Addressing Critical Challenges in TB/HIV Research & Program Implementation
1 December 2009, Cancun, Mexico
About 70 activists, researchers, clinicians and public health experts participated in a TAG/Stop TB Partnership satellite meeting held prior to the 40th Union World Conference on Lung Health. The objectives were to (1) highlight current challenges for TB and TB/HIV programmes and research questions that are critical to help address these challenges, (2) bring attention to the important research initiatives that are attempting to address these program challenges, (3) highlight the role activists and NGOs play in addressing MDR-TB and the scale up of the 3Is and (4) strategise to increase the available funding and trial site capacity for TB research and development.
Javid Syed of Treatment Action Group (TAG), Jeremiah Chakaya, vice-chair of the Board of the Stop TB Partnership and Martin Castellanos, Director of Mexico’s national TB programme opened the meeting. Chakaya emphasised that the world needs new diagnostics, medicines and vaccines for TB patients. He said his organisation recognised the role of civil society and patient groups in fighting TB. Syed explained that on World AIDS Day we should remember that combating HIV is not only about having access to HAART but that as AIDS activists we must highlight the importance of combating TB, the leading cause of death amongst people living with HIV.
State of the epidemic
Lois Eldred of Johns Hopkins summarised the state of TB in the world. She explained that while prevalence has decreased steadily since 1990, incidence has increased, although this varies considerably by region. Importantly, sub-Saharan Africa will not meet the Millennium Development Goal of halving TB prevalence and mortality by 2015.
Eldred summarised the compelling evidence showing that HAART as well as HAART together with IPT reduces the risk of TB substantially. She described successful case finding strategies employed in high HIV prevalence settings. Challenges ahead include finding diagnostics with higher sensitivity and specificity that can ultimately be used at point of care, and developing new drugs. Eldred cited two promising developments, the GeneExpert diagnostic test for TB and rifampicin resistance and TMC207, a drug in phase II trials.
Eldred noted that more research on TB pathogenesis and phylogeny is also needed, as are better local epidemiological data. Models of TB infection control and universal HIV testing coupled with immediate HAART must be evaluated. Screening algorithms, treatment regimens and vaccines for pregnant women and children need to be developed. She also emphasised the need for a systems epidemiology approach to TB that takes cognisance of co-morbidities caused by tobacco, poor nutrition and socioeconomics.
Dr Salome Charalambous of the Aurum Institute of Health Research described research on South African mines, TB/HIV integration in prisons and taxi ranks and how her institute’s HAART programme had reduced TB incidence. She explained how TB/HIV activities and research can result in health systems strengthening.
Javid Syed of TAG presented his organisation’s findings on funding of TB research. He showed that the Gates Foundation has become the largest funder of TB research in the world, more than all the NIH institutes combined. There has been a steady rise in research funding for TB over the last decade, but at about $500m in 2008, it is still way below the $2 billion recommended by TAG. Also, the proportion of public sector funding is decreasing. He gave a detailed breakdown of funding, in order of size, by drugs ($176m in 2008), vaccines ($126m), basic science ($99m), diagnostics ($50m), operational research ($34m) and unspecified ($26m). During the ensuing discussion, Syed expressed concern that the Gates Foundation needs to continue its diverse portfolio for TB while other funders also should increase their investment in TB research and development as no one organisation will be able to provide the resources necessary to eliminate TB by 2050.
Panel 1: Research Gaps for TB Programmes
Salmaan Keshavjee of Partners in Health chaired this session. Martina Casenghi of Medecins Sans Frontieres explained the need for a point of care diagnostic test. She also presented the results of a survey of health professionals on what they believed were the most important characteristics such a test should have.
Claire Wingfield of TAG presented Anneke Hessling’s (Desmond Tutu TB Centre, South Africa) analysis of paediatric TB issues. She explained the diagnostic and treatment challenges for children, the importance of maternal screening and testing for TB, the lack of knowledge of the extent of BCG disease and the additional risk conferred by HIV. Top priorities include a rigorous scientific framework for high-quality research on TB diagnostics, increased access to children in TB trials and research on operational issues affecting children.
Hind Satti of Partners in Health described how Lesotho is implementing MDR-TB care. Lesotho has high TB prevalence (544/100k). Despite being one of the world’s poorest countries, it is implementing a comprehensive response to the epidemic that includes a community-based model to treat MDR-TB that uses treatment supporters to administer DOT. The programme enrolled its first patients in August 2007. To date there have been 380 patients on the programme. Some characteristics of the programme include: a laboratory has been built with capacity for drug-susceptibility testing, household contacts of people with MDR-TB are screened for TB and HIV and in-patient facilities have ventilation systems. Satti presented data on side-effects of MDR treatment, which appear to be worse than the rest of the world, albeit that her dataset was small. Despite the high level of side effects, the programme did not have any patients who had defaulted treatment. She concluded that diagnosis and management of MDR-TB in a high HIV-prevalence setting like Lesotho is challenging but possible.
Panel 2: Addressing Challenges in TB Research
Christian Lienhardt of the WHO chaired this session and Wim Vandevelde of the European AIDS Treatment Group was the discussant. Gerhard Walzl of Stellenbosch University summarised the state of TB diagnostics. Smear microscopy is a 120 year old technology. Its sensitivity can be improved by using various “add-on” technologies, although these add time, cost and complexity to the diagnosis. Walzl also described other diagnostic technologies: culture (highly sensitive and specific but takes too long), radiology (overused and too non-specific) and PCR (expensive, technically demanding and not as sensitive and specific as culture). He presented the scientific challenges that need to be overcome to develop a point-of-care (POC) test and then explained how using a combination of biomarkers might be useful for developing such a test.
Clair Wingfield’s presentation from the previous panel was complemented by Sharon Nachman of Stony Brook University. She explained the current best standards of care and also highlighted paediatric research needs. She highlighted several issues affecting children across all ages including the lack of PK data and the need for fixed dose combinations. Nachman concluded that future plans for paediatric trials must cut across age groups, include new diagnostic testing, include new and old therapies, be creative about what constitutes success and include HIV-positive populations.
Nathan Geffen of the Treatment Action Campaign discussed the need for a policy on accelerated access to promising TB drugs, such as TMC207, that are not yet approved, drawing on the experience with antiretrovirals. He noted that the policy has to balance the risks of using incompletely tested drugs and concerns about resistance with the desperate needs of drug-resistant patients without options. During question time, Geffen indicated that health workers, who have been shown in studies in Kwazulu-Natal to have a much higher risk of drug-resistant TB, should be prioritised for accelerated access.
David McNeeley of Tibotec, who is one of the TMC207 researchers, explained some of the complexities involved in testing new TB drugs. He described how for TMC207, Tibotec has used a two-stage Phase II design, with a shorter first stage, the results of which have been published in the NEJM and are promising. He explained how mouse models do not translate completely to humans. He also pointed out the potential ARV interactions with TMC207, considered Phase III trial issues and indicated that further trials to examine HIV drug interactions (with the purpose of adjusting doses) might be needed. He pointed out the vast number of players involved in drug development and asked the question, “Can these various groups and the sites that hold allegiance to them come together for the common good of advancing new TB drug development by sharing sites and resources at a reasonable cost or even contributing those resources together?”
In the ensuing discussion it became clear that more discussion and co-ordination is needed to resolve the complex issues raised in this panel. It was also noted that there are plans to convene regulators, TB developers and activists to facilitate sharing of information and determining a way forward that will bring drugs to market in the shortest period without compromising safety and efficacy.
Panel 3: Activists and NGOS improving programmes through partnerships and advocacy
Alasdair Reid of UNAIDS chaired this session and Jeremiah Chakaya of the Kenyan Medical Research Institute was the discussant. Thoko Phiri Nkhoma of the Tikondane PLWHA Women Support Group in Malawi explained how her organisation is helping to intensify TB case finding. Her organisation, started in 2004, comprises 13 HIV support groups. They conduct community education sessions on TB, aimed at people with HIV. They have initiated Stop TB clubs and have developed handouts and manuals. They also established a coalition of civil society organisations that assesses and analyses critical TB-related issues. They have trained 50 women from the support groups who assist with DOT and other TB interventions. They have also established a mobile clinic, developed a TB-HIV integration community education manual and mobilised 400 women living with HIV to join support groups where they are screened for TB. She noted some serious challenges, such as the government not involving civil society in intensified case finding, lack of finance to mount a comprehensive advocacy campaign and health workers not having up-to-date information, amongst others.
Carol Nyirenda described the work of Community Initiative for Tuberculosis, HIV/AIDS & Malaria (CITAM+) in Zambia. This organisation consists of 33 support groups comprising 384 members. Its activities include policy analysis, training, advocacy activities, community outreach activities and nutritional support. Nyirenda presented a survey the organisation conducted of the national TB documents and their availability. The survey found a lack of TB/HIV manuals and no clear information on infection control. She described clinic visits by her organisation in which they found that no protective masks were available in TB and HAART clinics, that TB screening has not been integrated into prevention of mother-to-child transmission services, that there is no IPT and that TB case finding is passive. Her organisation is now mobilising to rectify these problems.
Giselle Israel of the Rio de Janeiro Department of Health presented on an operational research study called THRio, whose objective is to determine if IPT in HIV-positive patients reduces the incidence of active TB in the HIV-positive clinic population. From 2005 to 2007, IPT was implemented at a rate of two clinics per month in Rio’s 29 public HIV clinics. She described the involvement of community organisations in the project. She showed data that associated the intervention with reduced TB incidence. In patients who did not receive either HAART or IPT, the TB incidence rate was 4.01/100 person years (95%CI: 3.4-4.68). For patients who received HAART only it was 1.9/100 person years (95%CI: 1.66-2.17). For patients who received IPT only it was 1.27/100 person years (95%CI: 0.41-2.95). For those who received both IPT and HAART it was 0.8/100 person years (95%CI: 0.38-1.47). Israel explained that her group was now working to have the intervention rolled out beyond Rio and even beyond Brazil. Bruce Margot of the Kwazulu-Natal Department of Health in South Africa had visa problems and could not make it to the meeting. However, participants have been given his presentation which presents data on intensified case finding and decentralised MDR-TB management. Perhaps the greatest challenges for these best practice examples is how they will be replicated and scaled up.
Panel 4: Increasing funding and expanding capacity for TB research
Mark Harrington of TAG chaired this session and Mercedes Becerra of Harvard Medical School was the discussant. Elsa Villarino presented the work of the Tuberculosis Trials Consortium (TBTC) which with a limited budget has carried out a wide range of work. She also gave a brief history of TB clinical trials from 1947 until present. TBTC is running trials in several countries. The goal is to find TB regimens that are shorter, safer and more effective. Examples of current and recent trials include: safety of linezolid 600mg in patients with MDR-TB, substitution of rifampin with rifapentine in the induction phase of treatment and substitution of isoniazid with moxifloxacin in the induction phase.
Claudia Giehl of the European Network for Global Cooperation in the Field of AIDS & TB explained the 7th Framework Programme (FP7) of the EU, a €53 billion mechanism running from 2007 to 2013 whose purposes include funding health research. She described the grant allocations of FP7 and made suggestions for how TB projects could access funding from it.
Christine Sizemore, Chief, TB, Leprosy and Other Mycobacterial Diseases Section of NIAID, described the institution’s TB funding strategy. She noted that NIH and NIAID funding had increased through the 1990s but dropped in 2008. She explained that most funding goes to basic/fundamental research. The further in the research and development cycle towards new products, the more other institutions and partners are needed for funding. She also explained that a substantial amount of projects that they fund were unsolicited. They usually fund for five years, but sometimes as long as seven and sometimes as little as two.
A lively discussion ensued on how to increase TB funding. There was consensus amongst speakers that positive messages and successes need to be stressed. There is also a need to tap into the growing number of public health students in the US to get them involved in TB. A next step of bringing lead funders of TB research and development was proposed. There is a need for funders to examine their portfolios, identify and co-ordinate funds for overlapping research priorities while also identifying gaps in funding and how these can be addressed.
This concluded an event that was packed with excellent presentations and useful discussions.