Potential Impact of Long-Acting Products on the Control of Tuberculosis: Preclinical Advancements and Translational Tools in Preventive Treatment

Abstract

A key component of global tuberculosis (TB) control is the treatment of latent TB infection. The use of long-acting technologies to administer TB preventive treatment has the potential to significantly improve the delivery and impact of this important public health intervention. For example, an ideal long-acting treatment could consist of a single dose that could be administered in the clinic (ie, a “1-shot cure” for latent TB). Interest in long-acting formulations for TB preventive therapy has gained considerable traction in recent years. This article presents an overview of the specific considerations and current preclinical advancements relevant for the development of long-acting technologies of TB drugs for treatment of latent infection, including attributes of target product profiles, suitability of drugs for long-acting formulations, ongoing research efforts, and translation to clinical studies.

This article presents an overview of the specific considerations and current preclinical advancements relevant for the development of long-acting technologies of tuberculosis drugs for treatment of latent infection, including attributes of target product profiles, suitability of drugs for long-acting formulations, ongoing research efforts, and translation to clinical studies.

Despite the fact that tuberculosis (TB) is a very treatable condition, in 2020, about 1.5 million people died from TB with an estimated 10 million active cases [1]. To make matters worse, the coronavirus disease 2019 pandemic reversed years of global progress in tackling TB. For the first time in more than a decade, TB deaths increased, according to the 2021 Global TB report from the World Health Organization (WHO) [1]. Far fewer people were diagnosed and treated in 2020 compared with 2019, a reflection of the decrease in overall attention to essential TB services. Even more tragic is that TB is preventable, even without access to an effective vaccine. Unlike many other infectious diseases, TB has a latent period which can be identified by indirect testing, or predicted based on geography, local disease prevalence, and presence of comorbidities [2]. TB preventive therapy (TPT, defined as treatment of latent infection to prevent active disease; Table 1), is highly efficacious but has several drawbacks and is woefully underused. The target set by the United Nations high-level meeting on TB for people to receive TPT was 30 million from 2018 to 2022, but the reality was 8.7 million (27%) from 2018 to 2020 [3]. Barriers to uptake of TPT include that TB is most prevalent in low- and middle-income countries (LMIC) that may lack public health infrastructure and the necessary resources to distribute medications to people at risk. The coronavirus 2019 pandemic has further illustrated the vulnerability of TPT programs among other competing priorities, as the 2021 WHO global report reported a 21% decrease in people receiving TPT [1]. Specific issues with available regimens include length of treatment (for example, commonly used courses of 6–9 months of isoniazid), side effects of the medications, which are not uncommon, and perceived but unfounded fears about the development of resistance. This last issue stems from the fact that excluding active TB can be difficult, especially in resource-poor settings, and so providers worry that they will inadvertently offer monotherapy to patients with active disease and thereby add selective pressure to promote the development of resistance. In fact, this phenomenon is not supported by available data [4, 5]. TPT regimens that include a rifamycin are also associated with risk of drug–drug interactions, particularly with antiretroviral therapy (Table 1) [6]. Prolonged courses of TPT are also associated with suboptimal adherence to the regimen and poor completion rates [7]. Although side effects contribute to low completion rates, they account for a small fraction of the patients who do not complete treatment. The likelihood of completion is improved with new, shorter regimens: 9 months of daily isoniazid has reported completion rates of 45% to 60%, 6 months of daily isoniazid 55% to 57%, 4 months of daily rifampin 69% to 78%, but 3 months of daily isoniazid and rifampin was 75%. One month of daily isoniazid and rifapentine had the highest rate yet reported at 97% [8, 9], and also represents a treatment duration that may be readily achievable with a long-acting (LA) technology.

Table 1.

Characteristics of TPT Regimens

TPT Regimen	CDC Recommendation	WHO Recommendation	Age Range	Compatible ART Regimens for Adults
Isoniazid	Alternative Note: 9-mo regimen recommended	Strong Note: 6-mo regimen recommended	Any	Any
Three mo of once-weekly isoniazid plus rifapentine (3HP)	Preferred	Strong	> 2 y old only	EFV [31], DTG 50 mg once daily [32] or RAL 400 mg twice daily [33]; avoid TAF [34]
Four mo of daily rifampin (4R)	Preferred	Conditional	Any	EFV [35] or DTG 50 mg twice daily [36] or RAL 800 mg twice daily [37]; avoid TAF [34]
Three mo of daily isoniazid plus rifampin (3HR)	Preferred	Strong	Any	EFV [35] or DTG 50 mg twice daily [36] or RAL 800 mg twice daily [37]; avoid TAF [34]
One mo of daily isoniazid plus rifapentine (1HP)	Alternative	Conditional	> 13 y old only	EFV [38] or DTG 50 mg twice daily [39]; avoid TAF [34]

Abbreviations: ART, antiretroviral therapy; CDC, Centers for Disease Control and Prevention; DTG, dolutegravir; EFV, efavirenz; RAL, raltegravir; TAF, tenofovir alafenamide; TPT, tuberculosis preventive treatment; WHO, World Health Organization.

LA technologies for TPT by injection have the potential to address the main barriers here; specifically, length of treatment and the resulting suboptimal adherence and poor completion rates. The potential for a single administration providing a “1-shot cure” would assure complete adherence with a single encounter, making directly observed therapy requirements obsolete. In addition, avoiding oral delivery and the associated first-pass metabolism in the liver may improve bioavailability and, although more research is needed, could decrease drug–drug interaction liability involving certain molecular mechanisms (eg, those mediated within the intestine). If people eligible for TPT could just be given 1-time administration that would be effective in preventing TB for years, this could have a major impact on the goal of TB eradication. However, some LA technologies in particular provide a long pharmacokinetic (PK) “tail” of suboptimal exposure, which will require careful evaluation before widespread rollout.

TARGET PRODUCT PROFILE OF LA DRUGS FOR TREATMENT OF AND POSSIBLE MODIFICATIONS FOR PREEXPOSURE PROPHYLAXIS AND ACTIVE TB TREATMENT

In 2018, members of the LA/Extended Release Antiretroviral Resource Program (LEAP) TB Working Group proposed a target product profile (TPP) describing minimally acceptable and ideal attributes of LA regimens for latent TB infection (LTBI) treatment [10]. This TPP, summarized in Table 2, was focused on preventive therapy for individuals with confirmed or suspected LTBI, with suspected LTBI referring to close contacts of patients with active pulmonary TB. In 2022, the WHO also presented a TPP describing product attributes that should be considered when developing and investigating TPT regimens [11]. Although the WHO TPP stated that exclusively oral regimens are preferred, it also noted that LA injectable regimens could also be considered as such regimens could minimize treatment interruption, extend protection, and reduce the frequency of drug administration. Importantly, the LEAP-developed TPP aligned well with the WHO-developed general TPP, with a few notable differences. The WHO TPP suggested less frequent injections (1× per month or less frequently) than the LEAP TPP (1× per week or less frequently); the WHO TPP also indicated that oral lead-ins could be combined with an LA injectable, and that implants should be sufficient for the entire duration of treatment and be dissolvable (Table 2). Part of the reason for this discrepancy is that the LEAP TPP embraced a wider spectrum of LA technologies, some of which are sufficiently less invasive so as to warrant consideration of weekly administration (eg, orally administered LA medicines, transdermal microarray patches). Originally based on the LEAP TPP but consistent with the WHO TPP, development of a monthly TPT intervention is now the subject of intensive research and development efforts through the Unitaid-funded LONGEVITY project (see the following section).

Table 2.

Target Product Profile for LA Formulations for LTBI and Possible Modifications for Preexposure Prophylaxis and Treatment of Active TB Disease

Attribute	LTBI, Preexposure, or Active TB	Minimal Regimen	Ideal Regimen
Indication	LTBI	Treatment of presumed drug-susceptible LTBI	Treatment of all LTBI, including contacts of patients with drug-resistant TB
	Preexposure	Prophylactic treatment of PWH in high TB burden settings; PWH who have successfully completed treatment for active TB disease	Prophylactic treatment of PWH in high TB burden settings; PWH who have successfully completed treatment for active TB disease
	Active TB	Continuation phase treatment of active drug-susceptible TB	Continuation phase treatment of active drug-susceptible or drug-resistant TB
Availability of DST	LTBI	For index case (if known), rapid, low-cost DST method that can be implemented locally	No requirement
	Preexposure	Not applicable	Not applicable
	Active TB	Patient has confirmed drug-susceptible TB	No requirement
Target populations	All	Adults and other age groups with regulatory approval	All age groups
Number of compounds in the regimen	LTBI	1 drug	1 drug
	Preexposure	1 drug	1 drug
	Active TB	2 drugs	2 drugs
Route of administration	All	IV infusion, IM/SC injection or implantation	IM/SC injection or implantation
Product presentation	All	2 × 2 mL injections, or implant WHO: injections may include an oral lead-in	Single injection (≤2 mL; 25-gauge needle or smaller), or implant WHO: injections may include an oral lead-in
Dosage form and schedule	LTBI	Suspension administered 1× per wk or less frequently for up to 3 mo, or 1× per mo for ≥6 mo; or implant lasting for up to 3 mo WHO: suspension administered 1 × per mo or less frequently and may include an oral lead-in; single, dissolvable implant for duration of treatment	Suspension administered less frequently than 1× per mo for up to 3 mo, or implant lasting up to 1 y WHO: suspension administered as 1 or 2 injections and may include an oral lead-in; single, dissolvable implant for duration of treatment
	Preexposure	Dosing on a schedule with minimal or no extra clinical visits outside of routine HIV care: 1× per mo or less frequently; or implant lasting up to 3 mo	Dosing on a schedule that does not require extra clinical visits outside of routine HIV are: 1× per 3 mo or less frequently; or implant lasting up to 1 y
	Active TB	For a 4-mo continuation phase (standard): 1× per mo or less frequently; for a continuation phase <4 mo (in development): 1× per 2 wk or less frequently; or implant lasting at least the entire duration of the continuation phase	No more than 2 injections to complete continuation phase treatment; or implant lasting at least the entire duration of the continuation phase
Expected efficacy	All	Noninferior to standard of care	Superior to standard of care
Contraindications, warnings, precautions, interactions, and use during pregnancy and lactation	All	No additional monitoring required and DDIs no worse compared to current therapy; mild injection site reaction	No contraindications or warnings; no significant side effects; no DDIs, safe for use during pregnancy and lactation; no injection site reaction
Shelf-life and storage	All	2 y at 4°C WHO: If cold chain required, it should be compatible with the current vaccine cold chain requirements	3 y at 40°C and 75% humidity
Product registration	All	Approved by FDA, EMA, WHO PQ, and national authorities of high TB burden countries	Approved by FDA, EMA, WHO PQ, and national authorities of high TB burden countries
Cost of treatment	All	No greater than current total health system cost	Less than current total health system cost

The profile for LTBI was originally developed by the LEAP TB Working Group [10], and characteristics from the WHO TPP [11] have been noted.

Abbreviations: DDI, drug-drug interaction; DST, drug susceptibility testing; EMA, European Medicines Agency; FDA, US Food and Drug Administration; IM, intramuscular; IV, intravenous; LA, long-acting; LEAP, LA/Extended release Antiretroviral Resource Program; LTBI, latent tuberculosis infection; PQ, prequalification; PWH, people living with HIV; SC, subcutaneous; TB, tuberculosis; WHO, World Health Organization prequalification.

In addition to using TPT for LTBI, the WHO consolidated guidelines for TB prevention recommend that TPT also be considered as preexposure prophylaxis in people with human immunodeficiency virus (HIV) (PWH) who are at particularly high risk of TB infection, including children ≥12 months who live in a setting of high TB transmission and PWH of any age who have successfully completed treatment for active TB disease because the rate of disease recurrence among PWH is high and has been shown to be predominantly from reinfection [12]. As part of comprehensive HIV care, TB preexposure prophylaxis may be administered for longer durations or even continuously, and therefore some modifications to the LA TPP could be considered (Table 2). For example, a TB preventive LA regimen that did not necessitate extra clinical visits outside of routine HIV care could significantly improve uptake and adherence, and ultimately TB prevention, in these populations at increased risk for TB infection. Additional benefits could also accrue through accessing the existing infrastructure in this way, and warrant further exploration in the coming years.

Another potential role for LA formulations in TB control is for use in the continuation phase of treatment for active TB disease. For drug-susceptible TB, current first-line treatment consists of a 2-month initial/intensive phase of 4 drugs (rifampin, isoniazid, pyrazinamide, ethambutol) intended to eliminate most of the bacterial burden before patients then transition to the continuation phase of treatment in which 2 drugs (rifampin and isoniazid) are administered for an additional 4 months [13]. Completion of the continuation phase is important for eliminating all persisting bacteria and curing the patient; unfortunately, the continuation phase is also a high-risk period for poor adherence and treatment discontinuation [14]. An LA formulation could significantly improve completion rates, reduce treatment administration time, and eliminate the need for daily directly observed therapy, which would help patients and alleviate burdens on TB control programs. The use of LA formulations could be considered not only for the current first-line TB treatment regimen, but also for novel regimens under development for both drug-susceptible and drug-resistant TB. Possible modifications of the LEAP TPP to include LA formulations for treatment of active TB are presented in Table 2 and include a minimal requirement of 2 drugs in the formulation with ideal dosing of 1 or 2 injections or 1 implant for the entire continuation phase. Thus, insights gained from the development of LA regimens for TB prevention could greatly facilitate downstream efforts to develop such regimens for active TB treatment.

TB DRUGS: SUITABILITY FOR LA FORMULATIONS

Many technologies are now being explored across indications in LA research and/or product development. Clinical products for other indications have been successful with injectable formulations (eg, oil depot, polymer microspheres, aqueous drug particle dispersions) and implants. Several other approaches, at different stages of technology readiness, are the subject of intensive research in academic and industry laboratories. Among others, these include microarray patches for transdermal LA drug delivery, gastric residence devices for oral LA delivery, and novel approaches to injectable formulations (eg, in situ–forming implants).

Drug selection for LA drug delivery is a critical component of successful product development and requires drugs with specific pharmacological properties to maximize success. Specifically, the duration of achievable exposures relies heavily on potency and the rate of systemic clearance. Drug potency dictates the target exposures for successful efficacy outcomes, thus setting the bar of plasma or tissue site concentrations that need to be maintained. The lower the bar for exposure, the more readily long durations can be achieved at volumes or format sizes that can be tolerated by the intended route of administration. For current small-molecule LA delivery formats, long PK half-lives are achieved through flip-flop kinetics, in which the rate of drug absorption is slower than the rate of systemic clearance. Therefore, unlike rapid-release formulations, the half-life is not dependent on the systemic clearance mechanisms but, rather, the drug cannot be cleared until it is absorbed and so half-life flip-flops from rate of elimination onto rate of absorption. Despite this, slow rates of elimination are highly desirable because they underpin the overall steady-state concentrations that may be achieved. Therefore, success from a pharmacological perspective requires an appropriate balance between potency and rate of elimination. Unfortunately, most first-line TB drugs do not have the optimal properties for LA formulation; specifically, they have low potency, short half-lives, and particularly for isoniazid, high aqueous solubility [10]. Rifabutin, rifapentine, bedaquiline, and delamanid have physicochemical characteristics that make them more attractive candidates for LA administration [15], and we now have proof of concept in preclinical studies for some of these, discussed in the following section.

Several emergent technologies rely on complex material manufacture, which likely limits the short-term applicability in LMIC contexts. Conversely, oil depot and particle dispersion technologies involve comparably simply manufacturing processes that may be more amenable to cost-effective interventions for diseases such as TB where the major burden resides in LMIC. Advanced materials can be more readily tailored toward the physicochemistry of a preferred drug molecule by providing functional materials able to control drug release and therefore drug absorption. Conversely, oil depot and aqueous particle dispersions require hydrophobic drug molecules either to maximize solubility in an oil, or to generate drug particles that can be dispersed into an aqueous vehicle without rapid drug dissolution. Aqueous particle dispersions have proven to be more tolerable than oil depot formulations, which have been associated with substantive pain at the depot site that can persist for months [16]. Thus, particle dispersions are currently a preferred approach, but careful optimization is required to obviate rapid drug dissolution, which limits the durations that can be achieved and can result in potentially dangerous exposures early in the profile. Highly hydrophobic drugs are therefore a prerequisite for these commonly used technologies.

Use of prodrug approaches to increase hydrophobicity in a bioreversible manner can address the incompatibility of polar anti-TB drugs for LA formulations, and enable their coformulation with other anti-TB agents. For example, isoniazid bears a single reactive functional group, N² of the hydrazide moiety that is amenable to bioreversible masking via hydrazine, amide, or carbamate linkages. Isoniazid hydrazones have been extensively studied as potential anti-TB agents. The Schiff base linkage to isoniazid can be used to introduce hydrophobic groups that can enhance drug–nanoparticle interactions and drug nanoencapsulation [17, 18], or to covalently link isoniazid to nanoparticles [19, 20]. Although relatively stable at neutral pH, the Schiff base is labile under acidic conditions characteristic of intracellular TB. Isoniazid release from isoniazid-hydrazone nanoformulations or nanoparticles loaded with hydrazone-linked isoniazid has been observed under infection-relevant conditions. Self-immolative hydrophobic isoniazid prodrugs amenable to nanoformulation should be achievable for rapid isoniazid release under neutral physiological conditions, via enzyme-mediated prodrug activation after release from nanoparticles.

PRELIMINARY DATA AND ONGOING STUDIES

In 2018, the LEAP TB Working Group summarized ongoing efforts in the development of LA formulations of anti-TB drugs [10] that, at the time, mainly consisted of chemistry and in vitro preclinical studies, as well as a seminal study conducted by the LEAP modeling core that used physiologically based PK modeling to simulate potential LA injection strategies for several key anti-TB drugs [15]. There have subsequently been several exciting and promising developments in this field, most notably the development of an LA injectable formulation of bedaquiline, the first-in-class diarylquinoline ATP synthase inhibitor, by Janssen. This LA formulation was developed as an aqueous microsuspension, and a single 160 mg/kg injection of this formulation in mice yielded plasma exposures above the minimum inhibitory concentration for Mycobacterium tuberculosis for at least 13 weeks postinjection and was associated with significant bactericidal activity—equivalent to daily oral rifampin monotherapy but not as potent as once-weekly oral isoniazid-rifapentine—in the validated paucibacillary mouse model of TPT [21]. These promising results led to a long-term follow-up study to assess the bactericidal and sterilizing activity of 6 different LA bedaquiline-containing regimens, with and without oral lead-ins, in the same mouse model [22]. This study identified several regimens with equivalent anti-TB activity as the oral 1-month daily isoniazid-rifapentine control and 2 regimens (both containing oral lead-ins) with superior activity to the control regimen. Thus, the LA bedaquiline formulation holds real promise for use in TPT.

Additionally, there is a pipeline building for development of other LA formulations. Unitaid and the National Institutes of Health (NIH) recognized the transformative potential of LA formulations on TB control, and both institutions established research initiatives to support the development of LA formulations of anti-TB drugs. The Unitaid-funded LONGEVITY project, initiated in 2020, is focused on product development of LAI formulations of rifapentine and isoniazid for TB prevention (as well LA formulations for malaria prevention and hepatitis C virus treatment) for LMIC (https://www.liverpool.ac.uk/centre-of-excellence-for-long-acting-therapeutics/longevity). Also in 2020, the NIH announced a funding opportunity to support development of LA treatments for HIV and HIV-associated co-infections (RFA-AI-20-024). According to the NIH RePORTER system (https://reporter.nih.gov/), 2 TB-related projects have been funded under this initiative: project R61AI161820, focused on the development of novel, synthetic injection depot technology; and project R61AI161809, focused on the development of LA formulations for TB prevention and treatment with next-generation diarylquinolines (TBAJ-876, TBAJ-587), as well as companion agents such as delamanid, pretomanid, and rifabutin. Furthermore, the NIH has authorized funding to support for the LEAP TB Working Group within the LEAP parent grant (project R24AI118397), and the recently issued a Notice of Special Interest for sustained release treatment of latent TB (NOT-AI-22-042). In addition to these funding initiatives, new TB drug LA-related projects have surfaced at conferences and workshops. For example, at the 2021 International Workshop on Clinical Pharmacology of Tuberculosis Drugs, there were 2 presentations focused on LA formulations for TB, including 1 focused on determining plasma exposure profiles of rifapentine and rifabutin for efficacious LA formulations for TPT [23, 24]. Similarly, at the 2022 Conference on Retroviruses and Opportunistic Infections, there were also 2 presentations about LA formulations for TB, including a presentation about an LA formulation of rifabutin comprising biodegradable polymers that solidify after subcutaneous injection, hence making the drug depot removable [25, 26]. Therefore, it is anticipated that the coming years will herald numerous advancements in the development of LA formulations for TB prevention and treatment.

TRANSLATION AND TRANSITION TO CLINICAL STUDIES

Because most research regarding development of LA formulations of anti-TB drugs has focused on preventive therapy, it is critical to consider how to bridge the preclinical studies to human trials. Animal models of infection are invaluable tools for defining drug exposures necessary for antimicrobial efficacy and ranking prospective treatment regimens. The development of new drugs and regimens for TB indications relies heavily on animal models, especially mouse models, to inform preclinical decisions and clinical trial designs. This is particularly true for the development of new TPT options because of the lack of a suitable biomarker for assessing treatment response in early clinical trials. The inability to culture or otherwise quantify viable bacteria during LTBI and the lack of validated surrogate biomarkers means that there is no opportunity to obtain initial proof of efficacy and characterize dose–response relationships for experimental TPT regimens, which is usually the domain of phase 2 trials. Instead, the development of new TPT regimens requires bridging directly from preclinical studies and phase 1 trials to phase 3 trials, which are themselves long and require large numbers of participants. The search for biomarkers that act as prospective signatures of risk for developing TB disease is a very active research area and an important scientific priority for the field [27]. A validated biomarker to target those at highest risk for disease progression may dramatically shorten the time and expense of clinical trials in TB prevention and could be an important tool to accelerate the development of new TPT regimens, including LA formulations.

Although a number of animal models of LTBI have been used to evaluate prospective treatments, the paucibacillary mouse infection model has the strongest evidence base supporting its utility. Past and present regimens used to treat LTBI are accurately ranked by their bactericidal activity in this model compared with the recommended treatment durations in the clinic, providing important validation of the model [28]. Recent studies have used the model to establish the efficacy of an LA formulation of bedaquiline [21, 22] and to estimate rifapentine and rifabutin exposures needed for efficacy to inform the future development of LA formulations [24]. Importantly, these studies have provided compelling evidence that predictions of efficacious drug exposures should be derived or confirmed in animal models because assumptions based on in vitro drug susceptibility testing are not sufficient. Moreover, the tractability and relatively low expense of mouse infection models makes them attractive for establishing initial proof of efficacy and deriving exposures necessary for efficacy for a drug or compound even before investing in development of LA formulations. Larger animal models of LTBI may play a complementary or confirmatory role in the development of LA formulations [28]. In particular, the development of caseating lesions in nonhuman primate and rabbit models may introduce new physical compartments altering drug partitioning within lesions that are sufficiently distinct from those in mice to affect the efficacy of some drugs. These models may also offer advantages when it comes to extrapolation of drug PK to humans.

Translational PK-pharmacodynamic (PD) modeling is a promising tool for bridging from preclinical studies to clinical trials. Animal models can provide key information on PK-PD relationships needed to predict efficacious human exposures, but interspecies differences in PK, host immune responses and pathology, as well as human variability in these parameters make it difficult to extrapolate results directly from animal models to humans. Recent work to establish translational PK-PD models of active TB and LTBI treatment that account for such interspecies differences has demonstrated their potential utility [29, 30]. For example, Radtke et al. built a mechanistic translational model of LTBI treatment to account for species-specific PK parameters, plasma protein binding, and host immune effects in the context of LTBI and used it in clinical trial simulations to predict the clinical efficacy of a 6-week rifapentine monotherapy regimen [30]. A baseline model of the mouse immune effect on bacterial growth and death was integrated with rifapentine and rifapentine-isoniazid combination PK and PD data from experiments in the paucibacillary mouse infection model to develop a PK-PD model describing the relationship between rifapentine exposure and bacterial killing and the impact of isoniazid on the combination. Integrating this model with human population PK models for rifapentine and isoniazid enabled prediction of the drug effects in a human population. Incorporating this type of translational modeling in the preclinical evaluation of LA formulations in preclinical animal models could therefore be extremely valuable for the interpretation and ultimate translation to clinical studies.

DISCUSSION

LTBI is highly prevalent across the global population and represents an immense reservoir for the development of active TB disease, which leads to further transmission of M. tuberculosis in the population. Accordingly, treatment of LTBI is an essential component of global TB control efforts [2, 3]. The use of LA technologies for the administration of TPT could help mitigate several of the key limitations associated with poor utilization of the current oral regimens. Challenges remain before this reality can be fully actualized, but recent advances in the development of LA formulations of TB drugs have significantly progressed this concept from an innovative idea to a foreseeable reality.

Currently, formulation development is known to be funded/under way for at least 7 anti-TB drugs/compounds, namely rifapentine, rifabutin, isoniazid, delamanid, bedaquiline, and the next-generation diarylquinolines (TBAJ-876 and TBAJ-587), with the Janssen-developed bedaquiline formulation in the most advanced stages of preclinical studies. Thus, there is an emerging preclinical pathway for the establishment of exposure-efficacy relationships specific to LA technologies, founded on the pathway utilized for assessment of oral TPT regimens. Further studies with different formulations, combined with translational PK-PD modeling efforts, will be critical factors in transitioning to clinical studies and validating the preclinical pathway for LA technologies for TPT. A key limitation that impacts assessment of any TPT regimen in clinical studies is that the bacterial burden cannot be measured before, during, or after treatment in humans with LTBI. Establishment of clinical efficacy biomarkers would thus greatly accelerate the evaluation of TPT regimens containing LA technologies in human LTBI and would also help in defining and validating the critical preclinical pathway required for LA technologies for this indication.

LA technologies hold great promise for improving the successful utilization of TPT. The numerous ongoing projects indicate that interest in this research area is growing, and the coming years should yield significant advancements in the field. This innovative and exciting work has the potential to revolutionize and transform global TB control.

Notes

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).