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Introduction and Executive Summary

July 2014

By Polly Clayden and Mark Harrington

INTRODUCTION

Last year we wrote:

[Getting] the best drugs to the most people as quickly as possible…
requires that the compounds and combination products be:

  • Discovered and developed in a high-quality research program;

  • Approved by a national or multinational regulatory authority;

  • Recommended by national or multinational guidelines groups;

  • Available in formulations suitable for use in the proposed population;

  • Affordable to public-sector programs and through private insurance; and

  • Accessible to patients through local health systems.1


One year later, the research, regulatory, and access landscape for people with HIV, hepatitis C virus (HCV), or tuberculosis (TB) remains one of stark contrasts among the three diseases, and between people with access to affordable health care—whether they live in rich or developing countries—and those without. The research pipelines described in this year’s report show substantial progress in new treatments and preventive interventions against HIV. Revolutionary changes are afoot in the treatment of HCV, which allow—for the first time—the prospect of universal cure and disease eradication—if only cost and access barriers can be overcome. But, in the case of TB, few new diagnostics, even fewer new drugs, poor access, and declining political will create a pipeline woefully underpopulated, slow-moving, and resource-deprived.

Here we highlight the first of the essential requirements outlined above, the requirement that new interventions be “discovered and developed in a high-quality research program.”

A quick scan of worldwide trials data maintained by the U.S. National Institutes of Health (NIH) at clinicaltrials.gov reveals many disparities between research and development programs for treatments of HIV, HCV, and TB. Newly approved drugs for the three diseases—dolutegravir (for HIV), sofosbuvir (for HCV), and delamanid (for TB)—have respectively 61, 67, and 6 clinical trials registered to investigate their use.

The 61 studies of dolutegravir cover: treatment-naive and -experienced patients (including those with resistance to other integrase inhibitors); comparisons, use, and interactions with the most commonly used antiretrovirals (and a couple of investigative ones); interactions with potential concomitant medicines that include studies with methadone, rifampin, and oral contraceptives; an investigation into how the drug performs in women; use in people with hepatic and renal impairment; pregnancy pharmacokinetics; a pediatric investigation program down to four weeks of age conducted by the International Maternal Pediatric Adolescent AIDS Clinical Trials Group (IMPAACT) network; and pharmacokinetics of the pediatric granule formulation. This list is not exhaustive. Despite the limitations of the registrational studies, with the usual underrepresentation of women, people with coinfections, etc., by the time all the studies are completed as well as several in the planning stage that are not yet registered, we will have a pretty good idea how the drug will perform across a diverse population (Polly Clayden looks at some of these that will help with our understanding of how the drug will perform in low- and middle-income settings in her chapter on antiretroviral dose optimization).

Registered sofosbuvir trials are also abundant and include patients with varying treatment experience, liver disease stage, and genotypes. But a closer look reveals limited investigations into regimens with other sponsors’ drugs, nothing in pregnant women or children, few in HIV coinfection (and nothing in other comorbidities), and just one (not yet recruiting) in people who inject drugs. As yet there are very few trials registered by independent investigators (and notably these are usually HIV networks or centers). Tracy Swan details the shortcomings of HCV trial enrollment in her chapter.

The tally for delamanid trials is a paltry 10 percent of those for the other two recently approved agents. It is at least encouraging that two of these trials will provide information for use in children with multidrug-resistant TB (MDR-TB). However, approval of delamanid by the European Medicines Agency (EMA) was delayed due to confusingly presented results from the phase II program, which included a two-month study, a six-month study, and an open-label study. The sponsor claimed a mortality benefit for those treated for six rather than two months, but neglected to mention that those not surviving or lost to follow-up between the two- and six-month endpoints were excluded from this survival analysis—producing a biased readout.2 The sponsor’s inexperience and the lack of validated treatment options in multidrug-resistant (MDR) TB cannot excuse the poor design and presentation of this phase II program. A phase III study, now fully enrolled, may shed more light on delamanid’s use.

The other recently approved drug to treat MDR-TB, Janssen’s bedaquiline, had stronger evidence of efficacy at two and six months, but in the “placebo-controlled C208 trial, however, an imbalance of all-cause mortality has been observed with more deaths reported in the bedaquiline group (10/79 versus 2/81 in the placebo group in C208 Stage 2). Causes of death were varied and all but one occurred after the treatment period with bedaquiline.”3 The U.S. Food and Drug Administration (FDA) carried out a thorough review of each death in the phase II program and could not rule out an association with bedaquiline,4 resulting in a black box warning on the label and a requirement that Janssen open a U.S. patient registry to monitor safety post-marketing.5 The excess mortality seen in phase II should have induced Janssen to accelerate its confirmatory phase III study, which has not yet even begun. Rather than mounting its own phase III study, Janssen is trying to piggyback onto an ongoing USAID/British Medical Research Council (BMRC) study of a modified so-called Bangladesh regimen compared with standard of care (SOC). Janssen does not want to compare SOC with or without bedaquiline—which would be the clearest and simplest confirmatory study—but rather wants to compare a bedaquiline-containing modified Bangladesh regimen to one without. This way lies madness. The low standards for TB clinical trials leading to these accelerated (FDA) and conditional (EMA) approvals must be improved in future licensing efforts.

Throughout this report, the authors will be pointing out the need for better-quality research in order to more clearly define how to use new interventions. We will be writing in more detail on the challenges of improving research quality over the coming year.


EXECUTIVE SUMMARY

HIV

The 2014 adult antiretroviral pipeline is robust. As Tim Horn and Simon Collins note, antiretrovirals in late-stage development include a handful of new fixed-dose combinations (FDCs) and coformulations including dolutegravir/abacavir/lamivudine (DTG/ABC/3TC), elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide fumarate (EVG/COBI/FTC/TAF), darunavir (DRV)/cobicistat/FTC/TAF, TAF/3TC, cenicriviroc/3TC, dolutegravir/rilpivirine, and a once-daily regimen of raltegravir (RAL). Five compounds are in phase II including doravirine, BMS-663068, and the long-acting injectables S/GSK1265744 LAP, rilpivirine-LA, and PRO 140. As noted in previous pipelines, another six compounds, some of which hold serious potential for people living with HIV that is cross-class resistant to current antiretrovirals, continue to languish in earlier phases with no relevant development advances since 2013.6

The past year saw FDA and EMA registration of the new, low-molecular weight, once-daily integrase inhibitor DTG (Tivicay, ViiV Healthcare), one of the most remarkable new antiretroviral drugs in memory. The sponsor’s development program is one of the most comprehensive ever. DTG as an anchor drug proved robustly noninferior, possibly superior, to regimens containing efavirenz (EFV), atazanavir/ritonavir (ATV/r), DRV/r, or RAL. This led the U.S. Department of Health and Human Services (DHHS) Panel on Antiretroviral Guidelines for Adults and Adolescents to recommend use of DTG as a preferred first-line antiretroviral with a background of either tenofovir disoproxil fumarate (TDF)/FTC or—in those without HLA-B*5701—ABC/3TC. However, if ABC/3TC is used with efavirenz or with ATV/r it is recommended only when baseline viral load is below 100,000 copies/mL.7

The sponsor’s new drug application package included adolescents 12 years or older, enabling DTG’s approval for that population alongside adults, and a pediatric development program, including a granule formulation for infants and young children, is well under way. Although the drug is unjustifiably expensive in the United States at $16,926/year at 50 mg/day, $33,852/year for those with prior integrase inhibitor resistant or when taken with EFV, fosamprenavir/ritonavir, or tipranavir/ritonavir,8 the sponsor has entered into a broad licensing agreement with the Medicines Patent Pool (MPP), allowing generic drug manufacturers to make lower-cost DTG in countries where over 90 percent of adults and children with HIV live.9 Thus, though the price in rich countries remains an issue, the sponsor has set a new standard for phase III development in adults, rapid pediatric advancement, and global licensing to allow low-cost generics access. Since FDA approval, the drug has been registered in nine other countries: Canada, Chile, Switzerland, Australia, Japan, Brazil, Uruguay, Argentina, Israel, as well as in the European Union.

Activists, researchers, and providers are interested in the potential of a once-daily combination pill containing DTG, generic 3TC, and TDF, which will become generic in the coming years. This FDC could provide potency, durability, low cost, and increased tolerability if licensing and intellectual property considerations don’t get in the way—and could warrant use of integrase inhibitor–based first-line therapy globally, especially if data continue to support a low risk of resistance. This would displace EFV-based regimens and their neurotoxicity, and allow protease inhibitor–based therapies to remain in second-line recommended regimens. When TAF is approved, an even-lower-molecular-weight DTG/3TC/TAF pill would be possible.

Polly Clayden reports encouraging progress on treatment optimization,10 noting that ENCORE1 showed 400 mg/day of EFV to be noninferior to the currently recommended 600 mg dose; potentially, this could mean a lower cost first line with slightly fewer adverse effects. Further research is needed to bring us closer to the optimal safe, effective, tolerable, durable, universal, and affordable ideal antiretroviral regimen for all.

To recommend DTG-based regimens as preferred global first line we need a bit more information. DTG has been studied in several treatment scenarios and regimens, but so far not in key populations who would be treated with DTG in low- and middle-income countries, such as pregnant women and people with TB coinfection. The registrational trials for DTG were about 80% men, had few non-white participants, and hardly anyone coinfected with other diseases (a few hepatitis B and none with TB or malaria). People with baseline NRTI resistance were excluded.

Clayden describes several planned investigator- and sponsor-led trials that should generate data to fill in some of the gaps. This research needs to be prioritized, funded, and conducted in a timely and coordinated fashion so that the time lag between recommendations and adoption in treatment programs does not take over half a decade between rich and poor countries.

Besides the 12-and-up approval of DTG noted above, Clayden shows how two additional new pediatric formulations have recently been approved, for the youngest age group with the least options: RAL for infants over four weeks of age and ATV for those at least three months old. Global pediatric HIV treatment remains far from ideal, however, with recently updated World Health Organization (WHO) recommendations “not very simple and somewhat aspirational,” with several missing suitable, child adapted formulations of currently approved antiretrovirals including AZT/3TC/lopinavir (LPV)/r, ABC/3TC/LPV/r, ABC/3TC/EFV, DRV/r, ritonavir granules. As with adults, DTG (in kids below 12), cobicistat, and TAF might offer improvement on current options. The UNITAID, Drugs for Neglected Diseases Initiative (DNDi), and the Medicines Patent Pool–cosponsored Paediatric HIV Treatment Initiative provide one granule of hope that these needed new pediatric drugs and formulations will be developed and brought to market more quickly without intellectual property barriers.11

Tim Horn and Richard Jefferys present a synoptic overview of recent developments in HIV preventive technologies, including antiretroviral therapy (ART) and vaccine development.12 Significant research, growing indications of effectiveness, considerable excitement and controversy accompany the newer field of preventive ART, with at least 10 agents being studied as oral or parenteral preexposure prophylaxis (PrEP), vaginal microbicides, tablets, or gels as single drugs (dapivirine, GSK1265744, ibalizumab, maraviroc, rilpivirine-LA, TDF) or in combination (TDF/FTC, already FDA-approved for this use; maraviroc/TDF, maraviroc/dapivirine).

Despite FDA approval of TDF/FTC in mid-2012, uptake has been slow, with fewer than 10,000 people in the U.S. being prescribed PrEP13 while, over the same period, over 100,000 Americans became infected with HIV. In mid-May 2014, the CDC issued the first comprehensive U.S. PrEP guidelines, which suggest that PrEP may be appropriate for as many as 500,000 Americans.14 Complementing this, and helping to provide guidance on who would benefit most from PrEP, Susan Buchbinder of the University of California, San Francisco, and colleagues, published an analysis of the iPrEx PrEP study in gay men and transgender women that assessed which baseline characteristics were most associated with HIV acquisition and with PrEP efficacy. Using these data they determined the population attributable fraction (PAF) of new infections and the number needed to treat based on baseline risk factors. A history of receptive anal intercourse without a condom in the three months before enrollment had the highest PAF (64% of new infections). Individuals most likely to benefit from PrEP in iPrEx included these, as well as those with a history of recent sexually transmitted infection (STI), syphilis, or cocaine use.15 Much work remains to be done to scale up use of effective preventive approaches including PrEP.

Horn and Jefferys note that an effective preventive HIV vaccine “remains frustratingly elusive” and show how ill-prepared the HIV vaccine field was to respond to success, citing the RV144 trial in Thailand and the underwhelming advancement of its findings, largely due to the need to produce a new envelope protein boost to replace the discontinued AIDSVAX.

They suggest that the greatest hope might lie in pursuing development of antigens based on the accumulating number of broadly neutralizing antibodies (bNAbs) that have been discovered, and recent advances in understanding both how these bNAbs are generated by the human immune system and how they interact with the HIV envelope to accomplish neutralization. They write: “A vaccine capable of inducing bNAbs remains the holy grail for the HIV vaccine field, and these developments suggest that it is possible.”16 Thirty-eight preventive vaccination approaches are in clinical trials, and Horn and Jefferys say there are reasons to be optimistic about long-term prospects, but a licensed product is not on the immediate horizon.

Jefferys provides a clear, concise overview of the growing activity in research toward an HIV-1 cure and sometimes-related immune-based therapies.17 Research toward the goal of curing HIV infection has rapidly assumed a central role within the overall scientific portfolio, but funding has not swelled at the same pace, although there have been signs of change over the past year. The number of clinical trials under way has increased substantially since 2013, as has the diversity of approaches being evaluated.

Efforts are under way to replicate the apparent cures seen in Timothy Ray Brown after his CCR5-Δ32 heterozygous stem cell transplant, and in the so-called Mississippi baby, now a child. One early transplant recipient has died, while two others rebounded virologically 12 and 32 weeks after stopping ART; both had received wild-type rather than CCR5-Δ32-mutated transplants. IMPAACT network study P1115, funded by the NIH, will attempt to treat immediately “babies infected with HIV because their mothers failed to receive appropriate prevention of mother-to-child transmission (PMTCT). While the possibility of sparing these newborns a lifelong burden of ART needs to be pursued,” notes Jefferys, “the goal of ensuring that no HIV-positive mother lacks access to PMTCT remains paramount.”18

Jefferys notes updates on Sangamo BioSciences’ SB-728-T autologous ex vivo disrupted CCR5 CD4 cell reinfusion therapy studies of cyclophosphamide to deplete CD4 cells, allowing greater growth space for reinfused gene-modified cells, latency-reversing agents, therapies targeting PD-1, exciting basic science research on broadly neutralizing HIV antibodies, therapeutic HIV vaccines, and immune-based therapies including the ill-starred interleukin-7 (IL-7), gut-targeted approaches to reduce immune activation, and a panoply of anti-inflammatories.

“The development of widely accessible interventions capable of curing the majority of HIV-positive people remains a stern challenge with no solution imminent,” he writes. And he stresses the continued need for advocacy to ensure that this work continues, funding support grows, and the understanding of the science among the HIV/AIDS community and broader public is enhanced.

The immune-based therapy field, he concludes, in contrast, remains fallow, with meager commercial interest. A broader dialogue among activists, scientists, funders, pharmaceutical companies, and other interested parties might be needed in order to assess whether the problems in this area can be solved—notably, the incomplete immune reconstitution and extra morbidity seen among immunologic nonresponders and excess morbidity associated with residual immune activation.19


Hepatitis C Virus (HCV)

Tracy Swan brilliantly summarizes the exploding universe of new HCV treatment and cure regimens, a boon for the 185 million people who have been infected with hepatitis C.20 In April 2014, the WHO issued its Guidelines for the Screening, Care and Treatment of Persons with Hepatitis C Infection.21 While the Guidelines support the use of these new regimens in low- and middle-income countries (LMICs), drug pricing has once again become the major barrier to access and the hope of global eradication of HCV.

A hefty pipeline will increase HCV treatment options, especially for people with genotype 1, by mid-to-late 2014. Cure rates above 95 percent—after only 12 weeks of treatment—have become commonplace in HCV clinical trials. DAAs [direct-acting antivirals] have been miraculous for people with cirrhosis, HIV/HCV coinfection, and before and after liver transplantation.

But the outrage about sky-high DAA prices is quickly overtaking excitement about these wonder drugs. Advocates and clinicians are forced to fight for access to outrageously expensive drugs for people who cannot wait for affordable options—or watch people die from a curable infection.

Gilead’s nucleotide polymerase inhibitor, sofosbuvir—the backbone of most DAA regimens—is US$1,000 per tablet. Such a price limits access to this lifesaving drug, even in high-income countries...

Global eradication of HCV is possible, if pharmaceutical companies will allow generic DAA production in LMICs....DAAs can be produced inexpensively, according to an analysis from the University of Liverpool (using molecular weight, chemical structure, complexity, dose, and cost of comparable HIV antiretroviral agents). The actual production cost for 12 weeks of a single DAA ranges from US$10 to US$270, assuming an annual volume of 1–5 million treatment courses.22,23

Clearing the way through a daunting forest of data, Swan identifies the key elements of an ideal HCV curative regimen—affordable, safe, highly effective against all HCV genotypes, tolerable, simple to administer and undergo, with limited drug-drug interactions—and matches these characteristics with nine of the most advanced regimens studied to date.24 Swan points out the lack of data on these regimens in people who use and inject drugs and in children; in addition, sponsors have failed to provide disaggregated data by gender in many studies.

Swan observes that HCV research has been undermined by commercial competition. Gilead has refused to continue promising clinical collaborations with Janssen and BMS, which has delayed or complicated access to promising DAA combinations. In phase II trials, simeprevir/sofosbuvir cured more than 90% of participants after 12 weeks of treatment—even prior null responders with compensated cirrhosis. Although sofosbuvir (Sovaldi) and simeprevir (Olysio) are licensed, this combination remains off-label; Janssen is supporting phase III trials. In a phase II trial, the combination of daclatasvir and sofosbuvir cured 100% of people with HCV genotype 1 (regardless of treatment experience), 92% of people with genotype 2, and 89% of people with genotype 3.25 BMS is supporting phase III trials of this combination in pre- and-post transplantation, HIV/HCV coinfection, and genotype 3. Approval of daclatasvir in the United States and the European Union is expected later this year. Gilead is developing its own daclatasvir analogues, ledipasvir and GS-5816, which will be co-formulated with sofosbuvir in FDCs, whose price one can only shudder to imagine.

The DAA era has been good news for people coinfected with HIV. They have experienced SVR rates similar to the monoinfected when an HCV protease inhibitor was added to pegylated interferon and ribavirin. Now, several interferon-free regimens have demonstrated proof of concept in HIV/HCV coinfection, with SVR rates equivalent to those in HCV monoinfection. Drug interactions between HCV and HIV regimens remain a concern, since they may limit antiretroviral treatment options during HCV treatment.

Swan criticizes the underenrollment of African Americans in U.S.-based HCV trials (below 20% in all but one industry-sponsored study), as well as people of other races and ethnicities. Gender differences are not broken out by race/ethnicity in many studies, limiting our understanding of possible differences in safety, toxicity, or efficacy.

Research and treatment access for people who inject drugs—who make up 80 percent of new HCV infections in developed countries and 10–15 million of the world’s 185 million people with HCV—remain abysmal.

Pregnant and nursing women are excluded from HCV clinical trials because ribavirin is highly teratogenic. At least 60,000 new infant infections occur each year; the advent of ribavirin-free regimens facilitates much-needed research to interrupt vertical HCV transmission. A search on clinicaltrials.gov reveals just nine open intervention studies for children with HCV, most of them with standard therapy with or without already-approved and quite toxic HCV protease inhibitors.

As Swan says, “[t]he hard work—transforming the HCV treatment cascade from scarcely a dribble into a waterfall—is just beginning.” Now that HCV treatment has become simple, safe, and highly effective, governments “must not continue to ignore HCV; it is time for national plans to address the epidemic. People with HCV and their allies, people who inject drugs, epidemiologists, medical providers, researchers,” policy makers, donors, and industry need to work together.

Activists have launched an ambitious global campaign to achieve universal access to HCV prevention, diagnostics, care, and treatment, which Karyn Kaplan and Tracy Swan summarize in their global brief.26 They have collaborated with allies around the world on the “Missing” campaign—targeting WHO Director–General Margaret Chan and highlighting the WHO’s tardy and underresourced response to HCV; the first HCV World Community Advisory Board meeting in Bangkok, Thailand; and the first-ever demonstration at the European Association for the Study of the Liver meeting, protesting the price of sofosbuvir, a DAA that costs less than US$136 to manufacture for a 12-week treatment course, yet costs US$1,000 a pill.

These are the opening moves in a long and hard-fought struggle for global, affordable HCV DAAs, with the potential to save hundreds of millions of lives.


Tuberculosis (TB)

TB Diagnostics

Tuberculosis research and development (R&D) continues to present a disappointing landscape compared with the healthy diversity of HIV R&D and the explosive advances in HCV treatment. Where HIV research combines substantial long-term public-sector investment with diverse pharmaceutical involvement, and HCV research is primarily driven by profit-seeking drug companies with a dearth of public-sector investment, TB research suffers from scant and falling public-sector investment and industry fleeing for the exits. The view is not pretty.

TB diagnostics research has not advanced much in the past year, with the exception of a vigorous ongoing series of implementation science studies connected with the rollout of the GeneXpert MTB/RIF DNA polymerase chain reaction (PCR) system for detection of Mycobacterium tuberculosis and rifampin resistance, and—to a lesser extent—advances in our understanding of the usefulness of the Alere Determine LAM urine dipstick for diagnosis of TB in people with advanced immunosuppression (including HIV-positive people with CD4 counts below 100/mm3 and children). A hoped-for wave of “fast follower,” putatively cheaper, and possibly portable molecular tests has failed to materialize, and the ideal instrument-free, cheap, and accurate point-of-care TB diagnostic test remains as elusive as ever. Seven molecular tests advanced in the past year, alongside two nonmolecular technologies (including LAM) and a single culture-based technology. Anemic investment—just US$43 million was spent on TB diagnostics R&D in 2012, versus the Global Plan to Stop TB’s target of US$340 million per year—has brought research in this area to a virtual standstill—a fragmented landscape with promising technologies stuck in early development with little funding and no cohesive strategy to bring them forward.27

TB Treatment

The last eighteen months have seen the first approvals—accelerated approval by the FDA in December 2012 of Janssen’s bedaquiline (Sirturo)28 and conditional approval by the EMA in November 2013 (reversing its previous rejection) of Otsuka’s delamanid (Deltyba)29—of new anti-TB drugs from new therapeutic classes in forty years. Nonetheless, as Erica Lessem points out in her 2014 TB treatment pipeline review, ”with limited access to these drugs, and with no data on how they can be used to shorten or otherwise optimize MDR-TB treatment regimens, this is more an incremental step than a leap forward.” She describes the slow progress toward identifying shorter and better regimens for treating drug-sensitive TB, noting that “there are no validated options for treating TB infection in contacts of people with MDR-TB.”

The scant TB drug pipeline features only six compounds from four different classes; the handful of novel drugs in phase II studies is slowly creeping forward, followed by a gaping hole of drugs in phase I studies.

Investments in TB drug research are paltry; several companies have departed from TB drug R&D in the past year; and pharmaceutical investments in TB R&D—which fell by 22 percent in 2012—are likely to drop further.

Because the new MDR-TB drugs have been studied as add-ons to existing, expensive, often difficult to obtain MDR-TB treatment combinations, they are likely to add cost to underfunded TB programs until phase III/IV studies can sort out whether these agents allow shorter treatment duration or fewer coadministered drugs. Unfortunately, however, Janssen has yet to begin its phase III study of bedaquiline, while current published data on delamanid—as the EMA noted tartly and deservedly in its November 2013 conditional recommendation—are limited to two months of a rigorous randomized comparison, with open-label follow-up on a subset of the original study population out to six months. Otsuka’s phase III study is fully enrolled and first results are expected later this year. The EMA requires a pediatric investigational plan, so Otsuka has a pediatric study under way, while Janssen has just pulled out of a planned collaboration with IMPAACT.30 Access to either new drug remains limited, with bedaquiline approved in just a handful of countries, while a compassionate use program continues. Otsuka has refused until quite recently to open compassionate use, which remains unduly restrictive. A preliminary analysis conducted for the WHO, however, indicates that adding bedaquiline to MDR-TB treatment is likely to be cost-effective, and potentially even cost-saving, at a price of US$900 for Global Fund–eligible countries and US$3,000 for other countries31 (the price in the United States is $30,000 for six months).

TB research has experienced a depressing series of market exits by big pharma in the past two years, including that of Pfizer, who licensed the oxazolidinone sutezolid to Sequella, a private Maryland-based company with no publicly available annual reports or visible capital, followed by AstraZeneca, which states that it is committed to developing its compound from the same class, AZD5847, through phase II and no further.

Due to the pharmaceutical exodus, the NIH and the Global Alliance for TB Drug Development are now supporting most current activity in TB treatment research. The NIH, through the National Institute of Allergy and Infectious Diseases (NIAID), supports a comprehensive TB treatment research agenda including adults and children, drug-sensitive and drug-resistant TB, active and latent infection, as well as TB/HIV and drug-drug interaction (DDI) and PK studies important to advancing new drugs and regimens, such as the long-delayed bedaquiline-delamanid DDI/PK study now in development.

The TB Alliance has conducted some of the most important and innovative TB regimen research in the past years, including combinations such as PA-824 (a drug in the same class as delamanid), moxifloxacin (an approved fluoroquinolone), and pyrazinamide, which is moving into phase III, as well as an earlier phase bedaquiline/PA-824/pyrazinamide combination, which is moving into phase IIb. Results from REMox, a potentially treatment-shortening study including moxifloxacin in first-line therapy, are expected imminently. The Alliance plans to begin enrolling in NIX-TB, an open-label study of a new combination for extensively drug-resistant TB, later in 2014. Thanks to support from UNITAID, the Alliance has begun efforts in pediatric TB drug development (see below).

The dearth of new anti-TB agents has led to a fairly broad re-examination of existing anti-TB agents including the rifamycins—rifampin, rifabutin, and rifapentine—for treatment of both active and latent disease, as well as formerly fifth-line drugs such as clofazimine and linezolid, which are now being evaluated in various combinations, mostly in drug-resistant disease. A handful of studies are evaluating shorter-course treatment for latent TB infection, including a proposed ACTG/IMPAACT adult/pediatric collaboration of preventive therapy for household contacts of people with MDR-TB, a group for whom no effective preventive therapy exists.

Lessem’s conclusions are sobering and her recommendations urgent: TB treatment research needs greater investment by industry and the public sector. Drug companies, nonprofit sponsors, and publicly funded clinical trial groups must collaborate more closely. Study populations must include all those affected by TB including those with drug-resistant, TB/HIV-associated, and pediatric disease. Sponsors should expand community involvement. Regulators must assure that postmarketing requirements are enforced. Sponsors must work with global and national authorities to streamline and accelerate rollout of pre- and postapproval access to new treatments and regimens. New drugs and regimens must be affordable to public-sector programs everywhere.

One area of (relative) progress is the renewed—or more accurately, unprecedented—effort now under way in pediatric TB treatment research, as Lindsay McKenna demonstrates; the need is great, as many TB drugs were developed over a half-century ago and still lack evidence-based doses in children. The WHO only released evidence-based pediatric dosing guidelines for first-line drugs in 2010. Four years later, we are still waiting for appropriately dosed child-friendly FDCs. The current treatment of MDR-TB in children is very much a guessing game, and treatment practice is guided by findings extrapolated from adult data.

As mentioned above, Otsuka has initiated pediatric studies of delamanid, and is enrolling the second age-banded cohort, while Janssen has yet to start pediatric studies of bedaquiline and, as mentioned above, has just pulled out of a planned collaboration with IMPAACT.

McKenna recommends that, whenever possible, studies in children be initiated earlier and adolescents over 10 years old be included in phase III trials. For studies in children younger than 10 years old, cohorts should be recruited in parallel, as sequential enrollment does not necessarily offer any additional protection for the younger age groups, whose physiology differs from that of older children.

A pediatric TB treatment research agenda that looks at ongoing and planned studies in adults, and identifies missing data in children and trials where adolescents can be included, is urgently needed, as are substantially increased funding and a push from regulatory authorities.

TB Vaccines

The failure of the candidate TB vaccine MVA85A in a phase IIb study published in spring 2013 stimulated researchers in the field to renew their exploration of fundamental scientific questions regarding the relationship between infection with Mycobacterium tuberculosis and the susceptible and infected human host. This “back to basics” approach is explored by Mike Frick in his 2014 TB vaccines pipeline update. Research is needed to better understand the interaction between the human immune system and TB—in those who are susceptible as well as those infected. The predictive value of animal models used in preclinical development needs to be explored. Clinical trialists are developing innovative designs with earlier endpoints, which in turn depend on better surrogate markers of protection. As Frick notes, “[f]indings from basic research have cast doubt on the core assumptions that steered TB vaccine R&D from its revitalization in 2000, when the pipeline sat empty, to the present day, when the pipeline now has 16 candidates or vaccine combinations under active clinical development.” (see “The Tuberculosis Vaccines Pipeline,” table 1.)32

Key recommendations include prioritizing basic science, improving use of animal models, promoting innovative trial designs, striving to validate new surrogate endpoints, expanding community involvement—sadly deficient in TB vaccine R&D compared with TB drug development—and mobilizing the full complement of resources—scientific, political, financial, and community-based—needed to fully realize the promise of new TB vaccine discovery, development, and dissemination.

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REFERENCES

All web links were accessed on June 21, 2014.

  1. Clayden P, Harrington M. Seven ways to speed up the pipeline. In: Clayden P, Collins S, Daniels C, et al.; HIV i-Base/Treatment Action Group. 2013 pipeline report. Edited by Andrea Benzacar. New York: Treatment Action Group; 2013. p. 1–26. http://www.pipelinereport.org/2013/seven-ways.
  2. Skripconoka VDanilovits MPehme L, et al. Delamanid improves outcomes and reduces mortality in multidrug-resistant tuberculosis. Eur Respir J. 2013 Jun;41(6):1393–400. doi: 10.1183/09031936.00125812.
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  4. Food and Drug Administration (U.S.). Center for Drug Evaluation and Research. Briefing Package. Division of Anti-Infective Products. Office of Antimicrobial Products. CDER, FDA. NDA 204-384: Sirturo™ (bedaquiline 100 mg tablets) for the treatment of adults (≥ 18 years) as part of combination therapy of pulmonary multi-drug resistant tuberculosis (MDRTB). 28 November 2012. p. 44. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Anti-InfectiveDrugsAdvisoryCommittee/UCM329258.pdf.
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  8. Ibid., table 16, p. K-22.
  9. Medicines Patent Pool (Press Release). Medicines Patent Pool, ViiV Healthcare Sign License for the Most Recent HIV Medicine to Have Received Regulatory Approval. 1 April 2014. http://www.medicinespatentpool.org/medicines-patent-pool-viiv-healthcare-sign-licence-for-the-most-recent-hiv-medicine-to-have-received-regulatory-approval/.
  10. Clayden P. Fit for purpose: treatment optimization. In: Clayden P, Collins S, Daniels C, et al.; HIV i-Base/Treatment Action Group. 2014 pipeline report. Edited by Andrea Benzacar. New York: Treatment Action Group; 2014.
  11. Clayden P. The pediatric antiretroviral pipeline. In: Clayden P, Collins S, Daniels C, et al.; HIV i-Base/Treatment Action Group. 2014 pipeline report. Edited by Andrea Benzacar. New York: Treatment Action Group; 2014.
  12. Horn T, Jefferys R. Preventive technologies: antiretroviral and vaccine development. In: Clayden P, Collins S, Daniels C, et al.; HIV i-Base/Treatment Action Group. 2014 pipeline report. Edited by Andrea Benzacar. New York: Treatment Action Group; 2014.
  13. Donald G. McNeil, Jr. “Advocating Pill, U.S. Signals Shift to Prevent AIDS,” New York Times. May 15, 2014. http://www.nytimes.com/2014/05/15/health/advocating-pill-us-signals-shift-to-prevent-aids.html.
  14. Public Health Service (U.S.). Preexposure prophylaxis for the prevention of HIV infection in the United States – 2014: a clinical practice guideline. 14 May 2014. http://www.cdc.gov/hiv/pdf/PrEPguidelines2014.pdf.
  15. Buchbinder S, Glidden DV, Liu AY, et al. HIV pre-exposure prophylaxis in men who have sex with men and transgender women: a secondary analysis of a phase 3 randomised controlled efficacy trial. Lancet Infect Dis. 2014 Jun;14(6):468–75. doi: 10.1016/S1473-3099(14)70025-8. Epub 2014 Mar 7.
  16. Horn T, Jefferys R. Preventive technologies.
  17. Jefferys R. Research toward a cure and immune-based and gene therapies. In: Clayden P, Collins S, Daniels C, et al.; HIV i-Base/Treatment Action Group. 2014 pipeline report. Edited by Andrea Benzacar. New York: Treatment Action Group; 2014.
  18. Ibid.
  19. Ibid.
  20. Mohd Hanafiah K, Groeger J, Flaxman AD, Wiersma ST. Global epidemiology of hepatitis C virus infection: new estimates of age-specific antibody to HCV seroprevalence. Hepatology. 2013 Apr;57(4):1333–42. doi: 10.1002/hep.26141.
  21. World Health Organization. Guidelines for the screening, care and treatment of persons with hepatitis C infection. April 2014. http://www.who.int/hiv/pub/hepatitis/hepatitis-c-guidelines/en/.
  22. Hill A, Khoo S, Fortunak J, Simmons B, Ford N. Minimum costs for producing hepatitis C direct acting antivirals, for use in large-scale treatment access programs in developing countries. Clin Infect Dis. 2014 Apr;58(7):928–36. doi: 10.1093/cid/ciu012. Epub 2014 Jan 6.
  23. Swan T. Hepatitis C pipeline. In: Clayden P, Collins S, Daniels C, et al.; HIV i-Base/Treatment Action Group. 2014 pipeline report. Edited by Andrea Benzacar. New York: Treatment Action Group; 2014.
  24. Ibid.
  25. Sulkowski MS, Gardiner DF, Rodriguez-Torres M, et al; P05411 study investigators. Daclatasvir plus sofosbuvir for previously treated or untreated chronic HCV infection. N Engl J Med. 2014 Jan 16;370(3):211–21. doi: 10.1056/NEJMoa1306218.
  26. Kaplan K, Swan T. Global brief: hepatitis C treatment activism. In: Clayden P, Collins S, Daniels C, et al.; HIV i-Base/Treatment Action Group. 2014 pipeline report. Edited by Andrea Benzacar. New York: Treatment Action Group; 2014.
  27. Daniels C. TB diagnostics development. In: Clayden P, Collins S, Daniels C, et al.; HIV i-Base/Treatment Action Group. 2014 pipeline report. Edited by Andrea Benzacar. New York: Treatment Action Group; 2014.
  28. Food and Drug Administration (U.S.) (Press Release). FDA approves first drug to treat multi-drug-resistant tuberculosis. 31 December 2012. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm333695.htm.
  29. European Medicines Agency. Questions and answers: Positive opinion on the marketing authorisation for Deltyba (delamanid) – Outcome of re-examination. 22 November 2013. http://www.ema.europa.eu/docs/en_GB/document_library/Medicine_QA/human/002552/WC500155462.pdf.
  30. De Marez, Tine (Janssen Infectious Diseases, Titusville, NJ). Personal communication with: Lindsay McKenna (Treatment Action Group, New York, NY). 2014 June 13.
  31. World Health Organization. Cost-effectiveness of introducing bedaquiline in MDR-TB regimens – an exploratory analysis. 26 January 2013. http://who.int/tb/challenges/mdr/CEA_bdqreport_final.pdf.
  32. Frick M. The tuberculosis vaccines pipeline: back to basic science. In: Clayden P, Collins S, Daniels C, et al.; HIV i-Base/Treatment Action Group. 2014 pipeline report. Edited by Andrea Benzacar. New York: Treatment Action Group; 2014.