A response to this letter from Director Dieffenbach is provided via link at the bottom of this page.
28 August 2017
Carl Dieffenbach, PhD
Director of the Division of AIDS
National Institute of Allergy and Infectious Diseases
5601 Fishers Lane, MSC 9806
Bethesda, MD 20892
Dear Dr. Dieffenbach:
Thank you for the opportunity to provide comments to the Division of AIDS (DAIDS) in advance of the recompetition of its clinical trials networks. We applaud the Division’s commitment to refining its science-driven HIV research enterprise and we appreciate your consideration of our input as DAIDS continues to shape its focus and priorities for the 2020 to 2027 funding cycle.
Treatment Action Group (TAG) is an independent, activist and community-based research and policy think tank fighting for better treatment, prevention, a vaccine, and a cure for HIV, tuberculosis (TB), and hepatitis C virus (HCV). We are science-based treatment activists working to expand and accelerate vital research and effective community engagement with research and policy institutions. Our HIV, TB, and HCV projects continue to closely monitor and advise the DAIDS pluripotent clinical trials networks to ensure the advancement of science critical to the lives of people affected by HIV, TB, and HCV.
We urge DAIDS to consider the following five recommendations, elaborated upon below:
- maintain the HIV Prevention Trials Network (HPTN), HIV Vaccine Trials Network (HVTN), and Microbicide Trials Network (MTN)—rather than combine all three networks into a single HIV prevention network—to continue important early-stage research, and to strengthen HPTN to ensure the infrastructure and multi-disciplinary expertise necessary to fully evaluate combination-based HIV prevention modalities;
- maintain the important work of the AIDS Clinical Trials Group (ACTG), and continue to support a separate network focused on maternal, pediatric, and adolescent populations to ensure their appropriate inclusion in research;
- conduct research relevant to populations mono-infected with TB and HCV, in addition to including populations co-infected with HIV;
- Ensure that any plans to strengthen trials networks to be scalable and flexible to respond to other infectious disease outbreaks do not detract from network and trial site resources and infrastructure dedicated to HIV, TB, and HCV clinical research;
- maintain and expand research in:
- biomedical prevention and vaccines for HIV, TB, and HCV;
- antiretroviral drug and biologics discovery and development;
- the management of comorbidities associated with HIV infection;
- diagnostics and treatments for TB;
- and diagnostics and treatments for HCV.
1. Maintain and strengthen biomedical prevention clinical trials networks.
We read with interest your May 12, 2017, online editorial describing the intersections in biomedical HIV prevention and the need for combining biomedical HIV prevention research in a single network structure. We agree that the next decade will usher in requirements and opportunities for biomedical prevention modalities with unique mechanisms of actions—preventive vaccines, passive immunotherapy, and antiretroviral-based products—to be combined to maximize efficacy or incorporated into clinical trial control groups to ensure comparisons with an evolving standard of care. However, we are concerned that a single biomedical prevention research network will stymie the rigorous early-phase research necessary to advance promising compounds, formulations, and delivery technologies. Furthermore, given the wide range in study design, participant populations, site requirements that research into new preventive therapy, vaccines, and microbicides require, it may not be logical to combine these into a single network.
The HIV Prevention Trials Network (HPTN), HIV Vaccine Trials Network (HVTN), and Microbicide Trials Network (MTN) have all yielded significant contributions to the field of biomedical HIV prevention science, each benefiting from its own leadership, oversight, governance, research management, operations, and administration.
Importantly, these three networks benefit from cross-network leadership and logistical support provided by the Office of HIV/AIDS Network Coordination, which, since 2004, has fostered multi-disciplinary integration, collaboration, and flexibility among the five existing clinical research networks funded by DAIDS.
HPTN is now charged with the development and implementation of not only clinical trials of novel antiretroviral-based products, but also the evaluation of integrated strategies to prevent HIV infection. It should remain the research network primarily responsible for registrational and operational studies combining or comparing two or more biomedical prevention strategies in adults and adolescents, including vaccine candidates in late-stage development.
Early-phase clinical research must still be prioritized, however, particularly in the areas of vaccine development and multi-purpose technologies. We are concerned that this work will be deprioritized with research network consolidation emphasizing integrated, large trials. The primary HIV prevention toolbox must be expanded to include antiretroviral, vaccine, and immune-based products with favorable pharmacokinetics, safety, and efficacy data in all populations of people vulnerable to HIV infection. This will require continued support of, and robust investments in, sound clinical trials that can be designed, implemented, and enrolled quickly with focused scientific, community, and operational leadership.
As such, we recommend maintaining all three networks to ensure high-caliber translational research and early-phase product development, with HPTN strengthened to ensure the infrastructure and multi-disciplinary expertise necessary to fully evaluate combination-based HIV prevention modalities. If consolidation is ultimately necessary—which we caution against—DAIDS should commit sufficient resources to ensure that proof-of-concept and other early-stage clinical science remains a priority.
2. Maintain the important work of the AIDS Clinical Trials Group (ACTG), and continue to support a separate network focused on maternal, pediatric, and adolescent populations to ensure their appropriate inclusion in research.
The clinical trials network focused on the treatment of HIV and its sequelae—the AIDS Clinical Trials Group (ACTG)—and the International Maternal, Pediatric, Adolescent AIDS Clinical Trials Group (IMPAACT) also benefit from their own leadership, operations, and high levels of expertise in conducting the research necessary to address the needs of specific populations and sub-populations. IMPAACT has made considerable progress in advancing research in children, adolescents, and maternal populations living with HIV, TB, and HCV (in the case of the ACTG).
NIAID recently noted that a “network dedicated to pediatric, adolescent and maternal research may not be the most strategic method of delivering the innovative, efficient results needed to turn the corner on the HIV/AIDS pandemic” and that “NIH is seeking to create an integrated network model that will cover adults, pediatrics, adolescents, and pregnant women in the areas of vaccines, prevention, and therapeutics.” NIAID indicates these suggestions are based on assessments of the existing separate research networks, yet the methodologies and results of these assessments are not cited or discussed in detail. We would appreciate the opportunity to review NIAID’s findings so that we may provide more informed feedback. At present, we have several concerns about integrating the work currently done by IMPAACT into a single network model.
An integrated network model that spans ages and populations in practice could stymie the investigation of new drugs in children and risks loss of specialization and expertise. Pharmaceutical companies, a majority of which currently lack the clinical trial site infrastructure, expertise, and incentive to conduct HIV and TB research in children and pregnant/post-partum women, rely on the IMPAACT network to advance research in these special populations. The availability of the IMPAACT network’s established trial sites, procedures, and expertise also enables more rapid investigations of new drugs. For efavirenz, studied outside of the IMPAACT network, it was 15 years before an indication for use in infants and young children (3 months to 3 years of age) was achieved. In contrast, dolutegravir is being studied in children as young as four weeks old (P1093) just four years after its approval. In terms of pediatric investigations of new TB drugs, it is only through the efforts of the IMPAACT network that bedaquiline and delamanid will be investigated in children co-infected with HIV (P1108 and P2005). Maintaining the IMPAACT network’s operational capabilities and the generation of researchers with expertise and interest in these populations it has cultivated will remain important through 2027 and beyond.
In addition, research conducted by the IMPAACT network has been critical to filling knowledge gaps for TB treatment and prevention in pregnant/ post-partum women. P1026s has enrolled 900 pregnant women and 400 mother-infant pairs, providing data on the use of 17 ARVs in pregnant women. The protocol remains open and is now also collecting data on first- and second-line medications used to treat pregnant women with TB. For example, P1078 has enrolled 950 mother-infant pairs and will inform the use of nine months of daily isoniazid (9H) for the prevention of TB among pregnant women with HIV. These data come 51 years after the initial recommendation for the use of 9H for the prevention of TB (1965). P2001, which opened in May 2017, will determine the pharmacokinetics and safety of three months of once-weekly rifapentine and isoniazid (3HP) in pregnant women with and without HIV. If all goes according to plan, data from this study can be used to inform the use of 3HP in these populations as early as 2019– this time, just eight years after its initial recommendation (2011). Without a dedicated network focused on pregnancy, it is likely that exclusion of pregnant women from research and lack of data on prevention options in this population would persist.
Moreover, as IMPAACT focuses on both prevention and treatment in these populations that are extremely vulnerable to developing HIV and TB or other co-morbidities, folding IMPAACT under a broader treatment network would risk jeopardizing dedicated prevention work in these populations.
Whether other DAIDS networks and sites are even capable of accommodating studies in these special populations, which present to different sectors of the health system, often outside of TB and HIV programs, and have unique needs, remains an open question of critical importance for DAIDS to address.
We therefore recommend maintaining IMPAACT as a separate network, to allow it to continue its success, as well as to continue investing in ACTG.
3. Conduct and coordinate TB and HCV monoinfection alongside TB/HIV and HCV/HIV coinfection research at DAIDS.
The expansion of the DAIDS clinical trials networks to include tuberculosis (TB) mono- and co-infection studies has significantly improved TB clinical trials capacity globally and built multi-disciplinary support and leadership for TB research previously absent within DAIDS and its research networks, as well as provided opportunities for collaboration and efficiencies with other research networks, including the U.S. Centers for Disease Control and Prevention’s Tuberculosis Trials Consortium. We were heartened to see that the Q&A document on the recompetition webpage acknowledge that “data and results from studies involving HIV-TB co-infected people may also be relevant to TB mono-infected people,” and encourage DAIDS to continue to conduct research relevant to both mono- and co-infected populations.
We also note the FAQ language stating that “Viral hepatitis is another important co-infection that needs to be discussed and considered for the agenda.” The ACTG’s early prioritization of research on HIV/HCV coinfection contributed significantly to the development of effective treatments in these patients, including determining the natural history of treated coinfection; initial evaluation, timing and optimal regimes for interferon and direct acting antiviral (DAA) based treatments; drug-drug interactions between DAAs and HIV therapies; hepatotoxicity and steatosis in coinfected patients; and the development of strategies for improved hepatitis vaccine responses. Continued coordination of HCV coinfection studies within the ACTG, and the expansion of this work to include emerging needs such as pediatric patients, prevention of parent to child transmission, drug-drug interactions with newly approved DAAs, and prevention of HCV transmission among men who have sex with men is needed within the ACTG and DAIDS clinical trials networks, and is best approached via the current coordination of DAIDS.
Opportunities to collaborate with other departments within NIAID should be explored. However, DAIDS should continue to pursue studies relevant to TB and HCV to mono-infection, given the high overlap of affected populations, and the excellent work being done to date. Decentralization of efforts would be counterproductive, less efficient, and risk losing progress made in the current cycle.
4. Ensure continued focus on HIV, TB, and HCV clinical research if expanding to interoperable sites for clinical research on infectious disease outbreaks.
We are interested in learning more about the creation of a pool of interoperable trial sites funded and supported by DAIDS that can be mobilized quickly to address clinical research needs that emerge during outbreaks of infectious diseases, such as influenza, Ebola, Zika, and Chikungunya.
TAG strongly supports the strengthening of coordinated clinical trials networks, particularly those with significant expertise in infectious disease research, to ensure scalable and flexible responses to future outbreaks. We appreciate that NIH is exploring a fee-for-service funding model to support this research through 2027, but recommend strong safeguards to protect network and trial site resources and infrastructure dedicated to HIV, TB, and HCV clinical research.
5. Maintain and expand research in priority areas.
In addition to the above considerations regarding the structure of the renewed networks, TAG raises the following clinical research and implementation science priorities for the HIV, TB, and HCV researched conducted by the future DAIDS clinical trials networks:
HIV clinical research and implementation science priorities
To adequately address the emerging areas of science that can impact HIV/AIDS prevention, treatment, and cure, we need research to:
- develop novel technologies that allow for extended release of drug and biologic products emerging as significant scientific advances in the field of biomedical HIV prevention that demonstrate the potential for significant uptake and effectiveness in key vulnerable populations, both domestically and globally;
- although DAIDS may not play a significant role in the development of innovator therapies, it must continue to conduct or support research addressing unmet safety and efficacy needs, including pediatric treatment across age/weight bands and salvage options for highly treatment-experienced patients;
- compare generic drug-inclusive regimens optimized for safety, efficacy, and acceptability to support HIV treatment cost containment, both domestically and globally;
- describes the causes of immunologic non-response, and develop and evaluate therapies capable of promoting immune recovery and reducing the risk of morbidity and mortality caused by immunologic non-response;
- fill critical gaps in the research of curative strategies, notably combination antibody activity (including BNAbs optimized for therapy), B-cell follicle disruptors, immune modifying agents that enhance T cell function (including checkpoint blockers and chimeric antigen receptors) and blunt the detrimental effects of chronic inflammation and immune activation, gene therapy, and vaccines;
- fill critical gaps in the research of prevalent comorbidities, notably continued evaluation of circulating biomarkers to predict clinical and subclinical cardiovascular disease, immune modulating drugs to treat HIV-associated neurocognitive disorders, the development of cancer treatment vaccines (including CGX-3100 for HPV-related neoplasia, dysplasia, and cancer), immune system modulators to activate natural killer cells and dendritic cells, and gene therapy.
TB clinical research and implementation science priorities
To improve the woefully inadequate current prevention, diagnosis, and treatment of TB, we need research to:
- advance biomarker discovery and validation to inform TB diagnostic and treatment monitoring development, reduce the length of clinical trials for TB treatment, predict who is at most risk of progressing from TB infection to active disease, and provide insight into immunity for vaccine development;
- improve, shorten, and simplify treatment for drug-sensitive and drug-resistant TB disease and infection in people with and without HIV, including children and pregnant women;
- establish drug-drug interactions (DDIs) between TB and HIV medications. This includes DDI studies between a) new antiretroviral (ARV) agents and existing TB drugs, and b) new TB drugs and new ARVs. In our experience, industry groups have little incentive to conduct these studies, meaning that public funders such as the NIH will continue to play an important role in this area either by directly supporting such studies or by facilitating collaborations between TB and HIV drug sponsors; and
- further our understanding of and approach to treating special forms of TB such TB meningitis and TB IRIS.
HCV clinical research and implementation science priorities
To make significant gains with the all-oral, pangenotypic direct-acting antivirals and advance towards national and global HCV elimination, we need:
- research on the safety, tolerability and efficacy of DAAs to prevent parent to child transmission;
- continued funding for research towards a HCV vaccine that shows efficacy in people at risk for HCV infection because they inject drugs; the ability to elicit immune response in people living with HIV who are not at high risk for HCV infection; and safety in combination with HIV vaccine administration in healthy volunteers;
- research and development for dosage and effective treatment regimens for infants and children (aged 3-12 years) and weighing less than 35 kilograms (77 pounds);
- post-treatment studies on the efficacy and long-term health effects for sofosbuvir and sofosbuvir/ ledipasvir in adolescents (aged 12-17 years);
- research and development for more options in point-of-care RNA assays to fill critical gaps in screening programs and put more patients on treatment;
- additional research on sensitivity assay to make progress on core antigen diagnostics
- research and development for comprehensive diagnostic technologies (including those that use dried blood spot and point-of-care core antigen tests) that ensure rapid test results in a single visit, inform treatment regime choice, and confirm curative rates in patients;
- research to develop a new class of DAAs to cure in four weeks, which match current SVR12 rates of 90% or greater across genotypes, levels of disease severity, and comorbidities and infections, including HIV/HCV co-infection;
- research on HCV treatment as prevention among HIV-positive men who have sex with men;
- research on how PrEP affects the HCV epidemic and global transmission networks;
- research on the timing of liver transplantation and HCV treatment;
- continued monitoring of HCV treatment resistance (such as in treatment-experienced populations) and research to cover these treatment gaps
We appreciate your consideration of our suggestions, and look forward to them being incorporated in the recompeted networks.
Mark Harrington, Executive Director
on behalf of
Treatment Action Group
Click here to read Dr. Deiffenbach’s response August 31, 2017, response.
 Dieffenbach CW. Thought starter: filling the gaps in HIV prevention research. National Institute of Allergy and Infectious Diseases. 2017 May 12. Available from: https://www.niaid.nih.gov/research/filling-gaps-hiv-prevention-research
 National Institute of Allergy and Infectious Diseases. Questions and answers: refining the science-driven HIV research enterprise. 2017 March 9. Available from: https://www.niaid.nih.gov/research/questions-answers-refining-science-driven-hiv-research-enterprise
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