Executive summary – tuberculosis

14 July 2016. Related: Pipeline report, TB coinfection.

Tuberculosis diagnostics

The year 2015–2016 saw more concrete progress in moving new TB diagnostic tests from research to recommendation by the World Health Organization (WHO) than any year since 2010, when the WHO recommended GeneXpert MTB/RIF.

As Erica Lessem shows in this year’s Tuberculosis Diagnostics Pipeline, in the past year, the WHO “approved Alere’s lipoarabinomannan (LAM) test – a very affordable, simple, rapid, noninvasive, point-of-care (POC) rule-in test for people with HIV with very low CD4 counts… New versions of line-probe assays [LPAs] – Hain’s MTBDRplus and MTBDRsl and a product from Nipro [NTM+MDR-TB Detection Kit 2] – received WHO recommendations… Improvements on nucleic acid amplification tests such as GeneXpert Omni and Ultra and Molbio’s TrueNAT are being validated… Further upstream, encouraging research into gene sets that can predict active TB disease and reliably distinguish it from latent TB and other infections may eventually underpin new blood tests… Incremental advances are being made to improve the detection of pediatric TB.” [1]

Lessem cautions, however, the deployment of new TB diagnostic tests remains abysmal, with 3.6 million of the world’s estimated 9.6 million new TB cases in 2014 undiagnosed; “59% of cases of multidrug-resistant (MDR-TB) undetected… [and] a mere US $65 million in 2014 funding out of an estimated annual need of $340 million in research investment in new TB diagnostics tests.” Furthermore, WHO guidance on how to implement recently-approved tests remains in development, while the funds to scale-up their use remain elusive. Disappointingly, fourteen TB diagnostic test candidates are in later stages of development or already marketed (in some countries) without any new published data since the 2015 Pipeline Report [see table 2].

An implementation science study carried out in in South Africa, Tanzania, Zambia, and Zimbabwe showed that “among 578 people with HIV… using LAM was associated with an absolute reduction of all-cause mortality at eight weeks of four percent, and a relative risk reduction of 17 percent… [apparently] attributable to the test’s allowing earlier initiation of … anti-TB therapy.” [2] The LAM test should be deployed rapidly in hospitals and clinics in high-HIV burden settings so that this benefit may help to prevent some of the hundreds of thousands of cases of TB disease and death among people with HIV.

The newer line probe assays (LPAs) are a step forward in making drug-susceptibility testing (DST) more available, but their drawbacks include technical difficulty, requirement for separate rooms for each stage of the process, and the possibility of contamination, which could yield inaccurate results. The newer innovations with Xpert platforms such as Xpert XDR, Omni, and Ultra, will each be a step forward, and less difficult to carry out than the LPAs, but suffer from incomplete penetration of the health care sector, maintenance issues, and the high cost of the machine itself.

As Lindsay McKenna points out in a special section on diagnosing pediatric TB, in the past year, WHO doubled the estimated annual number of TB cases among children to one million. TB diagnosis among infants and children is more difficult than in adolescents or adults. Research to improve the situation remains insufficient and lags behind the advances mentioned above. The next-generation Xpert tests are expected to have increased sensitivity and ability to diagnose paucibacillary disease common in children. The LAM urine dipstick was not particularly sensitive or specific in pediatric studies to date, but the WHO recommendation to use the test includes HIV-positive children with CD4 counts below 100/mm3 along with adults. As with all aspects of pediatric tuberculosis, more research, program implementation, resources, and political will are needed to move forward. [3]

Tuberculosis prevention – vaccines and preventive therapy

After two-and-a-half decades when efforts to contain tuberculosis focused principally on treating the disease – especially in its drug-sensitive form – the TB policy and research world has recently begun to expand its focus to include greater emphasis on prevention, as Mike Frick demonstrates in “The Tuberculosis Prevention Pipeline.” [4]

Last year the WHO released its first-ever Guidelines on the Management of Latent Tuberculosis Infection [5]. Earlier this year UNITAID adopted TB prevention as a new area of emphasis for intervention [6]. In spite of the flatlined infectious diseases research agenda at the U.S. National Institutes of Health (NIH), the White House issued an (unfunded) National Action Plan for Combatting Multidrug-Resistant Tuberculosis last December [7]. (The President’s proposed fiscal year 2017 budget, proposed in January of this year, recommended cutting global TB control funding by $45 million, or 19% [8, 9].) WHO’s new “End TB Strategy” concludes that reaching the proposed elimination targets will required intensified efforts to prevent TB transmission through chemoprophylaxis and – when available – a vaccine. [10]

Frick discusses a number of high-priority questions in TB prevention research, including efforts to identify genetic signatures of risk for progression of TB infection – whose discovery and validation could help speed up research in both TB vaccines and preventive therapy – disparities between measurable immune responses in the blood and in the lung where most TB disease occurs, the mystery of the mycobacterial granuloma, and the perennial question of MTB persistence in the face of a partially-effective immune response and sometimes-curative chemotherapy.

The TB vaccine field is experiencing a move back towards basic and early-phase clinical research, one reminiscent of what happened with the HIV vaccine field after the setback of the STEP trial, in which the adenovirus-5 vector in which the HIV immunogens were delivered actually caused increased HIV infection as compared to the study’s placebo arm [11, 12]. Just one trial is in phase III, one in phase IIb, six in phase IIa, and five in phase I. The predominant approaches include whole-cell preparations of M. vaccae, genetically attenuated MTB, recombinant BCG, whole-cell M. obuense, and ‘fragmented’ MTB; prime-boost studies of various TB antigens with various adjuvants; while the phase I studies are all prime-boost approaches using viral vectors and TB proteins [see Table 1. TB Vaccines in Development].

TB vaccine R&D is massively underfunded – investments in 2014 totaled just $111.3 million, less than one-third of the Global Plan-recommended $380 million annual target [13] – and it is difficult to see how the TB vaccine field will produce a safe, effective vaccine by the 2025 target required by The End TB Strategy [10: Figure 2. Projected acceleration in the decline of global tuberculosis incidence rates to target levels; p. 5]. The field is moving towards earlier-stage translational studies and novel clinical trial designs targeting TB incidence rather than prevention of disease as a primary endpoint. The problem here is that diagnosing TB infection definitively is even harder than diagnosing TB disease. We already know that 3.6 million of the world’s annual 9.6 million cases of active disease already go unreported. Proving that TB infection has been prevented would require a test better than the currently-used tools of tuberculin skin testing (TST) and interferon gamma release assays (IGRAs), which are all too unspecific, insensitive, and likely to give contradictory results in different hands or in different settings. Other approaches such as targeting TB reactivation or reinfection suffer from the same lack of a definitive measurement tool, except for genetic fingerprinting in cases of active TB disease when reactivation can be distinguished from reinfection by a different molecular fingerprint, in cases where the original disease-causing strain is still on hand for comparison.

Lack of resources is leading to excessive caution in the populations prioritized for research, as Frick points out: “[b]y conducting fewer clinical trials in children and people with HIV, TB vaccine developers are effectively making the decision to direct research away from the two groups most vulnerable to TB… developers should acknowledge that the current strategy risks leaving behind two key TB-affected populations with greatly enhanced risks of disease and death that rightly draw significant attention from global health actors.” [4]

Luckily, this is not the case in TB preventive therapy research, where “children and people with HIV still occupy the center of efforts to develop new or improved preventive therapies.” [4]. According to Frick, “Eight studies are underway or in late development, six of which are examining different dosing schedules of rifapentine, administered either in combination with other drugs such as isoniazid or alone. Two studies are investigating preventive therapy for individuals exposed to DR-TB, one looking at daily delamanid vs. INH and the second comparing 6 months daily levofloxacin vs. placebo.” (See Table 2, Clinical trials of TB treatments to prevent tuberculosis disease; and Lindsay McKenna’s Table 1: Ongoing and Planned TB Prevention and Treatment Studies in Children.)

Tuberculosis treatment

TB treatment remained largely unchanged in 2015 with five new drugs at various stages of clinical development. Of these, two – bedaquiline and delamanid – have approved accelerated approval from the US FDA (in 2012 for bedaquiline) and conditional approval from the European Medicines Agency (EMA, in 2014 for delamanid) as additive therapies to use with background regimens to treat multidrug resistant (MDR) TB. Pretomanid, formerly PA-824, a drug similar to delamanid but further behind in clinical trials, is being studied in various combinations for drug-sensitive, MDR, and extensively-drug resistant (XDR) TB. Sutezolid, a drug which spent the first decade on the shelf after the acquisition of Pharmacia and Upjohn by Pfizer, then came to life briefly when an early bactericidal activity (EBA)/phase IIa study showed anti-TB activity in the clinic, and is now paralyzed due to the inaction and lack of resources of Sequella, Inc., which bought the drug from Pfizer when the latter abandoned infectious disease research. The past year saw the abandonment of AstraZeneca’s AZD5847 due to lack of anti-TB activity and the emergence into the clinic of Qurient’s Q203, a new drug from a new class developed by a company in South Korea.

As Erica Lessem shows in “The Tuberculosis Treatment Pipeline: Activity, but No Answers,” the rollout of both bedaquiline (BDQ) and delamanid (DLM) has been painfully slow. Safety concerns following the apparent excess of late deaths in the phase IIb study of bedaquiline, along with the general and pervasive delays of TB programs in adopting new technologies, have slowed its uptake. It took almost four years for the sponsor, Janssen, to start its phase III study following accelerated approval in December 2012 – surely a massive abuse of the accelerated approval system. Similar delays afflicted a long-agreed-to drug-drug interaction study of BDQ and DLM to determine if their QTc-prolonging activity (a marker of cardiac toxicity) was additive and compromised safety, or whether the two drugs could safely be co-administered; legal foot-dragging by Janssen means that the study still has not begun today, even though both sponsors agreed to conduct it in December 2012.

Increasing amounts of programmatic data, particularly from South Africa, indicate that the addition of BDQ to background treatment appears to be increasing cure rates for pre-XDR and XDR-TB, without an excess of cardiac deaths. Otsuka, the maker of delamanid, has been so tardy in registering the drug or even allowing its compassionate use, that few safety and no additional efficacy data are yet available. The ongoing phase III study is expected to be reported out in 2018. Meanwhile, the company has an ethical obligation to register the drug in the many high-TB-burden countries where it carried out its phase II studies, and in places with high burdens of DR-TB. The soon-to-launch ACTG/IMPAACT PHOENIx study, which will compare 6 months of DLM to INH among household contacts of people with MDR-TB, will provide considerable new safety data on the drug, as well as showing whether it can prevent MDR-TB acquisition or disease among these high-risk individuals.

Ambitious plans for pretomanid came to a standstill last fall when the ongoing STAND study of pretomanid-moxifloxacin-pyrazinamide (PaMZ) among people with DS and DR-TB was put on clinical hold because of three sudden hepatic deaths among people in the DS-arm who were receiving PaMZ. Nine months later the study’s data safety monitoring board has signaled that the study can proceed with additional safeguards.

Sutezolid remains paralyzed by the sponsor’s lack of funds or willingness to cooperate with other players. However, the drug’s patent status suggests that outside manufacturers could make the drug, and it is hoped that this will allow phase IIb studies to begin in the next 18 months.

A number of studies are looking at repurposed older drugs in new indications or at new dosing levels. High-dose studies of rifampin and rifapentine are ongoing. One study, TRUNCATE-TB, seeks to accelerate the validation of a super-short-course two-month regimen for DS-TB by comparing four two-month regimens. It’s understood that failure levels will be higher than with six months of the current regimen, but it is hoped that the majority of people would be cured in two months and that the others would still respond to standard therapy.

Other studies continue to look at, and sometimes to compare, fluoroquinolones such as levofloxacin and moxifloxacin in drug-resistant disease . (and – controversially – gatifloxacin, which was removed from developed-world markets for toxicity some years ago, has also been re-recommended by the WHO for the treatment of MDR-TB) in drug-resistant disease.

Dose-ranging studies are being planned at last for two old drugs whose importance in TB treatment has recently become clearer, clofazimine and linezolid.

An EBA study presented at the 2016 CROI showed that the carbapenem meropenem, given with amoxicillin/clavulunate intravenously [IV] three times a day, had measurable anti-TB activity without grade 3/4 toxicity. Another drug in the class, ertapenem, may also have activity, though it too requires IV administration. [14]

Pediatric TB treatment research is one of the brighter spots in the overall clinical TB research landscape, as Lindsay McKenna shows in “The Pediatric Tuberculosis Treatment Pipeline: Beyond Pharmacokinetics and Safety Data” [15]. Long-neglected formulations suitable for children have finally advanced towards market and new studies in preventive therapy, dose optimization, and treatment for drug-resistant disease are finally beginning to be carried out. McKenna shows five studies are planned or underway for TB prevention, five for treatment using new drugs (3 DLM, 2 BDQ), and fourteen studies of various existing drugs, combinations, and interaction studies with commonly-used antiretrovirals (see Table 1: Ongoing and planned TB prevention and treatment studies in children). Researchers continue to try and optimize dose-levels for first-line therapy in young children, where achieving pharmacokinetic levels similar to those of adults has proven challenging. Co-treatment for HIV and TB remains an issue for children, again because of the lack of previous drug-drug-interaction studies and necessary formulations. Meanwhile, research on second-line drugs and how to shorten and simplify treatment for drug-resistant disease in children is even further behind.

Otsuka has completed pediatric dosing studies of delamanid for 12-to-17-year-olds and 6-to-11-year-olds; a study using the DLM pediatric formulation in children aged 5 and younger is expected to be complete in time for the launch of PHOENIx, which will compare delamanid to INH among household contacts – including children 5 years and under, TST-positive persons, and those living with HIV – of MDR-TB cases, to see whether six months of DLM can better prevent transmission and progression to active disease of MDR-TB.

Janssen has been further behind in its pediatric research on BDQ, principally because the FDA – unlike the EMA – lacks the power to mandate pediatric studies, even of drugs where there is such a high global burden of pediatric disease. Its first PK/safety study in HIV-negative children opened in May 2016, 3.5 years after FDA approval in adults – another unacceptable delay by Janssen.

McKenna highlights the importance of conducting TB treatment research in pregnant women, where data are lacking not only on drug safety and activity, but even on TB incidence, though it is estimated that almost a quarter-million women may develop active TB each year. The IMPAACT network is conducting two studies of TB prevention and one TB treatment study in pregnant women. (See Table 2: Ongoing and planned TB prevention and treatment studies in pregnant women.) McKenna recommends the establishment of a TB Pregnancy Registry, similar to the Antiretroviral Pregnancy Registry which that has been underway since 1989.

Finally, McKenna reviews current progress on pediatric formulations for first-line therapy (several fixed-dose combinations of HRZ, HR, or HP from five companies; four single-drug dispersible tablet forms of E, H, Z, and P from Macleods and Sanofi; and 7 second-line drugs in dispersible tablets or mini-capsules; see Table 3: Pediatric formulations in development). [15]

2016 tuberculosis pipeline recommendations

TB Diagnostics Recommendations

• “Both R&D on and access to evidence-based TB diagnostic tests need dramatic infusions of funding and political will.
• National governments and donors must substantially increase funding for TB programs to allow for best diagnostic practices. This includes the widespread scale-up of NAAT to supplant microscopy, universal DST using liquid culture or LPAs, digital X-ray, and the rapid adoption of LAM testing in areas with high HIV burdens.
• National governments, donors, and the private sector must invest far more in TB R&D to advance better tests, including those for children. This should include a commitment to rapidly and rigorously evaluating new technologies and to publishing peer-reviewed results.
• National governments and donors should work closely with the nonprofit and private sectors to ensure only quality and affordable tests are used. In countries with large proportions of care-seeking in the private sector, access to appropriate diagnostics is extremely limited and can be catastrophically expensive.
• Developers must commit to timely and rigorous validations of their tests prior to marketing, and health and regulatory authorities and private practitioners should hold them accountable for doing so. Epistem and other companies who market ineffective or as-yet-unproven tests must cease doing so immediately. National governments should ban the import and use of inappropriate tests and enforce those bans. Those working in TB globally should call to task companies such as Epistem that inappropriately market them.” [1]
• “Greater efforts to identify children at risk for TB – especially within maternal and child health programs, where sick children often first present for care – and referral systems and decentralized capacity to diagnose childhood TB, clinically or with available tools, are urgently needed.
• Developers should validate tests in adults and children in parallel to expedite access to improved diagnostic technologies for children. These evaluations should include a variety of sample types in children with and without HIV and should assess age-related performance.
• Developers and donors should increase investments in research to discover and validate biomarkers and innovation to translate these biomarkers into simple and affordable tests that can rapidly and accurately diagnose TB, monitor treatment, and predict disease progression in children. In 2014, less than $2.3 million and $2.8 million was spent globally on research and development for pediatric TB diagnostics and basic science, respectively;
• Developers and research networks should establish and support harmonized and collaborative pediatric biorepositories important for biomarker discovery and development.
• Developers and researchers should support and create networks of sites that support rigorous evaluation of new diagnostics and can pool data to more rapidly demonstrate the impact of new tools.
• Programs should scale up and decentralize the use of existing technologies and strategies to diagnose pediatric TB infection and disease, especially within maternal and child health programs.
• Programs should train health care workers to improve their ability and confidence to clinically diagnose children with TB when tests are unavailable or come back negative.” [2]

TB Prevention Recommendations

• “For funders: Ensure financing mechanisms are sufficiently flexible and durable to support the multi-year, collaborative research endeavors that will be required to make progress against a challenge as complex and intractable as MTB infection. For example, nearly ten years passed between when the South African adolescent cohort enrolled its first participant in 2005 and when it published results announcing the discovery of a risk signature of disease progression in The Lancet in 2016. This was not time wasted, and the cohort will likely yield publications and results for years to come. Further advancing our knowledge of MTB infection and TB disease may require larger cohorts with even longer periods of follow-up. In addition, funding agencies should support translational work to bridge advancements in basic science with clinical development and maintain openness to a wide range of approaches that probe the nature of MTB infection from the perspective of both host and pathogen, and through the application of new assays and imaging technologies in both humans and animal models.
• For vaccine researchers and developers: Continue to explore a greater diversity of approaches to TB vaccine development through the use of experimental medicine studies and trials designed around novel endpoints. Ultimately, this will likely require developers to introduce wholly new vaccine candidates whose designs look beyond the narrow focus on cell-mediated immunity that has dominated past efforts. The development and introduction of new assays that are able to translate signals of immunogenicity between lung and blood (or capable of safely measuring vaccine responses directly in the lung itself) should also be a priority. Developers and their sponsors should not foreclose on clinical trials among infants and people with HIV, two of the groups most in need of a new TB vaccine. Although previous trials in these two populations have fallen short of expectations, there is much that can be learned from past failures. Rather than wholly abandon vaccine concepts and constructs that did not work, vaccine researchers and developers should more forthrightly interrogate the reasons behind disappointing results.
• For drug researchers and developers: Accelerate research to understand MTB persistence and the nature of latency to develop new drugs targeting latent infection. Efforts to understand MTB persistence would benefit from initiating a dialogue with researchers involved in vaccine development about differences in how the TB drug and vaccine fields approach preclinical testing. Each field is confronting challenges related to MTB persistence and the nature of latency, but vaccine and drug developers do not always measure the same pathology or immunological events using relatable endpoints or definitions of scale in the animal models in which much of this work will be conducted. Closer collaboration with their vaccine counterparts might also open the door for drug developers to use vaccines as adjuncts to shorten therapy or reduce the risk of relapse. In the meantime, ongoing efforts to shorten and simplify TB preventive therapy for children, people with HIV, pregnant women, and household contacts of people with DR-TB should continue. The advanced stage of many of TB prevention trials obligates pharmaceutical companies involved in this research – namely, Sanofi and Otsuka – to take steps to register their products more widely and facilitate equitable access through measures such as affordable pricing.
• For all researchers and developers: Recognize community engagement in research as the ethical complement to good clinical practice and take steps to involve representatives from TB- affected communities in all stages of R&D. The potential of ongoing or planned TB preventive therapy and vaccine studies to refashion clinical practice in ways that could render many more people with asymptomatic MTB infection eligible for medical intervention makes it imperative that developers create meaningful spaces for community voices, concerns, and priorities to enter the research process. Communities must become true partners in TB prevention research, and not merely its silent beneficiaries.
• For activists: Take up TB prevention as a unified cause and break with the habit of advocating for vaccines, preventive therapy, and infection control as separate and unrelated technological fixes. With the exception of TB PROOF – a South African advocacy group founded by doctors who contracted TB that is dedicated to preventing MTB infection among healthcare workers – activist voices in TB prevention have been few in number and modest in volume. This absence does not reflect a lack of need. A global shortage of BCG continues into its third year, needlessly endangering the lives of millions of infants. Rifapentine, the cornerstone of TB preventive therapy research, is registered for the treatment of MTB infection in just one country, despite being studied in at least a dozen more. Individuals exposed to MDR-TB have few evidence-based options to treat probable drug-resistant infection. And countries remain slow to rollout proven interventions such as IPT to people with HIV, 400,000 of whom died from TB in 2014. We are one year closer to 2025, the year WHO says new prevention tools must be introduced to reach the End TB Strategy’s goal of eliminating TB by 2035, and there is no new vaccine or transformative preventive drug regimen on the immediate horizon. The clock is ticking.” [4]

TB Treatment Recommendations

1. “Government agencies, pharmaceutical companies, and foundations must dramatically scale up funding for TB R&D. In line with the third pillar of the WHO’s End TB strategy, which calls for R&D, countries must commit more resources to TB drug development.77 The U.S. government, which is the leading funder of TB R&D, should increase funding levels to $300 million by 2018 to keep its critical investments at pace with inflation. TAG suggests that this should entail an additional $17 million from the NIH, $15 million from USAID, $16 million from the U.S. Centers for Disease Control and Prevention, and $5 million from the FDA for TB R&D.78 European Union countries, particularly Germany, should double their TB R&D funding, and Brazil, China, India, Russia, and South Africa should each triple their funding for TB R&D.79 Activists in other countries should call for commensurate increases in their own settings. Companies such as Otsuka and Sanofi should maintain strong levels of investment, and Janssen needs to recommit to further developing bedaquiline, as significant work remains despite bedaquiline’s conditional approval, and to moving the most promising of its pipeline of bedaquiline analogues further toward clinical study. Other pharmaceutical companies and philanthropic organizations should also begin to invest in TB R&D.
2. Donor and high-TB-burden governments should create and invest in mechanisms that build access to TB drug development, and drug developers should participate in them. The inability to access data hampers collaborative TB drug development, which is essential because TB must be treated with a combination of drugs to prevent the development of resistance. The inability to access drugs hampers TB treatment and cure and threatens to render the limited R&D that is occurring less useful. Fortunately, members of the TB community have proposed feasible and appealing solutions that should be actively pursued. These include remedying loopholes in the FDA’s priority review voucher system to ensure innovation and drug availability and fair pricing and should also entail product developers licensing their compounds to and sharing data with the MPP, which recently received a mandate to work on TB drug development and could possibly play a key role in brokering combination drug development.81 MSF’s proposed 3P (“Push, Pull, Pool”) project may also provide an interesting, innovative, and potentially transformative approach to spur the development of regimens and ensure their availability post-approval, though the devil here will lie in the details of how it is actually executed.
3. Drug and trial sponsors must expedite the development of preclinical and clinical candidates. Delays in TB research and development are widespread and atrocious. The TB drug development pipeline remains frighteningly sparse, pointing to the urgent need to advance preclinical work to allow viable candidates into clinical studies. Clinical development for the few products in the pipeline has been unacceptably slow, with drugs taking over five years to advance from one stage to the next. In particular, Janssen’s and Sequella’s failures to rapidly move bedaquiline and sutezolid, respectively, through important studies are deplorable.
4. Ministries of health, regulatory authorities, and ministries of finance should prioritize the timely introduction of evidence-based TB treatment, and donors and providers of technical assistance should ensure they are supporting rather than hindering scale-up. Drug development will not affect the TB epidemic and improve the lives of people affected by TB unless new interventions are available to communities and people who need them. Unfortunately, country-level demand for important new products such as delamanid and bedaquiline has been weak, and implementation slow. USAID, which has partnered with Janssen to make bedaquiline available via a donation program, literally cannot give the drug away for free to enough people. Poor advice from technical assistance providers has worsened the situation and excused complacency. All parties, national and global, must be much more ambitious and supportive of new ways to find and treat TB.

Pediatric TB Treatment Recommendations

“For researchers:

• Consider children when planning adult studies. Building PK investigations into studies that evaluate higher doses of TB drugs in adults is necessary to inform future PK targets in children.
• Determine which PK value(s) correlate best with efficacy for TB drugs in children and establish PK targets based on adult data, taking into consideration the variability in severity and type of TB disease among, and challenges defining efficacy in, children.
• Enroll children two years of age and younger in pediatric studies, as this is the period during which drug disposition changes the most for children, increasing risk for high or low drug exposures.
• Include HIV-positive children in studies of new TB drugs and regimens.
• Include pregnant women in studies of new TB drugs and regimens.

For policy makers:

Incorporate emerging data into guidelines for children more rapidly, especially those for new and second-line TB drugs in children.

For regulatory authorities:

• Enforce more thoughtful requirements to ensure comprehensive and timely investigations of TB drugs in children. Mandatory and time-bound pediatric investigational plans that also require studies in HIV-positive children will help to shrink the persisting evidence and access gaps that exist between adults and children for new TB drugs.
• Follow the important precedent set by the EMA and allow parallel enrollment of pediatric cohorts in PK and safety studies.
• Be transparent and clear about requirements to register pediatric formulations for both existing and new drugs.
• When possible and appropriate, consider waived requirements and registration fees to facilitate access.” [15]

For donors:

• Maintain and adequately fund momentum in pediatric TB drug R&D, for which global investments totaled $11.6 million in 2014. Recent attacks on the budget for and AIDS research priorities of the NIH are particularly concerning for pediatric TB R&D. Not only is the NIH the leading funder, but its investments support studies that are critical to improving treatment of pediatric TB and to filling both long-standing and new gaps in pediatric PK and safety data, especially for HIV-positive children taking ARVs.
• Further attention to and investments in pediatric TB trial infrastructure and site capacity development are urgently needed to support the increasingly full research agenda for prevention and treatment of TB in children.
• UNITAID, whose investments have led to the market introduction of appropriately dosed FDCs of first- line TB drugs for children, and whose planned investments will ensure global uptake of these new formulations, should invest in a project modeled after STEP-TB that is focused on expediting development and market introduction of pediatric formulations of second-line TB drugs.

References

1. Lessem E. The Tuberculosis Diagnostics Pipeline. HIV i-Base/TAG 2016 Pipeline Report.
2. Peter JG, Zijenah LS, Chanda D, et al. Effect on mortality of point-of-care, urine-based lipoarabinomannan testing to guide tuberculosis treatment initiation in HIV-positive hospital inpatients: a pragmatic, parallel-group, multicountry, open-label, randomised controlled trial. Lancet. 2016 Mar 19;387(10024):1187-97. doi: 10.1016/S0140-6736(15)01092-2.
3. McKenna L. Tuberculosis Diagnostics Research for Children. HIV i/Base/TAG 2016 Pipeline Report.
4. Frick M. The Tuberculosis Prevention Pipeline. HIV i-Base/TAG 2016 Pipeline Report.
5. World Health Organization. Guidelines on the management of latent tuberculosis infection. Geneva: World Health Organization, 2015. Available from:
   http://www.who.int/tb/publications/ltbi_document_page/en/. (Accessed 25 June 2016.)
6. UNITAID. UNITAID to invest in effective approaches to end tuberculosis. 2016 March 18. Available from:
   http://unitaid.org/en/statements/1524-unitaid-to-invest-in-effective-approaches-to-end-tuberculosis. (Accessed 2016 May 25).
7. The White House. National action plan for combatting multidrug-resistant tuberculosis. Washington, D.C.: The White House. 2015 December. Available from:
   https://www.whitehouse.gov/sites/default/files/microsites/ostp/national_action_plan_for_tuberculosis_20151204_final.pdf (Accessed 25 June 2016).
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   http://kff.org/global-health-policy/issue-brief/the-u-s-global-health-budget-analysis-of-the-fiscal-year-2017-budget-request. (Accessed 25 June 2016.)
9. Office of Management and Budget. The President’s budget for fiscal year 2017.
   https://www.whitehouse.gov/omb/budget. (Accessed 25 June 2016.)
10. World Health Organization. Global strategy and targets for tuberculosis prevention, care and control after 2015: report by the Secretariat. Geneva: World Health Organization Executive Board 134th Session. EB134/12. 2013 November 29.
    http://www.who.int/tb/strategy/End_TB_Strategy.pdf?ua=1 (Accessed 25 June 2016).
11. Buchbinder S, Mehrotra DV, Duerr A, et al. Efficacy assessment of a cell-mediated immunity HIV-1 vaccine (the Step Study): a double-blind, randomised, placebo-controlled, test-of-concept trial. Lancet 2008 Nov 29; 372(9653):1881-1893. Published online 2008 Nov 13. doi:10.1016/S0140-6736(08)61591-3.
12. Duerr A, Huang Y, Buchbinder S, et al. Extended follow-up confirms early vaccine-enhanced risk of HIV acquisition and demonstrates waning effect over time among participants in a randomized trial of recombinant adenovirus HIV vaccine (Step Study). J Infect Dis. 2012 Jul 15; 206(2): 258-266. Published online 2012 May 4. doi:10.1093/infdis/jis342.
13. Frick M. 2015 Report on tuberculosis research funding trends, 2005–2014: a decade of data; p. 23. Treatment Action Group, New York. November 2015.
    http://www.treatmentactiongroup.org/tbrd2015 (accessed 25 July 2016).
14. Lessem E. The tuberculosis treatment pipeline: activity, but no answers. HIV i-Base/TAG 2016 Pipeline Report.
15. McKenna L. The pediatric tuberculosis treatment pipeline: beyond pharmacokinetics and safety data. HIV i-Base/TAG 2016 Pipeline Report.
16. Frick M. personal communication. 28 June 2016.