Responding to children and adolescents who have been sexually abused: WHO clinical guidelines: web Annex 3a: adherence to HIV post-exposure prophylaxis: evidence-to-decision table

1 | P a g e RESPONDING TO CHILDREN AND ADOLESCENTS WHO HAVE BEEN SEXUALLY ABUSED WHO CLINICAL GUIDELINES* Web Annex 3a: Adherence to HIV post-exposure prophylaxis: evidence- to-decision table *Full guide: https://apps.who.int/iris/bitstream/handle/10665/259270/9789241550147-eng.pdf 2 | P a g e WHO/RHR/17.25 © World Health Organization 2017 Some rights reserved. This work is available under the Creative Commons Attribution-NonCommercial- ShareAlike 3.0 IGO licence (CC BY-NC-SA 3.0 IGO; https://creativecommons.org/licenses/by-nc-sa/3.0/igo). Under the terms of this licence, you may copy, redistribute and adapt the work for non-commercial purposes, provided the work is appropriately cited, as indicated below. In any use of this work, there should be no suggestion that WHO endorses any specific organization, products or services. The use of the WHO logo is not permitted. If you adapt the work, then you must license your work under the same or equivalent Creative Commons licence. 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Evidence-to-decision table: adherence to HIV postexposure prophylaxis (PEP) Recommendation 4 Question – Among children and adolescents (0–18 years) who have or may have been exposed to sexual abuse (P), do any interventions to provide enhanced adherence support for HIV PEP (I), as compared to no adherence support (C), prevent HIV and/or improve adherence to PEP (O)? Table 1. Summary of the assessments based on which decisions were made Criteria Judgement Research evidence Problem Is the problem a priority? ☐ No ☐ Probably no ☐ Probably yes ☒ Yes 1. Various national and international guidelines recommend PEP for occupational, accidental and sexual exposure, to inhibit virus replication and thereby prevent the establishment of chronic HIV infection. 2. Data from animal studies (1) support the efficacy and use of PEP. 3. Indications for PEP have expanded over time to cover nonoccupational exposure, including accidental exposure, noncoercive sex and sexual assault. 4. If started soon after exposure, PEP can reduce the risk of HIV infection by over 80%. 5. A systematic review and meta-analysis conducted in 2014 found that completion rates for PEP are suboptimal across exposure types, with only 57% of individuals eligible for PEP completing the full 28-day course (2). PEP completion rates are lowest for people exposed following sexual assault (40%) and adolescents (37%) (2). ☐ Varies ☐ Don’t know Values Is there important uncertainty about or variability in how much people value the main outcomes? ☐ Important uncertainty or variability ☐ Possibly important uncertainty or variability ☐ Probably no important uncertainty or variability 1. Both health providers and patients value avoiding HIV infection. 4 | P a g e Criteria Judgement Research evidence ☒ No important uncertainty or variability ☐ No known undesirable outcome Desirable effects (Benefits) How substantial are the desirable anticipated effects? ☐ Trivial ☐ Small ☐ Moderate ☐ Large Summary of findings 1. Three randomized controlled trials (RCTs) assessing the impact of enhanced adherence counselling for PEP found a small improvement in adherence among participants receiving the intervention. 2. This effect was non-statistically significant for two RCTs (Abrahams et al. (3) and Roland et al. (4)):  Abrahams et al. (3): odds ratio (OR) 1.32 (0.80–2.18) (sexual assault exposure)  Bentz et al. (5): OR 3.85 (1.19–12.47) (sexual exposure)  Roland et al. (4): OR 1.14 (0.72–1.81) (sexual exposure). 3. The meta-analysis indicated a trend towards a modest improvement in adherence: pooled OR: 1.4; 95% confidence interval (CI) 0.9–2.3. Small sample sizes relative to the number of events in all the RCTs resulted in wide CIs around point estimates, and one cannot rule out the possibility that the improvements measured were due to chance. 4. None of the three reported findings specific to the population of interest: children and adolescents who were sexually abused. The Abrahams et al. (3) trial in South Africa included sexually assaulted adults and female children, but did not disaggregate for children. 5. A review of 12 qualitative studies on barriers and facilitators to adherence (full report available upon request) found that barriers to adherence included concerns for side effects, forgetting to take medicines, fear of stigma, being busy, traumatic associations with rape, poor knowledge and mental health problems. 6. These studies highlighted the importance of encouragement from health care providers to take PEP and counselling as being facilitative for adherence. ☐ Varies ☒ Don’t know Undesirable effects (Harms) How substantial are the undesirable ☐ Large ☐ Moderate ☐ Small ☒ Trivial No study reported that enhanced adherence counselling for PEP had undesirable effects. 5 | P a g e Criteria Judgement Research evidence anticipated effects? ☐ Varies ☐Don’t know Certainty of evidence What is the overall certainty of the evidence of effects? ☒ Very low ☐ Low ☐ Moderate ☐ High 1. While there was moderate heterogeneity (I2 43.8%) in results, the results were consistent across studies. 2. The rating of certainty in the evidence graded as “Very low” for the following reasons.  The evidence was indirect. Two of three RCTs were carried out in patients presenting for sexual exposure and not sexual assault, and included only adult patients. The one study (Abrahams et al. (3)) that included sexually assaulted adults and children was not statistically significant and reported similarly poor levels of adherence across both intervention and comparison groups; the evidence was therefore indirect for the population of interest: children and adolescents who were sexually assaulted.  Sample sizes were small and effect sizes imprecise. Small sample sizes relative to the number of events of all RCTs resulted in wide CIs around point estimates (i.e. imprecise effect size), meaning that, while there is a tendency towards an effect, the possibility cannot be excluded that the apparent benefit was due to chance.  The exact nature, intensity and resource implications of “enhanced adherence” counselling could not be ascertained, as the strategies varied across the three trials. ☐ No studies included Balance of effects Does the balance between desirable and undesirable effects favour the intervention or the comparison? ☐ Favours the comparison ☐ Probably favours the comparison ☐ Does not favour either the intervention or the comparison ☐ Probably favours the intervention ☐ Favours the intervention 1. While the initial assessment of the balance of effects was presented as probably favouring the intervention, because no undesirable effect of intervention could be ascertained, the Guidelines Development Group (GDG) disagreed with this assessment and noted that the evidence on the balance of harms versus benefits could not be ascertained because children and adolescents who have been sexually abused may also be dealing with trauma, stigma and concerns for safety that are distinct from most other patients who may require HIV PEP. 2. The GDG therefore reclassified the initial judgment of balance of effects from “Probably favours” the intervention to “Don’t know”. 6 | P a g e Criteria Judgement Research evidence ☐Varies ☒Don’t know Resources required How large are the resource requirements (costs)? ☐ Large costs ☐ Moderate costs ☐ Negligible costs and savings ☐ Moderate savings ☐ Large savings 1. Resource requirements were not formally assessed, but the associated costs – training and supervision of counselling – are likely minimal compared to the lifetime cost associated with treating HIV infection. One of the RCTs (Abrahams et al. (3)), however, reported that the enhanced adherence intervention, comprising telephonic support in addition to standard of care, was “fairly labour intensive”. 2. Most PEP services will already include capacity to undertake counselling. In many settings where PEP is provided, counselling services are available, and counselling is also provided to victims of sexual assault for reasons other than PEP adherence. However, in primary health care it will be necessary to upgrade skills. ☐ Varies ☒ Don’t know Certainty of evidence of required resources What is the certainty of the evidence of resource requirements (costs)? ☐ Very low ☐ Low ☐ Moderate ☐ High 1. Resource information was not found; no studies were included. ☒ No included studies Cost– effectiveness Does the cost– effectiveness of the intervention favour the intervention or the comparison? ☐ Favours the comparison ☐ Probably favours the comparison ☐ Does not favour either the intervention or the comparison ☐ Probably favours the intervention ☐ Favours the intervention 1. Information on cost–effectiveness was not found; no studies were included. 7 | P a g e Criteria Judgement Research evidence ☐ Varies ☒ No studies included Equity What would be the impact on health equity? ☐ Reduced ☐ Probably reduced ☐ Probably no impact ☐ Probably increased ☐ Increased 1. PEP completion rates are lower among victims of sexual assault than the general population (40% vs 57%). 2. The intervention has the potential to improve completion rates for HIV PEP in this vulnerable population, and may provide other indirect benefits through increased health-service interaction. 3. Since none of the RCTs included the population of interest, there is no direct evidence for enhanced adherence support. Nevertheless, providing such support is an important element of PEP provision given the challenges to adherence among sexual assault victims. ☐ Varies ☒ Don’t know Acceptability Is the intervention acceptable to key stakeholders? ☐ No ☐ Probably no ☐ Probably yes for clinician/referral source ☐ Yes 1. Evidence from the three RCTs indicates willingness to accept the intervention.  Bentz et al. (5) report the following. o Twelve percent of patients refused to participate in the trial. Among trial participants, 61% of scheduled counselling sessions took place. The fact that most patients are working, not easily available and under stress may be a challenge to follow-up counselling sessions. o The limited time that nurses may have available in emergency clinics and other settings may limit implementation.  Abrahams et al. (3) report the following. o Ten percent of eligible patients refused to participate in the trial, and 2% discontinued the intervention. o The authors describe the intervention as “fairly labour intensive” (telephonic support in addition to standard of care).  Roland et al. (4) report that recruitment to the study “took great effort despite increasing awareness (of PEP) to nearly 70%”. 2. Sexual-assault or rape survivors may also be dealing with factors (trauma, stigma and concerns for safety related to sexual abuse) that are distinct from those affecting most other patients who may require HIV PEP. ☐ Varies ☒ Don’t know Feasibility ☐ No 8 | P a g e Criteria Judgement Research evidence Is the intervention feasible to implement?? ☐ Probably no ☐ Probably yes ☐ Yes 1. Information about feasibility was not sought, but see the comment above relating to the existence/desirability of counselling support (beyond PEP adherence). 2. All three included RCTs assessed enhanced counselling interventions as a way to improve adherence, but the frequency, content and mode of delivery varied. ☐ Varies ☒ Don’t know Recommendation 4 Question – Among children and adolescents (0–18 years) who have or may have been exposed to sexual abuse (P), do any interventions to provide enhanced adherence support for HIV PEP (I), as compared to no adherence support (C), prevent HIV and/or improve adherence to PEP (O)? Table 2. Conclusions of the GDG Conclusions Content Type of recommendation Strong recommendation against the intervention ○ Conditional recommendation against the intervention ○ Conditional recommendation for either the intervention or the comparison ○ Conditional recommendation for the intervention ○ Strong recommendation for the intervention ○ Recommendation 4. Adherence counselling should be an important element in HIV PEP provision to survivors of sexual assault (strong recommendation, very low quality). Justification 1. The 2014 WHO guideline on PEP for preventing HIV infections among adults, adolescents and children (6) recommends “enhanced adherence” counselling for PEP adherence for all populations exposed to HIV. The HIV PEP guidelines did not, however, look at the evidence for children and adolescents exposed to sexual abuse, who face particular challenges related to the trauma and stigma of the abuse. 9 | P a g e Conclusions Content 2. For these guidelines, the GDG considered the evidence of the effectiveness of enhanced adherence counselling, as well as the qualitative data on barriers and facilitators. It noted the evidence that PEP adherence/completion following sexual assault has been found to be lower than in the general population and that it can be a challenge for children and adolescents who have been sexually abused, because they are often traumatized. The GDG therefore agreed that support and counselling for PEP adherence are an important component of HIV PEP provision to survivors of sexual assault. Members did not, however, agree that the evidence was convincing to make a specific recommendation on offering enhanced adherence counselling for children and adolescents who have or may have been sexually abused, for the following reasons. a. The evidence on effectiveness for the population of children and adolescents who have been sexually abused has very low certainty owing to its indirectness. Specifically, two of the three RCTs included were carried out in patients presenting for sexual exposure and not sexual assault, and included only adults. The third included adult women and female children who were sexually assaulted, but did not disaggregate for children, and found no statistically significant differences in adherence rates across the intervention and comparison groups. b. Moreover, owing to the small sample sizes relative to the number of events in all RCTs, the resulting CI around the pooled point estimate was wide, and two of the three RCTs showed no statistically significant effect. c. The evidence on the balance of harms versus benefits could not be ascertained because children and adolescents who have been sexually abused may also be dealing with trauma, stigma and concerns for safety that are differ from the concerns of most other patients who may require HIV PEP. d. The exact nature, intensity and resource implications of “enhanced adherence” counselling could not be ascertained, as the strategies varied across the RCTs; no studies were included to ascertain feasibility, resources or cost–effectiveness. 3. The GDG therefore proposed to use the recommendation on PEP adherence from the existing WHO guideline for responding to intimate-partner and sexual violence against women (2013) (7),as is currently reflected in the recommendation above. It asked to update the remarks with specific considerations for children and adolescents. Subgroup considerations • PEP adherence is lower in sexual-assault survivors than in general population, so adherence support may improve completion in this population and have other indirect benefits through increased contact with health services 10 | P a g e Conclusions Content Implementation considerations • Many survivors of sexual assault provided with HIV PEP do not successfully complete the preventive 28-day regimen because HIV PEP results in physical side effects such as nausea and vomiting. These issues may be accentuated in adolescents (e.g. there may be increased side effects in smaller adolescents). • In addition, taking HIV PEP may trigger painful thoughts or trauma associated with rape, and other issues may overtake the lives of survivors/victims. The stigma associated with sexual assault may also contribute to low adherence among this population (e.g. due to concerns related to secrecy). Specific attention should therefore be paid to these issues. • Health care providers should be aware that adherence is very difficult to attain and efforts should be made to ensure that it is maintained. Side effects should be communicated in a way that is accurate but does not induce fear, and the impact of the traumatic event needs to be considered. • Adherence counselling for young children also needs to involve their caregivers. • It is important to improve or upgrade basic counselling skills to support PEP adherence and to offer ongoing counselling support. While most HIV services already have the capacity to undertake counselling, in primary health care, the counselling skills of health care providers may need to be upgraded. • Given the stigma associated with sexual abuse, the first visit to the health care provider may be the only visit, and thus the only opportunity to provide adherence counselling to the child or adolescent. If the decision is made to take HIV PEP, the provider should give counselling on adherence as comprehensively as possible. • Age-specific needs should be taken into consideration in offering adherence counselling to a child or adolescent (i.e. adherence counselling strategies for children need to be different than those for adolescents, taking into account evolving capacities). Children and adolescents can be expected to face different barriers to adherence and completion, so interventions to support them and their caregivers will have to differ as relevant. For example, it is important to ascertain whether adolescents wish to engage caregivers. References 1. Irvine C, Egan KJ, Shubber Z, Van Rompay KK, Beanland RL, Ford N. Efficacy of HIV postexposure prophylaxis: systematic review and meta-analysis of nonhuman primate studies. Clin Infect Dis. 2015;60(Suppl. 3):S165–9. Epub 2015/05/15. doi: 10.1093/cid/civ069. PubMed PMID: 25972498. 11 | P a g e 2. Ford N, Irvine C, Shubber Z, Baggaley R, Beanland R, Vitoria M et al. Adherence to HIV postexposure prophylaxis: a systematic review and meta- analysis. AIDS. 2014;28(18):2721-7. Epub 2014/12/11. doi: 10.1097/qad.0000000000000505. PubMed PMID: 25493598. 3. Abrahams N, Jewkes R, Lombard C, Mathews S, Campbell J, Meel B. Impact of telephonic psycho-social support on adherence to post-exposure prophylaxis (PEP) after rape. AIDS Care. 2010;22(10):1173–81. Epub 2010/07/20. doi: 10.1080/09540121003692185. PubMed PMID: 20640949. 4. Bentz L, Enel P, Dunais B, Durant J, Poizot-Martin I, Tourette-Turgis C et al. Evaluating counseling outcome on adherence to prophylaxis and follow-up after sexual HIV-risk exposure: a randomized controlled trial. AIDS Care. 2010;22(12):1509–16. Epub 2010/09/09. doi: 10.1080/09540121.2010.484457. PubMed PMID: 20824548. 5. Roland ME, Neilands TB, Krone MR, Coates TJ, Franses K, Chesney MA et al. A randomized noninferiority trial of standard versus enhanced risk reduction and adherence counseling for individuals receiving post-exposure prophylaxis following sexual exposures to HIV. Clin Infect Dis. 2011;53(1):76–83. Epub 2011/06/10. doi: 10.1093/cid/cir333. PubMed PMID: 21653307; PubMed Central PMCID: PMCPMC3110285. 6. Guidelines on post-exposure prophylaxis for HIV and the use of co-trimoxazole prophylaxis for HIV-related infections among adults, adolescents and children. Recommendations for a public health approach - December 2014 supplement to the 2013 consolidated ARV guidelines. Geneva: World Health Organization; 2014 (http://www.who.int/hiv/pub/guidelines/arv2013/arvs2013upplement_dec2014/en). 7. Responding to intimate partner violence and sexual violence against women. WHO clinical and policy guidelines. Geneva: World Health Organization; 2013 (http://www.who.int/reproductivehealth/publications/violence/9789241548595/en).