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

2. 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

3. 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.

4. 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.

5. 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

6. 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.

7. 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

8. 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

9. 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.

10. 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.

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

12. Grant and Smith OFID 2015

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