i-base HiV, tuberculosis, and Viral Hepatitis: drugS, diagnoStiCS, vaccineS, immune-BaSed theraPieS, and Preventive teCHNOLOGIES in develoPment TAG 2010 pipeline report july 2010 treatment action group Polly Clayden, lei Chou, Simon CollinS, mark harrington, riChard JefferyS, eleonora Jimenez, SCott morgan, traCy Swan, Javid Syed and Claire wingfield About TAG the treatment action group is an independent AIDS research and policy think tank fighting for better treatment, a vaccine, and a cure for AIDS. TAG works to ensure that all people with HIV receive lifesaving treatment, care, and information. aBOUT HIV i-BaSe HIV i-Base is a london based HIV treatment activist organization. i-Base work in the UK and internationally to ensure that people living with HIV are actively engaged in their own treatment and medical care and are included policy discussions about HIV treatment recommendations and access. i-base you can reach TAG by phone at +1.212.253.7922. to find out more about TAG’s projects go to www.treatmentactiongroup.org. treatment action group 611 Broadway, Suite 308 new york, ny 10012 tel 212.253.7922 fax 212.253.7923 [email protected] www.treatmentactiongroup.org iSBn 978-0-9819863-5-7 thiS rePort iS dediCated to vuyani Jacobs a fierce advocate for access to care and treatment for people with hiv, gender equality, and human rights. a dedicated activist, vuyani’s leadership contributed to the success of the treatment action Campaign, médicines Sans frontières, and Community health media trust. through his media work, his community organizing, and his compassion he contributed to a world where people could live free from stigma and have access to life-saving information and treatment. he died on 30 June 2010 of meningitis. table of Contents introduction & executive summary 1 the antiretroviral pipeline 7 Activity since 2008 The Pipeline in 2010 Other Compounds and targets in Preclinical research Patent expiry and generic Compounds the HiV diagnostics pipeline 25 Requirements for Point-of-Care tests The Cd4 initiative Point-of-Care viral load test the pediatric antiretroviral pipeline 29 Why not avoid Pediatric hiv in the first Place? When to Start Children on antiretroviral therapy Identifying Children with hiv and Starting them on treatment What to Start with? Dosing / formulations The innovator Pipeline The generic Pipeline the immune-based therapies and preventive technologies pipeline 44 Vaccines Vaccine approaches in human trials Preexposure Prophylaxis Immune-based therapies HIV Cure Box Hepatitis b drugs in development 70 Oral antivirals Immune-based therapies Preventive vaccine the Hepatitis c treatment pipeline 77 HCv treatment: Population-specific issues HCv treatment access Moving forward: hCv drug development Characteristics of the Class: hCv Protease inhibitors Characteristics of the Class: hCv Polymerase inhibitors Characteristics of the Class: nS5a inhibitors Nitazoxanide TAG research recommendations the tuberculosis pipeline introduction 101 the tuberculosis diagnostic pipeline 107 what is in the tB diagnostic Pipeline Health Post Peripheral laboratory Reference laboratory Immune-based tests for latent tB infection Policy and research recommendations the tuberculosis treatment pipeline 125 introduction: a robust Pipeline, but uncertain Support If tB is Curable why are new drugs needed? Accelerating research Getting Back to Basics The Pipeline So what’s new Second-generation Compounds Latent tB infection Drug Susceptible tB Rethinking last-Chance drugs Recommendations the tuberculosis Vaccine pipeline 140 BCg: the Current tB vaccine Strategy Challenges for vaccine research The tB Pipeline What is needed acknowledgments 150 introduction By mark harrington and SCott morgan For the sixth time, Treatment Action Group (TAG), now in collaboration with HIV i-Base (UK), presents the current clinical pipeline for new drugs and vaccines for HIV, hepatitis C virus (HCV), and tuberculosis (TB), along with new sections on the hepatitis B virus (HBV) pipeline and diagnostics for TB and HIV. Despite the global economic crisis and the erosion of political will to continue scal- ing up effective, lifesaving, evidence-based preventive and treatment interventions for HIV and its most common coinfections worldwide, TB, HBV and HCV, the scien- tific outlook is unexpectedly positive. Continuing growth and maturation in the HIV therapeutics market space have not yet led to a visible diminution of efforts by industry to discover and develop new antiretroviral drugs and classes. A pair of antiretroviral drugs approved in 2006 and 2007—the protease inhibitor darunavir (Prezista, Tibotec/ Johnson & Johnson) and the first-in-class integrase inhibitor raltegravir (Isentress, Merck)—joined efavirenz (EFV) and boosted atazanavir (ATV) as preferred first-line anti-HIV drugs in combination with tenofovir (TDF)/emtricitabine (3TC) (combined as Truvada) in the U.S. Department of Health & Human Services adult and adoles- cent HIV treatment guidelines published in December 2009. These advances show that there is a continued market for innovation in HIV treatment and that industry, regulators, and public health authorities agree on how best to study new drugs in order to rank them relative to existing regimens. In the coming years there may be fewer per- sons experiencing multidrug class failure to participate in earlier phase studies, which means that new trial designs will be needed; thus, the over $10 billion yearly market for HIV therapy will continue to experience dynamic changes and evolution. Five new compounds and combinations are in advanced phase III studies and expected to be filed for U.S. Food and Drug Administration (FDA) review in 2010–2011: Tibotec’s nonnucleoside reverse transcriptase inhibitor rilpivirine (TMC278); the triple combi- nation with tenofovir/3TC/rilpivirine; Gilead Science’s integrase inhibitor elvitegravir; the novel pharmacokinetic enhancer cobicstat; and the so-called Quad pill containing elvitegravir/cocibstat/tenofovir/3TC. Additional drugs in existing and new classes, the latter including maturation and attachment inhibitors, are in earlier phases of testing. The global HIV market is estimated to be growing toward over $16 billion by 2016, around the time when a wave of patent expiries will make it ever more essential for new market entries to possess qualities that are measurably superior to what will then be a much more generic sales–centered market. 1 TAG 2010 Pipeline report This year, in addition to Simon Collins’s overview of the adult HIV pipeline, Polly Clayden, also of HIV i-Base (UK), presents an update on a much-neglected area of HIV research, the pediatric antiretroviral pipeline. Shockingly, some of the most critical agents used in adult therapy, such as tenofovir, are still not available for very young infants and chil- dren; indeed, the pediatric HIV standard of care globally resembles adult HIV care about ten years ago. This must change, and Clayden’s chapter explains what will be required. In a foretaste of things to come, Clayden also provides a quick overview of global needs in HIV diagnostics, with particular focus on point-of-care diagnostic tests for early infant diagnosis, CD4 counts, and HIV RNA load. Richard Jefferys once again presents a sweeping overview of the vast areas of the HIV clinical research agenda that have yet to provide a convincing advance in either preventive or therapeutic vaccines, microbicides, immune-based therapies, cytokine treatment, or gene-/cell-based therapies, including a new section on HIV cure and eradication research. Despite the difficulties in these research areas, activity is exten- sive and the ultimate solution to the pandemic can only come from the development and worldwide distribution of an effective vaccine and a cure for HIV. The vast unmet needs in these portfolios make it even more essential to increase investments in basic and translational science over the coming years. Lei Chou’s overview of the virtual paralysis afflicting HBV research in the past year makes for much more depressing reading. There is no visible drug development for HBV in North America or Europe, with only scanty activity in east Asia, and no clinical trials from the new U.S. National Institutes of Health-funded HBV research network despite almost two years of funding. Relying exclusively on HBV vaccination for the uninfected, public health authorities seem to be consigning the fate of the hun- dreds of millions of people infected with chronic HBV infection to a very short list of effective drugs to which HBV may well develop pan-resistance before new agents are in the pipeline. The world must move beyond a vaccination-only strategy and focus on saving the lives of the many who have chronic HBV-related disease. TAG’s Hepatitis/HIV Project Director Tracy Swan has been predicting a revolution in HCV treatment since the mid-2000s. This year, her prediction has come measurably closer to reality as phase III results from trials of two HCV protease inhibitors, bocepre- vir (Merck/Schering Plough) and telaprevir, (Vertex/Tibotec) are expected by the end of 2010. Although both drugs come with added toxicity, boceprevir and telaprevir have considerable promise, offering the potential to significantly increase cure rates for the most difficult to treat genotype 1 infections, and, in some cases, to reduce treatment -du ration from 12 to 6 months. Farther back in the pipeline but even more promising are combinations of oral, direct-acting HCV antiviral compounds that