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An injectable HIV and AIDS treatment that could offer HIV-positive individuals an option other than taking daily pills is entering late-stage clinical-trials. In previous studies, the drug—PRO140—was shown to be successfully in suppressing viral loads to an undetectable level for at least one month in 98 percent of patients. Most HIV-positive patients take nearly 30 antiretroviral pills every week. In some patients, these pills cause kidney and liver damage as well as resistance to further treatment. The developers of this new treatment hope PRO140 could become available in once-a-week, two-dose treatments by 2017, pending success of clinical trials. Former US Treasury Secretary Lawrence Summers and Lancet Commission member Gavin Yamey write in a Huffington Post op-ed that the development of game-changing health technologies will be critical to reaching the health goal in the Sustainable Development Goals (SDGs). They argue that reaching the SDG health targets is not possible with today’s health tools and that new medicines, vaccines, diagnostics, and other innovations will be required. To spur such innovation, they call for increased investment in global health research and development from all nations. A new observational study suggests that taking daily pills to prevent HIV infection—known as pre-exposure prophylaxis (PrEP)—is working to prevent HIV infection in the real world. Kaiser Permanente of San Francisco announced last week that none of its 657 clients receiving PrEP have become infected over a period of more than two years. When PrEP was introduced, many critics predicted that it could decrease condom use, in turn leading to more HIV infections. Advocates of PrEP say this study shows that such concerns were unwarranted, as PrEP is proving effective in nonclinical settings. CNN reports in-depth on the global spread of Dengue and efforts to control and treat the disease. While Dengue fever was once a problem only in pockets of South America and Southeast Asia, today more than 100 countries harbor risk of infection. Currently, there is no treatment or vaccine against for the disease and no effective prevention options; because the mosquitoes that carry Dengue bite during the day, bed nets that have been critical in preventing malaria are not effective for Dengue prevention. New mosquito control interventions, drugs, and vaccines are needed to tackle the disease.

In this guest post, Lindsay McKenna, TB/HIV project officer at GHTC member Treatment Action Group (TAG), writes about a newly released report examining advancements in tuberculosis (TB) research and development (R&D). TAG’s 2015 Pipeline Report looks at advances in diagnostics, treatment, and prevention that offer hope for those engaged in the global fight against TB. The report, which also covers HIV and hepatitis C, highlights scientific potential while recognizing that the realization of innovations in the pipeline is conditional on our ability to mobilize political will, resources, and collaboration. Indeed, the direction of TB R&D is positive relative only to decades of stagnation, which has resulted in lengthy therapy, a lack of options for treating children, cumbersome diagnostics, and a vaccine of waning efficacy. Improved tools are therefore not only possible, but urgently needed. This article highlights key findings from the report and its recommendations for researchers, funders, regulators, and advocates to ensure continued and accelerated progress. The TB treatment pipeline: moving beyond “making the most of what we’ve got” TB treatment researchers are making progress, though it is slow. There are few new TB drug candidates and limited funding to develop them. A number of advances to shorten preventive therapy for TB and evaluate the possibility of preventing multidrug-resistant TB (MDR-TB) offer potential for markedly improving TB prevention, though they raise questions about implementation strategies. For active TB disease, studies to determine the best drug combinations, dosing, and strategies to shorten treatment are ongoing and may answer long-standing questions. TRUNCATE-TB, a bold new design to shorten treatment for drug-susceptible TB, will attempt to bring TB treatment for most cases down from six to just two months. Trials to test new drugs in better combinations are at varying stages of development and, although results are still years away, offer the prospect of improved treatment for MDR-TB. CDC research studying drug-resistance. Photo: CDC/ Hsi Liu, Ph.D., MBA While R&D is advancing for existing—and a few late-stage—TB drugs, the small number of new early-stage compounds, the lack of diversity in the TB drug pipeline (i.e., only six compounds from three drug classes), and the slow pace at which they are progressing is worrisome. Furthermore, access to new TB drugs and those used off-label for TB treatment remains a challenge for researchers, programs, and patients, slowing scientific advancements and their impact on those in need of them. To ensure the development and availability of improved treatments for TB, the 2015 Pipeline Report calls for increased funding for TB R&D, wise investments of this funding, early planning for access to new treatments, and improved regulatory systems to facilitate adoption of innovations once developed. Momentum in the pediatric TB treatment pipeline Pediatric formulations of TB drugs are urgently needed. Photo: PATH/Gabe Bienczycki Inadequacies in TB treatment are magnified for children, and major data gaps on TB treatment in children persist. However, research currently planned and underway aims to optimize treatment with existing drugs and inform the use of new treatments for children with TB. A movement toward including children at an earlier point in TB drug research may also help shorten the time between adult and pediatric approvals and improve access in the future. Studies underway will evaluate preventive therapy in children exposed to MDR-TB and whether it is possible to shorten treatment for less severe forms of TB and TB meningitis in children. Appropriately dosed pediatric formulations of first-line TB drugs are approaching market introduction, but those for second-line and new drugs are farther behind. Much work remains to study regimens and new drugs in children and to develop missing pediatric formulations. The 2015 Pipeline Report recommends earlier and expedited investigation of new drugs in children, in which both developers and stringent regulatory authorities play an important role. The report also urges the immediate advancement of guidelines for and development of pediatric formulations of second-line drugs. Increased investments in pediatric TB R&D will facilitate all of these important steps. The TB diagnostics pipeline We urgently need new diagnostic tests for TB. Fortunately, we now have a clearer-than-ever picture of what types of tests are most essential: a more effective but low-tech test to replace smear microscopy in detecting TB, a rapid drug-susceptibility test to guide treatment, a biomarker test, and a triage test. Yet the pipeline for TB diagnostic tools remains stagnant, with several products in line but little high-quality evidence being generated towards an effective, accessible, point-of-care test. Eiken TB-LAMP (loop-mediated isothermal amplification) and Alere Determine LAM (urine lipoarabinomannan lateral flow test) underwent World Health Organization (WHO) expert review and are awaiting decision. WHO review is expected soon for Hain Lifescience MTBDRsl, a test to detect resistance to fluoroquinolones and injectable agents. Results were published for several molecular diagnostic and drug-susceptibility test candidates, including Xpert MTB/RIF Ultra, a platform that claims improved sensitivity and ability to detect isoniazid resistance. However, appropriate field evaluations and more evidence is required in order for any tests in the pipeline to be considered for WHO expert review and to inform national TB program policies. To improve detection of TB, the 2015 Pipeline Report recommends that we invest in TB R&D and diagnostics research, including for new biomarker-based triage/point-of-care tests, and integrate TB diagnostics research into ongoing treatment studies. The report also argues that access to validated new tests and to drug susceptibility testing should be universal, and linkages to treatment ensured. Countries and donors must prepare for the launch of next-generation tests while eliminating the current use of inaccurate and misleading tests. As with drugs, regulatory capacity to oversee TB diagnostics research needs improvement. The TB vaccines pipeline: a new path to the same destination? A researcher conducting a vaccine clinical trial. Photo: AERAS Attention and resources for TB vaccine R&D are moving away from late-stage clinical trials and back to basic discovery and preclinical science. Motivating this welcome shift is emerging evidence that encourages a reexamination of the assumptions that have guided the last ten years of TB vaccine research. Candidates in the current TB vaccines pipeline only contain a few of the vast number (4,500) of targetable antigens and focus on stimulating just one of the many parts of the immune system. The shift “to the left” of the development pipeline will allow exploration of more vaccine concepts and help to de-risk vaccine development. The report highlights progress in basic science and preclinical development, including the pursuit of biomarkers of protective immunity to TB infection or disease, the application of radiology to study immune activity against mycobacterium TB and to better understand host-pathogen interactions, and vaccine design concepts to trigger robust cell-mediated immunity. The development of a more efficacious vaccine with longer-lasting immunity will require us to: increase funding and support for basic science and create opportunities for immunology work in clinical trials; establish meaningful partnerships with civil society organizations and TB-affected communities; and be guided by principles of equity while preparing for access to future vaccines.

Pharmaceutical company AbbVie is paying United Therapeutics US$350 million for its priority review voucher (PRV)—which expedites the US Food and Drug Administration’s (FDA) review of a product by four months—and EP Vantage speculates on their motive. The FDA awards PRVs to pharmaceutical companies that receive FDA approval for drugs to treat neglected tropical diseases (NTDs) or rare pediatric diseases. The PRVs provide an incentive for companies to invest in research and development for these diseases. To date, six PRVs have been awarded—three each for NTD and rare pediatric disease treatments—and four have been sold. The PRVs have been sold at increasing prices, with the previous three purchased for $67, $125, and $245 million. While AbbVie has seven products currently in phase 3 clinical trials, EP Vantage argues that the PRV will likely be saved for use with filgotinib—a treatment for rheumatoid arthritis (RA)—which is currently in phase 2 trials and on track for a 2018 market introduction. For chronic conditions such as RA, patients are hesitant to switch medications, meaning an earlier launch can have an impact on sales for years. However, a number of new RA drugs are expected to reach the market before filgotinib: Eli Lilly's baricitinib could be launched as early as 2016, and as the US patent for AbbVie’s blockbuster RA drug Humira expires in late 2016, filgotinib could face competition from generic or biosimilar versions of Humira as well. Researchers at the University of California, Santa Barbara (UCSB) are proposing a novel approach for identifying drug-resistant bacteria, challenging the standard method that has been used for more than 70 years. Normally, doctors collect biological samples from sick patients, and the sample is placed on petri dishes filled with a medium known as Müller-Hinton agar, on which nearly any bacteria in the sample will readily grow. They can test the bacteria’s drug-resistance by monitoring how it grows or subsides when exposed to different antibiotics. Patients are then prescribed an antibiotic that caused the bacteria to subside on the petri dish. However, the chosen antibiotic is sometimes unable to fight off the infection in the body, despite its demonstrated ability to combat it in the lab. In these cases, the bacteria can develop resistance to new drugs, making it even harder to treat. Led by Dr. Michael Mahan, the team at UCSB used a less common medium, LPM, which mirrors the conditions within human cell (i.e., it is much more acidic and is low in phosphate and magnesium) and discovered that bacteria may be more sensitive or more resistant to different antibiotic compounds in different settings. According to Mahan, the use of a medium such as LPM could enable doctors to more accurately predict how a patient will react to a certain antibiotic. Furthermore, their findings could lead to the identification of new antibiotic compounds. According to Mahan, there are “millions of chemical compounds that were excluded as antibiotics…but they were never tested since standard [Müller-Hinton agar] petri plates ruled them out.” Photo: PATH/Aaron Joel Santos NBC News reports on three recently released studies that show progress toward the development of an oral flu vaccine and a universal flu vaccine. Biotech company Vaxart, Inc. recently completed early phase 1 clinical trials of an experimental oral flu vaccine, which proved to be both safe and effective. These results have prompted the production of antibodies that are “strongly associated with protection in humans” in three-fourths of participants, according to flu vaccine expert Dr. John Treanor. An injectable vaccine goes straight to the bloodstream and is rapidly detected by the immune system; however, Vaxart had to “come up with a different way of getting the flu gene into the intestines and have the immune system recognize the flu gene as foreign,” according to Vaxart Founder and Chief Scientific Officer Sean Tucker. Meanwhile, teams of researchers at the National Institute of Allergy and Infectious Diseases (NIAID) and Scripps Research Institute have been working on universal flu vaccine candidates. There are several different types of influenza strains that affect humans, including H1 and H3 strains of influenza A as well as influenza B strains. Seasonal flu vaccines protect against three to four strains, based on which are predicted to be most virulent that year, and they train the immune system to detect and attack the virus’ hemagglutinin protein, which is uniquely shaped for each strain. Both NIAID’s and Scripps’ universal flu vaccine candidates use the stem of hemagglutinin, which looks the same for, and should grant protection against, all H1 and H5 (avian influenza) strains. Both candidates have proved safe and effective in mice.

A new paper-based diagnostic can test for Ebola, dengue, and yellow fever in just ten minutes without running water, electricity, lab equipment, or highly-trained personnel. “We purposely designed it to be very simple not only to assemble but also to use and to read out,” says lead developer Dr. Kimberly Hamad-Schifferli, a Massachusetts Institutes of Technology professor. Initial symptoms for these three hemorrhagic fevers are nonspecific, making them hard to diagnose, and existing diagnostic methods—while more accurate—are impractical for low-resource settings. This paper-based diagnostic currently costs US$20, although Hamad-Schifferli believes it could be manufactured for even less. The test uses red, orange, and green nanoparticles to test for Ebola, yellow fever, and dengue respectively, and just by identifying the colors that appear on the strip, a diagnosis can be made. Photo: PATH/Gabe Bienczycki An experimental vaccine against Middle East Respiratory Syndrome (MERS) will be tested on humans later this year in clinical trials run by Inovio Pharmaceuticals and GeneOne Life Science. The vaccine, which was developed by researchers at the University of Pennsylvania in partnership with Inovio, the US and Canadian governments, and the Universities of Washington and South Florida, will be the first against MERS to advance to human clinical trials. The team took a novel approach to developing the vaccine, using an artificially engineered DNA sequence, rather than material from the MERS virus itself. The DNA prompts the recipient’s immune system to produce a protein that is unique to the MERS virus, which in turn triggers the production of protective proteins—known as antibodies—that detect that unique MERS protein and attack it. The vaccine successfully induced the production of these protective proteins in mice, monkeys, and camels, and as it does not contain any live viral material; it’s anticipated to be safer than traditional vaccines. Gilead Sciences Inc., a California-based biotechnology company, is aiming to cure HIV and AIDS and hepatitis B and one candidate—GS-9620—has shown promise in combatting both infections in animal studies. “Gilead is the leader in HIV,” according to Andrew Cheng, executive vice president of Clinical Research and Development Operations at Gilead Sciences, and he’s got a point: 80 percent of new HIV and AIDS patients start treatment using a Gilead product. Their expertise in antivirals expands beyond HIV and AIDS; the company has doubled its sales over the past two years, due to the market introduction of Sovaldi and Harvoni—drugs that cure Hepatitis C in 90 percent of patients. Existing treatments for HIV and AIDS prevent active, HIV-infected cells from reproducing, however, inactive cells are able to escape detection, effectively hiding from the immune system. GS-9620 is one of several drug candidates that uses a method known as “shock and kill” to wake the latent, infected cells, enabling the immune system to identify and attack them. The treatment successfully triggered viral activity in monkeys and is now being tested in humans. The treatment has also been tested in woodchucks infected with Hepatitis B, and within a month, the virus was completely undetectable. Researchers at the University of Pennsylvania and the University of Ulm in Germany have discovered a molecule that attacks both HIV-infected cells and a protein in semen that enhances the infectivity of the HIV virus. The molecule—CLR01—latches onto viral membranes, known as viral envelopes, but passes over cell membranes. This suggests that the molecule is unlikely to have any major side effects and that it might be successful in combatting other sexually transmitted viruses. The tweezer-shaped molecule also targets and suppresses molecules in the semen that attach to the HIV virus and help it bind to human immune cells, ultimately making the virus 10,000 times more virulent. CLR01 has been successfully tested in zebrafish and mice and will next be tested for safety in efficacy in nonhuman primates. According to the researchers, mass producing CLR01 is relatively simple, making it a microbicide candidate.