Kevin L Ard MD MPH October 20 2016 Learning objectives Summarize the indications for and management of pre and postexposure prophylaxis Understand clinical uncertainties in preexposure prophylaxis management ID: 714694
Download Presentation The PPT/PDF document "Pre- and Post-Exposure Prophylaxis for H..." is the property of its rightful owner. Permission is granted to download and print the materials on this web site for personal, non-commercial use only, and to display it on your personal computer provided you do not modify the materials and that you retain all copyright notices contained in the materials. By downloading content from our website, you accept the terms of this agreement.
Slide1
Pre- and Post-Exposure Prophylaxis for HIV
Kevin L. Ard, MD, MPH
October 20, 2016Slide2
Learning objectives
Summarize the indications for and management of pre- and post-exposure prophylaxis
Understand clinical uncertainties in pre-exposure prophylaxis managementSlide3
Antiretroviral-based prevention
Post-exposure prophylaxis (PEP)
Pre-exposure prophylaxis (PrEP)
Treatment as prevention (TasP)Slide4
A case
A 22-year-old man presents approximately 32 hours after unprotected, receptive anal and oral sex with another man.
He does not know the HIV status of his partner, and the individual is not available for testing.
The patient has never had an HIV test.
He has no known chronic medical problems.Slide5
When is PEP indicated?
Recommended:
Sexual, other mucosal, or percutaneous exposure to infectious body fluids from a person living with HIV
Case-by-case determination:
Exposure as above, but the source individual’s HIV status is unknown
Not recommended:
Presentation more than 72 hours after exposure, negligible risk for HIV acquisition
Updated guidelines for antiretroviral
postexposure
prophylaxis after sexual, injection drug use, or other
nonoccupational
exposure to HIV – United States, 2016.
Available at: https://
stacks.cdc.gov
/view/
cdc
/
38856.Slide6
The evidence base for PEP is limited.
Animal studies
(Tsai, J Virol, 1998)
Earlier initiation is better than later
28 days is better than 3 or 10
Efficacy of tenofovir
Case-control study
(Cardo, N Engl J Med, 1997)
Population:
33 case patients, 665 controls with occupational, percutaneous exposure
Results:
Z
idovudine decreased risk of HIV infection by 81%Slide7
Baseline laboratory evaluation
HIV antibody/antigen
on the exposed and, if possible, source individuals
Serum
creatinine
, liver enzymes
Hepatitis B and C antibodies
on the exposed and, if possible, source individuals
Pregnancy testing,
if applicable
For sexual exposures, testing for
syphilis, gonorrhea, and chlamydia
Updated guidelines for antiretroviral
postexposure
prophylaxis after sexual, injection drug use, or other
nonoccupational
exposure to HIV – United States, 2016.
Available at: https://
stacks.cdc.gov
/view/
cdc
/
38856.Slide8
Prescribing PEP
Preferred
Tenofovir-emtricitabine
+
raltegravir
or
dolutegravir
for 28 days
Alternative
Tenofovir-emtricitabine
+
darunavir
+ ritonavir for 28 days
Updated guidelines for antiretroviral
postexposure
prophylaxis after sexual, injection drug use, or other nonoccupational exposure to HIV – United States, 2016. Available at: https://stacks.cdc.gov/view/cdc/38856.Slide9
Special circumstances may affect regimen choice.
Renal
dysfunction (creatinine clearance < 60)
Use dose-adjusted
zidovudine
and lamivudine instead of
tenofovir-emtricitabine
Source with drug-resistant HIV
Tailor the PEP regimen based on the source’s genotype
Updated guidelines for antiretroviral
postexposure
prophylaxis after sexual, injection drug use, or other
nonoccupational
exposure to HIV – United States, 2016. Available at: https://
stacks.cdc.gov
/view/cdc/38856.Slide10
Follow-up for the exposed person
4-6 weeks
12 weeks
24 weeks
HIV
Ab
/Ag
Syphilis
GC/chlamydia
Pregnancy
Creatinine
Liver enzymes
HIV
Ab
/Ag
HIV
Ab
/Ag*
HBV and HCV antibodies
*Only if HCV was contracted from the exposure
Updated guidelines for antiretroviral
postexposure
prophylaxis after sexual, injection drug use, or other
nonoccupational
exposure to HIV – United States, 2016. Available at: https://
stacks.cdc.gov
/view/
cdc
/38856.Slide11
Case, continued
The patient has negative baseline HIV testing and takes PEP with tenofovir-emtricitabine and dolutegravir.
Follow-up HIV testing at 4 weeks is negative.
Additional history reveals that he has had 8 male partners in the past 6 months; he uses condoms ~50% of the time.
10 months ago, he was treated for gonococcal urethritis.Slide12
When is PrEP indicated?
MSM
Condomless anal sex
Recent sexually-transmitted infection
HIV-infected partner
Condomless sex with a partner who injects drugs or is a bisexual man
HIV-infected partner
Heterosexual adults
Injection drug users
Use of shared injection equipment
Preexposure prophylaxis for the prevention of HIV infection in the United States – 2014. CDC. Available from: http://www.cdc.gov/hiv/pdf/prepguidelines2014.pdf Slide13
RCTs have demonstrated the efficacy of oral PrEP in several groups.
Men who have sex with men
(iPrEX, N Engl J Med 2010)
Population:
2,499 MSM and transgender women in 6 countries
Intervention:
Oral tenofovir-emtricitabine
Results:
Reduced HIV acquisition by 44%
Serodiscordant heterosexual couples
(Partners PrEP, N Engl J Med 2012)
Population:
4,747 serodiscordant couples in Kenya and Uganda
Intervention:
Oral tenofovir-emtricitabine or tenofovir alone
Results:
Reduced HIV acquisition by 67-75%
Heterosexual adults
(TDF2 Botswana, N Engl J Med 2012)
Population:
1,219 heterosexual men and women in Botswana
Intervention:
Oral tenofovir-emtricitabine
Results:
Reduced HIV acquisition by 62% Slide14
2 RCTs in African women have not shown a benefit to oral PrEP.
FEM-PrEP
(N Engl J Med 2012)
Population:
2,120 women in sub-Saharan Africa
Intervention:
Oral tenofovir-emtricitabine
Results:
No HIV risk reduction with PrEP
VOICE
(N Engl J Med 2015)
Population:
5,029 women in sub-Saharan Africa
Intervention:
Oral tenofovir-emtricitabine, oral/vaginal tenofovir
Results:
No HIV risk reduction with PrEP
In VOICE and FEM PrEP, fewer than 50% of participants ever took the study drug.Slide15
PrEP
may work in transgender women, but adherence is crucial.
No benefit to
PrEP
in a post-hoc analysis of 339 transgender women.
Protective drug levels: 18% of transgender women vs. 36% of MSM
No transgender women who contracted HIV had detectable drug levels.
No infections occurred in transgender women taking 4 doses of
PrEP
per week.
Deutsch MB, Glidden DV,
Sevelius
J, et al. HIV pre-exposure prophylaxis in transgender women: a subgroup analysis of the
iPrEX
trial. Lancet HIV. 2015;2(12):e512. Slide16
Differences in study outcomes likely relate to adherence.
Effectiveness (%)
0 10 20 30 40 50 60 70 80 90 100
Participants Samples With Detectable Drug Levels (%)
AVAC Report 2013
. http://
www.avac.org/sites/default/files/resource-files/AVAC%20Report%202013_0.pdf.
Partners PrEP (FTC/TDF)
Partners PrEP (TDF)
TDF2
iPrEx
CAPRISA
VOICE (TDF gel)
FEM-PrEP
VOICE
(FTC/TDF)
VOICE(TDF)Slide17
But biological differences may also play a role.
Preexposure prophylaxis for the prevention of HIV infection in the United States – 2014. CDC. Available from: http://www.cdc.gov/hiv/pdf/prepguidelines2014.pdf Slide18
Adverse effects of PrEP
Nausea
Renal dysfunction
A
small decrease in bone mineral density, of unknown significance.
Rarely, antiretroviral drug resistanceSlide19
In the real world, PrEP may work at least as well as in RCTs.
PROUD
(Lancet 2015)
Population:
545 high-risk MSM in the United Kingdom
Intervention:
Immediate or deferred oral tenofovir-emtricitabine
Results:
Reduced HIV acquisition by 86%
TDF2 OLE
(IAS 2015)
Population:
229 men and women in Botswana
Intervention:
Oral tenofovir-emtricitabine
Results:
0 HIV infections; 5-6 expected
Kaiser
(Clin Infect Dis 2015)
Population:
657 people in San Francisco, predominantly MSM
Intervention:
Oral tenofovir-emtricitabine
Results:
0 HIV infections; ~9% incidence expectedSlide20
PrEP prescribing g
uidelines
Determine eligibility:
Document negative HIV test and high risk of infection, confirm intact renal function (eGFR > 60)
Assess for conditions of concern:
HBsAg for everyone, pregnancy test for fertile women
Prescribe:
Tenofovir-emtricitabine, 1 tablet by mouth daily, ≤ 90-day supply
Monitor:
Creatinine, HIV status, pregnancy status every 3 months; STI screening every 6 months; counsel regarding risk reduction
Pre-exposure prophylaxis for prevention of HIV infection in the United States – 2014. CDC. Available from: www.cdc.gov
. Slide21
Case, continued
The patient initiates PrEP.
At a 6-month follow-up visit, he remains HIV negative.
He says that he is now having sex only once or twice per month and wonders if he can take PrEP intermittently.Slide22
IPERGAY supports “on-demand” PrEP in MSM with frequent sex
Population:
400 MSM reporting unprotected sex with 2 or more partners in the past 6 months
Intervention:
Event-driven PrEP versus placebo
Results:
86% reduction in HIV incidence
IPERGAY regimen:
4 pills, 3 doses over 3 days
Molina JM, et al. On demand preexposure prophylaxis in men at high risk for HIV-1 infection. N Engl J Med 2015;373:2237.
Monday
Tuesday
Wednesday
Thursday
Friday
SaturdaySlide23
HIV acquisition is rare in MSM taking ≥ 4 doses of PrEP per week.
Grant RM, et al. Uptake of pre-exposure prophylaxis, sexual practices, and HIV incidence in men and transgender women who have sex with men: a cohort study. Lancet Infect Dis. 2014;14(9):820-829. Slide24
Case, continued
The patient continues daily PrEP at your urging.
One year later, at a follow-up visit, he remains HIV negative.
He reports now being in a monogamous relationship with another man who has HIV but is virologically suppressed on ART.
He asks if PrEP is worthwhile for him since his partner is undetectable. Slide25
The utility of PrEP on top of HIV treatment is unknown.
No
HIV treatment
prevents transmission; the
additional benefit of PrEP may not outweigh its risks, however small
.
It’s not cost-effective.
Yes
Viral rebound may occur because of poor ART adherence or other reasons.
People may not be monogamous
.
Some patients desire an HIV prevention method they themselves control.Slide26
Treatment as prevention works.
Study: PARTNER
Population: 548 heterosexual and 340 MSM serodifferent couples
Median follow-up: 1.3 years
Exposure: 22,000 and 36,000 condomless sex acts for MSM and heterosexual couples, respectively
Results:0 within-couple HIV transmissions
10 MSM and 1 heterosexual subjects contracted HIV
Rodger AJ, et al. Sexual activity without condoms and risk of HIV transmission in serodifferent couples when the HIV-positive partner is using suppressive antiretroviral therapy. JAMA. 2016;316(2):171. Slide27
A case
A 36 year-old woman and her 39 year-old husband present to discuss conception.
He’s HIV infected and virologically suppressed on ART; she’s HIV-negative.
They want to conceive a child and do not have access to sperm washing.
They ask if you would recommend PrEP for her and condomless sex in this situation.Slide28
PrEP may be part of a safe conception strategy.
No increased birth defects with
tenofovir-emtricitabine among
women
in the Antiretroviral Pregnancy
Registry
No difference in birth outcomes among women receiving PrEP versus placebo in the Partners PrEP study
However, modeling suggests PrEP adds little, assuming ART and other factors are optimized.
Antiretroviral pregnancy registry interim report. 2014. Available from:
www.apregistry.com/forms/exec-summary.pdf
.
Mugo NR, et al. Pregnancy incidence and outcomes among women receiving preexposure prophylaxis for HIV prevention: A randomized clinical trial. JAMA. 2014;312(4):362.
Hoffman RM, et al. Benefits of PrEP as an adjunctive method of HIV prevention during attempted conception between HIV-uninfected women and HIV-infected male partners. J Infect Dis. 2015;212(10):1534.Slide29
What might the future of PrEP look like?
I
njections of long-acting PrEP
(e.g., cabotegravir?)
Other oral agents
(e.g., TAF, maraviroc?)
Rectal microbicides
PrEP-impregnated vaginal rings
(e.g., dapivirine)Slide30
Paying for PrEP
Coverage by commercial and governmental insurance varies.
Assistance for insured or uninsured patients is available through the manufacturer:
www.gileadadvancingaccess.com
Assistance for insured patients with high copays or deductibles:
www.copays.com
(Patient Advocate Foundation)Slide31
Take-home points
Use of antiretrovirals as PEP and PrEP can significantly reduce the risk of HIV acquisition from a single high-risk exposure (PEP) or ongoing high-risk exposures (PrEP).
Event-driven PrEP may be efficacious for MSM with frequent sex.
The utility of PrEP in serodiscordant relationships in which the HIV-infected partner is effectively treated is unknown but is likely low.
Additional PrEP options for women are needed; injectable and vaginal ring formulations are under development.Slide32
Thank you
Kevin L. Ard, MD, MPH
kard@mgh.harvard.edu