Long-Acting Treatments for Hepatitis B

Abstract

There are an estimated 257 million persons living with chronic hepatitis B for whom there are multiple potential applications of long-acting antiviral compounds. Current efforts include both injection and implant approaches to formulating derivates of existing anti-HBV compounds such as tenofovir or entecavir. Substantial progress has already occurred especially as aligned with the development of long-acting tenofovir-based medications with dual activity against human immunodeficiency virus (HIV) and hepatitis B virus (HBV). Nonetheless, substantial challenges will need to be overcome before these agents are available.

CLINICAL AND PUBLIC HEALTH OPPORTUNITIES

Safe and effective long-acting (LA) treatments for HBV infection would meet important clinical and public health needs. An estimated 257 million persons worldwide are living with chronic hepatitis B (PLWHB), and international guidelines continue to expand the subset for whom treatment is recommended [1–3]. Once started, treatment of most PLWHB continues indefinitely, making maintenance therapy of tens of millions of persons an enormous challenge that could be addressed by LA treatments.

Although surveys of PLWHB are urgently needed to characterize user preferences, the experience of HIV and hormonal contraception suggests that LA treatments may overcome the inconvenience and stigma that can be associated with daily pills. Weekly injection of pegylated interferon alpha is already used to treat HBV infection [3, 4]. Long-acting formulations of nucleoside (-tide) inhibitors may strongly complement future drug development since HBV transcription inhibitors are formulated as LA injectable compounds. Long-acting treatments of HBV might be particularly important for persons dually infected with HIV. Some nucleoside (-tide) inhibitors of HBV polymerase also inhibit reverse transcription of HIV, and medications like tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide (TAF) remain first line treatments for each virus and the obvious choice for those dually infected. Notably, the existing injectable antiretroviral regimen cabotegravir and rilpivirine does not have HBV activity underscoring the niche a long-acting treatment that inhibits both viruses might play for those dually-infected [5].

In addition, LA HBV treatments may contribute to prevention of mother-to-infant transmission of HBV, which is by far the leading cause of chronic hepatitis B worldwide [6, 7]. Mother-to-infant transmission contributes disproportionately to the burden of infection because up to 90% of infants develop chronic infection, which drives most of the morbidity and mortality. Mother-to-infant transmission is principally prevented by giving HBV vaccination immediately at birth (birth dose vaccination), when possible, with HBV immunoglobulin. However, in 2019, birth-dose vaccination was given in just 43% of deliveries [7]. Delivering any medical care at the time of delivery is exceptionally difficult where most deliveries occur in homes. In contrast, antenatal care is much easier to deliver. For example in 2019, antiretroviral treatment was provided during pregnancy to 85% of women living with HIV [7]. Anti-HBV treatment of mothers with high HBV DNA levels reduces infant HBV transmission even when birth dose vaccination and HBV immunoglobulin are given [6, 8]. This finding raises the question of whether anti-HBV treatment of pregnant women might reduce the mother-to-infant transmission in settings where delivery of birth dose vaccination has been difficult but where women have antenatal visits. This principle was illustrated in a study in Congo [9]. Even with the added resources of a research study, of 88 infants born to 90 women with chronic hepatitis B enrolled during pregnancy, only 46 received a timely birth-dose vaccination. However, TDF 300 mg/day was given to women who had HBV DNA levels ≥200 000 IU/mL or were HBV e antigen positive, and there were no instances of HBV mother-to-child transmission.

POTENTIAL LA AGENTS

The ideal properties for a LA anti-HBV compound include high tolerability including in pregnancy, lack of hypersensitivity, lipid solubility, high potency, stability, slow predictable release from tissue, and lack of toxicity in tissue of drug or excipients/packaging material. Notable differences may exist between the properties for extended-release compared to oral treatments and represent challenges to adapting existing oral compounds for LA uses. For example, with liver infections, high first pass metabolism of an oral drug in the liver may be advantageous but a challenge with parenteral applications (discussed below). In addition, the volume of drug (cargo) that can be used with injections and implants is limited and requires that the active molecule be very potent and, ideally, have a long terminal half-life. Nonetheless, most LA strategies involve adaptation of existing oral treatments.

The most recommended treatments for chronic hepatitis B are oral entecavir, TDF, or TAF (Table 1) [3, 4, 10]. Other oral treatments such as emtricabine, lamivudine, adefovir, or telbivudine are not preferred because they have lower barriers to resistance and/or lower potency. Subcutaneous injection of pegylated interferon is still preferred in some settings due to slightly higher rates of durable responses than with oral medications but often is avoided due to toxicity. As mentioned, several compounds like TDF, TAF, emtricabine, and lamivudine share activity against HIV and are integrated into some antiretroviral treatment strategies, especially for persons infected with both HBV and HIV.

Table 1.

Medications Approved and/or Recommended for Use for Treatment of Chronic Hepatitis B [3, 4, 10]

Medication	Dose/Route	HIV Active	Pregnancy	Children	Notes
Tenofovir disoproxil fumaratea	300 mg oral/d	Yes	B	>12 yb	Generic available worldwide; MPP license agreements for HIV
Tenofovir alafenamide	25 mg oral/d	Yes	?Bc	?b	MPP license agreements for HIV
Entecavira	0.5–1.0 mg/d	Yes	C	≥2 y	Dose varies depending on likelihood of resistance and/or cirrhosis. WHO recommends 1 mg for cirrhosis
Pegylated interferon alpha 2a	180 mcg subcutaneous/week	Not clinically significant	C	Interferon alpha 2b	Not first-line for WHO
Tenofovir disoproxil fumarate/emtricitabinea	300/200 mg oral/d	Yes	B	…	Not first-line AASLD
Not preferred by AASLD [3]
Lamivudine	100 mg oral/dd	Yes	C	>2 y: 3 mg/kgb	Low resistance threshold
Emtricitabine	200 mg oral/d	Yes	B	NAb	Low resistance threshold
Adefovir	10 mg oral/d	Not clinically significant	C	>12 y	Lower potency and resistance threshold than TDF
Telbivudine	600 mg oral/d	No	B	?	…

“?” indicates data are insufficient.

Abbreviations: AASLD, American Association for Study of Liver Diseases; HIV, human immunodeficiency virus; MPP, medicines patent pool; NA, not applicable; TAF, tenofovir alafenamide; TDF, tenofovir disoproxil fumarate; WHO, World Health Organization.

^aOn the 2021 WHO list of essential medications; emtricitabine/TDF listed for HIV, “and is recommended for children with HIV/HBV coinfection”.

^bApproved for the treatment of HIV in younger age groups.

^cData from the antiretroviral pregnancy registry indicates no difference between risk of birth defects from TAF compared with the background rate in the US (apregistry.com/forms/interim_report.pdf).

^dAlthough 100 mg/d is sufficient for HBV in adults with normal renal function, alternative higher doses are also used in HIV/HBV due to various formulations for treatment of HIV.

STATE OF THE ART—EXISTING STUDIES OF LA ANTI-HBV TREATMENTS

Tenofovir and Related Drugs

Injectable Products

The high aqueous solubility of tenofovir (TFV) and its prodrugs, TDF and TAF, both as the free-base or the hemifumarate salt, represents an impediment in the development of LA, injectable nanoformulations. This obstacle has been overcome by several research groups using a number of different approaches.

Destache and colleagues adapted the established water-in-oil-in-water emulsion method to prepare polylactide co-glycolide nanoparticles loaded with TAF in combination with other antiretroviral drugs [11–13] and evaluated their efficacy against human immunodeficiency virus type 1 (HIV-1) in humanized mice. The focus of this work was primarily directed at HIV prevention and treatment, as evidenced by the multiple agents included at fixed concentration ratios in the nanoparticles. A combination of TAF and bictegravir (BIC), an integrase inhibitor, was formulated as spherical nanoparticles (size distribution, 229 ± 15 nm, with polydispersity index (PDI) 0.124 ± 0.035) containing 6.1 ± 1.0% TAF and 6.5 ± 1.2% BIC [13]. PDI values describe the degree of non-uniformity in the particle size distribution within a given sample. It is a dimensionless quantity: highly monodisperse samples will have PDIs around 0.05, whereas samples that contain broad particle size distributions will lead to PDI values exceeding 0.7. Subcutaneous administration of this formulation to BALB/c female mice (200 mg kg⁻¹ for each drug) led to rapidly declining plasma TFV concentrations from ca. 10⁴  to 10 ng mL⁻¹ over 1 week, and similar trends were observed for vaginal and colon tissue samples [13]. The ability to coformulate 2 or more antiviral agents, including TAF, in resorbable nanoparticles with uniform size distribution could be appealing for the treatment of HBV or HIV-HBV coinfections. However, the delivery platform would need to be improved in terms of drug release burst and nanoparticle mass loading.

Ho and colleagues have developed so-called targeted-long-acting-antiretroviral-therapy product candidate 101 (TLC-ART 101), an optimized nanoparticle formulation that combines the HIV protease inhibitors lopinavir (LPV), ritonavir (RTV), and TFV (ie, not in prodrug form) in a 4:1:3 molar ratio [14]. The nanoparticles were prepared by evaporating solutions of the three agents and a mixture of lipids, 1,2-distearoyl-sn-glycero-3-phosphocholine and the sodium salt of N-(carbonylmethoxypolyethyleneglycol-2000)-1,2-distearoyl-sn-glycero-3-phosphoethanolamine [15]. The resulting dry films were rehydrated in a buffered lipid solution, and nanoparticle generation was achieved by sonication or high-pressure homogenization followed by a 30-minute annealing step. The TLC-ART 101 mean particle diameter was 69.0 ± 8.3 nm, and subcutaneous injection in pig-tailed macaques (N = 4; dosing: TFV, 10.6 mg kg⁻¹; LPV, 25.0 mg kg⁻¹; and RTV 7.0 mg kg⁻¹) led to sustained TFV plasma and PBMC exposure over 2 weeks [14]. It is noteworthy that the TFV concentration in these compartments was high (C_max: plasma, 4.4 µg mL⁻¹; peripheral blood mononuclear cells (PBMC), 13.2 µg mL⁻¹) and only decreased by ca. 1 order of magnitude over the 14-day period. The high TFV intracellular accumulation in lymph nodes was interpreted as active drug targeted delivery.

The TLC-ART 101 formulation was expanded to also include lamivudine (3TC) and maintained similar PK profiles in pig-tailed macaques [16]. PBMC and lymph node mononuclear cell TFV and 3TC concentration-time profiles were comparable. These results are promising for the management of HBV, possibly using drug combinations in a self-administered injectable format every 2–4 weeks. Another advantage of the lipid-based nanoparticle formulation approach lies with the use of TFV and 3TC, rather than prodrugs, which could have cost and stability implications.

The third injectable nanoparticle technology discussed here originated from the laboratories of Edagwa, Gendelman, and colleagues. It is based on the synthesis of lipophilic prodrugs followed by nanocrystal formation using high-pressure homogenization in aqueous buffers stabilized by a non-ionic surfactant [17]. Recently, the ProTide synthetic strategy was applied to prepare TFV [18] and 3TC [19] prodrug nanocrystals. Cobb and colleagues compared nanocrystals of TAF and two new ProTide TFV prodrugs, M1TFV and M2TFV [18]. NM1TFV accumulation in macrophages over 8 hours was between 4 (M2TFV) and 23 (TAF) times higher, but the intracellular TFV diphosphate (TFV-DP, the active metabolite against reverse transcriptase) concentrations were nearly 2 orders of magnitude higher for the TAF nanocrystal group. Long-term macrophage nanoparticle storage following a single 10 µM administration was most pronounced for NM1TFV, whereas NM2TFV maintained a higher intracellular TFV-DP concentration plateau over the 30-day period. When the formulations were evaluated in Sprague–Dawley rats via intramuscular injection (single dose, 75 mg kg⁻¹ TFV-equivalents), all 3 prodrug nanocrystals exhibited a rapid, ca. 100-fold decline in plasma TFV concentrations over 28 days, although the TAF nanoformulation had an inferior PK profile to NM1TFV and NM2TFV. Surprisingly, all 3 formulations maintained similar PBMC TFV-DP concentrations over 56 days, equilibrating at ca. 250 fmol/10⁶ cells. The 2 new prodrugs also led to significantly higher immune tissue TFV exposure than the TAF nanocrystals. The TFV ProTide nanocrystal approach holds promise for HBV management, possibly even by combining LA formulations of TFV and 3TC in a single injection. However, increased stability of TFV plasma concentration-time profiles would be desirable.

Subdermal Implants

There are few available antiviral agents with the appropriate pharmacologic properties, especially potency, required for use in a subdermal implant platform that would have the desired duration of 6 months, or longer. It therefore is not surprising that several groups have focused on the delivery of TAF from a range of subcutaneous implant platforms. The state-of-the-art of these technologies was described in a recent review [20], so only key aspects are discussed here.

Grattoni and collaborators have described an innovative capsule-shaped nanofluidic TAF implant that can be transcutaneously refillable [21], likely due to the relatively large device dimensions (5 × 20 × 12.3 mm; 550 µL) making surgical replacement every 6–12 months burdensome. The implant exhibited zero order (linear) in vitro TAF release kinetics, and in vivo evaluation in rhesus macaques (N = 4) exhibited a gradual accumulation of plasma TFV (from ca. 1 to 10 ng mL⁻¹) and PBMC TFV-DP concentrations (from 72 to 533 fmol/10⁶ cells) over the 70 days the implant was in place. Aside from the expected seroma formation following implantation, which resolved within a week, no notable toxicity was observed, particularly drug-related. A placebo-controlled, repeated low-dose rectal SHIV_SF162P3 challenge study in rhesus macaques using the nanofluidic TAF implant led to a 62.5% reduction (95% confidence interval [CI]: 1.72–85.69%; P = .068) in risk of infection per exposure compared to the control [22]. The implants were filled initially with 300–457 mg TAF hemifumarate and exhibited a linear cumulative release of ca. 4 mg day⁻¹ TAF, although drug degradation in the devices was observed over time. A 4-month PK study showed that steady-state concentrations of TFV in plasma (ca. 10 ng mL⁻¹) and TFV-DP in PBMCs (median, 390 fmol/10⁶ cells) were achieved. Immunohistochemical analysis of the tissue surrounding the implants after 4 months of use revealed fibrotic capsules and limited cellular infiltration, consistent with a foreign body response, with no significant differences between the medicated and placebo groups.

Johnson and co-workers used a different approach to LA, subcutaneous TAF delivery based on a reservoir-style implant made of a biodegradable polymer, poly(ε-caprolactone) (PCL) sheath, initially consisting of a thin film [23] and later an extruded tube [24, 25]. The rod-shaped device characteristics (outer diameter, 2.5 mm; length, 40 mm) were based on the dimensions used historically for contraceptive implants, thereby allowing device placement via trocar. The tubes were filled with a paste consisting of TAF free-base, suspended in castor oil (2:1 mass ratio) [24]. The in vitro TAF release from implant prototypes was linear and tunable over the 0.15–0.91 mg day⁻¹ range by varying parameters such as implant length, wall thickness, and PCL molecular weight. A cumulative TAF release rate of 0.28 ± 0.06 mg day⁻¹ over 180 days was achieved with a 100-µm wall thickness.

Kiser and colleagues described a nonbiodegradable reservoir-type, rod-shaped implant consisting of extruded polyurethane tubing filled with TAF hemifumarate microtablets [26, 27]. The impact of implant lumen length and outer diameter, polymer membrane thickness and composition, and excipients on in vitro release rate was investigated [27]. Overall, in vitro TAF release rates in the 1–100 µg cm⁻¹ days⁻¹ were achieved, with formulations using tubing with the large outer diameter of 3.6 mm enabling release rates of ca. 250 µg cm⁻¹ days⁻¹. In vitro daily release rates gradually increased over time before reaching a plateau. This lag time was considerable in some device iterations (up to ca. 30 days) but was somewhat remedied by the use of sodium chloride as an added excipient.

Devices spanning 2 generations and in vitro TAF release rates between 0.13 and 0.78 mg day⁻¹ were evaluated for safety and PK in rabbits and macaques [26]. Implants releasing 0.4 mg day⁻¹ TAF in vitro led to median PBMC TFV-DP concentrations (weeks 1–12) in macaques of ca. 400 fmol/10⁶ cells, comparable to those observed by Pons-Faudoa and Grattoni at 10 times higher TAF release rates [22]. This discrepancy has not been explained and suggests possible saturable processes that come into play at higher TAF release rates. Unfortunately, the polyurethane TAF hemifumarate implants resulted in severe local inflammation with associated tissue necrosis, particularly in macaques.

Baum and collaborators have developed a nonbiodegradable subdermal implant technology consisting of a drug-impermeable silicone tube (outer diameter, 2.0–2.5 mm; length, 10–40 mm) perforated with delivery channels that control the drug release kinetics [28, 29]. An outer implant polymer membrane (eg, heat-treated polyvinyl alcohol) provided additional control of TAF release rate. Implant cores consisted of TAF powder [28] or microtablets [29]. The 2015 report by Gunawardana and colleagues was the first on LA TAF delivery from a subdermal implant and established preliminary safety and PK in dogs [28]. Linear, lag-free in vitro TAF release (0.92 mg day⁻¹) was achieved with this early prototype, and similar release rates (0.85 mg⁻¹) were observed in vivo leading to median TFV plasma concentrations of 15 ng mL⁻¹ and PBMC TFV-DP concentrations of 179 fmol/10⁶ cells at pseudo steady-state. The authors subsequently found that mice and sheep were valid small and large animal models, respectively, for the development of TAF implants, especially at release rates below 0.3 mg day⁻¹ [29]. No concerning safety findings beyond the expected foreign body response were observed in mice, dogs, and sheep at in vivo TAF release rates below 1 mg day⁻¹. To our knowledge, this technology is the only one to have progressed to clinical trial evaluation, ongoing at the time of writing [30].

The heterogeneous preclinical safety outcomes observed for the various TAF implant technologies have been discussed in detail elsewhere [31]. One explanation for the high degree of local toxicity observed by Kiser and coworkers could lie with a combination of the polyurethane device material, the implant mechanical properties, and the drug species responsible for exacerbating the inflammation. The detailed and transparent report by Su and colleagues indicated that TFV and TFV-DP concentrations were either very low or unquantifiable in tissue samples collected adjacent to the implant at necropsy in macaques following 12 weeks of implantation, coinciding with the highest degree of observed toxicity. These results suggest that a different TAF-derived species is responsible for enhancing the inflammatory response from the device. Using matrix-assisted laser desorption/ionization (MALDI) imaging mass spectrometry (IMS), Gunawardana and coworkers analyzed the distribution of TAF and its 5 main in vivo metabolites in dermal tissue specimens collected adjacent to their silicone implants in mice [31]. All analytes were present throughout the 28-day study, and their concentration profiles adjacent to the implant differed greatly.

Entecavir

Oral entecavir is a potent guanosine analog reverse transcription inhibitor. After oral administration, entecavir reaches peak levels in blood within 1 hour and steady state within 10 days; the estimated effective half-life is 24 hours. High safety and efficacy was shown for the oral 0.5 mg and 1.0 mg doses in phase 3 studies [32]. The high potency suggests entecavir might be adapted to a LA treatment. Henry and coworkers at Merck prepared hot melt extrudates of entecavir polymer blends [33]. Tablets were prepared by dip-coating in polymer solutions. Although in rodent models >180 days of drug release was demonstrated, entecavir (but not the polymer-based implant) was toxic in the tissues. Others have made entecavir-loaded microspheres and microcrystals to extend entecavir dosing [34, 35]. Questions have been raised about the safety of entecavir in pregnancy based on rodent models. Thus, additional clarification of the safety in this important group of PLWHB is necessary.

Others

Higashi-Kuwata and coworkers synthesized a LA 4′-modified nucleoside reverse transcriptase inhibitor named E-CFCP [36]. High in vitro potency was shown even against HBV resistant to other agents and the early phase studies suggested once-weekly oral dosing might be possible.

CHALLENGES AND FUTURE DIRECTIONS

Drug Delivery to the Liver

Nucleoside (-tide) analogs are administered as prodrugs that undergo phosphorylation by host kinases within cells to become pharmacologically active. Entecavir oral bioavailability is at least 70% in the fasted state; however, TFV is hydrophilic and has poor bioavailability. TFV is therefore formulated as TDF or TAF to enhance absorption and cellular delivery. TDF is hydrolyzed to TFV monoester and subsequently TFV in the intestinal tract, liver, and blood by various hydrolyzing enzymes (eg, carboxylesterase 2, phosphodiesterases, etc) [37]. TAF is more stable through the gut and liver and can therefore deliver intact to various cell types. TFV-DP concentrations differ for TDF and TAF across cell types. For instance, TFV-DP concentrations are higher in PBMCs with TAF vs TDF, but lower in red cells. When given orally, TDF (and TFV monoester) and TAF are delivered directly to the liver through the portal vein on first pass (Figure 1). The pharmacologic profile will differ for an injectable or subdermal implant which requires drug reach the circulation before it travels to the liver. Oral nucleosides (-tides) deliver a bolus of drug to the liver with each daily dose whereas a continual delivery at a lower exposure is expected for LA therapies. Release from the injection or implant and esterase expression in the skin and blood will impact the amount of drug ultimately delivered to the liver.

Figure 1.

Conceptual difference of blood compartment with enteral (A) vs parenteral (B) administration of drugs for viral hepatitis. A, When drug is taken orally, drug absorbed in the gut is delivered directly to the liver via the portal vein. For the nucleotide prodrugs TDF and TAF, a large amount of the prodrugs and hydrolysis intermediates are delivered directly to the liver during first pass. Once phosphorylated by host kinases intracellularly to the active form, TFV-DP, the drug is trapped until incorporated or degraded. B, When drug is given via subdermal implant, injectable, or patch, the drug must be released from skin (or muscle) and travel through the circulation to the liver. A steady amount of drug is likely to be delivered to the liver rather than a large bolus observed with enteral administration. Abbreviations: TAF, tenofovir alafenamide; TDF, tenofovir disoproxil fumarate; TFV-DP, tenofovir diphosphate.

Concentration Targets

The Food and Drug Administration (FDA) recently released guidance on hepatitis B drug development (https://www.fda.gov/media/117977/download). The guidance encourages use of mechanistic models to define pharmacokinetic–dynamic associations for HBV therapies. A pharmacokinetic (PK) target used to assess and compare drug delivery with LA HBV therapies would be highly desirable. Ideally, this PK target would be strongly associated with HBV viral suppression and obtained through a minimally invasive matrix such as blood or blood cells since liver sampling is impractical. TFV-DP concentrations associated with protection from infection and viral suppression in blood cells have been established for HIV. In PBMCs, TFV-DP concentrations of > 40 fmol/10⁶ cells are associated with protection from HIV infection in the presence of emtricitabine [38]. In dried blood spots (primarily composed of red blood cells), TFV-DP >700 fmol/punch (derived from TDF) and >950 fmol/punches (derived from TAF) are associated with protection from HIV infection in the presence of emtricitabine [39, 40]. A plasma TFV trough of 40 ng mL⁻¹ has been proposed as a target as well, but the associations with protection are not as strong as with TFV-DP because plasma levels are a biomarker of recent dosing rather than a measure of cumulative drug exposure. Among PWH on TDF-based antiretroviral regimens, TFV-DP concentrations in DBS <800 fmol/punch were associated with 4-times the odds of future viremia [41]. Analogous targets should be established for HBV. Individuals with HIV/HBV coinfection appear to maintain HIV suppression with imperfect adherence to TFV-based regimens but fail to maintain HBV suppression [42]. This may indicate higher exposures of tenofovir are necessary to maintain HBV suppression compared with HIV, but this is confounded by the presence of other antiretroviral agents and warrants further study.

Significantly less is known about the pharmacokinetic-dynamic associations for entecavir, and there are very limited data on entecavir triphosphate pharmacokinetics. The mean (SD) entecavir steady state plasma AUC and trough with 0.5 mg/day are 21.3 ng hour/mL and 0.53 ng/mL, respectively, and 53.9 ng hour/mL and 3.5 ng/mL with 1.0 mg/day, respectively. A small study examined the relationship between entecavir plasma trough concentrations when given at a dose of 0.5 mg/day and HBV decline. Entecavir plasma troughs of <0.4 ng/mL after 1 month of treatment were associated with greater declines in HBV viral loads compared with those with entecavir plasma troughs >0.4 ng/mL [43]. Investigators suggested individuals with lower plasma levels have greater drug delivery to the liver and hence greater HBV efficacy. This finding requires confirmation in a larger study. This same group described a total entecavir concentration (mono-, di-, tri- plus parent) in PBMCs of 85.2 ng mL⁻¹ [44], but there are no data on the associations with this PK measure and clinical outcomes.

Modeling to Inform Drug Delivery and Dosing

Physiologic based-pharmacokinetic (PBPK) models will be highly beneficial for modeling drug release, hydrolysis, hepatic transport and delivery, and concentrations of the active di- or tri-phosphate in hepatocytes with LA agents. In vitro and animal data will be needed to inform model parameters. Animal studies evaluating tenofovir-based LA agents for HBV and the prevention and treatment of HIV should include assessments of plasma, PBMC, and red cell PK but also liver tissue and ideally, quantification of TFV-DP, and other nucleoside (-tide) triphosphates in hepatocytes. A pharmacometrician would be a valuable member of the drug development team for LA products.

Pregnancy and Infants

LA therapies would be extremely advantageous to prevent perinatal transmission. However, there are physiologic changes during pregnancy and postpartum that may necessitate higher doses or shorter dosing intervals. Similarly, injection/implant volumes, rapid weight gain, and enzyme and transporter ontogeny add complexity to use of LA therapies in infants. There is great interest in evaluating LA cabotegravir, an HIV integrase inhibitor, for HIV prevention and treatment in pregnant women and infants. These efforts may provide a roadmap for studies of LA agents for HBV in pregnant women and infants. Given the proven safety and efficacy of oral tenofovir and related molecules for prevention of mother to infant transmission of HBV, PBPK studies focused on those are clearly needed. For a more comprehensive discussion of long-acting formulation in this context, please see in this supplement Abrams et al for use in infants and children and Olagunju et al for use in pregnant women.

CONCLUSIONS

There already has been exciting progress in the development of LA approaches to the treatment of HBV infection. However, much more must be done to understand the preferences of PLWHB as well as to promote the multiple potential products. Development of LA treatments for chronic hepatitis B are likely to be economically sustainable. With 258 million persons LWCHB and an estimated 12–25% needing treatment, even if a small fraction of persons opted for a LA option, there is a large opportunity since HBV infection cannot be cured and treatment has to be sustained indefinitely [1, 2]. Given the potential gains for low- and middle-income regions of the world, there may also need to be programmatic support for development of such treatments from national, global, and civil society sources. Fortunately, the overlap in activity with HIV medications provides added value to development of LA tenofovir based approaches.

Notes

Acknowledgments. This supplement was sponsored by the Long-Acting/Extended Release Antiretroviral Research Resource Program (LEAP).

Financial support. This work and the related research were supported by the US National Institutes of Health (NIH) grants: R24AI118397 (D. T.) and R01AI162151 (M. B.).

Supplement sponsorship. This article appears as part of the supplement “Long-Acting and Extended-Release Formulations for the Treatment and Prevention of Infectious Diseases,” sponsored by the Long-Acting/Extended Release Antiretroviral Research Resource Program (LEAP).