There are particular challenges to encouraging and accurately measuring adherence in research trials of pre-exposure prophylaxis (PrEP), researchers reported in a series of presentations at the Fifth International Conference of HIV Treatment Adherence in Miami this week.
Participants feel healthy but associate pill-taking with being sick, the drugs link the person with HIV infection, and admitting to missing doses can be challenging.
As the research studies are investigating whether once-a-day Truvada helps prevent HIV infection or not, optimal adherence will help researchers answer this question. Nonetheless, one study’s principal investigator questioned whether adherence to once-a-day treatment will ultimately be expected of people taking PrEP, should it work.
Pre-exposure prophylaxis (PrEP) is the use of antiretrovirals prior to exposure to HIV to prevent infection. PrEP is intended for use by people who may be at frequent risk for HIV and a series of studies known as iPrEx are being conducted among men who have sex with men in six countries.
Adherence is being measured in the iPrEx studies through pill counts, self-report during an interview with a staff member, self-report through computer-assisted self-interview (CASI), testing of drug levels in the blood and testing of drug levels in hair (in a smaller sub-study). Data on actual levels of adherence will be presented at a later date.
Albert Liu presented qualitative findings on how men participating in the study in San Francisco dealt with adherence. A number of the themes were comparable to studies on adherence to treatment: barriers to pill-taking included changes to routines, the use of alcohol or drugs and stress.
Perceived side-effects also came up, but in a way which has a particular impact on a drug to prevent the sexual acquisition of HIV. Truvada can cause diarrhoea and flatulence, and some men didn’t take it to avoid such problems on days when they planned to meet a new sexual partner.
Stigma was also an issue – taking the drug could suggest that the person is at risk of HIV infection or has HIV already. This affected the adherence of some men, especially men of colour.
These focus groups and interviews were conducted by a different person and at a different location from the participants’ other interactions with the research study. It was reported that discussing lapses in adherence with the research staff could be difficult, with some participants being nervous about the repercussions and fearing being excluded from the rest of the study. Nonetheless, staff were generally described as helpful and non-judgemental; reporting poor adherence generally became possible once a trusting relationship had been built up (after several months).
Confirming this, Lorena Vargas presented findings from Peru and Ecuador, looking at the experiences of 1183 men participating in iPrEx there.
Almost all respondents reported often being told by staff to “take a pill every day”. Just under half (47%) reported some concern that study staff would be upset if missed doses were revealed; 63% reported the perception of possible negative consequences if missed pills were reported; and 42% said that telling staff about a missed pill would be less than ‘easy’.
As in many other settings, there was a tendency for clinic staff to emphasise the goal of 100% adherence, to be directive or persuasive, and not to explore problem-solving.
To counteract this, a number of iPrEx sites are implementing new strategies both to collect data from participants on their adherence levels and to support participants with adherence. Firstly, these functions are strictly separated. Staff recording adherence data have been trained to do so in a neutral way, with no comment on the responses. They are encouraged to draw attention to the fact they are just working through a form and to emphasise that they hear about missed doses each day.
On the other hand, the counsellors who are charged with supporting participants with adherence are now discouraged from focusing the conversation on the desired behaviour (complete adherence). Instead they discuss what makes adherence hard for the individual in particular situations and encourage the participant to develop their own solutions. Discussion focuses on small steps rather than the final objective, which may be unachievable in the immediate future.
Rivet Amico, presenting, described these approaches as ‘neutral assessment’ and ‘next step counselling’ respectively.
Speaking at the conference, Robert Grant, protocol chair of the iPrEx study, explored the possibility that total adherence to daily PrEP may not turn out to be necessary.
Grant suggested that fears of the use of PrEP leading to the development of drug resistance may possibly be unfounded. While if a person started or re-started PrEP in the first weeks of infection, the selection of resistant mutations would be probable, it was unclear that poor adherence to daily PrEP (or deliberate intermittent dosing) would otherwise lead to drug resistance.
When treating a person with HIV, the virus population is huge and so there are many opportunities for mutations to generate. “The prevention setting is different: we’re not treating a multi-million population of virus, we’re treating about 15ml of genital secretion,” he said.
Grant also said that it remained unclear whether the appropriate frequency of PrEP would be daily, or could be less often.
He pointed out that whereas methods exist to determine the best frequency and dosing of treatment regimes, researchers do not know what levels of a drug might protect against infection and do not have any surrogate markers that would indicate an increased risk of infection (the only marker in a study is infection itself).
As a consequence he questioned whether the term “adherence” could be appropriately used, as it suggests that there is an optimised regimen that patients ought to stick to. He pointed out that in the case of other prevention techniques, such as condoms, any use of them is encouraged – people are not told that if they can’t use them 100% of the time, they shouldn’t bother at all.
He suggested that a desire for intermittent PrEP was coming from the communities hoping to benefit from it, rather than from researchers. People taking PrEP may prefer to see their doctor not as someone who instructs them to adhere to their treatment, but as someone who can help them identify when there will be a risk of HIV exposure and plan for this.
Liu A et al. Barriers and facilitators to prevention pill use in iPrEx: capturing the experience of MSM PrEP study participants in the United States. Fifth International Conference on HIV Treatment Adherence, abstract 62191, Miami, 2010.
Vargas L et al. Pill-taking support and assessment: self-reported perceptions of participants in a PrEP trial. Fifth International Conference on HIV Treatment Adherence, abstract 62257, Miami, 2010.
Amico KR et al. Developing an innovative approach to adherence counseling and assessment in a pre-exposure prophylaxis (PrEP) trial: next step counseling and neutral assessment in the iPrEx study. Fifth International Conference on HIV Treatment Adherence, abstract 62253, Miami, 2010.
Grant R. Antiretroviral regimens as pre-exposure prophylaxis: adherence considerations. Fifth International Conference on HIV Treatment Adherence, Miami, 2010.