Benefits of pre-exposure prophylaxis relative to drug resistance risk Robert Grant, Virginia Fonner, Michelle Rodolph, Teri Liegler, David Glidden, Rachel Baggaley

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

Methods This is a systematic review of published resistance testing results from seroconverters in randomized placebo-controlled 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.

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.

Clinical Genotypic Drug Resistance in Oral TDF vs. Placebo Comparisons Infected at Entry Incident Infection Study Drug Placebo Study Resist/Tot Partners PrEP 1/5 0/6 0/15 0/51 VOICE 0/5 0/1 0/58 0/60 BKK 0/0 0/2 0/17 0/33 Total % (95% CI) 1/10 10% ( 2 to 40%) 0/9 - (0 to 18%) 0/90 (0 to 2%) 0/144 (0 to 1%) “PrEP Paradox” 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

Clinical Genotypic Drug Resistance in Oral FTC/TDF vs Clinical Genotypic Drug Resistance in Oral FTC/TDF vs. Placebo Comparisons Infected at Entry Incident Infection Study Drug Placebo Study Resist/Tot iPrEx 2/2 1/8 0/48 0/83 Partners PrEP 1/3 0/6 0/13 0/52 TDF2 1/1 0/2 0/9 0/24 FEM-PrEP 0/1 4/33 1/35 VOICE 2/9 1/61 0/60 Total % (95% CI) 6/16 37.5% (18 to 61%) 1/18 5% (1 to 26%) 5/164 3% (1 to 7%) 1/254 0.3% (.06 to 2%) FTC/TDF PrEP averted 98 infections in the trials (270 infections in the placebo arms and 172 in the active arms).  In these same studies, there occurred 11 infections with mutations associated with resistance to TDF, FTC, or both in the active arm, and 2 infections with drug resistance in the placebo arm, yielding an excess of 8 drug resistant infections.  Hence, there were 12 new infections averted for every drug resistant infection associated with FTC/TDF PrEP (98/8 = 12) 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.

Clinical (+Low Abundance) Drug Resistance in Oral FTC/TDF vs Clinical (+Low Abundance) Drug Resistance in Oral FTC/TDF vs. Placebo Comparisons Infected at Entry Incident Infection Study Drug Placebo Study Resist/Tot iPrEx 2/2 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 4(+1)/33 1(+3)/35 Total % 5/7 71% 1/17 5% 10/103 10% 9/194 FTC/TDF PrEP averted 98 infections in the trials (270 infections in the placebo arms and 172 in the active arms).  In these same studies, there occurred 11 infections with mutations associated with resistance to TDF, FTC, or both in the active arm, and 2 infections with drug resistance in the placebo arm, yielding an excess of 8 drug resistant infections.  Hence, there were 12 new infections averted for every drug resistant infection associated with FTC/TDF PrEP (98/8 = 12) 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. 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

Clinical Screening for Acute Viral Syndromes and Acute HIV infection in iPrEx OLE No HIV Acute HIV No Sx 1573 Sx 28 2 30 1601 1603 Eligible for PrEP N=1603 Deferred PrEP due to Acute Viral Syndrome N=30 (1.9%) Sensitivity = 100% Specificity = 98% PPV = 6.7% NPV = 100% Acute HIV infections N=2 (6.7%) HIV RNA negative N=28 (93.3%) Delayed Start on PrEP N=25 (83.3%) Never started PrEP N=3 (6.7%) Grant et al, Lancet ID, 2014.

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.

PrEP was made possible study participants who believed that research by mostly young study participants who believed that research could improve their lives

Grant and Smith OFID 2015

Regions hosting PrEP trials between 2008-14 finding: Active arm serconverters with 3% M184V and no K65R/K70E. TenoRES group, Lancet Inf. Dis. 2016