Acceptability of HIV Vaccine - Efficacy Trials in Drug Users and Sexual Partners of HIV Infected Patients in Barcelona, Spain

The epidemiology of HIV infection in Spain has changed during the past decade. Surveillance of HIV infection occurs in 15 of the country’s 17 regions, and 2,264 new HIV infections were diagnosed in 2009 (Ministerio de Sanidad y Politica Social, Ministerio de Ciencia e Innovacion, 2010). As previously reported (Hernandez-Aguado, 1999), the HIV epidemic in Spain has been largely driven by injecting drug users (IDUs). Reductions in the rates of new infections among drug users were reported a decade ago for the first time since the beginning of the epidemic (Castilla, 2006). In 2009, 77.0% of new infections were acquired through sexual transmission, and IDUs represented less than 10% of reported cases (Ministerio de Sanidad y Politica Social, Ministerio de Ciencia e Innovacion, 2010). The HIV epidemic among IDUs continues to develop heterogeneously across different parts of Europe. In the European Union, the reported rates of newly diagnosed cases of HIV infection in IDUs are mostly stable or in decline (European Monitoring Centre for Drugs and Drug Addiction, 2009). Data on newly reported cases of HIV infection in IDUs for 2007 suggest that rates of infection are still declining in Europe following a peak in 2002, which was caused by outbreaks in Estonia, Latvia and Lithuania. In 2007, the overall rate of newly reported infections of HIV among IDUs in the 24 EU member states for which national data


Introduction
The epidemiology of HIV infection in Spain has changed during the past decade. Surveillance of HIV infection occurs in 15 of the country's 17 regions, and 2,264 new HIV infections were diagnosed in 2009 (Ministerio de Sanidad y Política Social, Ministerio de Ciencia e Innovación, 2010). As previously reported (Hernandez-Aguado, 1999), the HIV epidemic in Spain has been largely driven by injecting drug users (IDUs). Reductions in the rates of new infections among drug users were reported a decade ago for the first time since the beginning of the epidemic (Castilla, 2006). In 2009, 77.0% of new infections were acquired through sexual transmission, and IDUs represented less than 10% of reported cases (Ministerio de Sanidad y Política Social, Ministerio de Ciencia e Innovación, 2010). The HIV epidemic among IDUs continues to develop heterogeneously across different parts of Europe. In the European Union, the reported rates of newly diagnosed cases of HIV infection in IDUs are mostly stable or in decline (European Monitoring Centre for Drugs and Drug Addiction, 2009). Data on newly reported cases of HIV infection in IDUs for 2007 suggest that rates of infection are still declining in Europe following a peak in 2002, which was caused by outbreaks in Estonia, Latvia and Lithuania. In 2007, the overall rate of newly reported infections of HIV among IDUs in the 24 EU member states for which national data hepatitis B vaccine, among MSM (in part due to a lack of information (Jacobson, 2007;Schutten, 2002)), it is important to anticipate and understand the characteristics of potential volunteers for an HIV vaccine trial in detail. The main objective of this study was to assess HIV risk behavior in drug users and sexual partners of HIV-infected patients and to analyze the degree of acceptance and willingness to participate (WTP) in HIV vaccine efficacy trials in metropolitan Barcelona.  , 2000) and had been referred for substance abuse treatment. The primary drugs of abuse were stimulants (cocaine) and depressants (opiates and alcohol). To be considered for inclusion in the study, drug users had to 1) be 18 years of age or older, 2) be actively using drugs, 3) have HIV-negative status at the time of inclusion, and 4) give informed consent. Drug users at risk of infection who met the inclusion criteria answered a 56question survey, which collected data on personal history (age, sex, place of origin, educational level, and employment status), drug use (the quantity, frequency, and treatment history for alcohol, cocaine, heroin, and other substances), sexual behavior (sexual orientation, number of partners, characteristics of the sexual partners regarding drug use and paid sex, and condom use), history of sexually transmitted diseases, knowledge and opinions about a potential HIV vaccine, WTP, and the subject's availability for an extended follow up. The survey questions were presented by doctors and nurses from both recruiting centers, individually and in a quiet setting with no other people present.

Patients and methods
To be considered for inclusion in the study, sexual partners of patients with HIV infection had to 1) be 18 years old or older, 2) have been a stable partner for at least 6 months, 3) be HIV-negative at the time of inclusion, and 4) give informed consent. Participants were given a shortened version of the previously described questionnaire that collected data on personal history, sexual behavior, and WTP. The questionnaire was given in the HIV/AIDS unit and was conducted by trained personnel.
In For each of the questions, we created an indicator, 0/1, corresponding to no risk/risk. We then summed the indicators obtained for all ten questions. A value between 0 and 3 points was defined as low risk, between 4 and 6 points as moderate risk, and more than 6 points as high risk.
We performed a descriptive analysis and a bivariate analysis by risk group for HIV infection, WTP, and other variables of interest. The outcome variable of WTP was dichotomized so that there were enough subjects in each category for comparison: the variable was "yes" if WTP was "definitely willing" or "probably willing" and "no" if the answer was "probably not" or "definitely not". We used the chi-square test, Fisher's F-test, and Student's t-test when appropriate to detect significant differences. In addition, we calculated the odds ratio to quantify the probabilities of WTP. Logistic regression methods were used to determine predictive factors for participation in a phase III clinical trial. Variables that were statistically significant in the bivariate analysis were used as co-variables in the regression. Data were entered into a Microsoft Access 2003 database. All statistical analyses were performed using Stata software (version 8.0; StataCorp, College Station, TX). Values of p < 0.05 were considered statistically significant.

Results
A total of 232 HIV-seronegative individuals were analyzed. The median age at study entry was 39 years (interquartile range (IQR), 33-45 years), and 64% were men. Almost 17% of participants had attained at least a high school education. Seventy-nine individuals (34%) were drug users, and 153 (66%) were sexual partners of HIV-positive patients. Among drug users, 82.3% were men, the median age was 35.4 years (IQR, 29.4 -40.0 years), most (57.7%) had finished elementary school, and 96.2% were heterosexual. Among the sexual partners, 54.2% were men, the median age was 41 years (IQR, 35.6 -46.6), 40% had completed middle school, and 67.5% were heterosexual. These and other results can be seen in Table 2, which summarizes the characteristics of the study population overall and by risk group. The overall prevalence of HCV was 20.5%. This prevalence was higher among drug users than in the other group (41.6% vs. 8.3%). Among drug users, 22.4% (11/49) had a serologic pattern of HBV-vaccine-induced immunity [i.e., HBsAg (-), HBsAb (+), and HBcAb (-)], and the serology of 7 of 49 (14.3%) users reflected immunity from natural infection. None of the sexual partners of the HIV-positive patients had the three serological markers of HBV. In the same blood sample, we confirmed that all participants were negative for HIV. Notably, nearly 30% of the stable partners of HIV-infected people did not consistently use condoms, and 23.2% acknowledged having had sex under the influence of drugs. Table 5 summarizes risk behaviors in this population. Overall, 47.4% of participants answered that they would definitely be willing to participate in HIV vaccine efficacy trials, 31.5% were probably willing, 9.1% wrote they were probably not willing, and 12.1% indicated they were definitely not willing to join vaccine trials. Among drug addicts, 13.9% were definitely willing to participate, in contrast to 64.7% of sexual partners of HIV-infected patients (p<0.05). Figure 1 shows the characteristics of WTP according to both study populations. Among drug users, it should be noted that only one person indicated a shift in WTP from "probably no" to "probably yes" if the study were to involve remuneration.

N=153 n (%)
Have you used drugs in the past month?    Table 6. Willingness to participate in HIV vaccine trials among drug users and sexual partners of HIV-positive patients.
There were also significant differences between drug users by gender. The probability that a female drug user agreed to participate in a future vaccine trial for HIV was more than three times higher than in men (OR = 3.52, 95% CI: 1.05-11.77). Having a moderate or high risk of HIV infection (> 3 points) was also associated with WTP (OR = 4.48, 95% CI: 1.70-11.83). Figure 2 shows WTP according to the level of risk of HIV infection in drug users.
In the multivariate analysis, being female (OR = 5.6, 95% CI: 1.4-22.4) and having a moderate-to-high level of infection risk (OR = 6.6, 95% CI: 2.2-19.6) were predictors of participation in a phase III vaccine trial among drug users.

Conclusion
Understanding the candidate population of volunteers is crucial for analyzing the efficacy of a potential preventive vaccine trial. In Spain, drug users have exhibited an elevated risk of HIV infection. In anticipation of a safe and effective vaccine candidate, it is appropriate to assess potential sites and populations for future vaccine trials. Accordingly, this study was developed to analyze WTP in a hypothetical HIV vaccine efficacy trial among current drug users in an urban area, many of whom have been affected by HIV/AIDS and parenteral drug addiction for many years. Sexual partners of HIV-infected patients are, by definition, another population at risk and therefore also potential trial participants.
In this study, we observed that WTP is clearly higher in sexual partners of HIV-positive patients and falls far short of 40% in potentially eligible drug users. To the best of our knowledge, this is the first study to report WTP in HIV vaccine trials in sexual partners of HIV patients in Spain. A high rate of acceptability of an HIV vaccine trial in this risk group has not been reported in other countries, although one study has demonstrated WTP in an overwhelming majority of monogamous married women (Suhadev, 2006). A predisposition toward WTP is already known among homosexuals (Newman, 2010b; and, more particularly, in those who report family support for participation and expect that the vaccine will protect them against HIV infection . The WTP of drug users in this study was lower than that of other studies conducted in our area and in other areas. For example, a study recently conducted in our area on 326 drug users found WTP in 83% of cases (51% would definitely participate, and 32% would probably participate) (Etcheverry, 2011). In China, a study conducted among 401 IDUs showed a rate of definite WTP of approximately 75%; the rate reached 94% if the group that indicated a probable WTP was included (Yin, 2008). One of the findings among drug users is noteworthy: those who showed an increased risk of infection were the most likely to agree to participate in a phase III vaccine trial. A recent meta-analysis of HIV vaccine acceptability indicated a significant impact of selfidentification as a member of a risk group and perceived susceptibility to HIV infection on HIV vaccine acceptability, thus suggesting potentially modifiable factors beyond vaccine characteristics that may influence uptake (Newman, 2010a). This finding may explain the high rate of WTP in this subgroup of drug users compared to the mean of this population (83.3% vs. 39.2%). Among active drug users, women showed greater willingness to participate in a phase III vaccine trial. Greater availability and motivation of women has also been noted in other studies, although in different risk groups (Aliyu, 2010;Colfax, 2005). The rate of HIV incidence among IDUs in our area is half that found in a similar population in Thailand (Suntharasamai, 2009;. In the study by Muga et al., the proportion of IDUs admitted for substance abuse treatment had decreased considerably in recent years . When combined with the relatively low incidence of HIV infection in recently recruited IDUs, these data suggest that drug users may not be included in future studies on preventive HIV/AIDS vaccine efficacy trials. The results from this study indicate that the prevalence of HCV in drug users and in sexual partners of HIV-positive patients is relatively high (41.6% and 8.3%, respectively). These results suggest the possibility that some of the individuals in the drug users group who selfreported as non-IDUs may have injected drugs in the past. However, the risk of sexual transmission of an HCV infection is associated with a history of multiple sexual partners and a lack of condom usage (Alter, 1990;Osmond, 1993;Rauch, 2005). Thus, the high prevalence of HCV infection in both risk groups in this study could be explained by the large number of subjects who said that they never use condoms. It was also noted that over 20% of drug users had been vaccinated for HBV. Although the percentage of people vaccinated against HBV is low globally, these results are consistent with others noting that vaccine-induced immunity to HBV infection in Spain has been increasing . Several limitations of this study should be mentioned. First, the survey did not include issues related to vaccine trial attributes, such as vaccine-induced infection, side effects, or false-positives on HIV tests, which are associated with lower WTP (Mills, 2004). Thus, the results of this study may overestimate WTP. In addition, self-reported data on risk behaviors related to drug use and sexual behavior could overestimate current risk behaviors. This study has a cross-sectional design and therefore cannot analyze changes in the WTP that might be seen following retention strategies and vaccine education. This is the first study in Spain to evaluate WTP among sexual partners of HIV-positive patients. The number of people at risk who participated is high, and the study environment is appropriate because the involved facilities have the ability to implement phase I or II vaccine trials.
In the case of a phase III preventive vaccine trial in Spain, it could become necessary to recruit a large number of people at risk of infection. The stated WTP in hypothetical HIV vaccine trials was high among sexual partners of HIV-positive patients. Specific interventions are needed to increase the acceptability of vaccine trial participation among drug users at risk of HIV infection.