When PrEP fails. Laura Waters MD FRCP Mortimer Market Centre London

When PrEP fails Laura Waters MD FRCP Mortimer Market Centre London

www.aidsunited.org

PrEP works If people at risk take it If it s taken in the right way If it s available Commissioned/licensed Affordable Supported

But. European PrEP coverage ranges from non-existent to low We do not know if wide scale roll-out will be feasible We do not know if intermittent-intermittent PrEP will be effective Prevention is better than cure But right now we have too little of one and none of the other!

EPIDEMIOLOGY

Diagnosed HIV in the EU/EEA & WHO European Region* 1984-2014 142,000 new cases in 2014 highest since reporting started in 1980s *excluding Russia European Centre for Disease Prevention and Control, WHO Regional Office for Europe. HIV/AIDS surveillance in Europe 2014. Stockholm: ECDC; 2015 http://www.euro.who.int/en/media-centre/sections/press-releases/2015/11/highest-number-of-new-hiv-cases-in-europe-ever.

PHE: New HIV Diagnoses HIV New Diagnoses, Treatment and Care in the UK: 2015 report 3,360 2,490

IMPROVING DIAGNOSIS

Globally 54% of HIV is UNDIAGNOSED Of 35 million people living with HIV 19 million do not know their status http://www.unaids.org/sites/default/files/en/media/unaids/contentassets/documents/unaidspublication/2014/unaids_gap_report_en.pdf

Cascades Raymond A et al. Journal of the International AIDS Society 2014, 17(Suppl 3):19507

Estimated number PLWH UK 2014: diagnosed and undiagnosed Overall: 18% % undiagnosed has declined Men who have sex with men: 14% Black more African than heterosexuals: the numbers 12-15% Other heterosexuals: 29-31%

Implications of undiagnosed HIV Undiagnosed HIV Individual Late presentation Illness Death Society Transmission Costs of advanced disease Prevention Prevention efforts must include testing

Late diagnosis Definition: Late presentation: Persons presenting for care with CD4 <350 or and AIDS-defining event, regardless of CD4 Presentation with advanced HIV disease: Persons presenting for care with <200 an AIDS-defining event, regardless of CD4 cell count Almost 50% across Europe are diagnosed late Declining cases of AIDS across Europe but in 2014 2/3 AIDS conditions in newly or recently diagnosed Antinori A et al. HIV Medicine 2010

Late diagnosis http://www.cph.org.uk/wp-content/uploads/2015/12/late-hiv-diagnosis-rapid-evidence-review_final_covers.pdf

Late diagnosis in the UK by risk group CD4 <350 within 3 months of diagnosis 28% >50% >50%

UK: late diagnosis over time

Issues associated with late presentation Transmission Health care costs Increased mortality UK: ten-fold increased risk of death within 1 year of HIV diagnosis if late vs prompt (3.8% vs. 0.35%) Impact of AIDS diagnoses on mortality and long-term co-morbidity risk Legacy effect of immunosuppression and prolonged viraemia

Risk factors & reasons for late diagnosis Risk factors Older age Heterosexual Non-national Male Reasons Testing (1 st test for 32-55%) Risk perception Feeling well Stigma, fear, migration status Lack of access Lack of offer http://www.cph.org.uk/wp-content/uploads/2015/12/late-hiv-diagnosis-rapid-evidence-review_final_covers.pdf

Risk factors & reasons for late diagnosis Risk factors Older age Heterosexual Non-national Male Reasons Testing (1 st test for 32-55%) Risk perception Feeling well Stigma, fear, migration status Lack of access Lack of offer http://www.cph.org.uk/wp-content/uploads/2015/12/late-hiv-diagnosis-rapid-evidence-review_final_covers.pdf

PrEP & perception of risk Validated risk assessment 420 MSM in Toronto Of men at objective high risk: 68.3% did not perceive themselves to be at moderate to high risk 23.6% unaware of PrEP 40.1% not willing to use PrEP 47.6% lacked a family physician with whom they felt comfortable discussing sexual health 31.6% had no means to cover the cost of PrEP Wilton J et al. J Int AIDS Soc 2016 Jun; 19(1): 20777

Risk factors & reasons for late diagnosis Risk factors Older age Heterosexual Non-national Male Reasons Testing (1 st test for 32-55%) Risk perception Feeling well Stigma, fear, migration status Lack of access Lack of offer http://www.cph.org.uk/wp-content/uploads/2015/12/late-hiv-diagnosis-rapid-evidence-review_final_covers.pdf

European HIV testing guidelines

Who to test? Risk groups People attending higher risk clinical services People with conditions suggestive of HIV Routine testing

Who to test? Risk groups MSM, IDU, people from high prevalence areas People attending higher risk clinical services Sexual health, TOP, DDU, hepatitis, oncology People with conditions suggestive of HIV AIDS-defining illnesses, indicator diseases Routine testing eg. all medical admissions and primary care registrations where HIV prevalence >2/1000 (UK)

http://hiveurope.eu/portals/0/guidance.pdf.pdf accessed 27/02/2016 Indicator conditions

HIV prevalence by indicator condition 0.1% and LL 95%CI>0.1% 0.1 0.1 95% CI > 95% CI > 0.1 95% 95% CI CI < 0.1 Test ed 73 734 401 722 188 1 84 175 1 299 112 6 133 9 588 276 53 144 HIV+ 7 39 16 32 61 2 41 6 13 13 4 1 0 0 Slide courtesy of Dr. Michael Rayment

Overcoming barriers Access Testing in more settings, skilling all health workers Stigma Knowledge, home testing, non-sexual health clinics Pre-test counselling Quick, simple, verbal, assess risk & window periods Anxiety Extra support, rapid testing (point of care)

ECDC guidance

TREATMENT

Benefits of ART Individual Population Improved life expectancy Reduced morbidity Reduced risk to partners Lower health care costs Better productivity Reduced transmission

START: Primary results Median CD4 at ART 408 Median CD4 at ART 651 (95% confidence interval [CI], 0.30 to 0.62; P<0.001) n=2,359 n=2,326 1. Lundgren D, et al. IAS 2015. Vancouver, CAN. Oral # MOSY03; 2. Lundgren D, et al. NEJM 2015 Published Epub ahead of print July 20, 2015 DOI: 10.1056/NEJMoa1506816

START: AIDS vs non-aids related events Kaplan Meier estimates of the cumulative percentage of patients with a composite primary endpoint Serious AIDS-related events HR 0.28 (95% CI, 0.15 to 0.50; P<0.001) Serious non-aids-related events HR 0.61 (95% CI, 0.38 to 0.97; P=0.04) INSIGHT START Study Group. NEJM 2015;373:795 807

When to start IAS-USA 1 DHHS 2 WHO 3 EACS 4 BHIVA 5 ART is recommended for treatment of HIV infection and prevention of transmission of HIV regardless of CD4 cell count (AIa-BIII) ART recommended for all regardless of pretreatment CD4. Strength of recommendation A1 (strong recommendation based on RCT) for all Start ART in all regardless of WHO clinical stage or CD4. Prioritise severe/advance clinical disease (WHO stage 3 or 4) and adults with CD4 350 ART should always be recommended irrespective of the CD4 count. Strong recommendation if CDC B or C (including TB) or CD4 <350 All people living with HIV should start ART 1. Günthard et al, JAMA, 2014; 2. http://aidsinfo.nih.gov/guidelines 09/05/2016; 3. http://apps.who.int/iris/bitstream/10665/186275/1/9789241509565_eng.pdf 09/05/2016; 4. http://www.eacsociety.org/files/2015_eacsguidelines_8_0-english_rev-20160124.pdf 09/05/2016; 5. http://www.bhiva.org/hiv-1-treatment-guidelines.aspx 09/05/2016.

START: sub-studies & subgroups Sub-studies: Liver: annual fibroscan data pending Cardiovascular: no difference in arterial elasticity Pulmonary: no difference in impact on lung function Neurocognitive: no difference in rates of NCI Bone: more hip/spine bone loss in immediate arm Subgroups (IAS 2016): Benefit of immediate ART attenuated/negated if: age <50, CD4 >800, CD4:CD8 ration >0.8, Framingham <1% and, particularly, VL <3000,

Treatment as prevention: serodifferent couples HPTN 052 96% reduced transmissions initially 93% reduction in final analysis: 8 transmissions in ART arm 4 virological failures 4 prior to suppressions PARTNER 16,400 CLSA in MSM and 28,000 CLSA in heterosexuals = ZERO transmissions (estimated 86 if HIV+ partner not on suppressive ART) 1. Cohen MS et al. N Engl J Med. 2011; 2.Cohen MS et al. IAS 2015 MOAC0106LB; 3. Eshleman SH et al. IAS 2015 MOAC0106LB; 4. Rodger A et al. CROI 2014. O153LB.

Final results 888 couples (340 MSM, 548 heterosexual) Couples had already been having CLSI for an average of 2 years before entering the study During study there were 58,213 condomless sex acts 20% of the reported anal sex was in heterosexuals ZERO TRANSMISSIONS FROM PRIMARY PARTNERS!! 11 transmissions from other partners Rodger A et al. JAMA. 2016 Jul 12;316(2):171-81. doi: 10.1001/jama.2016.5148.

Caveats Confidence intervals Narrower than at 2014 analysis Upper limit of 95% CI: 0.3% overall, 1% for anal sex in MSM where HIV+ partner insertive/top Higher estimated risk if +VL: 2.23% overall, 2.7% in MSM Author conclusion: We can fairly safely say that the chance of transmission from a virally suppressed HIV+ person during heterosexual sex is negligible However, we need to collect more data on gay men before saying this with the same degree of certainty Rodger A et al. JAMA. 2016 Jul 12;316(2):171-81. doi: 10.1001/jama.2016.5148.

Caveats from accompanying JAMA editorial People in stable relationships may not reflect all PLWH Consistent with findings from some PreP studies eg. PARTNERS PrEP vs VOICE & TDF-2 HIV+ participants had been on ART for average 7.5Y High self-reported adherence High levels STI screening + advice HIV- partners were still HIV- despite 2 years CLSI prior to study entry Daar E, Corado K. JAMA. 2016 Jul 12;316(2)

Test & Treat Examples of great success Africa USA London But.

ANRS 12249 First major study of test & treat approach KwaZulu-Natal where 30% are HIV+ (highest in SA) Cluster RCT Each cluster = geographical area of about 1000 residents 11 intervention clusters, 11 controls Intervention Whole population over age 16 in both groups offered home-based HIV testing every 6/12 Intervention clusters offered immediate ART, control according to national guidelines IAS 2016

Results 28,153 in study population, average age 30, 63% F 31% already living with HIV (34% of those on ART) 88% tested at least once If diagnosed HIV+ linkage poor: 28% had attended ART clinic by 3 months 36% by 6 months 47% by 12 months ALMOST IDENTICAL IN THE TWO GROUPS IAS 2016

ANRS 12249 TasP - Estimated cascade of care UNAIDS target TasP trial (1 st January 2016) Control Intervention IAS 2016 42

New HIV infections 2.21% per year (2.13% intervention clusters vs 2.27% controls) Further analyses required to explain lack of engagement in care Was the intervention sufficient? Community attitudes & stigma? IAS 2016

CONCLUSIONS

What we know People who are diagnosed, in care and on treatment do very well Our challenges are to improve diagnosis and improve prevention Treatment as prevention will reduce but not eliminate HIV transmission as long as PLWH remain undiagnosed Variable data regarding population impact of TasP

% UK MSM epidemic & limitations of TasP

100% 80% 60% 40% 20% 0% Global Estimates (2014-15) vs the Gap 36.9 million to reach 90-90-90 Targets Breakpoint 1: 13.4 million Undiagnosed Breakpoint 2: 14.9 million not treated 53% 19.8 million 41% 15.0 million 32%* 11.6* million HIV Positive People Diagnosed On ART Viral Suppression <1000 (ITT)* Ref: On ART = March 2015. How Aids Changed Everything. Fact Sheet. UNAIDS 2015. MDG 6: 15 YEARS, 15 LESSONS OF HOPE FROM THE AIDS RESPONSE July 2015. * Average viral suppression% Intention to Treat LMIC rate from a Systematic Review by McMahon J. et al. Viral suppression after 12 months of antiretroviral therapy in low-and middle-income countries: a systematic review." Bulletin of the World Health Organization 91.5 (2013): 377-385. Breakpoint 3: 15.3 million Not Virally Supressed

Test and Treat plus PrEP access since 2013 (estimate 15% HIV- MSM taking PrEP) Discussion of PrEP mandatory in public school 9 th grade classes Of 657 c/o PrEP no new diagnoses HIV (Kaiser P) New diagnoses HIV 2332 in 1992 vs 302 in 2014 Volk CID Nov 2015

Summary PrEP works ART works Combined approaches = SUCCESS

Thank you!? lwaters@nhs.net @drlaurajwaters