Transcript Slides - View the full AIDS 2016 programme

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