Overview of TB in pregnant and lactating women.

In most countries, TB incidence peaks in women of reproductive age, irrespective of HIV [22]. Pregnancy is not routinely included in national/international TB registries, but worldwide, at least 216,000 TB cases are reported to occur in pregnancy annually [2]. Immune changes in pregnancy may alter the risk of disease, TB presentation, and diagnosis [4,31,32]. Complications of TB developing during pregnancy and lactation are well known and can include maternal death, preeclampsia, vaginal bleeding, and maternal death as well as prematurity, low birth weight, and fetal or infant death, particularly if TB is inadequately treated [22,33,34]. Notably, many TB drugs are categorized by the US FDA as former category C (Table 1), and many have undetermined placenta crossing, fetal, or lactation compatibility [6] (Table 1). In addition, drug absorption, distribution, metabolism, and elimination may be modified in pregnancy and lactation [35,36], and increased clearance of some drugs requires dose modification, particularly in the third trimester [37]. Lastly, there is often a significant time gap between licensure of medicines and pregnancy-specific data being obtained. HIV antiretrovirals, which have more data in pregnancy, still had a median gap of 6 years from licensure to access [38].

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Table 1. FDA/WHO pregnancy classification and select maternal–fetal and reproductive toxicity characteristics of drugs used to treat TB.

https://doi.org/10.1371/journal.pmed.1002882.t001

TB trial design considerations and recommendations for pregnant and lactating women.

In 2018, the US FDA and the US Federal Task Force on Research Specific to Pregnant Women and Lactating Women (PREGLAC) issued separate documents to accelerate inclusion of pregnant and lactating women in clinical trials. The FDA draft guidance [23] outlines prerequisites for “reasonable” and “ethically justifiable” inclusion of pregnant women in premarketing studies (i.e., “adequate” preclinical data plus the potential to provide unique clinical benefit to the woman or fetus) and postmarketing studies (i.e., “adequate” nonclinical data plus established safety in nonpregnant women and no alternate means to extrapolate efficacy and/or assess safety). Generally, Phase I and II trials should be conducted in nonpregnant women of reproductive age, and inclusion of pregnant women should be considered in Phase III or IV trials based on clear risks and benefits assessment. Critical trial components include PK data with minimum requirements (i.e., gestational age at enrollment, gestational timing/duration of drug exposure, and pregnancy outcomes [adverse maternal, fetal, and neonatal events]), obstetrical care meeting recognized standards for pregnant women on trial, and follow-up safety data among infants of mothers with investigational drug exposure. The FDA also provides guidance regarding evaluation of systemic drug exposure to fetus/newborn, women who become pregnant on study, obtaining adequate nonclinical reproductive and developmental toxicology data, identifying trial populations standing to benefit most while minimizing risk, gestational timing of investigational drug exposure relative to fetal development, and appropriate control populations. In its report, PREGLAC highlighted 15 recommendations to encourage research on therapies during pregnancy and lactation, the majority of these being of particular relevance to TB therapeutics [18].

An international group of experts has also issued recommendations with particular reference to TB treatment trials: pregnant and lactating women should be eligible for Phase III MDR TB trials unless a compelling reason for exclusion exists, drug companies should be encouraged to complete reproductive toxicity studies of TB drugs before beginning Phase III studies, trials of shortened treatment regimens for latent TB infection (LTBI) should be designed to improve completion rates and reduce risk of progression in pregnancy and lactation, targeted PK studies should be nested in all TB studies when evidence is lacking, and a TB pregnancy registry should be established to accumulate data on maternal–infant outcomes [6]. These were discussed at the March 2018 WHO technical consultation discussions, and the following propositions were made.

Trial designs for active TB disease in pregnant and lactating women.

Inclusion in Phase III trials is likely the only way to access more optimal regimens/newer agents and generally the only way to obtain safety, PK, and outcome data in this population, as postmarketing studies are not prioritized for funding or by regulatory bodies. In this respect, because MDR TB has significant morbidity and mortality and because many MDR TB drugs are associated with substantial intolerance and adverse effects, it is reasonable to consider inclusion of pregnant and lactating women in Phase III MDR TB treatment trials when there is no teratogenicity signal from reproductive toxicity. However, to our knowledge, no Phase III trial of MDR TB treatment has included pregnant women to date. To counter the automatic exclusion of pregnant women that currently pervades the TB trial landscape, early discussion among trialists, pharmaceutical companies, maternal–child experts, ethicists, and regulatory bodies are needed to address risks, benefits, and compelling rationale for inclusion [7].

Another important approach is to capture pregnancy outcomes among women who become pregnant while participating in a therapeutic trial. Current practice is to discontinue study drugs at the time pregnancy is identified and define the participant as “unassessable.” Instead, newly pregnant participants should be reconsented, offering the option to continue the study drug unless teratogenicity is known or suspected. All current information concerning the drug/regimen during pregnancy should be reviewed and communicated, including any shifts in risk–benefit balance, and carefully described to the patient. Examples of such secondary consent forms have been developed and are already used in some clinical trials [4]. Furthermore, support and mandates to standardize systematic data collection and reporting to a global pregnancy TB treatment registry is urgently needed. Similar to the HIV antiretroviral therapy (ART) registry, data from pregnancy, delivery, and infancy until age 6 months should be mandated [39, 40]. Whether from trials or registries, collecting PK and outcome data among pregnant women will be invaluable and can be pooled for analysis once sufficient data have accumulated. Novel physiologically based PK and pharmacodynamics (PD) modeling can also be applied to estimate drug dosing in pregnancy, but prediction of safety and toxicity profiles still requires trial data [41].

The postmarketing opportunistic PK model illustrated by International Maternal Pediatric Adolescent AIDS Clinical Trials Network (IMPAACT) P1026s [42] is another approach to advance the evidence base (Table 2). This protocol is enrolling pregnant and lactating women to assess the safety and PK of first- and second-line TB drugs routinely used in clinical practice as regimens evolve [43]. Assessments are made by pregnancy trimester, at delivery, and postpartum, with careful monitoring/ascertainment of maternal, fetal, and infant outcomes. PK of multiple TB drugs are captured in maternal plasma by pregnancy stage and from cord blood, breast milk, and infant samples along with relevant maternal–fetal–infant safety and clinical outcomes. This model also allows for study of DDIs between TB drugs and both antiretrovirals and postpartum contraceptives [44,45].

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Table 2. Ongoing and planned clinical trials in pregnant and lactating women (as of December 2018).

https://doi.org/10.1371/journal.pmed.1002882.t002

Trial designs for TB preventive therapy in pregnant and lactating women.

Despite the large burden of LTBI and risk of progression to active TB, pregnant women have been systematically excluded from the >12 Phase III and postmarketing clinical studies of TB preventive therapy [6,46]. Data from nonpregnant individuals and small observational studies have informed the guidance for isoniazid preventive therapy (IPT) in pregnancy [47,48]. The first randomized placebo-controlled trial to assess safety and optimal timing of IPT in HIV-infected pregnant women in high-TB-burden settings (IMPAACT P1078) was recently completed (Table 2) [49]. The relative risks and benefits of immediate antepartum versus deferred postpartum IPT initiation was assessed and included careful monthly monitoring of maternal, fetal, pregnancy, and infant outcomes. No differences in maternal safety outcomes, maternal–infant TB, or infant safety outcomes were found between arms, but an increase in composite adverse pregnancy outcomes was observed in the immediate IPT arm. Shorter-course, efficacious TB preventive therapy regimens have been studied in nonpregnant adults [50,51]. With greater advocacy and effort on behalf of groups focused on high-quality data for pregnant women, postmarketing trials assessing shorter LTBI regimens are also now underway or in development for pregnant women (Table 2). These include IMPAACT P2001 (PK and safety of 3 months of weekly isoniazid and rifapentine [3HP]) and IMPAACT Concept 5021 (safety, tolerability, optimal timing, and PK of 3HP versus 1 month of daily isoniazid and rifapentine [1HP]).

The IMPAACT network serves as an excellent example of how a group focused on therapeutics in pregnant women can make major strides to close the evidence gap (Table 2). Establishing a global TB registry and inclusion of pregnant women into relevant Phase III TB trials should be the next step. TB therapeutic protocols under development should be reviewed by experts in the care of TB in pregnant women, maternal–fetal medicine specialists, regulatory authorities, and bioethicists who can further comment on the risks and benefits of including pregnant women during the trial planning stage.

Overview of TB in children.

Globally, approximately 10% of TB cases occur among children (0–14 years) annually. Of the estimated 1,000,000 cases in 2017, only 360,000 were notified to WHO, yet children < 5 years old are particularly vulnerable, accounting for >50% of child TB cases and approximately 80% of child TB-related deaths [1]. In contrast to the situation in adults, children display a wide spectrum of TB disease phenotypes ranging from nonsevere, often paucibacillary pulmonary/intrathoracic TB (usually uncomplicated lymph node disease) to severe disseminated TB and TB meningitis, a major cause of TB-related morbidity and mortality in children [52]. Paucibacillary intrathoracic TB (minimal or nonsevere TB) is more prevalent overall, and TB treatment outcomes are generally good for drug-sensitive (DS) and drug-resistant (DR) TB (provided treatment is initiated early), even when considerably lower doses of antituberculosis drugs were used for DS TB [53]. However, risk of progression from infection to active TB disease varies substantially by age and with HIV infection. PK also varies because of effects related to child age and size. Young children, particularly <2 years old, are at much higher risk of developing TB and severe disease forms [54] and typically require higher mg/kg doses of most TB drugs to reach adult therapeutic targets. Finally, TB diagnosis and treatment response monitoring rely on clinical, more subjective measures in at least 60% of children, as young children cannot spontaneously produce sputum for examination, and paucibacillary disease (sputum smear negative) is diagnosed by culture, the current diagnostic gold standard, in only 30%–40% of cases [55].

TB trial design considerations and recommendations for children.

With concerted effort and advocacy along with academic and government funding and recognition from regulatory agencies, the pediatric TB trial landscape has substantially improved, as evidenced by the number of ongoing and planned studies of treatment for the diverse forms of TB in children (Table 3). The ways in which pediatric and adult TB differ inform the type of pediatric TB drug trials needed and their key design considerations. If children are to be included in adult trials, different inclusion and exclusion criteria may be needed, and definitions used to determine study endpoints (e.g., unfavorable outcome) require careful consideration because of differing clinical features and diagnostic challenges of TB in children compared with adults. Diagnosis, treatment response monitoring, and characterization of treatment outcome in children often depend on clinical measures that are relatively imprecise compared with the diagnostic standard used in adults. Limited availability of pediatric-friendly formulations also poses a barrier to enrollment of younger children. Large Phase III clinical trials may not be feasible or always needed for children, yet timely PK and safety data in children, especially in young and HIV-infected children, is critical to inform policy guidance on new therapies deemed to be safe and efficacious in adolescent and adult populations. Modified study designs should be explored to accelerate implementation of PK and safety studies in children while ensuring the validity of the trial results and the safety of all child participants. Unlike younger children, adolescents (typically ≥10 years old) have TB disease characteristics similar to adults, including frequent cavitating disease. Adolescents should therefore be routinely considered for inclusion in adult Phase IIb and III trials. However, similar to pregnant and lactating women, legal requirements for child participation in clinical trials are often barriers (perceived or real) and vary by country. When feasible and justified through appropriate consultation, the inclusion of children should be carefully considered and supported early during protocol development. Summaries of considerations for the types of trials needed for children, including practical and ethical considerations regarding inclusion of children in TB trials, can be found elsewhere [5, 56]. Highlights and considerations discussed at the WHO technical consultation are discussed below based on updated information.

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Table 3. Ongoing and planned TB clinical trials in children (as of December 2018).

https://doi.org/10.1371/journal.pmed.1002882.t003

Trial designs for active TB disease in children.

Considering scenarios in which disease progression and/or response to an intervention are expected to differ among adults and children, the classical approach is to conduct PK studies in children to establish appropriate dosing followed by safety and efficacy trials. For example, because children often develop less severe, paucibacillary TB, it is plausible that children would respond equally well (i.e., treatment would have at least equal efficacy) to shorter, less intense, and less complex regimens than adults while potentially improving their tolerability, safety, acceptability, and adherence. Identifying such regimens would require an efficacy study in children, as regimens that could be effective in children may be rejected in adult trials. Based on these assumptions, the currently ongoing Shorter Treatment for Minimal TB in Children (SHINE) trial (ISRCTN63579542) investigates whether a shorter 4-month regimen can be used for children with less severe disease than the standard 6-month adult regimen (Table 3). Other examples include the treatment of LTBI (discussed below) and TB meningitis. TBM Kids (NCT 02958709) is the only currently open trial to assess the treatment of TB meningitis, which especially affects very young children.

In contrast, when considering scenarios in which children and adults are expected to have similar disease progression, response to an intervention, and exposure response, then it is logical to conduct PK studies to achieve drug exposures similar to adults, followed by safety trials at the proper dose. For individual TB medications, it is reasonable to assume that the response in children would be at least as good as in adults. Therefore, repeating formal efficacy studies for individual TB drugs in children is unnecessary. Instead, the focus should be on trials to establish PK, dose, and safety in children. Many of the trials shown in Table 3 are such studies, including the pediatric trials of the recently approved drugs bedaquiline and delamanid. Another example is the Opti-Rif Kids trial (South African trial identifier 27-0117-5411), which aims to characterize rifampin doses among children 0 to <12 years old that approximate exposures observed in adults receiving higher rifampin doses (≥35 mg/kg) in adult trials [57]. Both age and weight have an impact on PK in children and must be considered in the design of pediatric PK studies of TB drugs. It is especially critical to include young, small children given that the effects of age and weight are most pronounced in this subgroup. Traditionally, age-de-escalation studies have been a major feature of pediatric PK-focused Phase I/II trials whereby children have been studied in series, rather than in parallel, starting with older children and progressing to younger children. This approach, however, should be avoided if possible: it is costly and time consuming; older children may have limited ability to inform dosing and safety in the youngest children, for whom there is the most uncertainty; and regulatory agencies do not strictly require age de-escalation [5]. HIV infection and malnutrition are additional, important covariates to consider when designing pediatric trials, and these children should be included in TB therapeutic trials.

If the exposure response to an intervention is expected to differ among children and adults, then PK/PD should be conducted to establish the exposure response in children followed by safety studies. If a PD marker is unavailable to assess pharmacologic response, as is typically the case in bacteriologically unconfirmed TB (i.e., clinically diagnosed TB), then PK studies should be followed by safety and efficacy studies [56]. The traditional assumption that exposure response is similar among children and adults for all types of TB is being questioned. For example, most children with pulmonary TB are sputum smear and culture negative and therefore have different bacillary burden compared with adults with cavitating disease. Given that childhood TB may differ in disease type and severity compared with adult TB, target concentrations for treatment of many forms of childhood TB may differ from those in adults. This provides additional justification for efficacy trials in children in some instances. For example, there are no data from trials investigating regimens to prevent MDR TB in either adult or child household contacts. TB-CHAMP (ISRCTN92634082) is a Phase III cluster-randomized placebo-controlled study that is specifically powered to evaluate the efficacy of 6 months of levofloxacin versus placebo for the prevention of TB in young child household contacts (age < 5 years) of MDR TB cases. Although not powered for efficacy in children, the PHOENIx trial (A5300/I2003) plans to study adult, HIV-infected, and child contacts of MDR TB using delamanid versus isoniazid and is a good example of how key populations can be studied within a single Phase III efficacy trial (Table 2).

Lastly, child-friendly formulations are important to ensure accurate, acceptable, and palatable doses in young children. The development and implementation of bioequivalence studies of pediatric formulations is lengthy and should start much earlier during the drug development process. A potential temporary solution is to better understand how manipulating the adult formulation affects the PK to inform pediatric use. The TASK-002 study successfully assessed the relative bioavailability of 100-mg bedaquiline tablets suspended in water versus when administered in healthy adult volunteers to inform its use in children [58]. This does not eliminate the need for making pediatric formulations available but does improve access to much-needed medications during the timeframe following trial completion and drug registration until routine medication availability.

Overview of TB in HIV-infected persons.

Worldwide, an estimated 1,040,000 TB cases and 300,000 TB deaths occurred among HIV-infected persons in 2017–86% of reported HIV-associated TB deaths occurred in sub-Saharan Africa [1]. TB is 20–30 times more likely in the context of HIV and remains the leading cause of death in this population. Adults and children with advanced HIV disease (low CD4 count) are especially vulnerable. This subgroup has a particularly high mortality rate [59] and is more likely to have disseminated TB disease and more rapid disease progression. Despite this, a 2011 review revealed that many TB trials exclude HIV-infected persons with CD4 counts < 200–350 cells/mm³ [60]; our review of recent [61–64], currently enrolling, and registered (clinicaltrials.gov) randomized TB trials suggests recent expansion of inclusion criteria, but HIV-infected persons with very low CD4 counts (<50–100 cells/mm³) remain frequently excluded (Table 4). Overall, clinical management of dual TB–HIV disease is complex [12,65]. As in children, smear-negative TB disease is common in the context of HIV, which poses challenges for TB diagnosis and treatment monitoring. In addition, polypharmacy arising from treatment of HIV, TB, and new/existing comorbidities may increase adverse events and impact adherence and tolerability. Drug metabolism, absorption, and toxicity profiles may be altered in HIV, making longer courses of treatment and side effects, such as neuropathy, liver injury, and rash, more likely [66,67]. Immune reconstitution inflammatory syndrome (IRIS)/paradoxical worsening, specific cytochrome interactions, poor nutritional status, and chronic inflammation further impact HIV-infected populations. As in children and pregnant women, physiologically based PK modeling can help inform TB drug dosing in the setting of HIV but cannot replace data generated from trials. In recent years, high-quality evidence has dramatically evolved the use and timing of TB treatment in relation to ART [68]—persons with advanced HIV who are diagnosed with TB are currently recommended to start ART within 2 weeks [69,70]. However, potential DDIs remain a major concern for TB treatment in HIV-infected persons, particularly between antiretrovirals, such as protease inhibitors and integrase inhibitors, and rifamycins, key TB sterilizing agents [12,65]. DDIs and adverse effects cannot always be readily identified from observations in HIV-uninfected populations. A healthy-volunteer study assessing a TB-preventive regimen (rifapentine and isoniazid) and interaction with dolutegravir (HIV antiretroviral) found significant toxicity and was terminated early, yet these effects were not observed in a larger study of HIV-infected persons [71,72]. It is important that TB trials assess the full spectrum of HIV/TB and be sufficiently powered to evaluate the impact of HIV [41,60].

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Table 4. Ongoing and planned TB clinical trials in HIV-infected persons 12 years and older (as of December 2018).

https://doi.org/10.1371/journal.pmed.1002882.t004

Trial design considerations and recommendations for TB disease and preventive therapies in HIV-infected persons.

Inclusion of HIV–TB-coinfected populations in TB clinical trials poses a number of challenges. To enhance their enrollment, TB trials should be conducted, at least in part, in geographic locations where HIV and TB epidemics coincide and interact. Partnering with public-funded trials networks specializing in recruitment of HIV-infected persons can facilitate this. For example, the US CDC Tuberculosis Trials Consortium (TBTC)/AIDS Clinical Trials Group (ACTG) partnership has enhanced enrollment of HIV-infected people in the Phase III randomized trial of rifapentine-containing shortened treatment for pulmonary TB (NCT02410772). Requesting culture-confirmed disease for trial eligibility also limits enrollment of HIV–TB-coinfected persons. Sensitivity of sputum smear and culture are limited by low bacillary load of TB in the context of HIV [73]. As in young children, less stringent measures, such as clinical TB diagnosis, could be incorporated. To ensure balanced treatment assignments among various trial subgroups, randomization could be stratified by HIV status (i.e., HIV-infected versus -uninfected) or by specific eligibility criteria (i.e., culture-confirmed versus nonconfirmed). Incorporating clinical TB diagnosis as a secondary outcome measure (ideally reviewed by an expert committee blinded to treatment assignment) may also be important for interpreting results in the overall trial population and in key subgroups. Outcome rates could also be assessed by HIV infection/HIV disease status and/or ART use, as treatment outcomes in HIV–TB-coinfected patients may be highly dependent on the specifics of ART management. Consistent with HIV and TB treatment guidelines, ART should be required or expected to be initiated within 4–8 weeks of initiating TB treatment. It is important to understand whether mortality or other poor outcomes in HIV–TB-coinfected patients is related to HIV or TB. Thus, data analysis should be stratified by HIV infection/HIV disease status (i.e., HIV-uninfected, HIV-infected with high CD4 count, and HIV-infected with low CD4 count) to reduce concerns about any potential imbalances in subgroup numbers between randomized arms.

Carefully designed DDI studies are a major element of clinical research of TB therapeutics for treatment and prevention of TB in HIV-infected people, including HIV-infected adults and children [74]. DDIs may be bidirectional, and the potential impact of host genetics is difficult to predict from small PK studies alone. To facilitate enrollment of HIV-infected individuals, DDI studies should be conducted early in drug development and/or nested in major trials [41]. The Phase III randomized ACTG 5279 trial, “Short-Course Rifapentine/Isoniazid for Treatment of Latent TB in HIV-Infected Individuals” (NCT01404312)[51], is an example of a nested DDI study: the first 90 participants that were on efavirenz-based ART and randomized to the rifapentine arm entered into a semi-intensive PK study [75] and were evaluated for PK/PD and potential HIV virologic failure to confirm that efavirenz PK and ART outcomes remained adequate. As in this example, the risk to a TB trial may be lower if PK of an HIV drug is the concern, particularly for shorter periods of TB drug use. If the potential DDI involves one of the TB drugs and may affect the randomized comparison, then an alternative trial design might be used: HIV-infected individuals could be excluded from randomization to the TB intervention but entered into a parallel PK cohort to evaluate the DDI. Once the potential DDI has been resolved, including by testing different drug dosing, randomization of HIV-infected individuals might proceed expeditiously. Alternatively, an observational study could be conducted whereby HIV-infected people who are on a targeted HIV drug and start a TB drug of interest would undergo PK/PD evaluations. IMPAACT P1026s (NCT00042289) uses this design to evaluate routinely used dosing of ART and TB (DS and DR TB) drugs during pregnancy in HIV-infected and uninfected women. The key is to have an ongoing, approved protocol in place that allows for targeted drugs to be studied without needing to develop a new study for each potential DDI. Irrespective of the design used, the respective advantages and disadvantages of intensive versus sparse drug sampling should be considered to facilitate rapid enrollment and availability of information about potential DDIs.