Free 2013 Report: New HIV, HCV and TB Drugs, Diagnostics, and Vaccines in the Research Pipeline

HIV i-Base/Treatment Action Group 2013 Pipeline Report
calls on leaders to get the best HIV, hepatitis C virus (HCV), and tuberculosis drugs, diagnostics, and vaccines to the most people as quickly as possible
– Survey shows HIV pipeline healthy, HCV drug development surging,
while TB research moves forward much too slowly –

– Faster research, approval, and access demanded –

KUALA LUMPUR, Malaysia, 30 June 2013 – HIV i-Base and Treatment Action Group (TAG) called on global and national leaders, research sponsors, and regulatory authorities to work together to make the best HIV, HCV, and TB drugs, diagnostics, and vaccines accessible as fast as possible, according to a report released today at the 7th International AIDS Society (IAS) Conference on HIV Pathogenesis, Treatment and Prevention in Kuala Lumpur, Malaysia.

In the 2013 Pipeline Report, Polly Clayden of HIV i-Base (UK) and Mark Harrington of TAG (USA), set a seven-part agenda to speed the best medical products to all who need them everywhere. They call for research funders to continue investing in better products and to address global needs up front in their development. They demand that regulators expedite review of new medications in developing countries and close approval gaps between rich and poor countries and adult and pediatric indications. World Health Organization (WHO) and national guidelines groups must continue streamlining and simplifying treatment guidelines, they stress. Clayden and Harrington urge authorities in developing and developed countries to speed the rational use of the best possible drug combinations regardless of patent status or manufacturer and to expedite the transition to high-quality first-line generic products when preferred drugs go off patent.

Noting that the pharmaceutical industry has made billions from successful HIV therapies in the past two decades, Clayden and Harrington report that in the last decade alone, 47 new drugs and combinations were studied in phases II and III. An impressive 34 percent (16/49) were approved by the U.S. Food and Drug Administration (FDA), with 6.4 percent (3) awaiting approval and 21 percent (10) moving forward in phases II or III. “To get the best drugs to the most people as quickly as possible, global and national health leaders, regulators, and research sponsors must take concerted action to speed up the approval of pediatric, generic, and high-quality cross-sponsor fixed-dose combinations—as soon as they are available in rich countries—in those where they are needed most,” commented Clayden and Harrington.

Themes of the 2013 “Antiretroviral Pipeline” by Simon Collins (HIV i-Base) and Tim Horn (TAG) include the continuing wave of innovations bringing broader, and in some cases better, treatment options for people with HIV. They note “the possible conflicts these innovations will encounter due to global economic austerity.” Collins and Horn underscore “the potential for combining generic antiretrovirals as they move off-patent in many developed countries with innovator compounds to produce synergistic, often cross-sponsor, combinations and fixed-dose combinations (FDCs) that could offer people with HIV the best of the new and the old while saving cash-strapped health systems billions of dollars.”

Noting the current decade’s coming wave of patent expiries on first-line HIV drugs such as efavirenz and tenofovir, Collins and Horn note that, “savings from generics are essential if we are to retain public health services for those who remain uninsured or underinsured.” They call for generic manufacturers and governments to seize the opportunity posed by the coming wave of patent expiries to offer optimal combinations at prices much lower than for innovator compounds. It will be critical for rich and poor countries, to reinvest the savings generated by sensible use of generic-containing antiretroviral combinations into massively expanded HIV prevention and treatment programs to end HIV transmission and progression to AIDS and death and achieve an “AIDS-free generation” for everyone.
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In back-to-back chapters on pediatric HIV drugs and HIV treatment optimization, Polly Clayden calls for continued streamlining and rationalization of adult and pediatric HIV formulations and notes innovative partnerships such as those recently supported by the Drugs for Neglected Diseases Initiative (DNDi) and UNITAID to expedite production of optimized regimens for children. Clayden stresses the importance of developing generic combinations with the best target product profiles. “It’s time to move on from merely providing the world’s poor people with the cheapest medicines and time to give them the best – safest and most effective – treatments possible, and make them affordable” says Clayden.

Richard Jefferys (TAG), in his broad survey of research developments on preventive technologies, research toward a cure, and immune-based and gene therapies, calls for intensified basic and translational science on potential HIV vaccines and continued research on antiretroviral (ART)-based pre- and postexposure prophylaxis (PrEP, PEP). He stresses the need for immune-based therapy research to raise CD4 T cell counts among immunologic nonresponders to HIV therapy, and new research to address ongoing residual dysfunction of the immune system that persists in people on successful ART. Finally, Jefferys emphasizes further investigation of the role of very early treatment with potent ART combinations in infants and adults infected with HIV; better lab measurements to quantify the cells and tissue sources of the latent HIV-1-infected cell reservoir, the target for HIV cure research; and exploration of the potential contribution of therapeutic vaccine approaches as part of combination curative therapy.

In the 2013 “HCV Treatment Pipeline,” Tracy Swan (TAG) notes that the “confluence of a robust HCV drug pipeline, shortened regimens, and [shorter] posttreatment follow-up are extraordinary. The new FDA breakthrough therapy designation may speed things up as well. By the end of 2014, [new HCV drugs] from four different classes and fixed-dose combinations (FDCs) are likely to be approved by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA), offering the potential for off-label mixing and matching.” An impressive 26 new HCV drugs are being studied in phases II/III in at least 28 interferon-free regimens, which are bringing the potential of faster, all-oral HCV cures rapidly toward approval for the world’s 185 million people living with HCV.

Swan notes, however, that not all optimal combinations are being studied, with some sponsors preferring combinations of their own proprietary compounds, while many sponsors take too long to study their new drugs in people coinfected with HIV and HCV, and those with cirrhosis.

In her companion chapter, “Low- and Middle-Income Countries Defuse Hepatitis C, the ‘Viral Time Bomb,’” Karyn Kaplan (TAG) describes how a worldwide movement is forming to ensure that when new all-oral HCV cures are approved, that governments, health systems, and providers will be ready for them. Kaplan points to recent progress instigated by HCV activists in countries such as Egypt, Georgia, Thailand, and Ukraine.

In three chapters on tuberculosis (TB) diagnostics, treatment, and vaccine research, Colleen Daniels, Erica Lessem, and Mike Frick (TAG) find that lack of investment and political will make the TB pipeline the most anemic covered in the 2013 Pipeline Report.

Globally, one-third of active TB cases are never diagnosed, reported, or treated, meaning that 3 million people are walking around with undiagnosed disease, in danger of progression, death, and onward transmission.

Some progress has been made in rolling out new DNA tests, which can detect TB more rapidly. The tests still require high-tech laboratory equipment, electricity, and trained personnel though, meaning they are far from the majority of TB patients and those at risk. Manufacturers are trying out cheaper forms of DNA TB diagnostic testing with as yet little published data, and faster ways to detect TB mutations, which are associated with resistance to TB medications.

TB treatment is slowly moving forward following the first FDA approval of a new drug from a new class in over 40 years, and innovative combination TB studies under way for both drug-sensitive and drug-resistant disease. Most countries are not ready to review, approve, distribute, and assure rational use of new TB drugs and combinations, however, reinforcing HIV i-Base and TAG’s call for high-burden countries to modernize their regulatory research oversight and approval programs.

Research on TB vaccines remains slow and underfunded but there are some glimmers of hope, particularly on the basic science and early clinical front. Much more investment is needed in TB research and development overall, and in TB program scale-up to ensure access to the best diagnostics tests and preventive and curative therapies.
 

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The HIV i-Base/Treatment Action Group 2013 Pipeline Report: HIV, Hepatitis C Virus (HCV), and Tuberculosis (TB) Drugs, Diagnostics, Vaccines, Preventive Technologies, Research Toward a Cure, and Immune-Based and Gene Therapies in Development by Polly Clayden, Simon Collins, Colleen Daniels, Mike Frick, Mark Harrington, Tim Horn, Richard Jefferys, Karyn Kaplan, Erica Lessem, and Tracy Swan, edited by Andrea Benzacar, Tim Horn, and Scott Morgan, is online at:

            http://www.treatmentactiongroup.org/pipeline-report 

and as an interactive web report at:

            http://www.pipelinereport.org

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.

http://www.i-base.info 
About TAG – 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. We are science-based treatment activists working to expand and accelerate vital research and effective community engagement with research and policy institutions. TAG catalyzes open collective action by all affected communities, scientists, and policy makers to end AIDS. TAG is a nonprofit, tax-exempt 501(c)(3) organization.

http://www.treatmentactiongroup.org 

HIV, Active HCV, Low Income Tied to Shorter Telomeres, a Cellular Aging Marker

From Natap.org

HIV, Active HCV, Low Income Tied to Shorter Telomeres, a Cellular Aging Marker
3rd International Workshop on HIV and Aging, November 5-6, 2012, Baltimore

Mark Mascolini

HIV infection, active HCV infection, and income below $15,000 a year independently predicted shorter telomere length in a study of 229 HIV-positive people and 166 HIV-negative people in a Vancouver cohort [1]. HIV infection had a slightly greater negative impact on telomere length than 10 years of age.

Telomeres cap the ends of chromosomes and shield them from damage. Shrinking with each cell division, telomeres shorten with age. Thus telomere length offers a marker of cellular aging. Telomeres may shorten more rapidly than normal when exposed to the oxidative stress resulting from HIV-induced inflammation, chronic immune activation, or treatment with antiretrovirals. And antiretroviral therapy itself may inhibit telomere activity.

To assess the impact of HIV and non-HIV variables on leukocyte telomere length, researchers conducted this prospective study of adults between 19 and 75 years old enrolled in the Vancouver's CARMA cohort between 2008 and 2011. Heterosexual sex and injection drug use are the prime routes of HIV acquisition in this socioeconomically disadvantaged study group.

The study included 229 HIV-positive people and 166 HIV-negative people, most of them women (79% and 71%). The HIV-positive and negative people were similar in age (median 40 and 38). The HIV group had a significantly higher proportion of blacks than the HIV-negative group (17% versus 1%, P < 0.01). Proportions of participants with an annual income below $15,000 were 45% in the HIV group and 54% in the HIV-negative group, a nonsignificant difference (P = 0.51).

Maternal age at the cohort member's birth was slightly but significantly lower in the HIV group than in the HIV-negative group (24 versus 26, P = 0.02), but paternal age at birth did not differ significantly by HIV status. The researchers had maternal and paternal age data for only half of the study group, so these variables were not included in the final multivariate model.

HIV-positive people had a median HIV infection duration of 9 years and a median lifetime antiretroviral duration of 4 years. Median nadir and current CD4 counts were 190 and 450, and 60% of HIV-positive people had an undetectable viral load at the study visit.

Univariate statistical analysis identified several factors associated with shorter telomere length: HIV infection (P = 0.031), HCV infection (P < 0.0001), income below $15,000 (P = 0.0002), having an older father or mother at birth (P = 0.0006 and P = 0.029), being black versus white (P = 0.031), being South Asian versus white (P = 0.018), older age (P < 0.0001), pack-years smoking (P = 0.017), and illicit drug use (P < 0.0001). Smoking, illicit drug use, and low income were associated with shorter telomere length only in HIV-negative people.

In the final multivariate analysis including HIV-positive and negative people, four variables were independently associated with shorter telomere length:

-- Every 10 years of age, beta -0.24, P < 0.0001
-- HIV infection, beta -0.28, P = 0.004
-- Active HCV infection, beta -0.24, P = 0.004
-- Annual income below versus above $15,000, beta -0.32, P = 0.001

Cleared HCV infection did not predict shorter telomere length. Among the 229 people with HIV infection, shorter telomere length was not linked to current CD4 count, CD4 nadir, time since HIV diagnosis, antiretroviral duration, or number of treatment interruptions. Nor did those factors predict telomere length in 126 HIV-positive people with an undetectable viral load.

The Vancouver team concluded that--besides older age--HIV infection, active HCV infection, and low income predict shorter telomere length and "may therefore affect telomere maintenance and cellular aging." Because the beta value for HIV exceeded that for 10 years of age (-0.28 versus -0.24), they suggested that HIV infection has a greater impact on telomere shortening than a decade of age. The researchers speculated that low income may be a surrogate for lifestyle and environmental factors that directly affect telomere length.

The investigators proposed that the link between active HCV infection and shorter telomeres may mean ongoing HCV-induced immune activation or inflammation could affect leukocyte telomere length. They suggested that future research should weigh the impact of anti-HCV therapy on telomere length.

A workshop attendee observed that the study measured telomeres in all leukocytes--the collection of white cells in which granulocytes predominate. Lymphocytes (which include T cells) make up about 30% of leukocytes.

Reference
1. Zanet D, Thorne A, Sattha B, et al. Active hepatitis C virus (HCV) infection, HIV+ status and low income are associated with shorter leukocyte telomere length in a cohort of HIV+ and HIV- adults. 3rd International Workshop on HIV and Aging. November 5-6, 2012, Baltimore. Abstract: O_07.