Preventive HIV Vaccine Trials Research Articles

Contraceptive Use in Women Enrolled into Preventive HIV Vaccine Trials: Experience from a Phase I/II Trial in East Africa

BackgroundHIV vaccine trials generally require that pregnant women are excluded from participation, and contraceptive methods must be used to prevent pregnancy during the trial. However, access to quality services and misconceptions associated with contraceptive methods may impact on their effective use in developing countries. We describe the pattern of contraceptive use in a multi-site phase I/IIa HIV Vaccine trial in East Africa (Uganda, Kenya and Tanzania) and factors that may have influenced their use during the trial.MethodsPregnancy prevention counseling was provided to female participants during informed consent process and at each study visit. Participants' methods of contraception used were documented. Methods of contraceptives were provided on site. Pregnancy testing was done at designated visits during the trial. Obstacles to contraceptive use were identified and addressed at each visit.ResultsOverall, 103 (31.8%) of a total of 324 enrolled volunteers were females. Female participants were generally young with a mean age of 29(±7.2), married (49.5%) and had less than high school education (62.1%). Hormonal contraceptives were the most common method of contraception (58.3%) followed by condom use (22.3%). The distribution of methods of contraception among the three sites was similar except for more condom use and less abstinence in Uganda. The majority of women (85.4%) reported to contraceptive use prior to screening. The reasons for not using contraception included access to quality services, insufficient knowledge of certain methods, and misconceptions.ConclusionAlthough hormonal contraceptives were frequently used by females participating in the vaccine trial, misconceptions and their incorrect use might have led to inconsistent use resulting in undesired pregnancies. The study underscores the need for an integrated approach to pregnancy prevention counseling during HIV vaccine trials.Trial RegistrationClinicalTrials.gov NCT00123968

Willingness to participate in preventive HIV vaccine trials in a community‐based cohort in south western Uganda

To assess willingness to participate in HIV vaccine trials and possible barriers to participation. Questionnaire survey of participants completing a 2-year community-based HIV Vaccine Preparedness Study, followed by cross sectional analysis of data. 95% of participants were willing to participate in a trial with similar attributes to the Vaccine Preparedness Study. Certain hypothetical trial attributes significantly reduced willingness to participate: The requirement to delay pregnancy (for females) had the largest effect, reducing willingness to participate from 97% to 23% (P < 0.0001). Larger blood draws had the second largest effect: 95-55% (P < 0.0001). The possibility of receiving either candidate vaccine or placebo had the third largest effect: 95-73% (P < 0.0001). Monthly study visits had the fourth largest effect: 95-92% (P < 0.0001). Trial duration longer than 2 years had the least effect: 95-93% (P = 0.0025). Combined attributes reduced willingness to participate from 95% to 43% (McNemar's chi(2) = 521.00; P < 0.0001) overall and 97-11% (McNemar's chi(2) = 531.00; P < 0.0001) for female participants. Physical harm concerns (adjusted OR = 34.9; 95% CI, 10.4-118) and a low risk behaviour index (adjusted OR = 0.09; 95% CI, 0.01-0.73) were associated with unwillingness to participate. We found a high level of willingness to participate in HIV vaccine trials in this population. However, certain HIV vaccine trial requirements were associated with reduced willingness to participate. Community as well as individual concerns will have to be carefully addressed in planned HIV vaccine trials.

Pilot Study Assessing HIV Vaccine Trial Readiness Among Female Sex Workers, Injection and Non-injection Drug Users, and Men Who Have Sex with Men in Spain

The purpose of this study was to assess HIV risk and willingness to participate in HIV vaccine trials in three high risk populations in Spain. Eight hundred and forty-four participants, comprising female sex workers, injection and non-injection drug users (IDUs and NIDUs, respectively), and men who have sex with men were tested for HIV and surveyed for risk and willingness to participate in future preventive HIV vaccine trials. HIV seroprevalence was 3.8% (95% CI: 2-11). HIV infection was associated with transgender identification, IDU in the past year, and sex with an IDU or other drug-using partner. The majority (82%) expressed their willingness to participate in HIV vaccine trials. Substantial sexual and parenteral risk in all groups and concomitant willingness to participate in vaccine trials was found, particularly among women and IDUs. Additional longitudinal cohort studies in Spain are needed to plan future vaccine efficacy trials.

Inclusion of Adolescents in Preventive HIV Vaccine Trials

The search for a safe effective HIV vaccine has been a centerpiece of HIV research for almost 2 decades. More than 60 clinical HIV vaccine trials have been conducted to date. Several promising candidate HIV vaccines are in advanced clinical development. To date, however, no trial has included adolescents, one of the most important target groups for any preventive HIV vaccine. To license a vaccine for use in this age group, efficacy data or, at a minimum, bridging safety and immunogenicity data in this population are needed. To accomplish this, several critical issues and special challenges in the development and implementation of HIV vaccine trials in adolescents must be addressed, including regulatory considerations, potential differentials in safety and immunogenicity, alternative trial design strategies, recruitment and retention challenges, community involvement models, and approaches to informed consent/assent. This article examines these issues and proposes specific next steps to facilitate the routine inclusion of this high-priority population in preventive HIV vaccine trials as early and seamlessly as possible.

Social impact of preventive HIV vaccine clinical trial participation: A model of prevention, assessment and intervention

Preventive HIV vaccine trial participants may experience problems related to trial participation, including difficulties with personal relationships, employment, education, health care, housing, health insurance, disability insurance, life insurance, travel or immigration. During the 19 years that the U.S.-based National Institute of Allergy and Infectious Diseases (NIAID) has conducted preventive HIV vaccine trials, we have developed a model to prevent and resolve social impact related to study participation and assist study participants who report such events. Key elements of the model include: informing potential volunteers of risks prior to enrollment; standardizing data collection methods on social impact events; reviewing and following-up on reported social impact events; assisting participants, including provision of free HIV testing to differentiate HIV infection from vaccine-induced HIV antibody; implementing broad-based and targeted community education programs for achieving community support; communicating with scientific and health care communities; and working with government agencies, non-government agencies and industry on mechanisms to address SI. This approach, established in collaboration with NIAID-funded clinical trial groups, serves as a model for prevention, assessment, monitoring, and intervention for social impact related to preventive HIV vaccine clinical trial participation. Although further research is necessary, this model could be adapted for use in different clinical trials.

Laboratory expansion to large-scale international HIV preventive vaccine trials

The purpose of this article is to describe the requirements for clinical laboratories supporting large-scale multinational trials of prophylactic AIDS vaccine trials and review the progress made. There is an increasing need for laboratories in Africa, Asia and the Caribbean to support internationally initiated and funded clinical trials of preventive HIV vaccine candidates. A number of qualified laboratories are currently supporting AIDS vaccine trials in these regions, although there remains a need to develop capacity further. The standardization of all tests is key in order that data can be pooled and compared across multiple sites and products. Significant progress has been made towards this aim. The recent development of quality programmes including good clinical laboratory practices are key to ensuring data are reliable and meet the requirements of regulatory bodies. In addition, HIV diagnostic tests are being developed to distinguish true HIV infection from vaccine-induced antibodies. Significant advances have been made to develop laboratories capable of supporting multinational AIDS vaccine trials.

Local Knowledge and Experiences of Vaccination: Implications for HIV-Preventive Vaccine Trials in South Africa

This study forms part of the preparation of communities for HIV-preventive vaccine trials in South Africa. On the basis of the assumption that attitudes to any HIV vaccine or vaccine trials will partly be influenced by experiences of vaccination in general, this study aimed to investigate knowledge of, attitudes to, and experiences of vaccination in a small semirural community in KwaZulu-Natal, South Africa. The study also sought to investigate the effect of traditional, cultural, and religious beliefs on attitudes to vaccination, as well as to get some indication of willingness to participate in potential HIV vaccine trials. Overall, the findings reveal a good knowledge of, and positive attitudes to, vaccination, with little negative effect of traditional, cultural, and religious beliefs. The findings also reveal a generally positive attitude to HIV vaccines and vaccine trials. Barriers identified, such as anxiety about safety, were not surprising.

Willingness to participate in HIV vaccine trials: The impact of trial attributes

Objectives. To assess willingness to participate (WTP) in hypothetical Phase III preventive HIV vaccine trials, and the impact of trial attributes on WTP, among low socioeconomic, ethnically diverse adults from communities at elevated risk for HIV infection. Method. Participants ( n = 123; median age = 38; 69% male; 37% Latino; 14% African-American) were recruited in Los Angeles in 2003 using multi-site, venue-based sampling. WTP was assessed for eight hypothetical HIV vaccine trials that varied across seven dichotomous attributes, using a 2 7-4 fractional factorial experimental design. Individual-specific impact of vaccine trial attributes on WTP was estimated using within-individual ANOVA and then meta-analyzed across individuals. Results. Mean WTP for eight hypothetical vaccine trials ranged from 1.74 to 3.81 (1 = highly unlikely, 5 = highly likely). Lower WTP was associated with vaccine-induced infection risk (impact = 0.88, p < 0.0001), false HIV-positives (0.53, p < 0.0001), no provision of free HIV medications (0.52, p < 0.0001), and longer trial duration (0.27; p = 0.0002). Conclusion. HIV vaccine trial attributes may strongly influence WTP. Although existing candidate vaccines cannot cause HIV infection, perceptions of risk may impede WTP. Eliciting trial preferences and concerns prior to trial implementation may enable accommodation of participant preferences and support tailored interventions to address concerns and misconceptions to facilitate enrollment in safe and ethical trials among vulnerable communities.

Starting from scratch: Program development and lessons learned from HIV vaccine trial counseling in Thailand

Counseling for participants in preventive HIV vaccine trials has been an area of continuing concern because of the need to address possible behavioral side effects (e.g., increased risk behavior because trial participants believe they may have received an active, effective vaccine) and social harms (e.g., discrimination in health care or employment because of vaccine-induced seropositivity on commercial HIV tests). Yet, the data on behavioral effects and social harms are limited and rather little detail has been provided regarding the counseling provided in current or past trials. This paper summarizes conceptual, cultural, and practical considerations in the development of a counseling program for HIV vaccine trials and provides examples from work done in the context of Phase I/II vaccine trials in Thailand.

Enrolling Adolescents in Research on HIV and Other Sensitive Issues: Lessons from South Africa

With more than 6 million HIV positive individuals—the highest of any country in the world—South Africa is the epicentre of the HIV/AIDS pandemic. In much of sub-Saharan Africa, especially South Africa, the HIV/AIDS epidemic is growing fastest in teenagers, especially young girls (see sidebar) [1]. Hence, any future vaccination strategy in this setting will, of necessity, have to target young adolescents prior to sexual debut. The current candidate HIV vaccines that are being considered for efficacy trials are likely to act principally by reducing viral loads, hence reducing both transmission to sexual partners and progression to AIDS [2]. One of the limitations to conducting HIV vaccine trials is the dearth of data on important HIV disease parameters such as viral load, immune responses, and disease progression in African adolescents. While there is observational research currently being conducted in the United States on adolescents, such as the Reaching for Excellence in Adolescent Care and Health (REACH) study [3], there is a need for information on set point, HIV transmission, and disease progression in adolescents from Africa, even if only to confirm whether the disease process in African adolescents differs from those in developed countries. The Joint United Nations Programme on HIV/AIDS notes that children, including infants and adolescents, should be eligible for enrolment in HIV preventive vaccine trials, both as a matter of equity and because young adolescents and children are at high risk of HIV infection [4]. However, no distinction is drawn between adolescent participation with parental consent and the autonomous participation of adolescents. This distinction is particularly important in sub-Saharan Africa, where it is often difficult or impossible to obtain parental consent. The Centre for the AIDS Programme of Research in South Africa (CAPRISA), which is funded by the US National Institutes of Health, recently proposed a follow-up study of adolescents and young adults with acute HIV infection to obtain the essential information on subtype C viral set point, prognostic viral load measurements, and disease outcome—all important biological outcome markers in HIV vaccine efficacy trials. The study proposed to enrol, as one of its groups, adolescents as young as 14 years old from a prenatal and family planning clinic, where those who volunteered could do so without parental consent when parents or legal guardians were not available. Three ethics committees supported the enrolment of this cohort, although a fourth did not. As a result, the study protocol was amended to include participants only above the age of 18. Several works have highlighted the ethico-legal challenges implicit in enrolling adolescents in South African HIV vaccine trials [5–7]. However, the enrolment of autonomous adolescents in crucial HIV observational studies and in other types of sensitive non-HIV research in South Africa is equally problematic. We present the ethico-legal challenges, as well as the scientific and social grounds, to justify the autonomous participation of adolescents in HIV observational studies—such as the CAPRISA study—as well as in future HIV vaccine trials in South Africa and much of the rest of sub-Saharan Africa. We argue that the same reasoning applies to other types of sensitive non-HIV research involving adolescents. We also suggest how conflicts between restrictive laws and flexible ethics guidelines should be addressed.

Enrolling women into HIV preventive vaccine trials: an ethical imperative but a logistical challenge.

Enrolling women into HIV preventive vaccine trials: an ethical imperative but a logistical challenge.

Behavioral and Social Issues Among Volunteers in a Preventive HIV Vaccine Trial in Thailand

Behavioral and social issues were investigated in 363 phase I/II preventive HIV-1 vaccine trial volunteers in Thailand. These issues included risk behavior, HIV knowledge, distress, and social consequences of vaccine trial participation. Data were collected at baseline and at 4-, 8-, and 12-month follow-up visits. Volunteers reported relatively low levels of risk behaviors at baseline and at follow-up. Overtly negative reactions from family or friends were reported by 5.9%. No experiences of discrimination in employment, health care, or insurance were reported. Mean levels of distress were low throughout the trial, and HIV-related knowledge was high, although it was common to consider the possibility of HIV transmission through casual contact. Findings add to the evidence that preventive HIV vaccine trials are feasible in Thailand.

Enrollment of Racial/Ethnic Minorities in NIAID-Funded Networks of HIV Vaccine Trials in the United States, 1988 to 2002

The purpose of this study was to analyze enrollment of racial/ethnic minorities in Phase I and Phase II HIV vaccine trials in the U.S. conducted by National Institute of Allergy and Infectious Diseases (NIAID)-funded networks from 1988 to 2002. A centralized database was searched for all NIAID-funded networks of HIV vaccine trial enrollment data in the U.S. from 1988 through 2002. The authors reviewed data from Phase I or Phase II preventive HIV vaccine trials that included HIV-1 uninfected participants at low to moderate or high risk for HIV infection based on self-reported risk behaviors. Of 66 identified trials, 55 (52 Phase I, 3 Phase II) met selection criteria and were used for analyses. Investigators extracted data on participant demographics using statistical software. A total of 3,731 volunteers enrolled in U.S. NIAID-funded network HIV vaccine trials from 1988 to 2002. Racial/ethnic minority participants represented 17% of the overall enrollment. By pooling data across all NIAID-funded networks from 1988 to 2002, the proportion of racial/ethnic minority participants was significantly greater (Fisher's exact test p-value < 0.001) in Phase II trials (278/1,061 or 26%) than in Phase I trials (347/2,670 or 13%). By generalized estimating equations, the proportion of minorities in Phase I trials increased over time (p = 0.017), indicating a significant increase in racial/ethnic minority participants from 1988 to 2002. There has been a gradual increase in racial/ethnic minority participation in NIAID-funded network HIV vaccine trials in the U.S. since 1988. In the light of recent efficacy trial results, it is essential to continue to increase the enrollment of diverse populations in HIV vaccine research.

The South African Medical Research Council's Guidelines on Ethics for Medical Research--implications for HIV-preventive vaccine trials with children.

Children are at risk of HIV infection, stand to benefit from the development of HIV preventive vaccines, and therefore should be enrolled in trials of HIV vaccines in order to generate relevant safety, immunogenicity and efficacy data. In South Africa, the national vaccine initiative is considering the future conduct of trials involving children; this requires an analysis of the current ethical framework, including elements that facilitate or constrain the conduct of such trials. In this article, we examine the Medical Research Council (MRC)'s Guidelines on Ethics for Medical Research: General Principles (Book 1), and their provisions on research involving children. We argue that this set of influential guidelines includes provisions on research with children that are conceptually problematic and may prohibit critical research with healthy (but at-risk) child participants, including trials of HIV-preventive vaccines. We recommend that Book 1 provisions should be redrafted to reflect a balance between protecting children from research-related risks and testing interventions critical to their health.

Provision of HIV treatment in HIV preventive vaccine trials: a developing country perspective

HIV treatment for participants who become infected during HIV vaccine trials has been the focus of ethical controversy. The obligations of sponsors to ensure that participants have access to antiretrovirals have been a particular focus of this debate.This paper presents three arguments that have been made in this regard, and some of their limitations, in anticipation of HIV vaccine trials in South Africa.The first argument is that HIV risk behaviour increases in such trials, and HIV infection can be viewed as a research-related injury, justifying sponsor provision of treatment on grounds of compensation for harm. We conclude that risk-behaviour studies to date do not show general increases in risk behaviour that could constitute the basis for a general obligation. Participation may well adversely impact on risk behaviour for some individuals, and conceivably this could be demonstrated. This argument may, therefore, have merit at the individual level; however, it seems a weak platform from which to argue that sponsors should treat all HIV infections acquired during trials.The second argument is that treatment should be provided based on distributive justice. We conclude that traditional concepts of “distributive justice” in research appear limited in justifying obligations of sponsors to ensure access to antiretrovirals. Further, using research initiatives to reduce global health care inequities is controversial, and even proponents may disagree about the fairest use of finite resources.The third argument is that sponsors should ensure antiretroviral access on grounds of beneficence; namely, the maxim that if one can do something beneficial without sacrificing anything of comparable significance, it ought to be done. Thus, sponsors should provide more interventions than those minimally required to conduct the research. However, beneficence may demand levels of altruism that exceeds what is reasonable.While the latter arguments may provide stronger justifications than the first, it is difficult to use these arguments to establish that sponsor provision of antiretrovirals to infected individuals is obligatory.

Unmet ethical concerns of the proposed preventive HIV vaccine trials in India

Unmet ethical concerns of the proposed preventive HIV vaccine trials in India

Knowledge about vaccines and willingness to participate in preventive HIV vaccine trials: a population-based study, Rakai, Uganda.

The purpose of the study was to assess knowledge and beliefs regarding vaccines and willingness to participate in HIV vaccine trials. A baseline survey assessed knowledge and attitudes toward vaccination and potential HIV vaccines among 14,177 participants aged 15-49 years, in a population cohort. Willingness to participate in HIV-preventive vaccine trials was assessed during a follow-up survey 10 months later after providing community education on HIV vaccines. Knowledge of the preventive utility of vaccines was high (71%), but higher in men than women (P<0.001), and increased with education levels (P<0.001). Vaccines were considered appropriate for children and women (99 and 88%, respectively), but not for adult men (28%). Participants felt that adolescents were the most appropriate subjects for HIV preventive vaccine trials (93.7%) but also thought that HIV-positive persons were eligible for trials (60.2%), and only 20% thought a preventive vaccine could help control HIV. HIV vaccine awareness increased from 68% at baseline to 81% at follow-up (P<0.001). Willingness to participate in HIV-preventive vaccine trials was 77%. Vaccine knowledge and willingness to participate in trials are high in this population. However, there still is need for education on the potential role of preventive HIV vaccines in the control of the epidemic and the importance of vaccination for men, especially in the context of an HIV vaccine.

Determinants of enrollment in a preventive HIV vaccine trial: hypothetical versus actual willingness and barriers to participation.

To compare hypothetical and actual willingness to enroll in a preventive HIV vaccine trial and identify factors affecting enrollment. Participants previously enrolled in an HIV vaccine preparedness study (VPS) in 8 US cities were invited to be screened for a phase 2 HIV vaccine trial. Demographic and risk characteristics of those enrolling, ineligible, and refusing enrollment were compared using the chi2 or Fisher exact test. Multivariable logistic models were used to identify independent predictors of refusal. Of 2531 high-risk HIV-uninfected former VPS participants contacted for the vaccine trial, 13% enrolled, 34% were ineligible, and 53% refused enrollment. Only 20% of those stating hypothetical willingness during the VPS actually enrolled in this vaccine trial. In multivariate analysis, refusal was higher among African Americans and lower in persons >40 years of age, those attending college, and those with > or =5 partners in the prior 6 months. All racial ethnic groups cited concerns about vaccine-induced seropositivity; African Americans also cited mistrust of government and safety concerns as barriers to enrollment. Steps can be taken to minimize potential social harms and to mobilize diverse communities to enroll in trials. Statements of hypothetical willingness to participate in future trials may overestimate true enrollment.

HIV Risk Reduction in a Cohort of Injecting Drug Users in Bangkok, Thailand

To determine changes in risk behavior in relation to study participation among injecting drug users (IDUs) in Bangkok, Thailand. During 1995-1996, 1,209 HIV-seronegative IDUs were recruited from Bangkok Metropolitan Administration drug abuse treatment programs to participate in a prospective cohort study. Study visits occurred every 4 months, at which the participants underwent an interview to assess risk behavior and HIV counseling and testing. Eight hundred nine of the IDUs were considered "long-term" participants, who remained in the study through at least the first four scheduled follow-up visits (16 months). Injection risk behavior at each study visit was measured on a four-point scale strongly associated with incident HIV infections in the cohort. Individual regression slopes were used to assess changes in injection risk behavior (risk increase, no change, or risk reduction). Of the 806 long-term study participants, 79% showed declines, 4% showed no change, and 17% showed increases in injection risk behavior. The percentage of participants in the highest-risk category (injecting daily or more frequently and sharing needles and syringes) declined from 42% at baseline to 3% at the final follow-up visit. Being in methadone maintenance treatment was associated with stable low rates of injection risk behavior, while recruitment from the 45-day detoxification treatment was associated with reductions in injection risk behavior. The risk reduction was independent of decline in risk behavior among IDUs in the community at large. Participation in this cohort study was associated with substantial declines in injection risk behavior. This information is important in the evaluation of possible adverse behavioral effects of participation in future preventive HIV vaccine trials including IDUs, particularly in developing country settings.

Willingness to participate and enroll in a phase 3 preventive HIV-1 vaccine trial.

To assess the extent to which HIV-negative cohort study participants would be willing to participate (WTP) in future HIV vaccine trials, to explore enrollment into an ongoing phase 3 HIV vaccine trial, and to assess changing WTP in such trials over time. The Vanguard Project is a prospective study of gay and bisexual men in the greater Vancouver region, British Columbia, Canada. Sociodemographic characteristics, sexual risk behavior, beliefs around HIV, and reasons for not participating in the AIDSVAX B/B trial were collected from self-administered questionnaires. Contingency table analysis compared subjects who were WTP with subjects who were not WTP. Logistic regression analyses identified possible predictors of WTP. A subset analysis was conducted to assess changes in WTP in 2001 versus 1997. Of 440 respondents, 214 (48.6%) were WTP, and 97 (22.0%) were not WTP. Those WTP were disadvantaged, sexually risky, and had a high-perceived HIV risk (all p <.05). Reasons for not participating in the AIDSVAX B/B trial included fear of health problems and having missed the deadline for enrollment (all p < 0.05). Multivariate analysis revealed that having had a regular sex partner (adjusted odds ratio, 0.48 [confidence interval, 0.25-0.92]) was a negative predictor whereas having a high-perceived HIV risk (adjusted odds ratio, 5.35 [confidence interval, 1.57-18.25]) was a positive predictor of WTP. Comparing WTP in 2001 with that in 1997, 24% of 100 participants who had been previously WTP were now not WTP. Improving community and participant knowledge about preventive HIV vaccine trials may help ensure informed consent. However, whether informing potential participants will reverse or contribute to the declining trend in WTP observed in this cohort warrants further investigation.