LITERATURE REVIEW
2.3 THE ETHICS OF HIV PREVENTION TRIALS
attitudes towards the trial (Kruse et al., 2000; Searight & Miller, 1996; Weston, Hannah &
Downes, 1997). Robinson et al., (2005) report evidence that provision of adequate
information may actually lead to greater understanding, which may ultimately lead to lower consent rates.
therapeutic treatments, while that of false confidence is mainly associated with trials testing some preventive technologies such as microbicides and HIV vaccines. In the area of preventive HIV vaccine and microbicide trials, this phenomenon is commonly referred to as behaviour disinhibition (Abdool Karim & Baxter, 2009).
In the area of microbicide trials, there are always fears that some participants may believe that they are protected from HIV infection by the microbicide under study, thereby beginning to adopt some high risk behaviours or even reducing preventive actions (McGrath et al., 2001).
The phenomenon of false confidence may make trial participants not consider the facts that they are going to be randomised to various groups, that there is some chance that they may receive a placebo, that a placebo does not contain the active ingredient, that the purpose of the research is to test the product, that even the researcher or staff at the clinic may not know whether they are using the placebo or the active product, and that the active product may not be at all effective.
Cassell, Halperin, Shelton and Stanton (2006) also note that, in HIV prevention programmes and research, it is possible for individuals to increase their risky behaviour as a result of a decrease in perceived risk and they raise concern that this could undermine the protective effect of a particular intervention such as circumcision, microbicides or pre-exposure prophylaxis.
The authors suggest that, by so doing, such interventions may promote the spread of HIV by inhibiting the uptake of safe behaviours. The authors further suggest that the challenge of false confidence in HIV prevention research may be addressed in part by communicating clearly and broadly that the product being tested may not eliminate the risk of HIV infection. In
recognition of the possibility of individuals abandoning safe behaviours such as condom use, Foss, Vickerman, Heise and Watts (2003) conducted a study which attempted to estimate the reduction in condom use that can be tolerated following the introduction of an efficacious
microbicide without increasing an individual’s chance of HIV infection. They estimated that with a microbicide which is 50 percent effective, groups that use condoms with 25 percent consistency or less could stop using condoms without increasing their risk.
A study was conducted by Stolte, Dukers, Geskus, Coutinho and de Wit (2004) to investigate if men who have sex with men may change from protected to unprotected anal intercourse as a result of perceiving less need for highly active anti retroviral therapy (HAART). The study found that homosexual men were not more likely to engage in unprotected sexual intercourse under these circumstances. The findings from this study may be less applicable to HIV vaccine and microbicide trials in which the participants are individuals who are HIV negative. It is possible that the men who participated in this study were always aware of the need for continued protection as they were always reminded about their HIV status by the drugs that they were supposed to take each day. Bartholow et al. (2005) report on similar findings from a study which looked at men having sex with men and women taking part in a multi national HIV vaccine study. The study established that sexual risk behaviour did not increase beyond
baseline levels during the first three years of the vaccine trial. On reviewing the literature, Slack et al. (2005) suggest that behaviour disinhibition is seldom a reality.
In microbicide trials, the possibility of behaviour disinhibition or false confidence has implications as it may leads to several questions. Some of the important questions include:
Who may be to blame for those participants who get infected during a microbicide or HIV vaccine trial?
Does participation in a microbicide trial increase the chances of infection by creating a sense of false confidence among participants?
Who should be responsible for the treatment of those individuals who get infected during the course of the microbicide trial?
All these questions relate to the fact that, in microbicide trials, HIV sero-conversion is the primary end point and only HIV negative women are included in the study after some
prescreening procedures. Women have to be sexually active if a microbicide is to be tested and, as such, exposure to HIV is a precondition for the successful testing of the new product.
Microbicide trials are preventive trials in nature since they are mainly meant to protect uninfected women by protecting them from infection by their infected male partners. This difficult fact places a demand on the researchers to ensure that the trial participants adequately understand that they are participating in research and that they also take the necessary
precautionary measures as individuals to ensure that they protect themselves from possible infection (Chistakis, 1988).
Paradoxically, just as support and scientific prospectus for microbicide development are improving, the ethical challenges in the area of microbicide research are growing. For example the issue of false confidence and the issue of post trial antiretroviral therapy for those who become infected during the microbicide trial (Coplan et al., 2004). A significant volume of literature exists on the debates surrounding ethical issues in microbicide studies, much of which focuses on the questions of what happens to the participants who become infected during the trial (Barsdorf, Maman, Kass & Slack, 2009; de Zoysa, Ellias,& Bentley,1998; Lange, 2005;
Lavery, Grady, Wahl & Emanuel, 2007; Lindegger & Richter, 2000; Moodley, 2007; Richter, Lindegger, Abdool Karim & Gasa 1999; MacQueen, Abdool Karim & Sugarman, 2003;
Saelens, 1998; Singh & Mills, 2005; Slack et al., 2005; Slack & Stobie, 2008; Schuklenk, n.d;
Stobie, Strode & Slack, 2005; Tarantola et al., 2007; Tucker & Slack, 2003; UNAIDS, 2000, 2007; Wassenaar & IJsselmuiden, 2007; Weijer & LeBlanc, 2005; Wolf & Lo, 2001; Vallely et al., 2009). The various authors looked at this topic from various perspectives with some specifically trying to answer the question from the point of view of developing countries. The
availability of such a large volume of literature, suggests that the infection of trial participants during the course of a trial, is an important issue which needs serious attention if HIV
prevention trials are to be conducted using high ethical standards. Overall, there is some level of agreement among the various authors that some level of HIV prevention efforts are
necessary during the trial and some care is necessary for individuals who seroconvert during HIV prevention trials.
Preventive HIV vaccines are designed to prevent HIV infection whereas therapeutic HIV vaccines are designed to boost the immune responses of a person already infected with the virus (Esparaza, & Bhamarapravati, 2000). Several authors have argued that the commercial production and distribution of a preventative vaccine or microbicide might continue to remain an elusive dream due to the genetic mutation of the virus, which has led to failures in some of the products that appeared promising initially (Berkley, 2003; Barouch, 2008; Esparaza, &
Bhamarapravati, 2000; IAVI, 2010; Johnston & Fauci, 2008). Mathematical modeling studies have established that a partially effective microbicide used in half of coital acts by 20 percent of women at risk could prevent 2.5 million infections in three years (Coplan et al., 2004).
The field of HIV preventive microbicides has received attention in recent times after realization that, worldwide, nearly half of all individuals living with HIV are women who have acquired the virus largely by heterosexual exposure (Blayne & Justman, 2008). With an HIV vaccine likely to be years away, topical microbicide formulations applied vaginally or rectally are now being investigated as an important strategy for HIV prevention. Importantly, HIV preventive microbicides can become an important female-controlled method that can be used by women who cannot negotiate condom use for a variety of reasons. This in itself would be a way of empowering women in the fight against HIV. A review of research on HIV preventive microbicides conducted by Blayne and Justman yielded 118 studies at the time: 73 preclinical
and 45 clinical. Clinical research included phase I and II/IIb safety studies, and phase III efficacy studies. The authors noted that while some phase I and phase II clinical trials had found some microbicide compounds to be safe and well tolerated, phase III trials completed at that time had not demonstrated efficacy in preventing HIV transmission. The findings from the tenofovir trials have brought some hope into the HIV prevention arena (Abdool Karim et al., 2010, Keller, 2010). Before the tenofovir success story, HIV preventive microbicide trials faced some serious scientific and ethical issues including choice of placebo gel, the potential to cause viral resistance, the potential to increase false confidence, the issue of care for those who become infected during the trial, among others (Blayne & Justman, 2008).
Previous microbicide trials conducted in developing countries have posed several complex ethical challenges. One of the microbicide studies which encountered so many ethical challenges was the Nonoxynol-9 study which was conducted in several developing countries including Zimbabwe, South Africa, Kenya, Cameroon and Thailand. Before the initiation of the major phase III study using Nonoxynol-9, some studies had already indicated that multiple use of Nonoxynol-9 had adverse effects, which were possibly associated with enhanced vulnerability to HIV infection (Coggins & Elias, 2000). One earlier trial had even shown an increase in HIV incidence among those using a 1000mg dose of N9 using a sponge as compared to those using a placebo (Van Damme et al., 1998). This study was dismissed for methodological reasons (Van Damme et al., 1998). Another study conducted among sex workers in Cameroon using a 70mg dose of N9 in a vaginal film showed no effect, either harmful or beneficial (Van Damme et al., 1998, 2000, 2002). However, there were already reports on genital epithelial disruption and inflammation when N9 was used frequently in high doses (Stafford et al., 1998). The Phase III studies confirmed all the problems documented in the earlier literature. The women in the N9 arm had a higher rate of infection compared to those in the placebo arm (Van Damme et al., 2002). Some authors have concluded that the
Phase III trials were conducted even after some evidence had shown that N9 was not suitable since it was reasoned at the time that microbicide studies were a matter of urgency in view of the growing HIV epidemic in Africa (Coggins & Elias, 2000; Ramjee, 2007; Wassenaar &
IJsselmuiden, 2007).
The principle of nonmaleficence requires that all participants be provided with available measures known to reduce the risk of HIV infection, yet this simultaneously reduces the ability of the study to assess the protective effect of the microbicide under test. According to this principle, investigators (usually physicians) should not just watch while trial participants become infected. Instead, they are obliged to take all actions they can to ensure that those who are uninfected stay uninfected. On the other hand, providing extensive HIV/AIDS prevention services to participants as part of a microbicide trial may be construed by some critics as an undue influence, especially if the study is conducted among vulnerable populations such as sex workers and women from disadvantaged communities (Slack et al., 2005).
There are some reports on microbicide trials in developing countries that have targeted less educated, economically disempowered and vulnerable women. These women could have been selected for the sole reason that they are at most risk (Slack et al., 2005). This has implications for informed consent, as this group may have problems in understanding clinical trials and study procedures (Cohen, 2005; Moodley, 2002, 2007; Slack et al., 2005). In microbicide trials, at a minimum, the level of HIV infection risk should be no greater than if the participants had not participated in the trial. UNAIDS (2000) recommends that risk reduction measures such as counselling, condom promotion and training in condom negotiation skills should for part of the HIV prevention trials in order to ensure that infection risk behaviours do not increase over those reported at enrolment. These risk reduction measures should be extended to all trial arms. The same guidance is also echoed by Kilmarx et al., (2001) and UNAIDS
(2006). The guidance by UNAIDS is important as it is aimed at ensuring that HIV prevention trial participants are protected from obvious risk as they contribute towards the common good.
Kilmarx et al. (2001) note that research participants in microbicide trials are already
marginalized by the very characteristics and behaviours that initially put them at risk of HIV infection, including engaging in commercial sex work and also being resident in a developing country with high HIV infection rates. As a way of taking the above into consideration, microbicide trials are moving away from concentrating only on very high risk individuals such as sex workers to also including women who may not have many sexual partners (UNAIDS, 2007; Van Damme, 2002). Microbicide trials have provided risk reduction counselling and condom promotion as part of the study procedures so that researchers are not seen as waiting for infections to happen (Hearst and Chen, 2004; UNAIDS; 2007). Some countries such as South Africa and Kenya have even gone further to provide some national guidance on the conduct of HIV prevention trials (Kenya Ministry of Health, 2005; Medical Research Council, 2003; Uganda AIDS Commission, 2006). The efforts by the three counties are aimed at
supplementing UNAIDS guidance published in 2000 and revised in 2007 by providing national guidance on some of the ethical challenges that have affected some HIV prevention trials in the past. The issues discussed in this section provide evidence on the ethical challenges bedeviling HIV prevention trials. The advent of tenofovir will definitely influence the HIV prevention research landscape. The next section focuses on studies that have assessed HIV prevention trial participants’ understanding of research participation.