ART rapid scale up: the implications for patient care and retention Dr Francesca Conradie Southern African HIV Clinicians Society
Agenda Why do we need rapid scale up? Is there enough evidence for rapid treatment? Issues of the rapid scale up of ART Advanced disease Early disease ART: antiretroviral therapy
Why do we need rapid scale up? Critical for ending the AIDS epidemic Making HIV transmissions rare
Ending the AIDS epidemic 75 70 Trends in life expectancy during the AIDS epidemic World Zimbabwe Years 65 60 55 50 45 40 1960 1962 1964 1966 1968 1970 1972 1974 1976 1978 1980 1982 1984 1986 1988 1990 1992 1994 1996 1998 2000 2002 2004 2006 2008 2010 2012 Uganda Kenya Swaziland South Africa Botswana Sub Saharan Africa Source: The World Bank life expectancy data. http://data.worldbank.org/indicator /SP.DYN.LE00.IN. Accessed 15 September 2014
Making HIV transmissions rare Efficacy of available bio medical prevention interventions derived from randomised clinical trials Immediate antiretroviral therapy for HIV positive partner Medical male circumcision HTPN 052 2011 n=1763 ANRS1265 2005 n=3274 32 Rakai 2007 n=4996 51 3216 Kisumu 2007 n=2784 22 53 60 96 73 99 72 72 76 Modified from Marrazzo JM, et al. JAMA. 2014;312:390 409
Is there enough evidence for rapid treatment? (1) Old paradigm Pre test counselling Post test counselling Adherence counselling Treatment buddy Two weekly LFTS (NVP) 6 monthly CD4+, VL, LFTs, U&E, FBC Monthly drug pick ups
Is there enough evidence for rapid treatment? (1) Old paradigm Pre test counselling Post test counselling Adherence counselling Treatment buddy Two weekly LFTS (NVP) 6 monthly CD4+, VL, LFTs, U&E, FBC Monthly drug pick ups Restricted access to the physically well and perhaps unemployed
Stages of pre ART care HIV+ diagnosed population CD4 count sample provided CD4 count sample not provided Stage 1 CD4 results obtained (staged) CD4 results not obtained (not staged) Not yet ART eligible Stage 2 ART eligible Enroled in pre ART care Lost before enroling in pre ART care Pre treatment steps completed Lost before completing pre treatment steps Pre ART care until ART eligible Lost before ART eligible Stage 3 Initiate ART Lost before ART initiation Rosen S. and Fox MP. PLoS Med. 2011;8:e1001056
Is there enough evidence for rapid treatment? (2) Rethinking the Pre in Pre Therapy Counselling: No Benefit of Additional Visits Prior to Therapy on Adherence or Viremia in Ugandans Initiating ARVs Siedner MJ, et al. PLoS One. 2012;7:e39894
Univariable and multivariable models for association between completion of pre therapy adherence counseling and measures of medication adherence and persistent viremia during the first three months of ARVs in a cohort of HIV positive patients in rural Uganda Adherence measure Univariable analyses Measure of associa on 95% CI Multivariable analyses* Measure of associa on 95% CI Average adherence >90% OR = 0.69 0.37 1.31 AOR = 0.78 0.40 1.54 Absence of treatment gaps >72 hours OR = 0.59 0.22 1.60 AOR = 0.67 0.23 1.91 Persistent Viremia >400 copies/ml OR = 1.01 0.39 2.66 AOR = 1.13 0.41 3.12 OR: odds ra o for odds of outcome if completed pre ARV counselling vs no pre therapy counselling. AOR: adjusted odds ratio for odds of outcome if completed pre therapy counselling vs no pre therapy counselling. *Multivariable analysis adjusted for age, sex, time travel to from clinic, asset index quartile, baseline CD4 count, year of ARV initiation and history of opportunistic infection. Doi:10.1371/journal.pone.0039894.t002 Siedner MJ, et al. PLoS One. 2012;7:e39894
Standard initiation of treatment and rapid initiation procedures and visit schedule HIV positive patient Screening Consult and enrolment Randomisation STANDARD INITIATION PROCEDURES VISIT 1: Take blood sample for CD4 count; perform TB symptom screen; take sputum sample if needed VISIT 2: Provide CD4 count results; provide TB test results; initiate TB treatment if required VISIT 3: Provide group counselling (education/adherence) VISIT 4: Provide individual counselling (education/adherence) VISIT 5: Provide results of other blood tests; conduct physical exam; confirm treatment buddy VISIT 6: Dispense ARVs RAPID INITIATION PROCEDURES VISIT 1: Take blood sample for CD4 count and perform rapid CD4 count Perform TB symptom screen; take sputum sample if symptomatic and perform rapid TB test; initiate TB treatment if required (ART initiation delayed if TB treatment initiated); Perform other blood tests (rapid) Conduct physical exam (ART initiation delayed if referred off site for specific conditions) Conduct education/adherence session Conduct individual counselling session Dispense ARVs Follow up through medical record review Rosen S, et al. PLoS Med. 2016;13:e1002015
Study enrollment and randomisation 43 resided or intended to seek treatment elsewhere 9 did not speak a study language 16 had high or previous eligible CD4 count or were on ART 3 pregnant 24 physically unable 12 emotionally unable 2 other 603 screened for eligibility 109 excluded 463 randomised 31 declined to participate 18 in a hurry/no time to participate in study 6 refused/not interested in study 5 preferred routine clinic procedures 2 not willing to take ARVs 2 previously received eligible CD4 count result 229 standard initiation 234 rapid initiation 190 eligible for ART initiation and study procedures Rosen S, et al. PLoS Med. 2016;13:e1002015 2 excluded after randomisation 37 not eligible for ART 10 excluded after randomisation 37 not eligible for ART 4 previously received eligible CD4 count result 3 pregnant 2 medical complications 1 withdrew 187 eligible for ART initiation and study procedures
Baseline characteristics of study sample (n=463) Variable Standard arm Rapid arm n (randomised participants) 229 234 Enrolment site (n) Site 1 (primary health clinic) Site 2 (hospital based HIV clinic) 124 105 Age (median, IQR) 35.8 (29.5 41.6) 126 108 34.2 (29.0 40.1) Sex (% female) 132 (58%) 129 (55%) CD4 count (cells/mm 3 ) (median, IQR) 195 (103 322) Purpose of clinic visit (%) Have HIV test (diagnosed today) Provide blood sample for CD4 count Receive first CD4 count results Other Reason for treatment eligibility (%) CD4 count below threshold Clinical condition Stage 3 or 4 Excluded (not eligible for Tx or study) 100 (44%) 8 (4%) 109 (47%) 11 (5%) 182 (79%) 3 (1%) 44 (20%) 224 (128 327) 90 (38%) 10 (4%) 112 (48%) 22 (10%) 183 (78%) 4 (2%) 47 (20%) Variable Household composition Live alone (% yes) # other persons in house (median, IQR) Household type (%) Formal house or flat Informal dwelling or shack Travel time to clinic (minutes) (median, IQR) Employment status (%) Employed formally Work informally Unemployed, seeking work Unemployed, not seeking work Marital status (%) Married or long term partner Single, no long term partner Other (widowed, divorced) Standard arm 36 (16%) 2 (1 4) 146 (63%) 83 (37%) Rapid arm 41 (18%) 2 (1 3) 165 (71%) 69 (29%) 18 (9 24) 15 (9 27) 68 (30%) 62 (27%) 91 (40%) 8 (3%) 173 (76%) 41 (18%) 15 (6%) 90 (38%) 54 (23%) 84 (36%) 6 (3%) 157 (67%) 57 (24%) 20 (9%) Rosen S, et al. PLoS Med. 2016;13:e1002015
Time to ART initiation, by study arm 1.00 % initiating treatment 0.75 0.50 0.25 Standard arm Rapid arm 0.00 0 50 100 150 200 Time to treatment initiation (days after study enrolment) Rosen S, et al. PLoS Med. 2016;13:e1002015
Other examples of rapid start Option B+
Issues of the rapid scale up of ART Advanced HIV For adults and adolescents, and children 5 years of age, advanced HIV disease is defined as CD4 count <200 cells/mm 3 or WHO clinical stage 3 and 4 at presentation All children with HIV <5 years old should be considered as having advanced disease at presentation Waldrop G, et al. Trop Med Int Health. 2016;21:1124 30
Is advanced disease still a problem? 25 30% of HIV positive individuals starting ART in low and middleincome settings have a CD4 cell count below 200 cells/mm 3 10 20% have a CD4 cell count below 100 cells/mm 3
Clinical screening for advanced disease A seriously sick adult patient is defined as having Respiratory rate >30/min Temperature >39 o C Heart rate >120 bpm Unable to walk unaided
Challenges of advanced disease Tuberculosis (TB) Accounts for a third of the estimated 1.1 million HIV related deaths globally in 2015 Majority of these deaths (200,000) occurring among men Leading cause of HIV associated hospitalisation Severe bacterial infections Bloodstream Respiratory Brain Gastrointestinal infections Poorly characterised due to lack of diagnostics
Challenges of advanced disease Pneumocystis jirovecii causes mortality in: 13% hospitalised HIV+ adults 29% hospitalised HIV+ children Cryptococcal meningitis 1,000,000 cases annually 700,000 case in sub Saharan Africa 600,000 deaths 13% of deaths on hospitalised HIV patients
Recommended interventions for the advanced disease 1 Intervention CD4 Diagnosis and screening Xpert MTB/RIF as first test for TB diagnosis in symptomatic (pulmonary, meningitis and extrapulmonary) patients Any LF LAM for TB diagnosis with symptoms and signs of TB 2 100 cells/mm 3 Cryptococcal antigen (CrAg) screening <100 cells/mm 3 Prophylaxis and pre emptive treatment Cotrimoxazole prophylaxis <350 or stage 3 or 4 Fluconazole pre emptive therapy <100 cells/mm 3 1. WHO Guidelines, Sept 2016. Available at: http://apps.who.int/iris/bitstream/10665/208825/1/9789241549684_eng.pdf?ua=1. Accessed May 2017; 2. Peter JG et al. Lancet. 2016;387:1187 97
Issues of the rapid scale up of ART Asymptomatic HIV+ with a high CD4+ Diagnosed out of the clinic Self testing TEMPRANO and START HPTN 052
What do we need? Single day dose Low side effect No or little monitoring needed High barrier to resistance Safe in pregnancy and with TB treatment
Drug optimisation Science evolved: smarter and better HIV treatment options are now available Pre HAART Era (mono/dual therapy) HAART Era (triple therapy) Potency Toxicity AZT (1987) 2 tablets 3x day Potency Toxicity AZT/3TC + LPV/r (2001) 3tablets 2x day Potency Toxicity TDF/FTC/EFV (2006) 1 tablet once a day Zidovudine Zalcitabine Didanosine Etravirine Raltegravir Maraviroc Fosamprenavir Tipranavir Darunavir Emtricitabine Atazanavir Enfuvirtide Tenofovir Lopinavir/ritonavir Amprenavir Abacavir Efavirenz Delavirdine Nelfinavir Nevirapine Indinavir Ritonavir Saquinavir Lamivudine Stavudine Dolutegravir Elvitegravir 1985 1987 1989 1991 1993 1995 1997 1999 2001 2003 2005 2007 2009 2011 2013 UNAIDS 2012 12 Populations Slides. Available at: https://www.slideshare.net/unaids/gap report 12 populations slides. Accessed May 2017
In terms of first line therapy (TDF + XTC + EFV) Was 2013 just a brief harmonisation event? EFV now routinely substituted in developed world due to side effects (where TB is less of a problem) Increasing concern about CNS side effects (also lipids, hepatitis, rash, gynaecomastia) Raffi F, et al. J Antimicrob Chemother. 2014;69:1742 7
Tenofovir has taken over the world! First line recommendation by WHO; feature in every guideline (some have ABC) Well tolerated, FDCs galore, daily Cheap Hep B for free WHO Guidelines, Sept 2016. Available at: http://apps.who.int/iris/bitstream/10665/208825/1/9789241549684_eng.pdf?ua=1. Accessed May 2017
Tenofovir alafenamide Slightly better safety profile than TDF (at 10 or 25 mg versus 300 mg) Being tested as co formulations Preliminary results promising will it simply replace TDF? Less API, less toxicity Gallant JE, et al. Lancet HIV. 2016;3:e158 65; Wohl D, et al. J Acquir Immune Defic Syndr. 2016;72:58 64
Efavirenz Daily, cheap, co formulated, huge experience base, TB (and mostly everything else) friendly EFV side effects predictable, treatable, substitutions easy Everyone pretty happy regarding teratogenicity
But Increasing recognition of CNS side effect Africans stoic Asymptomatic Rash, hepatitis, gynaecomastia, lipids ENCORE (Lancet 2013) 400 mg versus 600 mg less discontinuations, but very little change in side effects Concerns about 400 mg dose in PMTCT and TB ENCORE1 Study Group. Lancet. 2014;383:1474 82
Depression Efavirenz (6%) 2x higher risk for suicidality Rilpivirine (8%) Elvitegravir/COBI (5%) Raltegravir (6%) Atazanavir/r (2%) Cumulative incidence 0.10 0.08 0.06 0.04 0.02 0.00 Meta analysis n=5332, 4 RCT Comorbidities Gray P=0.005 For composite endpoint Only trend for completed/attempted suicide (17 events occured) EFV EFV free 0 48 96 144 192 Weeks to suicidality Lack of association between use of efavirenz and death from suicide: evidence from the D:A:D study Cohen CJ, et al. Lancet. 2011;378:229 37; Molina JM, et al. Lancet. 2011;378:238 46; Elion R, et al. J Acquir Immune Defic Syndr. 2013;63:494 7; Mollan KR, et al. Ann Intern Med. 2014;161:1 10; Smith C, et al. J Int AIDS Soc. 2014;17(4 Suppl 3):19512 (#O315)
What about: Dolutegravir Integrase inhibitor 50 mg once daily (in naïve patients) Very good efficacy Minimal toxicity Pregnancy category B Superior to EFV at 48 weeks in naïve patients SINGLE study (compared ABC/3TC/DTG with TDF/FTC/EFV) but safer, not virologically better Potential to be low cost and co formulated Walmsley SL, et al. N Engl J Med. 2013;369:1807 18 FDA press statement. August 2013
Persistence of initial ART Proportion virologically suppressed 1,0 0,9 0,8 0,7 0,6 0,5 0,4 0,3 0,2 0,1 Time on initial ART, UCHCC 1996 2014 Initial ART INSTI (N=175) NNRTI (N=547) bpi (N=340): LPV/r, DRV/r, ATV/r Other (N=459): incl. unboosted and other bpi NRTI only (N=252) P<0.001 0,0 0 12 24 36 48 60 72 84 96 108 120 Time from ART initiation (months) In CNICS cohort integrase inhibitor use was strongly associated with HIV RNA suppression Simoni et al. Southern African HIV Clinicians Society Conference, 2016. #1034
Conclusions We have not really made a dent in late presentation of HIV infection There are risks with late presentation We need a very well tolerated option for initiation of well patients We need new strategies for hard to reach populations