THIRD JOINT CONFERENCE OF BHIVA AND BASHH Dr Laura Waters. Mortimer Market Centre, London. 1-4 April 2014, Arena and Convention Centre Liverpool

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2 THIRD JOINT CONFERENCE OF BHIVA AND BASHH 2014 Dr Laura Waters Mortimer Market Centre, London 1-4 April 2014, Arena and Convention Centre Liverpool

3 THIRD JOINT CONFERENCE OF BHIVA AND BASHH 2014 Dr Laura Waters Mortimer Market Centre, London COMPETING INTEREST OF FINANCIAL VALUE > 1,000: Speaker Name Statement Dr Laura Waters Date April April 2014, Arena and Convention Centre Liverpool

4 Translating HIV research into clinical practice Laura Waters Consultant GU/HIV Medicine Mortimer Market Centre, CNWL

5 Three themes When What How For each theme Review of recent abstract/paper How this translates to our clinical practice

6 WHEN

7 Major ART Guidelines Guideline AIDS or HIV-Related Symptoms CD4+ Cell Count CD4+ Cell Count < 200/mm /mm 3 CD4+ Cell Count /mm 3 CD4+ Cell Count > 500 cells/mm 3 DHHS-USA, 2013 Yes Yes Yes Yes 1 Yes 2 International AIDS Society-USA, 2012 British HIV Association, 2012 European AIDS Clinical Society, 2012 World Health Organization, 2013 Yes Yes Yes Yes 1 Yes 2 Yes Yes Yes Consider 3 Defer 3 Yes Yes Yes Consider 3 Defer 3 Yes Yes Yes Yes 4 Defer 5 (1) Strong strength recommendation based on observational data (A-II) (2) Moderate strength recommendation based on expert opinion (B-III). (3 ) But treat all HIV+ pregnant women, HBV co-infection, HCV co-infection, HIVAN, HIV related neurocognitive disorders, ITP, non-aids cancers and serodiscordant couples (4) Individuals with CD4 < 350 as a priority. (5) But treat all HIV+ pregnant women,tb co-infection with active disease and HBV co-infection with severe liver disease, and serodiscordant copuls

8 Major ART Guidelines Guideline AIDS or HIV-Related Symptoms CD4+ Cell Count CD4+ Cell Count < 200/mm /mm 3 CD4+ Cell Count /mm 3 CD4+ Cell Count > 500 cells/mm 3 DHHS-USA, 2013 Yes Yes Yes Yes 1 Yes 2 International AIDS Society-USA, 2012 British HIV Association, 2012 European AIDS Clinical Society, 2012 World Health Organization, 2013 Yes Yes Yes Yes 1 Yes 2 Yes Yes Yes Consider 3 Defer 3 Yes Yes Yes Consider 3 Defer 3 Yes Yes Yes Yes 4 Defer 5 (1) Strong strength recommendation based on observational data (A-II) (2) Moderate strength recommendation based on expert opinion (B-III). (3 ) But treat all HIV+ pregnant women, HBV co-infection, HCV co-infection, HIVAN, HIV related neurocognitive disorders, ITP, non-aids cancers and serodiscordant couples (4) Individuals with CD4 < 350 as a priority. (5) But treat all HIV+ pregnant women,tb co-infection with active disease and HBV co-infection with severe liver disease, and serodiscordant copuls

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10 HPTN 052 Prevention of HIV-1 Infection with Early Antiretroviral Therapy 10 Multicenter, international, randomized, NIH-funded Phase III study HIV serodiscordant adult couples ART-naïve, HIV-infected partner CD4 between N=1,763 couples HIV infected partner: 50% male Early Arm (n=886) Start ART when CD4 between Delayed Arm (n=877) Start ART when CD4 250 or AIDS diagnosis Primary Clinical Endpoint (in HIV-positive partner) Clinical Event: Pulmonary tuberculosis, severe bacterial infection, a World Health Organization stage 4 event, or death Primary Prevention Endpoint (in HIV-negative partner) Linked HIV transmission to HIV-1 negative partners DSMB recommended study be stopped early on 28 th April 2011 Adapted from Cohen MS, et al. N Engl J Med 2011; Cohen M, et al. IAS 2011; Rome. Oral #MOSY0302 Grinsztejn B, et al. IAS 2011; Rome. Oral #MOSY0305 HPTN Study 052 Fact Sheet. Available at: Accessed 04 August 2011

11 HPTN 052 Prevention of HIV-1 Infection with Early Antiretroviral Therapy 11 Multicenter, international, randomized, NIH-funded Phase III study HIV serodiscordant adult couples ART-naïve, HIV-infected partner CD4 between N=1,763 couples HIV infected partner: 50% male Early Arm (n=886) Start ART when CD4 between Primary Clinical Endpoint (in HIV-positive partner) Clinical Event: Pulmonary tuberculosis, severe bacterial infection, a World Health Organization stage 4 event, or death Primary Prevention Endpoint (in HIV-negative partner) Linked HIV transmission to HIV-1 negative partners Delayed Arm (n=877) Start ART when CD4 250 or AIDS diagnosis DSMB recommended study be stopped early on 28 th April 2011 Adapted from Cohen MS, et al. N Engl J Med 2011; Cohen M, et al. IAS 2011; Rome. Oral #MOSY0302 Grinsztejn B, et al. IAS 2011; Rome. Oral #MOSY0305 HPTN Study 052 Fact Sheet. Available at: Accessed 04 August 2011

12 Primary clinical outcomes Death New-onset WHO stage 4 HIV-1 disease Tuberculosis Severe bacterial infections Serious cardiovascular or vascular events Serious liver disease End-stage renal disease New-onset diabetes mellitus Non-AIDS defining malignant diseases

13 Study sites Botswana (one site) Brazil (two sites) India (two sites) Kenya (one site) Malawi (two sites) South Africa (two sites) Thailand (one site) Zimbabwe (one site) 15-16% South America 30% Africa 54-55% Asia

14 Median CD4 count Deferred ART arm Baseline 428 (IQR ( ) At start ART 230 (IQR ) Immediate ART arm 442 (IQR ) - Results page 4 of 4

15 PRIMARY OUTCOMES Early Delayed HR p value Any serious clinical event 57 (6%) 77 (9%) 0 73 ( ) Any AIDS event 40 (5%) 61 (7%) 0 64 ( ) TB 17 (2%) 34 (4%) 0 49 ( Severe bacterial infection 20 (2%) 13 (1%) Any WHO stage 4 9 (1%) 19 (2%) Chronic HSV 2 8 Oesophageal candidosis 2 2 Recurrent severe BP 2 1 Invasive CaCX 0 2 Wasting due to HIV KS 1 1 Recurrent septicaemia 2 0 Extrapulmonary crypto 1 0 HIV-1 related encephalopathy 0 1 PCP 0 1 PCNSL 0 1

16 including WHO stage 4, TB & severe bacterial infections PRIMARY OUTCOMES Early Delayed HR p value Any serious clinical event 57 (6%) 77 (9%) 0 73 ( ) Any AIDS event 40 (5%) 61 (7%) 0 64 ( ) TB 17 (2%) 34 (4%) 0 49 ( Severe bacterial infection 20 (2%) 13 (1%) Any WHO stage 4 9 (1%) 19 (2%) Chronic HSV 2 8 Oesophageal candidosis 2 2 Recurrent severe BP 2 1 Invasive CaCX 0 2 Wasting due to HIV KS 1 1 Recurrent septicaemia 2 0 Extrapulmonary crypto 1 0 HIV-1 related encephalopathy 0 1 PCP 0 1 PCNSL 0 1

17 PRIMARY OUTCOMES Early Delayed HR p value Any serious clinical event 57 (6%) 77 (9%) 0 73 ( ) TB: Any AIDS event 40 (5%) 61 (7%) 0 64 ( ) E-ART 17 (2%) D-ART 34 (4%) HR 0.49 P=0.018 TB 17 (2%) 34 (4%) 0 49 ( Severe bacterial infection 20 (2%) 13 (1%) Any WHO stage 4 9 (1%) 19 (2%) Chronic HSV 2 8 Oesophageal candidosis 2 2 Recurrent severe BP 2 1 Invasive CaCX 0 2 Wasting due to HIV KS 1 1 Recurrent septicaemia 2 0 Extrapulmonary crypto 1 0 HIV-1 related encephalopathy 0 1 PCP 0 1 PCNSL 0 1

18 SECONDARY EVENTS Early Delayed HR p value Non-AIDS events 12 (1%) 9 (1%) 1 35 ( ) 0.50 DM 4 5 nadm 3 3 Serious CVD 3 1 Serious liver disease 2 0 ESRD 0 0 MORTALITY Early Delayed HR p value All deaths 11 (11%) 15 (2%) 0 73 ( ) 0.43 Deaths associated with a primary event 1 4 Deaths from other causes 10 11

19 Conclusions Early ART (initiation at a CD4 count of ) can be expected to delay the time to ADI, TB. vs where ART delayed until CD4 <250 Absolute differences were modest Our results, combined with the striking reduction in risk of.transmission., provide strong support for early initiation of antiretroviral treatment.

20 Should our practice change? No! BHIVA 2013: updated text The BHIVA treatment guidelines were developed primarily with patients from the UK in mind. In other settings, where there are particularly high TB rates, constraints on delivery of care, and high losses through the care and treatment cascade, earlier ART initiation may be more important to increase retention of patients in care after diagnosis

21 Key messages Research setting is key to how applicable it is to our practice Have faith in BHIVA guidelines!

22 WHAT

23 WHAT - HCV

24 CROI Oral abstract 1493 Faldaprevir Plus Pegylated Interferon α-2a/ribavirin in HIV/HCV Co-infection: STARTVerso4 Douglas Dieterich 1, Cristina Tural 2, Mark Nelson 3, Keikawus Arastéh 4, Vicente Soriano 5, Josep Guardiola 6, Sanjay Bhagani 7, Jürgen K Rockstroh 8, Jerry O Stern 9, Anne-Marie Quinson 9, on behalf of the STARTVerso4 Study Group 1 Mount Sinai Medical Center, New York, NY, USA; 2 Hospital Universitari Germans Trias i Pujol, Barcelona, Spain; 3 Chelsea and Westminster Hospital, London, UK; 4 EPIMED / Vivantes Auguste- Viktoria-Klinikum, Berlin, Germany; 5 Hospital Carlos III, Madrid, Spain; 6 Hospital de la Santa Creu i Sant Pau, Barcelona, Spain; 7 The Royal Free Hospital, London, UK; 8 University of Bonn, Bonn, Germany; 9 Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, CT, USA

25 Study design: open-label phase 3 study in HCV GT1/HIV co-infected patients ARM A (N=123) a FDV 120 mg QD + PR 24 weeks ETS: NO ETS: YES PR 24 weeks STOP TREATMENT ARM B (N=187) a FDV 240 mg QD + PR 12 weeks FDV 240 mg QD + PR, 12 weeks PR, 12 weeks ETS: NO ETS: YES PR 24 weeks STOP TREATMENT Day 1 Wk 12 Wk 12 Wk 24 Wk 24 Wk 48 FDV dose: randomization (1:1) or allocation according to ART Re-randomization (1:1) ETS: HCV RNA <25 IU/mL at Week 4 and undetectable at Week 8 Primary endpoint: SVR12 a Number randomized/allocated. ART, antiretroviral therapy; ETS, early treatment success; FDV, faldaprevir; PR, pegylated interferon α-2a and ribavirin; QD, once daily; SVR12, sustained virologic response (HCV RNA <25 IU/mL, not detected) 12 weeks after the planned end of treatment.

26 Proportion of patients with SVR12 (%) SVR12: overall population 87/ / /308

27 Proportion of patients with SVR12 (%) SVR12 by cirrhosis, genotype & Q80K 100 p=0.807 a p=0.408 b /261 33/45 Cirrhosis c 0 171/242 GT-1a 50/66 GT-1b 173/244 48/64 Baseline Q80K a Adjusted for treatment dose and genotype. b Adjusted for treatment dose only. c Cirrhosis was determined by the investigator based on fibroscan, biopsy, and/or other clinical parameters.

28 Eligibility Exclusion criteria: Decompensated liver disease, as evidenced by ascites, hepatic encephalopathy, esophageal variceal bleeding, and/or laboratory values that add up to >/= 7 points according to the Child-Turcotte-Pugh classification

29 Availability Europe Sobusbuvir LICENSED Faldaprevir NOT LICENSED YET Simeprevir NOT LICENSED YET

30 Priorities & key messages Sofosbuvir expanded access programme imminent Post-transplant & cirrhotic patients Networks crucial to ensure patients who need treatment urgently have the chance to access it HCV treatment outcomes in HIV+ are now essentially same as HIV-

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32 HOW How do we counsel our patients about HIV transmission? How do we use PI monotherapy

33 PARTNER Study: HIV transmission risk through condomless sex if the HIV positive partner is on suppressive ART Aim: To evaluate the risk of within-couple HIV transmission (HT and MSM) during periods where condoms are not used consistently & the HIV+ partner is on suppressive ART Rodger et al. CROI O153LB.

34 HIV negative partners: characteristics MSM couples (n=282) Heterosexual couples (n=445) M -ve (n=245) W-ve (n=240) At study entry Age, median (IQR) 40 (32-47) 45 (37-50) 40 (34-46) Yrs CL sex, median (IQR) 1.5 ( ) 2.7 ( ) 3.5 ( ) During follow up Years in study, median (IQR) 1.1 ( ) 1.5 ( ) 1.5 ( ) Diagnosed with STI, % 16% 5% 6% CL sex with other partners, % 34% 3% 4% CL sex acts/year, median (IQR) 43 (18-79) 37 (14-77) 38 (14-71) Estimated total no. CL sex acts 16,400 14,000 14,000

35 HIV positive partners: characteristics MSM couples (n=282) Heterosexual couples (n=445) M -ve (n=245) W-ve (n=240) At study entry Age, median (IQR) 42 (36-47) 40 (34-46) 45 (40-49) Years on ART, median (IQR) 5 (2-11) 7 (3-14) 10 (4-15) Self-reported adherence 90% 97% 94% 94% Self report undetectable VL, % 94% 86% 85% CD4>350 cells/mm 3, % 90% 88% 84% During follow up Having missed ART for more than 4 consecutive days, % 2% 7% 4% Diagnosed with STI, % 16% 4% 5%

36 Results No transmissions! Despite high levels of STI in HIV- MSM If HIV+ partner not on ART would have expected a median of 86 transmissions at this interim 2 year analysis

37 HIV transmission rate by sexual behaviour reported by the negative partner Rate of within couple transmission (per 100 CYFU) year risk (%) of within couple transmission Any sex (CYFU=894) Anal sex (CYFU=374) estimated rate/risk 95% confidence interval

38 Key points Upper limit of 95% CI for transmission risk: 2% a year for vaginal sex with ejaculation 2.5% for receptive anal sex 4% for receptive anal sex with ejaculation. Excluded from analysis if HIV+ partner developed a viral load >200 Adds to HPTN052 plus much needed data for MSM Ongoing FU and more MSM recruitment to provide more precise estimates

39 PI monotherapy LPV/r studies Monotherapy inferior as initial therapy Reasonable as induction-maintenance Longer suppression and better adherence predictors of good virological outcomes DRV/r studies MONET & MONOI More VF (mainly low-level) Minimal/no resistance (all re-suppressed with + NRTI)

40 Cost ( million) azzard B et al, BHIVA 2010 ; Poster 3 UK cost impact of DRV/r monotherapy Cost saving 61 million Before switching to DRV/rtv monotherapy After switching to DRV/rtv monotherapy

41 PIVOT Triple ART Triple ART & VL <50 for >6/12 * ** Primary endpoint = PI monotherapy (n=296) Loss of future drug options: Intermediate 1:1 to high level resistance (Stanford) to any standard ARV to which the patient s virus considered sensitive at trial entry Triple ART (n=291) 5 years FU *return to triple ART permanently if VL >50 x 3 or toxicity or patient choice **return to triple ART temporarily for pregnancy/breastfeeding or short-term DDI

42 Selected baseline characteristics Median age 44 years 23% female Baseline CD years on ART

43 Results Primary end-point (loss of future drug option by 36 months): Triple ART 0.7% vs PI mono 2.1% Difference 1.4% (-0.4 to 3.4%); p=0.15 Virological rebound (confirmed VL >50 x 3): Triple ART 3.2% vs PI mono 35% Difference 31.8% (24.6 to 39%); p<0.001

44 PI monotherapy + - vs transmission?

45 vs risk?

46 Acknowledgements Mark Nelson Ian Williams Brian Gazzard Alejandro Arenas-Pinto

47 Thank you?

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