Creating demand for long-acting formulations for the treatment and prevention of HIV, tuberculosis, and viral hepatitis

INTRODUCTION

Long-acting drugs and formulations have radically altered the management of several important and common medical conditions, including chronic schizophrenia, osteoporosis, and contraception. In all three of the aforementioned circumstances, extended-release injectable versions of approved oral drugs are commonly used in settings where there is a need to improve adherence and/or convenience for the patient. In principle, any innovations that reduce the frequency of drug administration improve adher- ence. However, in this review ‘long-acting’ refers to an alteration in the delivery of a medication that results in dosing intervals of at least 1 week for oral
medications, at least 1 month for injectable formu- lations, and at least 6 months for implants [1].

In the case of HIV infection, adherence with daily oral pills remains the most important barrier to long-term suppression of virus replication and prevention of the emergence of drug-resistant virus variants [2]. Even short periods of nonadherence may endanger the health of the patient and narrow their choices for future treatment. This is true whether antiretroviral drugs are being used for treat- ment or prevention [3]. Long-acting drugs and for- mulations are the most promising approach to improve adherence to medications that must be taken chronically (see Table 1).

A number of important infectious diseases other than HIV would benefit from the availability of long-acting or extended-release drugs and formula- tions. Since 2014, tuberculosis (TB) has been the most common cause of infectious deaths worldwide [4&&]. The current epidemic of multidrug resistant TB is driven largely by poor adherence to daily oral therapy, resulting in resistance to the most com- monly used drugs for TB control, isoniazid, and rifampicin [5]. Estimated completion rates for 9 months of daily oral isoniazid therapy for treat- ment of latent tuberculosis infection (LTBI) are poor, less than 50% in many case series [6]. Thus, the availability of even a single effective long-acting formulation that could treat LTBI would dramati- cally simplify control of this infection [7&&].

Hepatitis C virus (HCV) is estimated to infect 71 million people worldwide and is a leading cause of global morbidity and mortality despite the availabil- ityofcurative oraltherapy[8&&]. Infact, complications of chronic HCV infection now kill more adults in the United States per year than HIV and 58 other reportable infections combined [9]. With existing direct-acting anti-HCV agents (DAAs), more than 95% of persons infected with any HCV genotype can be cured with 8–12 weeks of daily oral treatment [10&,11&]. However, a large fraction of those with chronic HCV infection are never linked to care. For example, in the United States, more than half of those who know they have HCV infection have never been treated [12]. A parenteral formulation that could be administered at the time of testing and provide 8–12 weeks of effective anti-HCV coverage could eliminate this substantial impediment to care and allow a ‘test-and-cure’ public health strategy to eliminate HCV infection.

Chronic hepatitis B virus (HBV) infection is a similarly widespread and consequential threat to global health. Together with HCV, chronic viral hepatitis in 2013 caused more deaths than TB, malaria, or HIV [13]. With an estimated 257 million persons chronically infected, the mainstay of con- trol of HBV infection is prolonged treatment with daily oral therapy. However, only an estimated 10.5% of those infected with HBV are aware of their status, and only 1.7% (4.5 million) are on treatment [14]. HBV is another globally important infection that could benefit from long-acting drugs and formulations.

A variety of approaches and technologies can be applied in generating well tolerated and effec- tive long-acting formulations. Their potential benefit in treating and preventing chronic infec- tions is obvious. A more challenging scenario, assuming such products become available in the next few years, is to promote their uptake into a low-cost or generic marketplace, and assure avail- ability to those who need them most. Interest and enthusiasm in supporting the development of long-acting formulations for these different appli- cations is likely to vary by disease and geography. For example, there has been substantial invest- ment in creating such products for HIV, but very little for TB, and essentially none for viral hepati- tis. This review will focus on the current state of development of long-acting drugs and formula- tions for HIV, TB, and viral hepatitis, and propose strategies to improve their uptake and create market demand.

LONG-ACTING FORMULATIONS FOR HIV INFECTION

Cabotegravir and rilpivirine

Long-acting nanocrystal suspensions of the inte- grase inhibitor cabotegravir and the nonnucleoside reverse-transcriptase inhibitor rilpivirine are in advanced clinical development, including their use in combination in large Phase 3 studies [15&&].

Cabotegravir was developed largely because of its suitability for long-acting formulation. A single intramuscular injection of 400 mg of this formula- tion given to HIV-seronegative volunteers produced detectable concentrations of cabotegravir in plasma for more than 48 weeks [16]. Rilpivirine was already approved as an oral agent for the treatment of HIV infection at a daily dose of 25 mg, but a single 1200 mg intramuscular injection of the nanoformu- lated drug produced detectable plasma concentra- tions for up to 84 days [17].

In a randomized open-label Phase 2b trial (LATTE-2), 286 treatment-na¨ıve HIV-infected adults received abacavir and lamivudine and oral cabotegravir 30 mg daily for 20 weeks, and were then randomized 2:2:1 to all-injectable mainte- nance antiretroviral regimens of cabotegravir 400 mg and rilpivirine 600 mg every 4 weeks, or cabotegravir 600 mg and rilpivirine 900 mg every 8 weeks, or to continue the oral therapy [15&&].

After 96 weeks, HIV RNA was undetectable (<50 copies/ ml) in 84– 94% of participants taking all three regimens. Mild injection site reactions occurred commonly, but <1% of participants discontinued the study as a consequence. Several large Phase 3 trials of this combination are ongoing, as well as large Phase 3 trials of cabotegravir for HIV prevention.

Broadly neutralizing monoclonal antibodies Anti-HIV broadly neutralizing antibodies (bNABs) isolated from HIV-infected individuals target spe- cific antigens on the membrane glycoprotein gp 120, and several of these have reached clinical devel- opment for both HIV treatment and prevention [18&]. In early clinical studies, bNABs were generally well tolerated, associated with short-term virologic activity, and enhanced immune function. Although bNABs must be given intravenously at this point, a two-amino-acid substitution increases their serum half-life by 2 to 3-fold, allowing dosing intervals as long as every 3 to 6 months [19]. Clinical studies of combination bNABs are currently underway, and there are plans to combine bNABs with other long-acting antiretroviral small molecules like cab- otegravir. Although currently expensive to manu- facture, a growing market for bNABs would motivate cost-saving innovations.

Antibodies and peptides targeting cell entry Several antibodies that target receptors for HIV-1 entry have activity in humans, and one of these – Ibalizumab – was recently approved for use in patients with resistance to multiple antiretroviral drugs. Ibalizumab is a humanized IgG4 antibody that inhibits HIV-1 entry by binding to the extracel- lular domain 2 of CD4, preventing entry of the virus into CD4 T cells allosterically, and is administered intravenously every 2 weeks [20]. In a Phase 3 clini- cal trial in heavily treatment-experienced patients, 43–50% of participants achieved viral loads
<50 copies/ml by week 25, when an optimized background regimen was added [21].

Compared to other long-acting antiretrovirals (ARV’s), Ibalizumab has the disadvantage of intravenous administration and a q2 week dosing interval. Subcutaneous adminis- tration and q4 week dosing of this drug have been investigated. Similar drawbacks apply to the human- ized CCR5 monoclonal antibody PRO140 that potently inhibits R5-tropic viruses only [22]. This antibody is being investigated as a weekly or q2 weekly infusion in patients with viremia on a cur- rent ART regimen.

Albuvirtide is a 32-amino acid synthetic peptide analog of the fusion region of HIV gp-41, similar to enfuvirtide (T-20) but with a much longer plasma half-life of 12– 14 days. This drug is approved in China for intravenous administration once weekly based on the results of a Phase 3 clinical trial [23],but a subcutaneous formulation is in development that would allow self-administration every 2– 4 weeks.

Antiretroviral implants

Nondegradable subcutaneous implants of two NRTIs – tenofovir alafenamide (TAF) and 4’-ethy- nyl-2-fluoro-2’-deoxyadenosine (EFdA; MK8591) – are likely to enter clinical testing in the next 12– 18 months. A TAF implant produced measurable plasma concentrations of tenofovir for more than 6 weeks, and delivered tenofovir at an approxi- mately constant rate for up to 40 days after implan- tation [24&].

Polymer implants of EFdA resulted in an appar- ent plasma half-life approaching 100 days in rats, suggesting the possibility of human implants with a dosing interval of 1 year or longer [25]. EFdA and TAF implants could be used for HIV pre-exposure prophylaxis as single agents, or in eventual combi- nation with other long-acting antiretroviral drugs for HIV treatment. TAF implants could also be used in the long-term management of chronic HBV infection.

Potential advantages of implant technology include the ability to remove the device in the case of side-effects or the desire to end therapy, less frequent dosing because of the slow release of drug and longer apparent half-life, a lower drug dose per day because of potency and formulation properties, and better protection from poor adherence as com- pared to daily oral drugs [26&&]. Medical implants can be placed discreetly so they are not obvious to partners, family members, or colleagues, affording better protection of health privacy than daily oral regimens. The widespread use of contraceptive implants in low-income countries proves that these devices can be implemented cheaply and safely in remote areas.

PATIENT INTEREST IN LONG-ACTING FORMULATIONS

Surveys of patients currently taking daily oral ARVs consistently find broad and enthusiastic support for switching to long-acting drug delivery technologies. Of 400 adult survey respondents in two US clinics, more than 80% indicated they would definitely or probably consider switching from oral to parenteral ARV’s if the injection frequency were once per month; interest was lower if injections were given more frequently [27&]. Adolescents with or at risk for acquiring HIV infection represent a special population of greatest need for alternative dosing strategies; of 303 adolescent patients surveyed (ages 13– 24), 86– 90% stated they would definitely or probably switch to parenteral ARV’s if the injection fre- quency were once every 1 to 3 months [28]. Attrac- tions of long-acting formulations for patients at risk of HIV or already taking oral treatment include the convenience of less frequent dosing, avoidance of pill fatigue, better protection of health privacy, and avoidance of treatment-related HIV stigma (Table 1).
Over 300 participants in the Phase 2b LATTE-2 trial of long-acting -cabotegravir and long-acting – rilpivirine were asked about their experiences receiv- ing these intramuscular ARV injections every 4 or 8 weeks for up to 96 weeks. Participants reported exceedingly high levels of satisfaction with these parenteral formulations, and almost all stated their enthusiasm for continuing long-acting injections as their sole form of HIV treatment [15&&]. Although participants in this study were self-selected for want- ing access to such formulations, and therefore may have had higher opinions of these products than the general population, their surprisingly high levels of satisfaction suggest the probability of high demand for and high uptake of injectable ARVs.

LONG-ACTING FORMULATIONS FOR PREVENTING AND TREATING TUBERCULOSIS

TB kills more people every year than any other infection, and is the most common cause of death for people infected with HIV [4&&]. We have known for more than 25 years that preventive therapy with isoniazid is effective in people with HIV, and yet global uptake of this strategy is woefully low [29]. Reasons for poor uptake of isoniazid preventive therapy include the length of treatment, risk of side-effects, perceived risk of developing drug-resis- tant TB, lack of acceptance by persons at risk, and suboptimal completion rates [30].

Curative antibiotic therapy for TB disease has also been available for decades, but the duration of treatment is long, and most treatment is delivered by directly observed therapy which is expensive and intrusive. Treatment for drug-resistant disease is even longer, and poor tolerability and high rates of adverse events are serious limitations [31&&].

Recent efforts to shorten TB treatment have yielded mixed results. Three trials in drug-sensitive disease were not successful, but shorter course treat- ment for drug resistant disease has produced better results and is now recommended by WHO in certain situations [32]. In contrast, preventive therapy for latent infection has been greatly improved with the addition of a regimen of three months of rifapentine plus isoniazid , which is as effective as 9 months of isoniazid and with a better completion rate [33]. Most recently, 1 month of daily rifapentine and isoniazid proved as effective as 9 months of isoniazid in people with HIV disease, with the best comple- tion rates reported to date [34&&].

These results combined with the early success of long-acting formulations for HIV have promoted a resurgence of interest of long-acting treatment for TB [7&&,15&&]. Several approaches have been investigated to increase the dosing interval of both orally and parenterally administered anti-TB drugs, although nearly all published literature consists of only in-vitro data, with minimal animal studies and no clinical pharmacology data either in healthy volunteers or in individuals with TB [35]. Some have explored pulmo- nary delivery of TB drugs to increase drug concen- trations at the anatomic site of disease [36]. Aerosol delivery methods have been shown to sustain thera- peutic drug concentrations for extended periods of time. Parenteral approaches to long-acting drug delivery include microsphere and liposomal formu- lations, but these were not developed further [37].

Ideal candidate drugs for long-acting formula- tion require low aqueous solubility (water-soluble particles dissolve rapidly and drug is released too quickly), high potency (to lower drug dose and mini- mize plasma concentrations), and long systemic half- lives. For existing TB drugs, these properties are gen- erally lacking, and are shown in Table 2 compared to successful candidates for long-acting treatment of other diseases. Rifabutin, rifapentine, delamanid, and bedaquiline have some pharmacological and physicochemical characteristics that make them potential candidates for long-acting administration using a nanoparticle suspension approach [7&&]. Physiologically based pharmacokinetic modeling has been used to simulate potential long acting injectable administration strategies for these four drugs, and the model identified 1500 mg of delam- anid and 250 mg of rifapentine as sufficient doses for monthly intramuscular administration [38]. Beda- quiline and isoniazid would require weekly or biweekly intramuscular dosing [38]. The goal of this work is to develop an efficacious long-acting treat- ment for LTBI, for example rifapentine with isoniazid for a month’s duration. This strategy could be an important tool to accelerate progress toward TB elim- ination for those co-infected with HIV.

LONG-ACTING FORMULATIONS FOR VIRAL HEPATITIS

Hepatitis viruses chiefly cause mortality and mor- bidity as chronic infections that lead to cirrhosis or hepatocellular cancer. In 2013, chronic viral hepa- titis (HCV and HBV) killed 1.45 million people, more than malaria, HIV, or TB [13]. Although they are clinically similar, the epidemiology, prevention, and treatment of HCV differ from HBV, and with respect to long-acting drug delivery they need to be considered separately. Tenofovir prodrugs are the most commonly used agents for HBV treatment, and an long-acting implant of tenofovir alafena- mide is described in detail above, as it is being developed for HIV prevention [24&].

All the tools already exist for cure of HCV infec- tion, and, in principle, HCV could be eradicated globally. There is no reservoir for this virus other than humans, and HCV infection can be diagnosed with 99% sensitivity, even at the point of care [39,40]. With 8–12 weeks of oral daily treatment, all strains of HCV can be cured, eliminating second- ary transmission and markedly reducing the health consequences of chronic infection [11&,41,42&,43]. The WHO goal is to eliminate HCV by 2030, but less than 10% of those infected have been cured with existing drugs [8&&].

There are multiple reasons for the low public health impact of these efficacious tools for testing and treating HCV. There is widespread lack of aware- ness of infection, estimated to be approximately 20% globally. Through point of care testing for HCV, the fraction who are aware of infection has already risen in most regions of the world. The chief obstacle is linkage to care. Even in high-income countries, the principal gap in care is between diag- nosis and linkage to care (Fig. 1). In the United States in 2016, it was estimated that 2.5 million were infected and 1.5 million were aware of their infec- tion, but only 250 000 were treated [12]. As the proportion diagnosed increases, the bottleneck in linkage will increase, further threatening goals for global eradication. As all who are tested have at least some access to care during testing, it is possible to envision the utility of an long-acting formulation. This would especially be the case if the full 8– 12 weeks of bioactive DAA therapy could be delivered with a single injection given immediately after test- ing – a true ‘test and cure’ model.

As HCV cure can be achieved with only 8– 12 weeks of treatment, the barriers for long-acting for- mulation development are lower than for most other chronic infections, and lower than those faced by long-acting formulations for HIV, schizophrenia, and contraception, as discussed previously. Most of the existing HCV DAAs are extremely well tolerated; compared to placebo, no difference in adverse event rate could be detected for many of these drugs. With some of the most commonly used DAAs, there were no hypersensitivity reactions reported despite their use in more than 1 000 000 treated patients [11&,42&,44]. This high safety and tolerability dimin- ishes the need to reverse adverse events and might eliminate the need for test dosing or oral lead-ins. Similarly, there would be no concerns regarding rapid development of resistance. There are regimens that cure all known HCV genotypes, eliminating requirements for genotyping prior to treatment [10&,11&]. In fact, the relative simplicity of HCV treatment has already spawned clinical trials com- paring a test-and-treat with minimal monitoring compared to standard of care.

What remains unclear is whether the chemistry and pharmacology of existing DAA treatments are suitable for long-acting formulation. There are two combinations that are already approved for treat- ment of all HCV genotypes [10&,11&]. One includes sofosbuvir, whose pharmacology is optimal for oral dosing, making parenteral administration challeng- ing. The other regimen includes glecaprevir and pibrentasvir. Daclatasvir is a pangenotypic DAA with a strong safety record that can be combined with sofosbuvir and theoretically other DAAs [45]. It is also possible that some compounds that were not developed clinically because of low oral bioavailabil- ity might be attractive for development as long- acting HCV treatments.

Cost is also an important consideration in creat- ing market demand for these products. Initially, high drug cost was an obstacle to the widespread use of HCV medications. However, the cost to produce these compounds is 100-fold less than the US aver- age wholesale price [46], and manufacturers in India already sell curative regimens for less than 1000 USD. One would hope the cost of long-acting HCV formu- lations will reflect important public health objec- tives. Given that the opportunity and urgency for long-acting HCV treatment is so high, these feasibil- ity questions should be addressed as soon as possible.

CONCLUSION

Long-acting parenteral drug delivery technologies have revolutionized the treatment and prevention of a variety of human diseases, and hold promise for infectious diseases like HIV, TB, and viral hepatitis. Important limitations to their use include avoiding and managing drug toxicities, preventing drug resis- tance when these products are discontinued, and managing drug interactions and pregnancy. These agents hold particular promise for disease preven- tion and public health eradication approaches such as test-and-treat strategies. Because these formula- tions are more complex to develop and manufacture and are delivered parenterally, their costs tend to be higher than for daily oral therapy, although transi- tion to a generic marketplace has been successfully achieved for contraceptive injections and implants. If these products prove to be highly efficacious, well tolerated, well tolerated and economical, they are well positioned for broader uptake based on GSK1265744 experience from noninfectious diseases settings.