Introduction and executive summary

1 July 2010. Related: Editorial, Pipeline report.

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 scaling up effective, lifesaving, evidence-based preventive and treatment interventions for HIV and its most common coinfections worldwide, TB, HBV and HCV, the scientific 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 adolescent 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 persons 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 combination 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.

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 children; 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 extensive 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 hundreds 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, boceprevir (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 duration from 12 to 6 months. Farther back in the pipeline but even more promising are combinations of oral, direct-acting HCV antiviral compounds that may render today’s standard of care—based on dauntingly expensive and toxic peginterferon-alpha and ribavirin—obsolete. But these drugs come with new challenges: optimal treatment strategies for the HIV/HCV coinfected, people with non-genotype 1 infections, and subgroups of treatment-naive and treatment-experienced people are needed. These drugs must be prescribed properly, and response to treatment must be monitored closely to avoid development of drug resistance. Global access to HCV treatment is limited and will become more so with the addition of expensive new drugs to the standard of care. But if three to six months of all-oral combination therapy can cure HCV, it would become easier to expand access to treatment worldwide, potentially saving hundreds of millions of lives.

While it would be premature to say that a revolution in TB diagnosis, treatment, and prevention is around the corner, it is possible to see a glimmering of hope on the horizon. There are now a handful of new highly sensitive nucleic acid amplification tests able to quickly detect Mycobacterium tuberculosis (MTB) itself and mutations associated with drug resistance, which indicate the presence of multi-drug resistant TB (MDR-TB). Although they are still too complex and expensive for use at the health post level, with economies of scale and engineering to make them simpler and more robust, some of these tests may be able to be used at the peripheral laboratory level. This is a significant advance, because more difficult TB diagnosis procedures would no longer be confined to central laboratories. Increasing access to much more rapid diagnostics for MDR-TB will be necessary to optimize use of new TB drugs. Two new drugs from two new classes of compounds—the diarylquinoline TMC207 from Tibotec/Johnson & Johnson and the nitroimidazole OPC-67683 from Otsuka—are likely to be submitted to the FDA and the European Medicines Agency for regulatory approval for treatment of MDR-TB.

These drugs could revolutionize the treatment of MDR-TB by making it shorter, safer, more tolerable, and more effective; but the world is not prepared for the advent of two new TB drugs. Inadequate preparation and lack of better diagnostic tools could cause a crisis in which laboratory capacity, human resources, and background second-line TB drug supply are all insufficient to meet increasing demand (currently just 5% of the world’s one million cases of MDR-TB are undergoing appropriate treatment).

TAG will continue to report on the developments in research to prevent, treat, and cure HIV, HBV, HCV, and TB. In the meantime, TAG and our comrades in activism around the world are threatened by a new and deadly foe—the global economic crisis and the indifference of the current generation of world leaders.

A shifting treatment landscape

A resurgence of political indifference coupled with a disastrous global economic situation has placed the lives of 33 million people around the world in danger. Only four million people in developing countries are receiving antiretroviral treatment. Complance with new treatment guidelines recommending initiation of antiretroviral treatment when CD4 cell counts drop below 350 cells/mm3 places new demands on countries striving to reach universal access targets (generally considered to be 80% coverage of essential prevention, testing, and treatment targets). Ever stronger evidence about the preventive value of reducing communitywide viral load through universal uptake of appropriate antiretroviral therapy (ART) is ignored by policy makers who claim their pockets are empty, even while the financial sector and the automobile and insurance industries have received billion dollar bailouts from overstressed public purses. This section reviews some of the key issues that affect global funding for treatment, the clear and present danger that we are losing ground on HIV treatment scale-up, the promise of treatment as prevention, and a review of the debate about when to initiate antiretroviral therapy.

On May 10, 2010, the New York Times front page stated, “At Front Lines, Global War on AIDS is Falling Apart.” This was not news to activists, program managers, political leaders in global health, clinicians in developing countries or people living with HIV/AIDS in those countries. But it was a salutary warning that the mounting global AIDS emergency has fallen off political leaders’ agendas. At least 29 million people who are HIV positive do not have access to necessary treatment. Without it, they will die from AIDS.

Despite evidence that the global HIV epidemic is far from under control, funding for prevention, care, and treatment is flattening at an alarming rate, and shrinking relative to the need as new infections outpace HIV treatment access.

Over the past years the AIDS backlash has been growing. Donor fatigue and changing political fashions have taken their toll. Political commitment for universal access to HIV prevention, care, and treatment has wavered in the shadow of the global economic crisis. The AIDS funding backlash pits activists, health professionals, and policy makers against one another in a circular, “disease versus disease” debate that shifts our focus from the true issues: the U.S. government allocated only 0.3% of its budget to global health initiatives in 2010 [1]; as of 2007 only 6 of 53 African countries have met their  commitment to the Abuja Declaration of 2001 to allocate a minimum of 15% of their national budgets to health; African heads of state accepting foreign aid for health shift monies to other budget priorities [2]; $427 million in donor commitments remain unpaid to the Global Fund to Fight AIDS, Tuberculosis and Malaria (GFATM) through 2009 [3]; and a $3 billion shortfall exists for GFATM funding in 2010. More than 2,090 people with HIV in eleven U.S. states are currently on waiting lists for AIDS drug assistance programs [4]; hundreds of thousands more are not yet linked to care.

Continued scale-up of effective evidence-based HIV prevention, treatment, and care programs is required to bring the pandemic under control and put it into reverse, while continuing to support research on a cure and a vaccine to end it forever.

Intensified research to develop a cure and safer, more effective, more tolerable and durable ART regimens is crucial. Exploration into novel targets for new drugs and optimized delivery must continue.

Treatment Action Group and our allies all over the world are working to keep AIDS on the forefront of the global public health agenda. Activists, people living with HIV, clinicians, civil society members, and policy makers must be tenacious if we are to continue to support healthy HIV treatment and prevention programs and keep the development of a preventive vaccine and a cure for HIV on the global research and policy agenda. We must continue to pressure the G8 to fulfill its 2005 commitment to universal access and we must hold African heads of state accountable to the Abuja Declaration on Health.

Surviving the AIDS backlash. We must not allow health economists or political leaders to pit disease groups against one another. We must take what we have learned from ART scale-up, which is the largest public health response in history, and apply those lessons to strengthening health systems as a whole. We must not scrap over meager allotments—0.3% of the entire U.S. budget to fund global health initiatives—but pressure our governments to expand their commitment to global health and lead other donor countries in responding to the global AIDS epidemic.

AIDS is still an emergency for the more than 16 million people who immediately need but cannot access lifesaving medicines. If the U.S. President’s Emergency Plan for AIDS Relief is to transition from an emergency response to a sustainable program, it must be adequately funded to make that transition. But we must move out of the emergency stage first—not through rhetoric, but with evidence that we have started to reverse the spread of HIV. The pandemic, not the programmatic response, must be reversed.

Support crucial research such as the Strategic Timing of Antiretroviral Treatment (START) study and thoroughly explore the potential of treatment as prevention.

Treatment decisions and prevention policy need to be based on evidence from randomized controlled trials. We need research that optimizes treatment benefits by balancing when to start with potential long-term side effects. We need research to strengthen the evidence base for continued scale-up. We also need better first-line regimens for potentially earlier initiation of ART.

A disastrous obsession with fiscal austerity has spread among the developed countries like an unstoppable airborne infectious virus. Millions of people’s lives are at risk because global leaders refuse to meet their commitments to scale up HIV, TB, malaria, immunization, and maternal and child health programs and to reverse global poverty by the year 2015. The emergency posed by AIDS funding freezes in the United States and around the world presents a challenge to front-line providers, researchers, policy makers, government officials, industry, and treatment activists—and most of all, people living with AIDS. We must work together as never before as a unified force to fight for human rights, public health, and social justice as truly achievable goals through universal access. We must redouble our efforts to carry out research that will end the epidemic as we continue to save lives now with effective prevention and treatment interventions.

References

1. Kaiser Family Foundation. US global health policy: Overview of financing and policy priorities in global health. Accessed 7 June 2010: http://www.kff.org/globalhealth/kedu041310.cfm.
2. Lu C, Schneider M, Gubbins P, Leach-Kemon K, Jamison D, Murray C. Public financing of health in developing countries: A cross- national systematic analysis, Lancet 2010; 375(9723):1382.
3. Global Fund to Fight AIDS, Tuberculosis and Malaria. Current grant commitments & disbursements. Accessed 24 May 2010: http://www.theglobalfund.org/en/commitmentsdisbursements/.
4. National Alliance of State and Territorial AIDS Directors. NASTAD The ADAP Watch. Update as of 2 July 2010. Accessed 3 July 2010: http://www.nastad.org/Docs/Public/InFocus/201072_ADAP%20Watch%20update%20-%207.2.10.pdf