ABOUT HIV i-BASE HIV i-Base is a London-based HIV treatment activist organization. HIV i-Base works in the United Kingdom and internationally to ensure that people living with HIV are actively engaged in their own treatment and medical care and are included in policy discussions about HIV treatment recommendations and access. www.i-base.info ABOUT TAG The Treatment Action Group (TAG) 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. www.treatmentactiongroup.org 2012 PIPELINE REPORT HIV, HEPATITIS C VIRUS (HCV), AND TUBERCULOSIS (TB) DRUGS, DIAGNOSTICS, VACCINES, AND PREVENTIVE TECHNOLOGIES IN DEVELOPMENT By Polly Clayden, Simon Collins, Colleen Daniels, Nathan Geffen, Mark Harrington, Richard Jefferys, Coco Jervis, Karyn Kaplan, Erica Lessem, and Tracy Swan Edited by Andrea Benzacar JULY 2012 i-BASE/TREATMENT AcTION GROUP AUTHORS Polly Clayden, Simon Collins, Colleen Daniels, Nathan Geffen, Mark Harrington, Richard Jefferys, Coco Jervis, Karyn Kaplan, Erica Lessem, and Tracy Swan. EDITOR Andrea Benzacar DESIGNER Lei Chou ACKNOWLEDGMENTS Thanks to the TAG staff, board, and donors for supporting the production of the 2012 Pipeline Report. i-Base thanks the Monument Trust and UNITAID for support for this work. Polly Clayden thanks Shaffiq Essajee, Di Gibb, Andrew Hill, David Ripin, and Marco Vitoria. Richard Jefferys thanks Jennifer Woolley from Aeras and Erna Balk from the TuBerculosis Vaccine Initiative (TBVI). Colleen Daniels and Erica Lessem thank Lindsay McKenna. Treatment Action Group 261 Fifth Avenue Suite 2110 New York, NY 10016 Tel 212.253.7922 Fax 212.253.7923 www.treatmentactiongroup.org [email protected] ISBN 978-0-9837221-3-7 TABLE OF CONTENTS Introduction and Executive Summary 1 The Antiretroviral Pipeline 29 The Pediatric Antiretroviral Pipeline 61 Retrofitting for Purpose: Treatment Optimization 83 Preventive Technologies, Research Toward a Cure, and Immune-Based and Gene Therapies 101 Hepatitis C Drug Development Goes from Pony Ride to Rocket Launch 137 Hepatitis C (HCV) Treatment Access: Spotlight on Thailand/Asia 185 The Tuberculosis Diagnostics Pipeline 193 The Tuberculosis Treatment Pipeline 217 The Tuberculosis Vaccine Pipeline 251 INTRODUCTION AND EXECUTIVE SUMMARY By Polly Clayden and Mark Harrington In nine countries, we enrolled 1763 couples in which one partner was HIV-1–positive and the other was HIV-1–negative; 54% of the subjects were from Africa, and 50% of infected partners were men. HIV-1–infected subjects with CD4 counts between 350 and 550 cells per cubic millimeter were randomly assigned in a 1:1 ratio to receive antiretroviral therapy either immediately (early therapy) or after a decline in the CD4 count or the onset of HIV-1–related symptoms (delayed therapy). The primary prevention end point was linked HIV-1 transmission in HIV-1–negative partners. The primary clinical end point was the earliest occurrence of pulmonary tuberculosis, severe bacterial infection, a World Health Organization stage 4 event, or death….As of February 21, 2011, a total of 39 HIV-1 transmissions were observed (incidence rate, 1.2 per 100 person-years; 95% confidence interval [CI], 0.9 to 1.7); of these, 28 were virologically linked to the infected partner (incidence rate, 0.9 per 100 person-years, 95% CI, 0.6 to 1.3). Of the 28 linked transmissions, only 1 occurred in the early-therapy group (hazard ratio, 0.04; 95% CI, 0.01 to 0.27; P<0.001). Subjects receiving early therapy had fewer treatment end points (hazard ratio, 0.59; 95% CI, 0.40 to 0.88; P=0.01). The early initiation of antiretroviral therapy reduced rates of sexual transmission of HIV-1 and clinical events, indicating both personal and public health benefits from such therapy. —MS Cohen et al.1 The fact that treatment of HIV-infected adults is also prevention gives us the wherewithal, even in the absence of an effective vaccine, to begin to control and ultimately end the AIDS pandemic....For the first time in the history of HIV/ AIDS, controlling and ending the pandemic are feasible; however, a truly global commitment...is essential. Major investments in implementation now will save even greater expenditures in the future; and in the meantime, countless lives can be saved. —AS Fauci2 The yearly cost of achievement of universal access to HIV prevention, treatment, care, and support by 2015 is estimated at no less than US$22 billion. Implementation of the new investment framework would avert 12.2 million new HIV infections and 7.4 million deaths from AIDS between 2011 and 2020 compared with continuation of present approaches, and result in 29.4 million life-years gained. The framework is cost effective at $1060 per life-year gained, and the additional investment proposed would be largely offset from savings in treatment costs alone. —B Schwartländer et al.3 1 2012 PIPELINE REPORT 2 INTRODUCTION AND EXECUTIVE SUMMARY Introduction Three papers published in the past year4,5,6 provide the scientific, public health, and policy framework for accelerating the response to the HIV pandemic such that within a few years the spread of HIV can be reversed, saving millions of lives and billions of dollars, using existing antiretroviral therapy (ART) introduced earlier and more broadly around the world. The only thing holding us back is the lack of economic and political leadership at the highest levels. Juxtaposed against a background of economic distress and political paralysis in the world’s rich countries not seen since the early 1930s, the abundance of promising advances documented in this year’s i-Base/TAG 2012 Pipeline Report may seen unattainably out of reach to many of the millions of people who need them most. It will be the task of the activists, implementers, policy makers, and scientists attending this year’s International AIDS Conference in Washington, D.C., to work together to turn the tide so that everyone who needs high-quality treatment and prevention interventions for the global HIV, hepatitis C virus (HCV), and tuberculosis (TB) pandemics receives them. Since the results of HPTN 052 were released last year,7 HIV prevention and treatment research have moved ever forward; the interventions that have saved over 7 million people’s lives since the advent of highly active antiretroviral therapy (HAART) in 1996 are also proving to be remarkably powerful as HIV prevention measures. The HPTN 052 study set a very high bar for performance, as the measured 96% reduction in HIV transmission was built upon a high-quality clinical trial design and implementation, good prevention practice in both arms, and evidently very high adherence rates. Although with less dramatic effect than HPTN 052, results of CAPRISA 0048 (which used tenofovir as a topical vaginal microbicide, like some other preexposure prophylaxis [PrEP] studies such as iPrEx9 which were released in the past two years, show that antiretrovirals can also offer protection when used by an HIV-negative partner, although the optimal use of these interventions is as yet uncertain. Table 1 shows the hierarchy of effect from clinical trial evidence using antiretrovirals for preventing sexual HIV transmission. But with all these studies, it is clear that adherence is required for treatment-as- prevention to work. Similarly, early studies in the HAART era showed that over 90% adherence was required for durable virological suppression among those taking treatment as treatment. 3 2012 PIPELINE REPORT TABLE 1. Clinical Trial Evidence Using Antiretrovirals for Preventing HIV Infection Study Effect Size % (CI) Treatment for prevention (HPTN 052) 96% (73–99) PrEP for serodiscordant couples (Partners PrEP) 73% (49–85) PrEP for heterosexuals (Botswana TDF 2) 63% (21–48) PrEP for men who have sex with men (iPrEx) 44% (15–63) Microbicide (CAPRISA 044 tenofovir gel) 39% (6–60) Source: Abdool Karim SS. CAPRISA 004 two years on: ten key lessons and their implications. Keynote address presented at: 2012 International Microbicides Conference; 2012 April 15; Sydney, Australia. Available from: http://www.microbicides2012.org/images/pdfs/m2012%20 -%20abdool%20karim%20-%20caprisa%20004%20lessons.pdf. (Accessed 2012 July 3) The potential contribution of these new discoveries to reduce the spread of HIV is directly threatened by today’s interlinked political and economic crises. Although a few administrative areas, such as the Canadian province of British Columbia and the city of San Francisco, California, have begun to provide universal offers of HIV treatment to all those referred to care, no country has yet started to fully implement these new interventions. The U.S. federal HIV treatment guidelines panel updated its recommendations in spring 2012 to recommend the universal offer of antiretroviral therapy (ART) to those with CD4 counts over 500 cells/mm3,10 but it is too soon to assess whether this change is affecting practice in the United States. The panel’s recommendation is based on disease stage, and its statement of the primary (therapeutic) and secondary (preventive) benefits of ART, and the evidence base for this recommendation is worth reading in full: The primary goal of antiretroviral therapy (ART) is to reduce HIV- associated morbidity and mortality. This goal is best accomplished by using effective ART to maximally inhibit HIV replication, as defined by achieving and maintaining plasma HIV RNA (viral load) below levels detectable by commercially available assays. Durable viral suppression improves immune function and quality of life, lowers the risk of both AIDS-defining and non-AIDS-defining complications, and prolongs life. Based on emerging evidence, additional benefits of ART include a reduction in HIV-associated inflammation and possibly its associated complications. The results of a randomized controlled trial and several observational cohort studies demonstrated that ART can reduce transmission of HIV.