St Paul’s Virology Laboratory system. Individuals with an isolated HBV core antibody were therefore not included. Baseline was defined as any available result 6 months prior to 3 months following PrEP initiation. We compared baseline demographic characteristics including median age, gender, PrEP-qualifying risk factors, and urban vs rural location (based on 3-digit postal code) between those with and those without HBV, using χ², Fisher exact, or Kruskal-Wallis tests. We assessed the proportion of HBV-positive individuals who underwent evaluation of HBV DNA status at baseline and at any time over the follow-up period, as a measure for engagement in HBV care.

Patient Consent Statement

Analyses from the BC-CfE Drug Treatment Program are approved under the University of British Columbia–Providence Healthcare Research Ethics Board (H05-50123).

RESULTS

The study population included 4760 individuals with a median age of 33 years (25th–75th percentile [Q1–Q3], 27–43 years) and consisted of 4680 (98.3%) males, 24 (0.5%) females, 53 (1.1%) transgender people, and 3 (0.06%) of unknown gender. There were 4686 (98.4%) individuals identifying as MSM, and 285 (5.9%) were reported as having a known HIV-positive partner not on stable or effective ART. Of 4310 (90%) PrEP recipients with a reported HIRI-MSM score, the median score was 19 (Q1–Q3, 15–24), and 955 (20.0%) were reported as having a prior bacterial rectal STI or syphilis infection. Most individuals (4559 [95.7%]) were from an urban area. Only 298 (6.2%) individuals were formally prescribed PrEP for use on an intermittent/on-demand basis, while 4462 (93.7%) were prescribed PrEP for daily use.

Hepatitis B Status

There were 19 laboratory-confirmed HBV cases among 1845 individuals in the overall cohort where laboratory results were available. Among the remaining 2915 individuals with missing laboratory data, an additional 22 physician-reported HBV infections were identified, for an overall HBV prevalence of 0.86% (n=41/4760). There were an additional 4 individuals reported to have HBV who were documented to be HBsAg-negative; these individuals were not considered to have HBV for this analysis.

The median baseline alanine aminotransferase (ALT) level for those with HBV was 44 IU/mL (Q1–Q3, 27–66 IU/mL); 17.0% had ALT greater than the upper limit of normal, compared with 4.5% for those without HBV (P=.005). Of the 19 individuals with confirmed HBsAg-positive status, only 8 (42.1%) were tested for HBV e antigen (n=2/8 [25%] positive), and 13 (68.4%) were tested for HBV e antibody (n=11/13 [84.6%] positive).

Of the 41 individuals who were recorded as being HBV-positive, 29 (70.7%) had at least 1 HBV DNA measurement, with 27 (65.8%) having a baseline HBV DNA measurement. Repeat HBV DNA measurements occurred in 22 (53.7%) individuals, with 95% (n=21/22) achieving viral suppression (<25 IU/mL) over the study period.

When comparing PrEP participants with chronic HBV infection and those without, in our bivariate analysis we found very few differences. The only statistically significant difference was in the prevalence of reported prior bacterial rectal STI or syphilis, which was lower in HBV-positive individuals (7.3% vs 20.1%; P=.048). There were no statistically significant differences in median age, gender, urban vs rural location, HIRI-MSM score, or other PrEP-qualifying criteria (Table 1).

Table 1.

Bivariate Analysis of Factors Associated With Chronic Hepatitis B Infection at Time of Enrollment in the British Columbia Human Immunodeficiency Virus Preexposure Prophylaxis Program

Characteristic	Reported/Laboratory-Confirmed Hepatitis B Status			Laboratory-Confirmed Hepatitis B Status
	HBV Positive (n=41)	HBV-Negative (n=4719)	P Value	HBV-Positive (n=19)	HBV-Negative (n=1826)	P Value
Age, y, median (Q1–Q3)	39 (29–47)	33 (27–43)	.112	37 (29–44)	31 (26–39)	.138
Gender, male	40 (97.5)	4654 (98.6)	.422	18 (94.7)	1810 (99.1)	.144
MSM	41 (100)	4645 (98.4)	.999	19 (100)	1800 (98.5)	.999
Urban address at time of enrollment	40 (97.5)	4519 (95.7)	.999	18 (94.7)	1745 (95.5)	.999
HIRI-MSM Risk Index, median (Q1–Q3)	18 (14–20)	19 (15–24)	.080	16.5 (13.5–23)	19 (15–25)	.165
HIRI-MSM Risk Index >25	3 (7.3)	758 (16.0)	.330	2 (10.5)	328 (17.9)	.751
History of prior STI	3 (7.3)	952 (20.1)	.048	1 (5.2)	361 (19.7)	.286
PrEP use due to HIV-positive partner	1 (2.4)	284 (6.0)	.514	0	105 (5.7)	.626
Intermittent/on-demand PrEP prescription	1 (2.4)	297 (6.2)	.516	1 (5.2)	130 (7.1)	.999

Data are presented as No. (%) unless otherwise indicated. Factors were compared using χ², Fisher exact, or Kruskal-Wallis test.

Abbreviations: HBV, hepatitis B virus; HIRI,HIV Incidence Risk Index; HIV, human immunodeficiency virus; MSM,men who have sex with men; PrEP, preexposure prophylaxis; Q1, first quartile; Q3, third quartile; STI,sexually transmitted infection.

Throughout the study period, 1 (2.4%) individual among the 41 with HBV was formally prescribed intermittent PrEP, which is considered inadequate in the context of chronic HBV infection. One (2.4%) individual experienced a gap in PrEP prescription supply >6 months compared with 132 (2.8%) among the 4719 without HBV (P=.999).

DISCUSSION

To our knowledge, this is the largest clinical experience of PrEP use in individuals with chronic HBV. In our study of >4000 individuals accessing PrEP in BC, the prevalence of chronic HBV infection was just below 1%. The prevalence of chronic HBV in our study is consistent with other reports in general populations of MSM in Scotland and in Seattle, Washington [11, 12].

For these individuals, FTC/TDF would constitute effective treatment for their HBV infection. In our study, 29.3% of those with HBV did not have any measured HBV DNA and 46.3% had only 1 baseline value, indicating an important gap in their HBV care. Four individuals were incorrectly reported by their provider as being HBsAg-negative, and 1 individual was incorrectly prescribed intermittent PrEP. These data suggest that prescribers may not be fully aware of what constitutes appropriate assessment and management of individuals living with HBV in the setting of PrEP.

HBV management in the context of PrEP use requires maximizing the benefits of HIV risk reduction and minimizing any inadvertent risks for HBV care. For some individuals, HBV therapy may therefore be initiated when not clinically indicated. In other clinical circumstances, baseline fibrosis state and DNA level would drive decisions regarding treatment initiation for HBV [4]. After treatment initiation, HBV DNA level monitoring is recommended every 3 months until DNA is undetectable, then every 3–6 months thereafter, and this should be integrated into PrEP follow-up in this context [4]. In general, long-term, if not lifetime, therapy is recommended for the management of chronic active HBV. Those with baseline liver disease would therefore require ongoing forms of HBV therapy if PrEP were to be discontinued to minimize the risk of posttherapy HBV flare, particularly in those with cirrhosis [5, 6]. Flares after antiviral therapy discontinuation have been reported to be as high as 39% in the setting of cirrhosis [6]. The phenomenon of HBV viral rebound is well described in the context of discontinuation of lamivudine or TDF during HIV therapy, occurring in 31%–33% of coinfected individuals [5].

Data on HBV in the context of PrEP are limited. In the iPrEx study, which included individuals with HBV, those with underlying cirrhosis or presence of treatment indications for HBV were excluded [1, 9]. As expected, among the 6 individuals with minimally active HBV randomized to FTC/TDF, evidence of HBV DNA decrease on therapy was documented [9]. After PrEP discontinuation, 1 of 5 participants had low-grade liver enzyme elevation, but this reassuring finding may underestimate the risk of flare if PrEP use were to be discontinued in individuals with more severe liver disease.

Limitations to our study include incomplete laboratory data for HBsAg. Physician report of HBV prevalence at enrollment may also have led to underreporting of HBV cases. We also had incomplete capture of other liver-related laboratory data, which precluded our ability to calculate fibrosis stage for those with HBV. Furthermore, we lack data regarding HBV therapy prior to initiation of PrEP; however, 25 of 27 individuals (92.6%) had detectable HBV DNA at baseline, suggesting that a majority were untreated. Finally, our study lacks data on postdiscontinuation monitoring as only 1 individual with HBV discontinued PrEP during the study period with no ALT measurements during follow-up.

In conclusion, our data underscore the need for proper HBV assessment in individuals initiating and undergoing long-term PrEP. Enhanced PrEP provider education with regard to HBV monitoring, as recommended in both HBV and PrEP clinical guidelines, may help close this gap in clinical care. Long-term HBV outcome data in those who interrupt PrEP is still required.

Notes

Potential conflicts of interest. M. W. H. has received honoraria for advisory boards and speaking engagements from Gilead Sciences and Merck, and has received research funding for an investigator-initiated study from Gilead. J. S. G. M.’s Treatment as Prevention research, paid to his institution, has received support from the BC Ministry of Health, Health Canada, Public Health Agency of Canada, Vancouver Coastal Health, and VGH Foundation. Institutional grants have been provided by Gilead and Merck. All other authors report no potential conflicts of interest.

All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.