Portal de Periódicos da CAPES

HIV/AIDS preventive vaccine ‘prime-boost’ phase III trial: foundations and initial lessons learned from Thailand

2006; Lippincott Williams & Wilkins; Volume: 20; Issue: 11 Linguagem: Inglês

10.1097/01.aids.0000237362.26370.f8

1473-5571

Supachai Rerks‐Ngarm, Arthur E. Brown, Chirasak Khamboonruang, P Thongcharoen, Prayura Kunasol,

HIV Research and Treatment

Introduction The disease epidemic The first case of AIDS in Thailand was reported in September 1984. The number of newly reported AIDS cases increased every year, peaking in 1998 with 27 528 cases. As of 31 December 2001 [1], the year of the decision to conduct a phase III vaccine trial, the cumulative number of reported AIDS cases was 196 373. Among those reported cases, unsafe sex accounted for 85.6%, the highest proportion by mode of transmission, followed by intravenous drug use (3.9%), and mother-to-child transmission (3.3%). As of the end of 2004, the estimated number of HIV/AIDS cases is summarized in Table 1. The HIV epidemic is now spreading into every subpopulation, depending on risk behaviors, and shifting from specific risk groups to the general population (Fig. 1, Table 2) [2].Table 1: Estimated numbers of HIV/AIDS cases in the year 2004.Fig. 1: Shift of HIV transmission from specific risk groups to more general population.Table 2: HIV prevalence among specific groups, 2004.Evolution of prevention and control strategies In the early responses to the HIV epidemic, prevention and control strategies were based on previous experiences in the successful control and prevention of many other infectious diseases. These mainly utilized conventional communicable disease control approaches, such as the early detection and control of disease spread by disease surveillance and epidemiological investigation. Health educational campaigns on the seriousness of the disease and mode of transmission were conducted to raise public awareness [3]. Unfortunately, these methods apparently did not work well because HIV/AIDS is not an acute infectious process and it has complex social implications. Also, the way people get HIV infection relates to individual behavior and legal issues in some cases (i.e. drug use and prostitution) [4]. In the early 1990s, prevention and control strategies were changed, approaching HIV/AIDS as a social problem associated with individual behavior. Control activities were developed and coordinated in a multisectoral manner. HIV education was strengthened with more concise messages, to increase public awareness of the disease epidemic. Mechanical barrier intervention was emphasized; a 100% condom use campaign was intensively promoted among the high-risk sexual behavior groups, with collaboration across many governmental ministries [5,6]. Epidemiological surveillance was strengthened by the Ministries of Public Health and Defense to monitor the situation and evaluate the programmes [7–9]. In the late 1990s, specific group empowerment, and community care and involvement were added as new strategies. Many research studies were carried out to develop and assess supplemental strategies; i.e. the prevention of mother-to-child transmission with short-course drug therapy [10–12], and the prevention of infection by vaccination. Jointly, the above-mentioned efforts resulted in some reduction in sexual risk behaviors among high-risk groups [13,14]. As a result, the number of newly HIV-infected individuals decreased from an estimated 143 000 in 1990 to 19 500 in 2004. However, this incidence is still unacceptably high: 50–60 new infections per day still occur in some specific groups, such as older teenagers in whom risk behavior remains frequent. Vaccine as a supplementary intervention measure International HIV vaccine collaborations in Thailand After being hit hard by the HIV/AIDS epidemic in the late 1980s, the Royal Thai Government decided to explore and find an appropriate vaccine to supplement its conventional HIV intervention programmes. In the early 1990s, Thailand was approached, and then selected, by the World Health Organization (WHO) as one of four developing countries to focus on collaborative efforts for HIV vaccine development [15–17]. A National HIV Vaccine Development and Evaluation Plan was developed, endorsed by the WHO/Global Programme on AIDS in 1993, subsequently approved by the Thai National AIDS Commission, and designated the Ministry of Public Health (MoPH) as a national focal point for collaboration [18]. The objectives of the plan were as follows: (i) to develop and evaluate the future availability of safe, effective and affordable HIV/AIDS vaccine(s); (ii) to promote infrastructure strengthening, training, and technology transfer; (iii) to expand epidemiological studies on HIV and AIDS to provide insight into the appropriate populations for involvement in vaccine development; (iv) to foster and coordinate collaboration on HIV/AIDS vaccine research among different institutions in Thailand, and with international institutions; and (v) to collaborate with international scientific communities, as well as other national authorities in HIV vaccine development and evaluation: to fight against AIDS especially in developing countries. In parallel with the preparation of the National Plan for HIV/AIDS Vaccine Development and Evaluation at the MoPH under the auspices of the National AIDS Commission, there was capacity strengthening in the areas of HIV/AIDS vaccine research and development at various Thai medical schools and research institutions. These have included Siriraj Hospital, Mahidol University, the Thai Red Cross Society, Chiang Mai University and the Armed Forces Research Institute of Medical Sciences (AFRIMS). In northern Thailand, the Research Institute for Health Sciences, Chiang Mai University, the MoPH and the Royal Thai Army Medical Department developed multiple collaborative research works with American scientists from the US National Institute of Health, the Johns Hopkins University and the Walter Reed Army Institute of Research. These were largely focused on obtaining a better understanding of HIV epidemiology and characterizing potential cohorts for vaccine studies [19–28]. After vigorous multisectoral prevention efforts undertaken in the early 1990s, it became noticeable from surveillance data that the prevalence of both HIV infection and sexually transmitted diseases was declining in most of the high-risk groups [8,13,14]. Meanwhile, an epidemic trend towards HIV in general populations was reported. This has made the identification of potential cohorts for vaccine trials more difficult, and assessments of community-based populations was added to assessments of high-risk and military recruit populations [29–31]. In 1999, AFRIMS, with both Thai and US medical components, in collaboration with the Chon Buri Provincial Heath Office (of the MoPH), enrolled 2500 adult volunteers from a general community for HIV counseling, hepatitis B virus immunization and a prospective study of HIV incidence. During the study, 17 individuals seroconverted (overall HIV incidence of 0.5/100 person-years). The incidence was highest (0.7/100 person-years) among the younger adults [31]. Building on this model of working within communities through the MoPH infrastructure, two provinces in this same area of southeast Thailand (Chon Buri and Rayong) were selected as the field site of the current phase III vaccine trial. In parallel with the cohort development efforts, infrastructure capacity as well as expertise in clinical trials have been further developed in Thailand. HIV vaccine manufacturers have collaborated in the design of HIV candidate vaccines that match the strains of HIV circulating in the country. Phase I and II clinical trials to demonstrate the safety and immunogenicity of candidate vaccines have been carried out successfully [28,32–37]. The first efficacy trial in Thailand of an HIV candidate vaccine (containing gp120 B and E subtypes) was initiated in 1999 [38,39] (Table 3).Table 3: HIV vaccine trials (preventive and therapeutic) conducted in Thailand.National policy commitment for HIV vaccine development The National Plan for HIV/AIDS Vaccine Development and Evaluation, 1993, states: '… Realizing the serious impact the HIV epidemic is having on the health and welfare of the people in Thailand, the Royal Thai Government (RTG) has decided to address HIV control as well as the social and economic consequences of HIV infection. The ultimate aim of the multi-sectorial strategy is to stop the spread of HIV infection and to provide care and support to those affected socially or physically by the epidemic. For these reasons, the RTG and specifically the National AIDS Committee (NAC) is committed to active participation in the worldwide effort to develop and evaluate HIV/AIDS vaccines. A major goal of the national strategy is to promote and support national and international collaborative research that will lead to the development and evaluation of effective HIV/AIDS vaccines for potential use in Thailand. …' [18]. The National Plan for the Prevention and Alleviation of HIV/AIDS in Thailand, 2002–2006, also emphasized HIV/AIDS vaccine development with the following objectives: (i) to support the efforts of various work units to research, develop, and evaluate an HIV/AIDS vaccine development plan; (ii) to promote the development of organizations, basic structures, staff, life science studies, and technology to support HIV/AIDS prevention and treatment research and the development of industrial production technology; (iii) to promote investment in industry and commerce; (iv) to work for the benefit of the Thai public by promoting rights protection for volunteers, research officers, and investors in research and development efforts; (v) to promote international cooperation in the development of equitable mechanisms to foster technology transfers and attract foreign investment to Thailand. At the same time, to support trade rights and Thai overseas investment. Preparation for the HIV vaccine phase III trial The current HIV preventive vaccine clinical trial in Thailand is the continuation of more than 10 years of effort to find an effective preventive measure to halt the HIV epidemic in the country. The National HIV/AIDS Vaccine Development and Evaluation Plan was initially intended to test candidate vaccines only at phase III. Later on, as a result of there being rather few candidate vaccines available in the pipeline, phase I/II trials were accepted in order to find a candidate vaccine appropriate to Thailand. Subsequently, the vaccine manufacturers were approached to develop candidate vaccines that matched with the HIV clades circulating in Thailand to be tested from phase I to III. In the late 1900s, an assessment of the 'prime-boost' vaccine concept was initiated with three candidate vaccine combinations in phase I/II testing [40]. One combination was chosen for further evaluation in a phase III trial, that is the ALVAC-HIV (vCP1521) 'prime' and AIDSVAX gp120 B/E 'boost'. The selection criteria were based on immunogenicity, postinjection reactogenicities, and manufacturing feasibility. ALVAC-HIV (vCP1521), produced by Aventis Pasteur, is a recombinant canarypox vector vaccine that has been genetically engineered to express antigens of subtypes B and E HIV-1: gp120 (subtype E) linked to the transmembrane anchoring portion of gp41 (subtype B), and HIV-1gag and protease (subtype B). It is lyophilized product using sterile 0.4% sodium chloride for reconstitution. AIDSVAX gp120 B/E, produced by VaxGen Inc., is a bivalent HIV gp120 envelope glycoprotein vaccine containing a subtype E envelope from the HIV-1 strain A244 and a subtype B envelope from the HIV-1 strain MN. The recombinant gp120 are produced in genetically engineered Chinese hamster ovary cell lines. The envelope glycoproteins are co-formulated and administered at an equal combined dose of each antigen with alum adjuvant. Protocol development and informed consent process Protocol drafting Based on a principle of collaboration with full and equal partnership, a protocol drafting committee was established in 2001. It was composed of members from each of the partner organizations. The protocol drafting process resulted in some 16 versions (if minor edits were included, the total number would be some 40 drafts). This fact reflects the complexity and sensitivity of a large, collaborative HIV vaccine field trial. Informed consent process The development of a volunteer consent form that met local and international ethical and International Conference on Harmonization standards while being understandable and of reasonable length from the volunteers' perspective was very challenging. One of the principles followed was to draft it directly in Thai rather than this being the result of a translation. Moreover, it was realized that the consent form was but one part of a wider informed consent process. The full approach was designed to include group and individual information sharing, oral, video and written media information, a test of understanding, and time to consult with friends and family. Approval process The protocol and consent form were submitted for review/approval to the many institutional review boards (IRB)/ethical review committees involved, as well as the regulatory authorities concerned. The review process started with a scientific review, which was followed by reviews that considered both science and ethics. The National AIDS Committee of Thailand (Subcommittee for HIV Vaccine Trials) requested an external review of the protocol from the HIV Vaccine Steering Committee of the United Nations Programme on AIDS. Comments, feedback, and recommendations from each review body were compiled, and suggestions leading to additional versions of the protocol were incorporated. The final revised version was resubmitted to the review bodies for final approval. The official approvals were obtained from the IRB/ethical review committees and regulatory bodies on both sides, Thai and the United States, before trial initiation in September 2003. Review/approval organizations The trial protocol was reviewed by the following agencies and organizations; note that some steps in this process occurred in an overlapping manner. Scientific review Walter Reed Army Institute of Research. Scientific and ethical review Subcommittee of the Thai National AIDS Committee (in consultation with the HIV Vaccine Steering Committee of the United Nations Programme on AIDS). Ethical review Royal Thai Army Medical Department; Mahidol University; MoPH, Thailand; US Army Medical Department. Regulatory review Food and Drug Administration, United States; Food and Drug Administration, Thailand. The study design for the phase III trial was presented to the scientific community in several fora, both at in-country and international meetings [41–44]. It was finally approved by policy makers as well as the regulatory authorities concerned. Study sites for the vaccine trial Previous surveillance and cohort studies had shown that the Chon Buri and Rayong provinces in southeastern Thailand had an optimal combination of factors for selection as the site of the phase III trial. They had a relatively high HIV incidence [30,31], good logistic and public health infrastructures, stable economies with in-migration, and an open and cooperative attitude among most of the community members and leaders towards addressing the HIV problem (Fig. 2).Fig. 2: Map of Chon Buri and Rayong Provinces.In preparing infrastructure for the trial, existing government facilities were largely used: health centers served as the screening sites, district hospitals for clinical sites, the Expanded Programme on Immunization vaccine storage facility for vaccine distribution, and a hospital building of the health promotion center in that region was used for conversion to a specimen processing and storage facility. The retrovirological laboratories of AFRIMS became the central HIV testing laboratory; the Data Management Unit at Mahidol University was expanded for a dedicated data processing and management facility. Field site selection In the Thai healthcare delivery system, district hospitals are responsible for the medical services within their district, including the local health centers, which provide primary care services at the subdistrict level. In the trial, district hospitals were designated as the focal point for clinical activities (including immunization), and a cluster of surrounding health centers were designated as sites for screening and follow-up activities. Based on the sample size calculation in the protocol (16 000 volunteers), demography and logistics, it was decided to have eight study sites. Four districts in each province were selected, with input from experts at the provincial chief medical office. HIV prevalence from annual serosurveillance was taken into account for district selection as the study sites. The district Chief Health Officer in each selected district was consulted to select three to seven health centers surrounding the district hospital for participation. The number of residents aged 20–30 years and their distance from the district hospital, as well as the convenience of local transportation, were the main criteria for selecting health centers. Altogether, there are 47 screening sites, 40 at health centers and seven at district hospitals. There are eight clinical sites, seven at district hospitals and one in a provincial health office for a district that has no district hospital. Other facilities Trial registry and repository center Developing local infrastructure for processing and storing study samples is one of the policies, as a long-term government commitment to future HIV vaccine development, specified in the National AIDS Vaccine Development and Evaluation Plan. This protocol projects that approximately 25 000 volunteers will be screened to reach the target of 16 000 volunteers enrolled in the vaccination protocol; they are followed up with blood sample collection at nine visits. Blood samples collected from field sites are processed centrally at the trial registry and repository center before aliquots are transported for laboratory investigation at AFRIMS in Bangkok. Remaining aliquots are stored in the trial registry and repository center facility. Vaccine distribution center The existing facility (cold room) for storage of Expanded Programme on Immunization vaccines and other supplies, which is the responsibility of the Department of Disease Control, MoPH, was renovated to provide security, power back-up and monitoring of the trial vaccines. Monitors were improved to ensure both warning of out of range concerns and optimal documentation of temperature for the trial vaccine and placebo. The back-up generator was upgraded to ensure good conditions for back-up power for the cold room. The delivery van with a mobile cold room was also refurbished to ensure a cold chain system during transportation of the vaccine and placebo to the eight clinics spread across the two provinces. Capacity building The trial involves health staff at all levels in the national healthcare system as well as staff from Mahidol University and the Royal Thai Army. They were trained to be familiar with good clinical practice, research ethics, and standard operating procedures before performing trial activities. Other relevant subjects, such as counseling and advanced cardiac life support, were also trained to ensure the safety and welfare of the study volunteers. In addition, training on the background and concept of the project was given. After protocol and standard operating procedure training, staff at both screening sites and clinics performed mock-up sessions and dry-runs before initiation of the study. These district teams consist of staff from both the MoPH and Mahidol University. Monitors from the sponsor performed pre-initiation visits to each site before the initiation of research activities. As community participation is one of the key factors required for success, community preparation and engagement at the very beginning of the study were implemented as an important strategy. Health staff and community volunteers were trained to communicate and inform community members about the trial as part of their AIDS education and awareness sessions. Management of HIV-infected volunteers in the trial Before project implementation, preparations were made for the management of HIV-related and non-HIV-related medical problems that might occur in volunteers. The participants in the study will be referred to MoPH facilities for medical services. HIV-related clinical management of infected volunteers is supported by the sponsor during the trial, including the use of antiretroviral therapy and laboratory investigations, e.g. CD4 cell counts, viral load measurements. After the end of the trial, HIV-infected cases will be continuously managed by Thai MoPH facilities under the national health insurance scheme and sponsor support for antiretroviral drugs. Non-HIV medical problems are managed through the national health insurance system, of which all volunteers are participants. Moreover, the investigators have also developed another protocol (RV152), which will be offered to volunteers with intercurrent HIV infections for close monitoring and follow-up. All individuals who become HIV infected during the trial will be eligible for participation if they received at least one vaccination. The decision to participate or not in RV152 will not have any impact on the medical services provided to the volunteer; care and treatment will be in accordance with the National Guidelines for HIV Management of Infected Adults and Children [45]. Those HIV-infected cases found during the screening process will be referred to the regular counseling and medical services in the MoPH healthcare system depending on each participant's place of residence. Trial initiation After the trial protocol was reviewed and approved by all IRB concerned, the pre-initiation visits were completed, and candidate vaccines for the trial were received, the trial was initiated in a phased manner. As the trial was to be carried out within the healthcare infrastructure in two provinces, this gradual site-by-site approach has allowed close supervision and adherence to research procedures in the protocol and the establishment of appropriate logistic support. This phased process, and the realization that community recruitment would require additional time, led to an increase in the time period originally projected for the enrollment phase, which was lengthened from 12 to 24 months. Monitoring, supervision, and assessment To appreciate the overall progress in the conduct of the protocol, the numbers of individuals enrolling in the screening protocol (RV148) and in the vaccine protocol (RV144) are monitored and summarized on a weekly basis. Data on visit attendance is summarized on a monthly basis. This information and other feedback from the field are compiled, analysed and regularly assessed to enable early problem detection in the areas of trial operation, workload and staff morale. When problems are found, new strategies or actions are launched to mitigate the negative impact on project activities. The monitoring of clinical sites, vaccine management, laboratory procedures and computerized systems is carried out by the sponsor's monitors (a clinical research organization) with feedback directly to the Principal Investigator and sponsor. Volunteer safety is overseen by a pharmaco-vigilence committee with representation from all collaborative partners; both data and safety are regularly assessed by an international, independent data and safety monitoring board. The Principal Investigator and the central project team work out of a central coordinating office and make regular visits to all field sites (Fig. 3 and Fig. 4). Any deviation from standard operating procedures should be detected early and allow for immediate correction.Fig. 3: Organization diagram: central. AFRIMS, Armed Forces Research Institute of Medical Sciences; Ass. PI, Assistant Principal Investigator; Co. PI, Co-Principal Investigator; DDC, Department of Disease Control; PI, Principal Investigator; TRRC, Trial Registry and Repository Center; QA/QC, Quality Assurance/Quality Control.Fig. 4: Organization diagram: field sites. DCHOs, District Chief Health Officers; PCMOs, provincial Chief Medical Officers; PI, Principal Investigator; VCT, voluntary counseling and training.Initial lessons learned Full and equal partnership is a key aspect of international collaboration, from study design to trial conduct and analysis. The time required for the protocol drafting, review and approval was underestimated. Preparation of the informed consent document in the local language from inception is crucial. The time required for site preparation and staff training may be underestimated. All training and training materials should be in the local language to allow research staff to comprehend the content of these subjects fully. The time required for the production and quality control of vaccine was underestimated. An initial period of gradual phasing-in of the trial was helpful in acquainting medical service staff with the conduct of clinical research. The close monitoring of both administrative and procedural aspects of the trial by dedicated staff is needed for early detection and problem solving. Community engagement before and during the trial is a key activity to get participant support. The support of non-governmental organizations and community leaders is important for the success of such a trial. Rumors and misunderstandings will arise among volunteers, their communities and even medical staff, which are not anticipated. Spirit building and some reward mechanism are essential for maintaining team motivation through such a multiyear trial. Biopolitical controversy around the trial, even in other countries, can lead to misunderstandings among local non-governmental organizations, the media, volunteers and staff. Keeping volunteers engaged and in contact through their 3.5 years of participation will be a continuing challenge. Conclusion Thailand has been able to play a major role in the development of HIV vaccines because of a confluence of factors. The direct and open approach by the government in addressing the HIV epidemic and the inclusion of a vaccine among the ideal set of interventions showed great vision. International collaboration, carried out in a way that has enhanced Thai capacities, has also been important. The performance of Thailand's two phase III HIV vaccine trials builds upon the many years of international collaborative clinical research in vaccinology generally and HIV specifically. Given the sensitive ethics and difficult biopolitics around HIV vaccine studies, this current HIV vaccine trial is only possible because of the full and equal partnership between the Thai and US governments. The trial is led by the Thai MoPH, and would have little chance of success otherwise. The foundations and initial lessons learned summarized in this paper have been shared with scientists from Africa and elsewhere in Asia. We hope this information will be valuable to those who plan future vaccine trials. With the great need for an HIV vaccine, it is our hope that the efforts in Thailand, jointly with those of colleagues working in other countries, will bring us all closer to that goal (Fig. 5 and Fig. 6).Fig. 5: Timeline. FU, Follow-up; IRB, institutional review board.Fig. 6: Decision-making process. DDC, Department of Disease Control; MoPH, Ministry of Public Health.Acknowledgements The authors are grateful to all collaborators in this trial: the MoPH provincial staff in Rayong and Chon Buri, the Royal Thai and US Army components of AFRIMS, the Faculty of Tropical Medicine at Mahidol University, the US Army Medical Research and Material Command, the division of AIDS at the US National Institutes of Health and the vaccines manufacturers, Sanofi Pasteur and VaxGen. The authors are very appreciative of the vision and sustained support of the leadership of the Thai MoPH and National AIDS Committee. They are also sincerely thankful to all study volunteers and their commitment to participate in the efforts to find a vaccine to help their society.