Adherence

4.1 Adherence and resistance

In conceptual terms the most significant development has been the emergence of evidence that different patterns of non-adherence may promote resistance by drug class: while for unboosted PIs, risk of viral resistance has been found to be greatest in those with high adherence [104–107], for NNRTIs the risk may be greatest for those with the lowest adherence [108] or those who take unplanned drug holidays > 2 days [109]. Whether level of adherence has an effect on emergence of resistance to RTV boosted PIs is unknown, but it is possible that it is most likely to occur within a narrow range of moderate adherence which is sufficient to permit replication of less fit resistant virus [110].

4.2 Treatment simplification strategies

Unexpectedly poor results from recently reported trials of combinations which might have had a role in constructing simplified regimens serve as a caution against the use of untested combinations [111–114] in this context. Where there is a desire to offer a simpler regimen in the hope of optimizing adherence, the chosen combination should have demonstrated clinical efficacy and safety. Once-daily HAART has yet to show a clear advantage over twice-daily treatment; in the field of hypertension a 6-month study showed that in a highly adherent population once-daily therapy did not significantly reduce the number of doses missed, but it did reduce the number of late doses [115]. A recent systematic review of all published studies of adherence interventions found only one study with adequate follow up in which adherence was shown to be higher on once daily versus twice-daily therapy [102,116].

4.3 Interventions to improve knowledge and skills

These are the most common forms of adherence support in current clinical practice. Several randomized trials have now been published; however many have significant methodological problems, principally the lack of a predefined primary endpoint. Rather than describing virological outcome, the effect on patient self reported adherence was most frequently measured in these studies which in this context may be particularly vulnerable to self-presentational bias.

Two studies reported a positive effects from educational interventions: a large study of four individual educational sessions compared with standard care reported increases in self reported adherence sustained for 18 months [117]. A smaller study using electronic means to measure adherence more objectively appeared to support these findings but the study was limited by inadequate follow up (12 weeks) and high rates of attrition of participants [118].

The only study powered to detect a protective effect against virological rebound showed no benefit from frequent contact with a trained staff member delivering an individually tailored programme of adherence support [119]; however, a secondary endpoint comparing prevalence of plasma HIV RNA ≤400 copies/ml did find a significantly lower rate in the intervention arm [119]. A large unpowered trial found no effect on either adherence (measured electronically) or virological response of a structured programme of 4 weekly small group training sessions compared with standard care [120]. A small pilot study showed no significant effect on adherence over standard care of motivational interviewing techniques in adherence support [121].

4.4. Cognitive-behavioural interventions

A large randomized controlled trial (RCT) of 3 sessions of a cognitive-behavioural intervention reported increases in self reported adherence compared with standard care sustained for 6 months and also a small effect on virological outcome [122]. A study of a similar brief intervention using an electronic measure of adherence was underpowered but showed superior adherence results on some but not all adherence measures at 4 weeks. By 24 weeks the rate of loss to follow up was too high to allow conclusions to be drawn [123]. Two trials comparing prolonged cognitive-behavioural interventions with either a video including similar content [124] or standard care [125] showed no overall beneficial effect on adherence or virological treatment outcome [125].

4.5 Pagers/ alarms etc.

A very large RCT powered to detect an effect on virological rebound showed a significantly higher rate of virological treatment failure in patients randomized to a dose time alarm compared to no alarm (relative risk 1.25; P=0.02) [119]. Whether the same applies to watch or mobile ‘phone alarms, which may be more acceptable to patients, is unknown.

4.6 Pre-HAART practice placebo dosing

A large RCT showed no benefit in terms of objectively measured adherence of a 2-week pre-treatment practice period taking placebo pills before commencing HAART [123].

4.7 Directly observed therapy (DOT)

In an institutional setting, DOT may be associated with improved adherence and virological outcome to standard care [126]. While lessons may be drawn from the treatment of tuberculosis, DOT for HIV presents unique difficulties including the need for indefinite treatment and the highly stigmatised nature of the condition. Modified DOT is being explored in randomized trials in marginalised populations in the USA; results are awaited. A small non-randomized study among methadone users starting a new HAART regimen showed significantly better virological responses at 6 months for those receiving modified DOT with their methadone dose than for those receiving standard care (58% versus 22%; P=0.002); adherence data were not reported [127]. Given the inherent difficulties of ensuring patient follow-up with DOT, modelling have suggested that large increases in adherence may reduces deaths and AIDS events but may increase the prevalence of drug resistance [128].

4.8 Injectable therapy

In a clinical trial setting, self-reported adherence to injectable therapy with enfuvirtide was high: 84% patients reported adherence of at least 95%; adherence to enfuvirtide did not differ from that reported for concomitant oral antiretrovirals [129].

4.9 Recommendations

Current evidence does not support specific adherence interventions that include intensive, frequent or prolonged contact with specialist staff or structured group interventions. However, brief individualized interventions have shown some benefits. Treatment simplification should not be at the price of reduced clinical efficacy. Medication alarms may impede adherence.

Adherence support should be part of the routine clinical care provided by all health professionals in HIV medicine rather than being the exclusive role of specialist staff members. Every prescribing unit should adopt a standardized approach to assessing adherence and have a written policy on provision of adherence support. Staff must be appropriately trained to make delivery of such support possible. Treatment adherence data should be recorded routinely alongside other clinical parameters in order to detect patients in greatest need of additional treatment support.

The leading determinant of a successful and durable virological and immunological responses to HAART is adherence sustained without lapse at extraordinarily high levels for many years. Therefore, a core component of the clinical care of HIV-positive patients must be adherence support. This should commence before HAART is introduced and continue at varying intensity throughout the treatment course.

High adherence to therapy is the sum of many daily decisions to take therapy under the influence of diverse factors internal and external to the patient which change over time. While clinical trials for adherence support can only explore single or structure interventions, it is implausible that any single intervention will be effective in a sustained manner for all patients. A systematic review of all published studies of adherence interventions across medical specialties found that only 33 were adequately powered to detect clinically important effects. Effective interventions were usually complex and included combinations of information, counselling, reminders, self- monitoring, reinforcement and more convenient care; large improvements in adherence were not observed [102]. Therefore, the approach to supporting adherence in the clinic should be to deploy a range of techniques (based on evidence as it emerges from clinical trails) individualized to the need of each patient at any given time in their treatment career. Increased support may be required not only when starting and changing therapy or when side effects occur, but also when other non-treatment related factors intervene (e.g. mental illness, social upheaval).

Readers are referred to comprehensive guidelines produced in 2003 by BHIVA and the Medical Society for the Study of Venereal Diseases (MSSVD) for a full exploration of these issues. These are available from the BHIVA website (http://www.bhiva.org) and have recently been published [103]. Developments in the field since this document was produced are summarised below: