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HIV-hepatitis B virus coinfection

epidemiology, pathogenesis, and treatment

Singh, Kasha P.a,b,c; Crane, Megana; Audsley, Jennifera; Avihingsanon, Anchaleed; Sasadeusz, Joea,b,c; Lewin, Sharon R.a,c

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doi: 10.1097/QAD.0000000000001574
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Combination antiretroviral therapy (ART) has dramatically reduced HIV-related mortality and morbidity and increased life expectancy among those living with HIV. In the setting of coinfection with hepatitis B virus (HBV), the availability of ART, with activity against both HIV and HBV, particularly tenofovir, has led to significant improvements in outcomes. However, even with effective suppression of both HIV and HBV replication, morbidity and mortality are significantly higher in those with HIV–HBV coinfection than with HIV alone [1–7] (Table 1). End-stage liver disease, cirrhosis, and hepatocellular carcinoma (HCC) account for an increasing proportion of deaths among HIV-infected individuals [13–15]. One of the main challenges in the management of both HIV and HBV is that antiviral treatment must be continued lifelong as both viruses have long-lived forms that persist on antiviral therapy. Research to find a cure for both HIV and HBV is being actively pursued and will have significant implications for coinfected individuals. In this review, we will focus on the major issues related to pathogenesis and management of HIV–HBV coinfection in the setting of optimal treatment with tenofovir-based ART.

Table 1
Table 1:
Impact of HIV–HBV coinfection in the era of HBV-active ART containing TDF.


Approximately, 37 million people are infected with HIV globally and 5–20% are also coinfected with HBV [16]. Rates of chronic HBV in HIV-infected individuals vary significantly between regions and risk-based groups, reflecting different patterns of transmission (Fig. 1) [5,18–85]. For example, in Vietnam, the prevalence of chronic HBV in HIV-infected individuals who inject drugs or who are sex workers, is 28 and 15%, respectively [56]. The prevalence of HIV–HBV coinfection overall in China has been estimated at 10% but varies between regions from 5 to 15% [31]. Accurate data are still lacking for coinfection in many parts of the world; however, rates appear to be highest in parts of West and South Africa (Fig. 1).

Fig. 1
Fig. 1:
Prevalence of chronic hepatitis B among HIV-infected individuals.Prevalence rates reported in the last 5 years from studies that included a minimum of 100 HIV-infected individuals are shown in graduated colours [5,18–85]. Many regions have not formally evaluated prevalence and these regions are represented in grey. Created using EMMa ECDC map maker. Adapted with permission [17].

The hepatitis B virus life cycle and effects of antiviral therapy

HBV replicates in hepatocytes [86–89]. Following entry and uncoating, the HBV genome-containing nucleocapsid is transported into the nucleus where the genome is released as relaxed circular DNA. In the nucleus, the relaxed circular DNA is converted by host cell repair mechanisms into an episomal covalently closed circular (ccc) DNA minichromosome. cccDNA is very stable, persisting indefinitely, and is the main barrier to cure [89].

cccDNA is the template for all HBV RNA transcripts, leading to the production of DNA polymerase; the structural HBV ‘core’ antigen (HBcAg); hepatitis B ‘e’ antigen (HBeAg) (a secreted, soluble form of the core protein); the multifunctional X protein, involved in control of cccDNA transcriptional activity, and the envelope or surface protein hepatitis B surface antigen (HBsAg).

The polymerase encodes the large pregenomic RNA (pgRNA) which is the RNA template for HBcAg and the polymerase protein. The polymerase and pgRNA is copackaged into nucleocapsids with assembly of core protein subunits, triggering reverse transcription of the pgRNA to form HBV-relaxed circular DNA. This is then enveloped with HBsAg and released from the cell as a mature infectious virion, or alternatively is ‘recycled’ to the nucleus to replenish/amplify cccDNA.

Reverse transcription of pgRNA can also lead to the formation of double stranded linear HBV DNA, which can become integrated into the host genome, similar to HIV.

Two classes of antiviral medications are approved for the treatment of hepatitis B. Pegylated interferon (IFN)-α is infrequently used because of side-effects and low rates of treatment success. Nucleos(t)ide reverse transcriptase inhibitors (NRTIs) inhibit reverse transcription and, therefore, inhibit HBV DNA production (Fig. 1), but do not eradicate cccDNA from infected cells, meaning that ongoing treatment is required to suppress viremia (Fig. 2). Furthermore, as HBsAg is produced from separate RNA transcripts to pgRNA, production continues in the presence of HBV-active NRTIs [89,90] (Fig. 2). An HBV cure has been described as ‘functional’ (HBsAg loss with undetectable serum DNA, allowing treatment cessation without rebound) or complete (physical elimination of cccDNA) [91–93].

Fig. 2
Fig. 2:
HBV replication.HBV enters the hepatocyte upon binding to the putative sodium taurocholate cotransporting polypeptide (NTCP) receptor. Following entry and uncoating, rcDNA and then cccDNA minichromosome is formed. cccDNA is then transcribed into pgRNA and ultimately HBV DNA (following reverse transcription) which can be blocked by NRTIs. HBsAg is transcribed from separate RNA transcripts coded for by the pre-S1 and pre-S2/S regions of the HBV genome, and is produced even in the presence of NRTIs. is transcribed from separate RNA transcripts coded for by the pre-S1 and pre-S2/S regions of the HBV genome, and is produced even in the presence of NRTIs. HBV can also become integrated into the host genome and produce HBsAg. cccDNA, covalently closed circular; HBsAg, hepatitis B surface antigen; HBV, hepatitis B; NRTI, nucleos(t)ide reverse transcriptase inhibitors; pgRNA, pregenomic RNA; rcDNA, relaxed circular DNA.

Natural history of HIV–hepatitis B virus coinfection in the era of hepatitis B virus-active antiretroviral therapy

Liver disease progression

Early studies of the natural history of HIV–HBV coinfection demonstrated that liver-related mortality in this population was 19 times that in HBV infection without HBV, and eight times higher than in individuals with HIV monoinfection. Mortality rates increased in individuals with lower CD4+ T-cell counts [94]. The NRTIs lamivudine (LMV), emtricitabine (FTC), and tenofovir disoproxil fumurate (TDF) and tenofovir alafenamide (TAF) all have dual activity against both HIV and HBV, with TDF and TAF a pivotal therapeutic agent in this setting because of a very high barrier to HBV drug resistance. The inclusion of tenofovir for management of HBV has led to significant improvements in HBV viral control and liver fibrosis and decreased HBV drug resistance [69,95–98]. However, recent studies continue to report that overall mortality, liver-related mortality, and hospital-utilization rates, and risk of HCC remain elevated in HIV–HBV coinfected individuals compared with HIV mono or HBV monoinfected individuals [2,3,5,6,13,74,99–103]. Furthermore, liver disease progression continues to occur in 10–20% of individuals on tenofovir-containing HBV-active ART [5,12,104] (summarized in Table 1).

Virological suppression

The vast majority of HBV-infected individuals treated with TDF have undetectable HBV DNA (lower limit of detection <20 IU/ml). In a large prospective multicentre international cohort of HIV–HBV coinfected individuals, we recently demonstrated that detectable HBV DNA persisted in close to 10% of coinfected individuals on TDF [96]. We observed several patterns of detectable HBV DNA. Interestingly, we and others have been unable to identify any signature drug-resistant mutations in the HBV polymerase even when TDF had been administered for over 5 years and in the presence of detectable HBV viremia [105–108]. Furthermore, using deep sequencing of virus in plasma, we recently demonstrated that residual viremia on HBV-active ART was associated with evolution of virus sequences over time consistent with active viral replication rather than passive release from long-lived reservoirs such as cccDNA [105]. Improved tools to measure low-level viremia and deep sequencing are needed to better understand the clinical implications of residual HBV viremia in HIV–HBV coinfection.

HBsAg and HBeAg seroconversion

The formation of stable episomal cccDNA and integrated HBV DNA to a lesser extent, leads to sustained production of HBsAg even on NRTI [89,90]. HBsAg is produced in large quantities in HBV infection and is generally considered to inhibit adaptive immunity and effective production of anti-HBV surface antibodies, which is required for long-term HBV control [109]. Persistent high levels of HBsAg have been associated with elevated risk of HCC in untreated HBV monoinfection [110,111]. Following antiviral treatment of HBV monoinfection, HBsAg loss is uncommon, and after 12-months treatment with NRTI or pegylated IFN, HBsAg loss occurs in of 0–3 and 3–7% of individuals, respectively [112].

Various studies have shown rates of HBsAg loss and/or seroconversion might be higher in coinfection compared with monoinfection. In studies of HIV–HBV coinfection up to 22% of participants lost HBsAg, depending on duration of follow-up [42,113–121]. A higher frequency of HBsAg loss has been associated with lower CD4+ T-cell count prior to initiation of HBV-active ART [117,118,120] and a greater increase in CD4+ T cells following ART [118,121] but many of these studies were retrospective or did not include individuals with low CD4+ T cells prior to ART. The relationship between low CD4+ T-cell count and enhanced HBsAg loss and seroconversion may potentially be secondary to brisk immune reconstitution that has been associated with high levels of interleukin 18 production which could enhance dendritic cell function, adaptive immunity, and antibody production [122].

HBsAg loss following treatment of HIV–HBV coinfection has also been associated with low-HBsAg levels at baseline or with a larger decline posttreatment [113,117,119,120,123] although this has largely been described in HBeAg-positive disease [117,119] and paradoxically associated with higher baseline HBV DNA [117,118]. In HIV–HBV HBeAg-negative disease, pretreatment HBsAg level of ≤100 IU/ mm3 was predictive of HBsAg loss. Other studies report no statistically significant associations between HBsAg titre and HBsAg seroconversion [116]. Understanding predictors of HBsAg loss is an important research priority in identifying novel strategies to achieve HBV remission and HIV–HBV coinfected individuals may represent a unique group to interrogate these associations.

HBeAg is a secreted protein that contributes to immune tolerance and viral persistence [87]. HBeAg has been shown to attenuate T-cell responses to the intracellular nucleocapsid protein, with which it shares T-cell epitopes, precluding elimination of HBV-infected cells by T-cell-mediated pathways [124].

Production of anti-HBe antibodies are considered to be indicative of virological control and precede the production of antibodies to HBsAg in the setting of acute cleared infection [86]. Mutations in the precore region that occur over time in chronic untreated HBV infection lead to viral mutants that do not produce HBeAg, and, therefore, HBeAg-negative disease, which is associated with periods of high viral replication and necroinflammatory activity in the liver [86]).

Following treatment of HIV–HBV coinfection with NRTIs, rates of HBeAg seroconversion range from 15 to 57% [114,115,117,119–121,125]. Lower baseline quantitative HBeAg level and a larger decline in quantitative HBeAg levels have been associated with increased HBeAg seroconversion [113,117,125]. Quantitative hepatitis B surface antigen (qHBsAg) level at baseline has been found to predict HBeAg seroconversion in HIV–HBV[96,113]. Studies are needed to further investigate the relationship between HBeAg seroconversion and HBsAg loss/seroconversion in HIV–HBV.

Hepatocellular carcinoma

There is an approximately five to six-fold risk increase in HCC incidence among HIV-infected individuals compared with the general population and this increased risk has persisted with ART [99,126,127].

HCC among individuals with HIV infection has been associated with lower CD4+ T-cell counts, and high-HBV DNA [128,129], however, the increased risk of HCC in coinfection in the era of TDF containing HBV-active ART suggests that other factors are also important. In patients with HBV monoinfection, HBV DNA suppression with NRTI has been demonstrated to lower, but not eliminate, the risk of HCC [130,131]. Similar large, long-term natural history studies of HCC risk in HIV–HBV coinfection are still needed.

HIV is not sufficient to cause HCC in itself, and the exact role of HIV in promoting HCC is not well understood [128]. A significant component of the increased risk of HCC is attributable to the increased prevalence of viral hepatitis among HIV-infected populations. The main predisposing factor for the development of HCC is the presence of cirrhosis, development of which is accelerated in the presence of HIV as discussed above. Other cofactors that may drive HCC among HIV-infected individuals include a higher prevalence of other known risk factors, including alcohol, and nonalcoholic steatohepatitis [132]. In HBV infection, HCC may also arise in the absence of cirrhosis, which may be related to intracellular persistent forms including integrated DNA. It is not known whether there is an increased risk in HCC in HIV–HBV in the absence of cirrhosis.

There is increasing evidence that certain mutations in the HBV viral genome are associated with a significantly increased risk of progression to HCC in individuals with HBV monoinfection. The double mutation T1762/A1764 in the HBV basal core promotor in HBV genotypes B and C, may be detected in plasma up to 8 years prior to HCC diagnosis and is a risk factor for developing HCC [133]. This same double mutation T1762/A1764 was found more commonly among those with HIV–HBV in some studies [134] but not others [135–137].

Deletions in the pre-S region of the HBV genome have also been significantly associated with increased risk of HCC in prospective studies of HBV monoinfected individuals [138], and were found to be more common in HIV–HBV coinfected individuals [134,136]. Mutations in the HBsAg can lead to accumulation of HBsAg in hepatocytes and consequent cytotoxicity of the endoplasmic reticulum, the generation of reaction oxygen species, DNA damage, and genomic instability [139]. Further long-term follow-up of HIV–HBV coinfected individuals with specific mutations in HBV is still needed to fully understand the risk for increased progression to HCC.

Drug resistance

TDF has been demonstrated in a wide range of studies to retain anti-HBV activity in individuals who have failed LMV [116,140,141]. In a recent study from India of TDF treatment in HBV monoinfected individuals with long durations of preceding LMV exposure, 40% of individuals had treatment failure [142]. A longer time to viral suppression in individuals with preceding LMV exposure has been demonstrated in other studies, in contrast to the antiviral response seen in treatment-naïve individuals [143].

The persistence of detectable HBV DNA in plasma in HIV–HBV coinfected individuals taking tenofovir has been investigated by a number of groups. In most cases, TDF-associated mutations have not been detected and adverse clinical outcomes have not been observed, with most individuals achieving an undetectable DNA with time [106,107,102]. Previous exposure to LMV as well as higher HBV DNA have been associated with a longer time to an undetectable HBV DNA on TDF [107]. The HBV polymerase mutations rtA282T/V and/or NS236T were reported as being associated with reduced potency of TDF [144], but this was not confirmed in subsequent studies [96,107] or in cases of virological failure, which is more commonly related to poor adherence [96].

Immune reconstitution disease

Immune reconstitution disease (IRD) or immune reconstitution inflammatory syndrome is defined as worsening symptoms related to an opportunistic infection or malignancy in an HIV-infected individual following initiation of ART [145]. In HIV–HBV coinfection, IRD is defined as a hepatic flare or a significant increase in hepatic transaminases following initiation of ART. We previously showed that, in a cohort of HIV–HBV coinfected individuals initiating ART with advanced disease (median CD4+ T-cell count being 50 cells/μl) in Bangkok, Thailand, 22% had a hepatic flare consistent with IRD. Our study confirmed the findings of others that a high pathogen load (as measured by HBV DNA prior to ART), high baseline alanine transaminase and a low CD4+ T-cell count were the biggest risk factors for developing HBV-related IRD [146,147]. The immunological drivers of IRD are still unknown although may potentially be secondary to persistent elevation of the IFN-stimulated gene chemokine (C-X-C motif) ligand (CXCL) 10 leading to enhance T-cell recruitment to the liver following ART initiation [147,148]. (Summarized in Fig. 2).

The occurrence of hepatic flares has been linked to seroconversion in hepatitis B monoinfection. In HIV–HBV coinfection, IRD may be reflecting a similar process and this may be the basis for the increased levels of HBsAg loss and seroconversion seen in HIV–HBV coinfecion. In three HIV–HBV-infected individuals with hepatic flare following commencement of TDF-containing ART, a significant decline in qHBsAg levels was observed [148].


The mechanism of how HIV infection accelerates the progression of HBV-related liver disease, particularly in the presence of HBV-active ART, is multifactorial. Potential factors include the direct interaction of HIV and HBV in target cells such as the hepatocyte, direct infection by HIV of multiple cells in the liver, increased microbial translocation, and elevated lipopolysaccharide (LPS) in the portal and systemic circulations activating Kupffer cell and hepatic stellate cell (HSC) activation, and exhaustion of HBV-specific T cells (Fig. 3).

Fig. 3
Fig. 3:
Effects of HIV and HBV on the liver and circulating HBV-specific immune cells.1. HIV has been shown to directly infect hepatocytes, hepatic stellate cells (HSC) or Kupffer cells, whereas 2. HBV only infects hepatocytes. 3. HIV can also significantly impair the integrity of the gastrointestinal tract leading to elevated levels of LPS. LPS can directly activate Kupffer cells and HSC leading to increased intrahepatic inflammation and fibrosis. 4. In HBV infection, liver disease can also be mediated by migration from the blood to the liver of HBV-specific and non-HBV specific T cells, chemokine (C-X-C motif) receptor (CXCR) 6 and NK cells [by chemokine (C-X-C motif) ligand (CXCL)10 and CXCL16, respectively] and monocytes [by C-C motif ligand (CCL) 2]. Adapted with permission [149]. HBV, hepatitis B; IFN-γ, interferon γ; LPS, lipopolysaccharide; NK, natural killer.

HIV replication in the liver

A number of studies, have shown various cell types in the liver are permissive to HIV infection in vitro including HSC [150], Kupffer cells [151,152], and hepatocytes [153,154]. HIV infection of these cells has also been demonstrated in vivo in individuals naïve to ART [155,156] and HIV sequences from the liver in individuals of ART have distinct compartmentalized sequences when compared to other tissue sites [157]. There have been few studies to determine whether HIV persists in the liver on ART but studies of animal models, including SIV-infected macaques and HIV-infected humanized mouse models both suggest that HIV can persist in the liver on ART, primarily in Kupffer cells [158,159]. Recently, infectious replication competent HIV was isolated from Kupffer cells obtained from liver at autopsy from three HIV-infected individuals who died on ART [151].

In the absence of virus replication on ART, HIV may also contribute to liver inflammation and fibrosis by binding of envelope glycoprotein, gp120 to CXCR4 which is expressed on hepatocytes and HSC [160]. The effect of HIV infection and or HIV proteins in the liver has primarily been studied in the context of HIV–Hepatitis C virus (HCV) coinfection in vitro but not in HIV–HBV coinfection. HIV infection alone, or in the presence of HCV, induced profibrotic processes in hepatocyte and HSC cell lines, including increased chemokine production, HSC migration, hepatocyte apoptosis, and expression of profibrotic genes [161,162].

HIV, microbial translocation, and immune activation

In untreated HIV infection, depletion of CD4+ T cells in the gastrointestinal tract leads to increased microbial translocation [163], resulting in elevated levels of circulating LPS. LPS binds to toll-like receptor (TLR) 4 and activates nuclear factor kappa B and other pathways leading to the production of proinflammatory cytokines. In HIV-infected individuals, there is dysregulation of the TLR4 response to LPS ex vivo[164]. As the liver is the first organ to filter blood from the gastrointestinal tract, the concentrations of LPS in the portal veins is elevated and Kupffer cells have a ‘tolerized’ or reduced response to LPS [165]. We have demonstrated persistently elevated levels of circulating LPS in HIV–HBV coinfected individuals compared with uninfected controls and HBV monoinfected individuals [166], however, we did not find a direct correlation between elevated circulating LPS and liver fibrosis consistent with similar studies in HIV–HCV coinfection [167–169]. It is possible that the concentration of LPS in the portal vein and/or in the liver, which are both difficult to measure, may be more important than LPS levels in blood in driving liver disease.

Recent studies in SIV-infected rhesus macaques suggest that increased microbial load in the liver can also trigger chemokine production and an increased infiltrate of CXCR6+-activated natural killer cells, which may contribute to liver fibrosis [170]. We have also demonstrated that the chemokine CXCL10, ligand for CXCR3 which is expressed on activated T cells, is associated with elevations in liver enzymes in HIV–HBV coinfection and may contribute to liver disease via migration of activated T cells to the liver [166]. Inhibition of these chemokines may potentially play a role in reducing liver disease in HIV–HBV coinfection and should be further explored.

Immune exhaustion and tolerance

Programmed death 1 receptor (PD-1) is upregulated on total and HBV-specific CD8+ T cells in treated and untreated chronic HBV infection but this has not been examined in HIV–HBV coinfection [171]. We have previously shown that HBV-specific T cells are infrequently detected in chronic HIV–HBV coinfection and do not increase in frequency following ART [172]. Immune checkpoint blockade with anti-PD-1 and anti-cytotoxic T-lymphocyte-associated protein 4 have recently been licensed for the treatment of malignancy [173] and may potentially have effects on both HIV-specific and HBV-specific T cells and clearance of persistent virus. The safety of these antibodies in the setting of HIV or HBV monoinfection for the treatment of malignancy and as strategies for cure are currently being explored (Table 2).

Table 2
Table 2:
Novel strategies for the cure of (a) HBV and (b) HIV and their potential impact in coinfected individuals.
Table 2
Table 2:
(Continued) Novel strategies for the cure of (a) HBV and (b) HIV and their potential impact in coinfected individuals.


The most common treatment for HIV–HBV coinfection is HBV-active ART, which includes two NRTI, usually either LMV or FTC together with tenofovir [218]. Limited studies of IFN have been performed in HIV–HBV coinfected individuals since the widespread availability of HBV-active ART, but recent studies have shown that the addition of pegylated IFN to HBV-active ART in HBeAg-positive coinfected individuals did not lead to increased rates of HBeAg or HBsAg clearance, despite faster declines of antigen levels during treatment [219,220].

New antivirals for hepatitis B virus

Tenofovir alafenamide

TAF is a prodrug of tenofovir that has activity against HIV-1, HIV-2, and HBV [221] with higher intracellular concentrations in PBMCs and hepatocytes relative to plasma compared with TDF, thereby allowing for lower dosing and reduced toxicity [221]. TAF has reduced adverse effects on renal function and bone mineral density seen, whereas maintaining high rates of viral suppression in both HIV and HBV [141,221].

In HIV–HBV coinfection, switching from a TDF to a TAF-containing regimen demonstrated similar high levels of HBV virological control ( number NCT02071082) [222,223].

Hepatitis B virus entry inhibitors and others

New antiviral agents currently in development for HBV include inhibitors of HBV entry, conversion of relaxed circular DNA to cccDNA, and capsid assembly, but none of these agents are licensed nor have they been evaluated in HIV–HBV coinfection (Table 2). The synthetic lipopeptide, Myrcludex-B (Universitatsklinikum Heidelberg, Heidelberg, Germany) which is derived from the HBV L-protein competes with the viral pre-S1 motif for binding of the sodium taurocholate cotransporting polypeptide (NTCP) receptor, blocking de novo HBV infection [224]. A large randomized phase 1b/2 clinical trial comparing Myrcludex-B to entecavir in chronic HBV is in progress ( NCT02637999). Other drugs already in use that block the in-vitro interactions of HBV with NTCP include the immunomodulatory agent cyclosporinA, antiretroviral ritonavir, ezetimibe (cholesterol lowering), and irbesarten (antihypertensive angiotensin II receptor antagonist) [225]. Recent studies have identified new small molecules (derivatives of cyclosporinA) which are able to inhibit HBV viral attachment, without impairing the NTCP-dependent uptake of bile acids, suggesting that these functions may be separated [226].

New antivirals/strategies for HIV and their impact in HIV–HBV coinfection

Integrase inhibitors

In the 2016 updated WHO adult HIV-treatment guidelines, first-line recommended regimens have been updated to include integrase strand transfer inhibitors (INSTI) [218], consistent with guidelines from high-income countries. Three INSTI dolutegravir (DTG), raltegravir (RAL), and elvitegravir/cobicistat are now in widespread use.

In phase three randomized studies of DTG, individuals coinfected with HIV and HBV or HCV (n = 324, 11% of total) were more likely to experience liver enzyme flares which was attributed to IRID [227]. In ART-naïve individuals less liver enzyme elevations were seen in those with HIV and HBV/HCV who were on DTG in comparison to RAL. In combined analysis of three double-blind, randomized-controlled studies of RAL in HIV, 6% of individuals (34 of 563) had hepatitis B or C coinfection [228]. Liver enzyme elevations were again more common in coinfected individuals; however, clinical sequelae were not seen, and there was no difference in efficacy in terms of HIV suppression between RAL and control groups. Similar results were seen in subsequent observational studies including over 150 individuals commenced on RAL, coinfected with either HCV or HBV [229].

Elvitegravir/cobicistat is of particular interest in new strategies to manage HIV–HBV coinfection as this was the first INSTI coformulated with TAF (in addition to cobicistat and FTC) as a single table regimen for treatment of HIV. The 48-week outcomes from an open-label, noncomparative study evaluating the efficacy and safety of switching to this combination in HIV–HBV coinfected adults without cirrhosis and with CD4+ cell count more than 200 cells/μl (n = 72) were recently published [223]. All individuals with suppressed HBV DNA at the time of switch (n = 62.86%) continued to remain suppressed, with seven of the remaining 10 participants becoming undetectable by week 48. Creatinine clearance improved and statistically significant decreases in markers of bone turnover were observed [223]. Drug interactions are important considerations in the use of cobicistat as with ritonavir and need to be considered when treating an individual with HIV–HBV coinfection.

Nucleos(t)ide reverse transcriptase inhibitor sparing regimens

Recent studies have looked at the feasibility of NRTI sparing ART regimens in HIV monoinfection to decrease toxicity and avoid drug resistance [230]. Cessation of HBV-active NRTI, including TDF, TAF, FTC, or 3TC would have significant implications for the treatment of HIV–HBV coinfected individuals and whether this is a well tolerated option, even after HBsAg seroconversion, remains unknown.

Impact of cure strategies for either hepatitis B virus or HIV

As in HIV, there has been recent increased interest in strategies that may lead to a cure for HBV. In contrast to HIV infection, there is a clear biomarker for HBV remission which is the development of antibodies to HBsAg [reviewed by Revill et al.[231]]. The main barriers to cure include the persistence of cccDNA and HBsAg [92] (Fig. 2). The use of currently available NRTIs can successfully suppress replication of HBV DNA and reduce but not eliminate HBsAg production but have little impact on cccDNA. Hence, in most individuals in the absence of HBsAg seroconversion, HBV DNA rebounds following cessation of NRTI [232]. Furthermore, although suppression of plasma HBV DNA leads to decreased levels of fibrosis, cirrhosis, and HCC, levels of HBsAg still remain elevated which may be related to the persistence of cccDNA.

Eradication of cccDNA is the ultimate goal of cure strategies for HBV; however, other interim goals including the clearance of HBsAg or seroconversion persisting of treatment which may also be beneficial in terms of clinical outcomes and is sometimes described as a ‘functional cure’. Current strategies to eliminate cccDNA include proapoptosis, gene editing, and immunomodulatory strategies as summarized in [92,224] and their potential effects on HIV infection are summarized in Table 2a. Similarly, some of the current strategies being developed for HIV cure, such as latency reversal using histone deacetylase inhibitors or reversal of immune exhaustion with immune checkpoint blockade have the potential to have adverse effects on HBV replication and/or hepatic inflammation [147] (Table 2b). HIV–HBV coinfected individuals have often been excluded from clinical trials of agents aimed at curing either HIV or HBV but in the future, it will be important for this population to have the opportunity to participate in these clinical trials.


Despite highly effective HBV-active ART, liver-related mortality remains elevated in HIV–HBV coinfected individuals and fibrosis is still accelerated in some individuals. There are multiple mechanisms through which HIV can adversely affect HBV pathogenesis, even on suppressive HBV-active ART. New treatment strategies should be explored to reduce fibrosis, which still occurs in a subset of HIV–HBV coinfected individuals on ART. In the future, specific consideration of HIV–HBV coinfected individuals will be required when assessing the role of new antivirals for HBV, nucleotide sparing regimens and any HIV or HBV-cure interventions.


The article was conceived by S.R.L., K.P.S, M.C., and J.A. reviewed the literature and drafted the manuscript. S.R.L. supervized the drafting and edited the manuscript. All authors provided comment on the manuscript and approved the final version.

S.R.L was supported by National Health and Medical Research Council of Australia (NHMRC) grants (1101836 and 1024406), NHMRC Practitioner Research Fellowship (1042654), and United States National Institutes of Health (U19 AI096109). K.P.S was supported by an NHMRC postgraduate fellowship (1039055).

Conflicts of interest

There are no conflicts of interest.


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