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Benefits of pre-exposure prophylaxis relative to drug resistance risk Robert Grant, Virginia Fonner, Michelle Rodolph, Teri Liegler, David Glidden, Rachel Baggaley Grant AIDS 2016, Durban #AIDS2016 | @AIDS_conference Background • Drug resistance could be a cause or a consequence of PrEP failure. • Starting FTC/TDF PrEP during acute HIV infection selects for FTC resistance.1 – Such FTC resistant infections are treatable; It is not known whether second line therapy is necessary. • Resistance to TDF occurs in 22 to 60% of first line treatment failures.2 – However, the majority of transmission occurs from undiagnosed and untreated persons.3 • Oral PrEP containing TDF has partial activity against resistant virus challenge in animals.4 – At least one case of PrEP failure has occurred with a HIV-1 strain resistant to both FTC and TDF.5 • Resistant infections during PrEP should be weighed against the numbers of infections averted, each of which will require life-long therapy with the attendant risk of virological treatment failure with resistance. 1. Grant NEJM 2010; Beaten NEJM 2012; Thigpen NEJM 2012; 2. TENRES Study Group, Lancet Inf. Dis. 2016; 3. Skarbinski JAMA Intern Med. 2015; Ratmann Science Transl. Med. 2016 4. Von Rompay J. Virol. 2000; Cong J. Virol. 2011; Cong Clin. Inf. Dis. 2013; 5. Knox CROI, Boston 2016 Grant AIDS 2016, Durban Methods • This is a systematic review of published resistance testing results from seroconverters in randomized placebocontrolled PrEP trials through May 2015. – All trials reported data from clinical genotyping assays. – 4 trials (iPrEx, TDF2, Partners PrEP, FEMPREP) reported data from sensitive genotypic assays capable of detecting resistant viral variants present in low abundance (>1%). – Trials used 2nd and 3rd generation antibody assays to screen for HIV infection before and during PrEP. • A clinical screen for acute infection was performed in one study (iPrEx OLE) – its performance was reviewed. Grant AIDS 2016, Durban Clinical Genotypic Drug Resistance (to TDF or FTC) in PrEP Trials Overall risk of FTC or tenofovir resistance is 5/9222 (0.05%); The Number Needed to Harm: NNH = 1844; The Number Needed to Prevent 1 HIV infection: NNT = 13 to 60. Fonner AIDS 2016. Grant AIDS 2016, Durban Clinical Genotypic Drug Resistance in Oral TDF vs. Placebo Comparisons Study Partners PrEP VOICE BKK Total % (95% CI) • • • • Infected at Entry Incident Infection Study Study Drug Placebo Drug Placebo Resist/Tot Resist/Tot Resist/Tot Resist/Tot 1/5 0/6 0/15 0/51 0/5 0/0 1/10 10% 0/1 0/2 0/9 - 0/58 0/17 0/90 - 0/60 0/33 0/144 - (0 to 2%) (0 to 1%) ( 2 to 40%) (0 to 18%) 1 case of TDF resistant infection, 53 infections averted by TDF PrEP = (144+9)-(90+10), 53 HIV infections averted and 1 TDF resistant infection Excluding acute infections when PrEP was started: 54 infections averted and no resistance Grant AIDS 2016, Durban Clinical Genotypic Drug Resistance in Oral FTC/TDF vs. Placebo Comparisons Study iPrEx Partners PrEP TDF2 FEM-PrEP VOICE Total % (95% CI) • • • • Infected at Entry Incident Infection Study Study Drug Placebo Drug Placebo Resist/Tot Resist/Tot Resist/Tot Resist/Tot 2/2 1/8 0/48 0/83 1/3 0/6 0/13 0/52 1/1 0/1 2/9 6/16 37.5% 0/2 0/9 0/24 0/1 4/33 1/35 0/1 1/61 0/60 1/18 5/164 1/254 5% 3% 0.3% (18 to 61%) (1 to 26%) (1 to 7%) (.06 to 2%) 9 excess DR infections: 11 active, 2 placebo 92 infections averted by FTC/TDF PrEP = (254+18)-(164+16) 8 (92/9) infections averted per DR infection overall Excluding acute infections when PrEP was started: 22 (90/4) infections averted per DR infection. Grant AIDS 2016, Durban Clinical (+Low Abundance) Drug Resistance in Oral FTC/TDF vs. Placebo Comparisons Study iPrEx 2/2 Incident Infection Study Drug Placebo Resist/Tot Resist/Tot 1/8 0(+2)/48 0(+2)/83 Partners PrEP 1(+1)/3 0/6 0(+3)/13 0(+2)/52 TDF2 1/1 0/2 0/9 0(+1)/24 FEM-PrEP 0/1 0/1 4(+1)/33 1(+3)/35 5/7 71% 1/17 5% 10/103 10% 9/194 5% Total % • • • • Infected at Entry Study Drug Placebo Resist/Tot Resist/Tot 5 excess DR infections: 15 active, 10 placebo 101 infections averted: (194+17)-(103+7) 20 (101/5) infections averted per DR infection overall Excluding acute infections when PrEP was started: 91 (91/1) incident infections averted per DR infection. Grant AIDS 2016, Durban Liegler JID 2014; Lehrman JID 2015; Thigpen NEJM 2012; Grant AIDS 2015 Possible Ways to Screen for Acute Infection in PrEP Programs • When Starting or Restarting PrEP – Symptoms of acute viral syndrome – HIV Ag assays – HIV nucleic acid testing Grant AIDS 2016, Durban Clinical Screening for Acute Viral Syndromes and Acute HIV infection in iPrEx OLE Eligible for PrEP N=1603 No Sx Sx Deferred PrEP due to Acute Viral Syndrome N=30 (1.9%) Acute HIV infections N=2 (6.7%) HIV RNA negative N=28 (93.3%) Delayed Start on PrEP N=25 (83.3%) Grant et al, Lancet ID, 2014. Grant AIDS 2016, Durban No HIV Acute HIV 1573 0 1573 28 2 30 1601 2 1603 Sensitivity = 100% Specificity = 98% PPV = 6.7% NPV = 100% Never started PrEP N=3 (6.7%) Conclusions • Drug resistance risk during PrEP use has been low, – Mostly when starting PrEP during acute HIV infection, – Almost all resistance is to FTC alone, – Occurs more frequently using FTC/TDF vs. TDF alone. • Symptom screens in iPrEx OLE. – Good sensitivity, – Low PPV given the low prevalence of acute HIV infection, – Require clinical training and judgment, – Delayed PrEP initiation for 2% of the cohort. • FTC/TDF PrEP prevented at least 8 infections for every FTC resistant infection that occurred overall. – Screening for acute infection would increase benefits relative to drug resistance risks, by more than 2 fold. – Yet such screens are not feasible in all settings, and are not required to achieve a favorable risk/benefit for PrEP. Grant AIDS 2016, Durban PrEP was made possible by mostly young study participants who believed that research could improve their lives Grant AIDS 2016, Durban #AIDS2016 | @AIDS_conference