JAIDS Journal of Acquired Immune Deficiency Syndromes:
Implementation of HIV-Related Clinical Research in the International Setting
Godfrey, Catherine MD, FRACP*; Schouten, Jeffrey T. MD, JD†; Swindells, Susan MBBS‡
*HIV Research Branch, Division of AIDS, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD;
†Office of HIV/AIDS Network Coordination, Fred Hutchinson Cancer Research Center, Seattle, WA; and
‡Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE.
Correspondence to: Susan Swindells, MBBS, University of Nebraska Medical Center, 988106 Nebraska Medical Center, Omaha, NE 68198-8106 (e-mail: email@example.com).
The Office of HIV/AIDS Network Coordination has been funded in whole or in part with Federal funds from the Division of AIDS, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, grant number UM01 AI068614, entitled Leadership Group for a Global HIV Vaccine Clinical Trials (Office of HIV/AIDS Network Coordination) with additional support from the National Institute of Mental Health. S.S. receives grant support from the Division of AIDS, National Institute of Allergy and Infectious Diseases, National Institutes of Health (AI 068636).
This introduction was written by CG in her capacity as an NIH employee, but the views expressed in this article do not necessarily represent those of the NIH.
The authors have no conflicts of interest to disclose.
The last 20 years have witnessed a dramatic increase in HIV-related therapeutic research conducted in international settings. Moving from a model of leadership based in a US or European institution, international sites have developed increasing autonomy and many now have the capacity for the conduct of high-quality clinical research. In tandem with the increased availability of antiretroviral therapy (ART) and laboratory monitoring, investigators from resource-limited settings (RLS) now set their own research agenda, one which is relevant for their local and regional priorities.
The development of this research capacity and expertise has included many challenges ranging from overarching ethical issues to the practicalities of maintaining continuous electrical power. Many RLS are in areas of very high disease burden and overwhelming need for clinical care and laboratory services, which compete with the resources needed for clinical trials. International aid agencies have appropriately focused on building clinical capacity for the prevention and treatment services, rather than research capacity. Inadequate health care infrastructure, understaffing, and complex regulatory hurdles also contribute to the difficulties.
The editors of this supplement have had the privilege of participating in the process of development of international sites for the National Institutes of Health–funded therapeutic trials networks. For example, the AIDS Clinical Trials Group now has 27 international clinical research sites. Developed under the leadership of Dr Constance Benson, the network has developed and implemented multiple pivotal clinical trials performed almost exclusively at the international sites that have changed both clinical practice and management guidelines.1 These include A5175, which evaluated alternative first-line antiretroviral treatment regimens,2 and A5199, which described the neurocognitive and neurologic complications of HIV and its therapies in RLS.3 The International Maternal Pediatric Adolescent AIDS Clinical Trials Group, in collaboration with the AIDS Clinical Trials Group, conducted A5207 and A5208, which evaluated alternative ART regimens for the prevention of mother-to-child transmission and the consequences of single-dose nevirapine therapy.4,5 Also performed in RLS, the SAPIT and CAMELIA studies demonstrated the benefits of early ART in patients with tuberculosis, a finding which was confirmed in A5221 and contributed to changes in treatment paradigms.6–8 The most recent groundbreaking study was the HIV Prevention Trials Network 052/A5245 demonstrating dramatic reduction in HIV transmission by ART in discordant couples.9 The primary article was voted the “Science Breakthrough of the Year.”10 This trial also informs on ongoing debate about when to start ART, by showing that early ART delayed the time to development of HIV-related clinical events, a finding originally shown by the CIPRA Haiti trial.11,12
An important component of the success of development of the international research capacity and agenda has been community engagement and capacity development.13–15 Community participation has been a key component of National Institute of Allergy and Infectious Diseases research activities since early in the HIV/AIDS epidemic and continues to be so with the expansion of the research into RLS.16 Community representatives are integrated at every level, from creation of the scientific agenda and priorities to approval of a concept proposal and subsequent development and implementation of a protocol.
We have developed strong collaborative relationships with many of the talented and hardworking site investigators and staff working in extraordinary conditions, and we have also had the opportunity to observe many of the issues encountered with research in the international RLS. Agenda setting, collaborating with multiple funding partners, negotiating an appropriate and achievable standard of care, and regulatory challenges, including supporting nascent institutional review boards and other topics associated with multinational research made for extremely interesting discussions that we felt might also be of interest to a wider audience.
This supplement describes some of the key issues encountered in the conduct of clinical research in RLS, with authors from representative international sites.
The authors are grateful for funding support from the Therapeutics Research Program at the Division of AIDS and in particular thank Sarah Read, program director. The authors also thank Deanna Hansen, Department of Internal Medicine, University of Nebraska for her support
2. Campbell TB, Smeaton LM, Kumarasamy N, et al.. Efficacy and safety of three antiretroviral regimens for initial treatment of HIV-1: a randomized clinical trial in diverse multinational settings. PLoS Med. 2012;9:e1001290.
3. Robertson K, Jiang H, Kumwenda J, et al.. Improved neuropsychological and neurological functioning across three antiretroviral regimens in diverse resource-limited settings: AIDS Clinical Trials Group study A5199, the International Neurological Study. Clin Infect Dis. 2012;55:868–876.
4. McMahon DK, Zheng L, Hitti J, et al.. Greater suppression of nevirapine resistance with 21- vs 7-day antiretroviral regimens after intrapartum single-dose nevirapine for prevention of mother-to-child transmission of HIV. Clin Infect Dis. 2013;56:1044–1051.
5. Lockman S, Hughes MD, McIntyre J, et al.. Antiretroviral therapies in women after single-dose nevirapine exposure. N Engl J Med. 2010;363:1499–1509.
6. Abdool Karim SS, Naidoo K, Grobler A, et al.. Integration of antiretroviral therapy with tuberculosis treatment. N Engl J Med. 2011;365:1492–1501.
7. Blanc FX, Sok T, Laureillard D, et al.. Earlier versus later start of antiretroviral therapy in HIV-infected adults with tuberculosis. N Engl J Med. 2011;365:1471–1481.
8. Havlir DV, Kendall MA, Ive P, et al.. Timing of antiretroviral therapy for HIV-1 infection and tuberculosis. N Engl J Med. 2011;365:1482–1491.
9. Cohen MS, Chen YQ, McCauley M, et al.. Prevention of HIV-1 infection with early antiretroviral therapy. N Engl J Med. 2011;365:493–505.
10. Cohen J. HIV treatment as prevention. Science. 2011;334:1628.
11. Grinsztejn B, Ribaudo H, Cohen MS, et al.; and the HPTN 052 Protocol Team. Effects of early versus delayed initiation of antiretroviral therapy (ART) on HIV clinical outcomes: results from the HPTN 052 randomized clinical trial. Paper presented at: 6th IAS Conference on HIV Pathogenesis, Treatment and Prevention; 2011; Rome, Italy.
12. Severe P, Juste MA, Ambroise A, et al.. Early versus standard antiretroviral therapy for HIV-infected adults in Haiti. N Engl J Med. 2010;363:257–265.
13. Morin SF, Morfit S, Maiorana A, et al.. Building community partnerships: case studies of Community Advisory Boards at research sites in Peru, Zimbabwe, and Thailand. Clin Trials. 2008;5:147–156.
14. Dickert N, Sugarman J. Ethical goals of community consultation in research. Am J Public Health. 2005;95:1123–1127.
15. Rennie S, Sugarman J. Developing ethics guidance for HIV prevention research: the HIV Prevention Trials Network approach. J Med Ethics. 2010;36:810–815.
16. Kagan JM, Rosas SR, Siskind RL, et al.. Community-researcher partnerships at NIAID HIV/AIDS clinical trials sites: insights for evaluation and enhancement. Prog Community Health Partnersh. 2012;6:311–320.
International clinical research; Implementation; ACTG
© 2014 by Lippincott Williams & Wilkins
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