Transcript HIV-Infected - Annals of Internal Medicine

© 2015 American College of Physicians
The information contained herein should never be
used as a substitute for clinical judgment.
BEYOND THE GUIDELINES:
Pre-Exposure Prophylaxis (PrEP) for HIV Prevention
Medicine Grand Rounds
May 14, 2015
Discussants
Kenneth Mayer, MD
Howard Libman, MD
Series Assistant Editor
Eileen Reynolds, MD
The Series Editors have no conflicts of interest to disclose.
Moderator
Deborah Cotton, MD, MPH
Conflict of Interest Disclosure
The speakers have no financial
relationships with a commercial entity
producing healthcare-related products
and/or services.
Eileen Reynolds, MD
Kenneth Mayer, MD
Howard Libman, MD
Deborah Cotton, MD, MPH
OUR PATIENT: Mr. X
Medical History
• 45 y.o. man who is healthy
– Husband acquired HIV infection during marriage
– In 2011, husband began ART
• Since 6 months later, VL undetectable
– Our patient began PrEP in 2013
• 4th generation HIV test and VL both negative
• Renal function normal
• Keeps Q3 month follow up appointments
– Received HBV vaccination in 2013
OUR PATIENT: Mr. X
Past Medical and Surgical History
• No major medical illnesses
OUR PATIENT: Mr. X
Social and Family History
• Works as an artist
• “Open” relationship
– Reports engaging in occasional oral sex
encounters outside his marriage
– Predominantly monogamous
OUR PATIENT: Mr. X
Medications
• Tenofovir disoproxil fumarate (TDF)
– 300 mg/day
• Emtricitabine (FTC)
– 200 mg/day
• Fixed dose combination (Truvada)
OUR PATIENT: Mr. X
Periodic Health Examination
• Noncontributory (essentially normal)
THE GUIDELINE
Background
• 50,000 new HIV infections annually in the US
– Rate flat after period of decline
• Recent increase in incidence among MSM
– 12% increase between 2008-2010
– Highest increases in young MSM and African
American MSM
• 63% of new HIV cases attributable to MSM
without any IDU
THE GUIDELINE
Background
• 2012: FDA approved fixed combination
tenofovir (TDF) and emtricitabine (FTC)
(TDF/FTC; Truvada) for daily use for
prophylaxis
– Based primarily on 2 RCTs showing benefit
• 2014: CDC announced a clinical practice
guideline recommending use in patients at
high risk of transmission
THE GUIDELINE
iPrEx Trial
• 2500 subjects: MSM and female to male
transgender who have sex with men
• 6 countries including US
• TDF/FTC vs. placebo; double-blind RCT
• Active medication: 44% reduction in HIV
• Effect strongly related to adherence
– 92% reduction in those with measurable cellular drug
levels
*Grant RM, Lama JR, Anderson PL, McMahan V, Liu AY, Vargas L, et al. Preexposure Chemoprophylaxis for HIV
Prevention in Men Who Have Sex with Men. N Engl J Med. 2010;363:2587-2599.
THE GUIDELINE
iPrEx Trial
• 100 patients infected after trial began
– None had drug resistance
• 10 were acutely infected at time trial started
– 2 were in active treatment group
• Both had FTC-resistance
– 8 were in placebo group
• 1 had FTC resistance
• Low rate of side effects; “start up” symptoms
Kaplan–Meier Estimates of Time to HIV Infection (Modified Intention-to-Treat Population)
*From the New England Journal of Medicine, Grant RM, Lama JR, Anderson PL, McMahan V, Liu AY, Vargas L, et al, Preexposure chemoprophylaxis for HIV
prevention in men who have sex with men, Vol. 363, pp. 2587-2599. © 2010 Massachusetts Medical Society. Reprinted with permission from
Massachusetts Medical Society.
Grant RM et al. N Engl J Med 2010;363:2587-2599
THE GUIDELINE
Partners PrEP Trial
• Serodiscordant heterosexual couples in Kenya and Uganda
• Average CD4 495
– Too high to be eligible for active treatment
• Interim analysis showed substantial reduction of transmission; trial
halted
– Efficacy 67% for TDF
– Efficacy 75% TDF/FTC
• Adherence again correlated with efficacy
– 90% reduction in transmission with measurable levels
*Baeten JM, Donnell D, Ndase P, Mugo NR, Campbell JD, Wangisi J, et al. Antiretroviral Prophylaxis for HIV Prevention in Heterosexual
Men and Women. N Engl J Med. 2012;367:399-410.
*Murnane PM, Celum C, Mugo N, Campbell JD, Donnell D, Bukusi E, et al. Efficacy of preexposure prophylaxis for HIV-1 prevention
among high-risk heterosexuals: subgroup analyses from a randomized trial. AIDS. 2013;27:2155-2160.
Kaplan–Meier
Estimates
of the
Primary
EndEnd
Point
in the
Modified
Intention-to-Treat
Analysis,
Kaplan–Meier
Estimates
of the
Primary
Point
in the
Modified
Intention-to-Treat
Analysis, According to StudyAccording
Treatmentto Study Treatment.
* From the New England Journal of Medicine, Baeten JM, Donnell D, Ndase P, Mugo NR, Campbell JD, Wangisi J, et al, Antiretroviral Prophylaxis for HIV
Prevention in Heterosexual Men and Women, Vol. 367, pp. 399-410. © 2012 Massachusetts Medical Society. Reprinted with permission from
Massachusetts Medical Society.
Baeten JM et al. N Engl J Med 2012;367:399-410
THE GUIDELINE
Evidence
• Two other trials did not show benefit
– FEM-PrEP
• Daily TDF/FTC heterosexual African women
• Low adherence
• Stopped early – unlikely to show benefit
– VOICE
• Oral TDF alone and vaginal topical TDF stopped due to futility
• Oral TDF/FTC arm concluded but did not show benefit
*Van Damme L, Corneli A, Ahmed K, Agot K, Lombaard J, Kapiga S, et al. Preexposure Prophylaxis for HIV Infection among African
Women. N Engl J Med. 2012;367:411-422.
*Peterson L, Taylor D, Roddy R, Belai G, Phillips P, Nanda K, et al. Tenofovir Disoproxil Fumarate for Prevention of HIV Infection in
Women: A Phase 2, Double-Blind, Randomized, Placebo-Controlled Trial. PLoS Clin Trials. 2007;2:e27.
THE GUIDELINE
*US Public Health Service. Preexposure prophylaxis for the prevention of HIV infection in the United States —2014: a clinical practice guideline.
http://www.cdc.gov/hiv/pdf/prepguidelines2014.pdf
THE GUIDELINE
• Before beginning PrEP:
– HIV test; rule out acute infection
• If symptoms of acute HIV are present, defer and retest
in 4 weeks, or check viral load
– Confirm normal renal function
– Document hepatitis B infection and vaccination status
• Education
– Including limitations, adherence, and criteria for
discontinuation
THE GUIDELINE
Follow up visits
• At every visit:
– Assess adherence
– Risk reduction counseling
– Provide condoms; needle safety
• Q 3 months:
– HIV test; pregnancy test; renal function
• At appropriate intervals:
– Test for other STIs
THE GUIDELINE
Discontinuing PrEP
•
•
•
•
•
Positive HIV test result
Acute HIV signs or symptoms
Nonadherence
Renal disease
Changed life situation; lower risk
QUESTIONS TO DISCUSSANTS
To help us decide how to apply these recommendations
for Mr. X, we asked our discussants the following
questions:
1. What is the risk that Mr. X will contract HIV infection from his
husband? From unknown contacts?
2. Does pre-exposure prophylaxis lower that risk, and by how
much?
3. What are the benefits and risks associated with using preexposure prophylaxis broadly (to the population) and
individually (to this patient)?
OUR MODERATOR & DISCUSSANTS
Deborah Cotton, MD, MPH (Moderator)
Professor of Medicine, Boston University School of Medicine
Deputy Editor, Annals of Internal Medicine
Kenneth Mayer, MD
Director, HIV Prevention Research, BIDMC
Professor of Medicine, Harvard Medical School
Professor, Department of Global Health & Population, Harvard Medical School
Howard Libman, MD
Director, HIV Program, Healthcare Associates, BIDMC
Chief, Education Section, Division of General Medicine and Primary Care
Professor of Medicine, Harvard Medical School
Kenneth H. Mayer, MD,
would counsel that PrEP may be indicated in
this case.
QUESTIONS TO DISCUSSANTS
What is the risk that this patient will contract HIV
infection from his husband? From unknown contacts?
HPTN 052: Early HIV Treatment ↓ Transmission in
Stable Heterosexual Couples
•
•
RCT evaluating the impact of early vs.
later initiation of HAART in HIV
transmission in 1,750 HIV discordant
couples
39 transmissions occurred despite
counseling
Linked HIV transmission to HIV-negative
partner (n=28)
– Early therapy (n=1)
• 0.1 per 100 person-years
– Delayed therapy (n=27)11
Early ART led to a 96% reduction of
sexual transmission of HIV in
serodiscordant couples
Linked HIV Transmission
HR: 0.04
(95% CI 0.01-0.27)
(P<0.001)
Cumulative Probability
•
*Cohen MS, Chen YQ, McCauley M, Gamble T, Hosseinipour MC, Kumarasamy N, et al.
Prevention of HIV-1 Infection with Early Antiretroviral Therapy. N Engl J Med. 2011;365:493-505.
Delayed
ART
Early
ART
0
1
2
3
Years
4
5
Lessons of HPTN 052
• Very few same sex couples (generalizable?)
• 1 pt infected by treated partner on HAART <60 days
• HIV+ partner needs to be virologically suppressed for
several (up to 6?) months
• HIV+ partner needs to remain adherent
• 39 transmissions documented in 10 analysis
• Eleven HIV- partners (i.e. >25%) were infected by a
different partner
• Treatment as prevention is not helpful if uninfected
partner is not monogamous
*Cohen MS, Chen YQ, McCauley M, Gamble T, Hosseinipour MC, Kumarasamy N, et al.
Prevention of HIV-1 Infection with Early Antiretroviral Therapy. N Engl J Med.
2011;365:493-505.
HIV Transmission According to Sexual Behavior
Reported by HIV-Negative Partner
•
•
•
•
•
Overall HIV transmission rate was
zero through condomless sex with a
partner on ART (HIV RNA <200
copies/mL), despite a significant
number of sex acts
Uncertainty over the upper limit of
risk remains
Particularly with receptive anal sex
with ejaculation
Additional follow-up needed to
provide more precise estimates for
transmission risk
Duration of prior ART without
transmission may have selected for
lowest risk discordant couples
*Rodger A, Cambiano V, Bruun T, Vernazza P, Collins S, Estrada V, et al. HIV
transmission risk through condomless sex if HIV+ partner on suppressive
ART: PARTNER Study. 21st CROI, 2014, Abstract #153LB.
Rate of Couple Transmission
(per 100 Couple-Years Follow-Up)
Heterosexual (Male)
Vaginal sex with ejaculation
(192 CYFU)
Heterosexual (Female)
Vaginal sex (272 CYFU)
MSM
Receptive anal sex:
With ejaculation (93 CYFU)
Without ejaculation (157 CYFU)
Insertive anal sex (262 CYFU)
CYFU: couple-years follow-up. 0
1
2
3
Rate (95% CI)
4
Per Contact risk of acquiring HIV
Type of Contact
Per contact
risk/1000
95% CI
Unprotected receptive anal w/ HIV +
8.2
2.4, 27.6
Unprotected receptive anal w/ HIV+/?
2.7
0.6, 4.9
Unprotected insertive anal w/ HIV +/?
0.6
0.2, 1.9
Unprotected receptive oral w/
ejaculation w/ HIV+/?
0.4
0.1, 1.7
Protected receptive anal w/ HIV+/?
1.8
1.0, 2.8
Protected insertive anal w/ HIV +/?
0.4
0.1, 1.1
*Vittinghoff E, Douglas J, Judson F, McKirnan D, MacQueen K, Buchbinder SP. Per-contact risk of human
immunodeficiency virus transmission between male sexual partners. Am J Epidemiol. 1999;150:306-311.
Hierarchical risks with HIV-positive or unknown
serostatus partners in seroconversion period
MSM
(n = 85)
%
Shared needles/injection equipment
4
4.8
Unprotected receptive anal sex
54
65.1
Unprotected insertive anal sex
7
8.4
Unprotected vaginal sex
N/A
N/A
Unprotected receptive oral sex
14
16.0
Protected anal &/or vaginal sex
2
2.4
No identifiable risk
2
2.4
*Celum CL, Buchbinder SP, Donnell D, Douglas JM Jr, Mayer K, Koblin B, et al. Early human immunodeficiency
virus (HIV) infection in the HIV Network for Prevention Trials Vaccine Preparedness Cohort: risk behaviors,
symptoms, and early plasma and genital tract virus load. J Infect Dis. 2001;183:23-35.
Seminal HIV may be detected in
sexually active MSM using HAART
• Single-cohort study
(n=101 sexually active MSMs on ART)
– HIV RNA in blood: 18% due to
medication non-adherence and
virological failure
– HIV RNA in semen: 30%
• Ready detection of HIV seminal
shedding in MSM fully suppressed on
ART:
– Consider use of condoms and
other risk-reduction strategies
throughout all stages of HIV
disease regardless of HIV
treatment status
*Politch JA, Mayer KH, Welles SL, O'Brien WX, Xu C, Bowman FP, et al. Highly active antiretroviral
therapy does not completely suppress HIV in semen of sexually active HIV-infected men who have sex
with men. AIDS. 2012;26:1535-1543..
Risk Factors for Detection of HIV in Semen From
HIV-Infected MSMs on ART with Undetectable
HIV in Blood (Multivariate)
Odds Ratio
(95% CI)
High TNF-α levels in seminal
plasma (yes versus no)
STI status
(STI/urethritis versus none)
UIAS with HIV-positive person
(yes versus no)
13.97
(2.85, 95.02)
(P=0.0003)
29.03
(2.60, 523)
(P=0.003)
7.34
(1.59, 47.73)
(P=0.007)
U.S. HIV Care Continuum
HIV-Infected:
>25 Years of Age (n=896,800)
HIV-Infected:
13-29 Years of Age (n=78,949)
~88%
~40%
~28%
HIV-Infected (%)
HIV-Infected (%)
~73%
40%
25%
11%
6%
Diagnosed
Linked
To Care
Retained
Viral
in Care Suppression
*Hall HI, Frazier EL, Rhodes P, Holtgrave DR, Furlow-Parmley C, Tang T, et al. Differences in
human immunodeficiency virus care and treatment among subpopulations in the United States.
JAMA Intern Med. 2013;173:1337-1344.
Diagnosed
Linked
To Care
Retained
Viral
in Care Suppression
*Zanoni BC, Mayer KH. The adolescent and young adult HIV cascade of care in the
United States: exaggerated health disparities. AIDS Patient Care STDS. 2014;28:128135.
Question 2
Does pre-exposure prophylaxis lower the risk of
transmission, and by how much?
*Mayer KH, Ramjee G. The current status of the use of oral medication to prevent HIV transmission. Curr Opin HIV AIDS. 2015;10:226-232.
PrEP works, but adherence is key
(Auerbach, Marrazzo, VanDamme, Van der Straten, Stadler, Tolley, Hendrix, Abdool Karim, Saethre, Corneli)
*Content was reprinted from AVAC Report 2013:Research & Reality, published by AVAC (www.avac.org).
PROUD Study:
PrEP Use in a Real World Setting (2012-2014)
Multicenter UK Study
13 Sexual Health Clinics
Open label
HIV-negative MSM
Condomless anal intercourse
No HBV
Immediate
Emtricitabine/tenofovir DF (n=276)
Deferred (12 months)
Emtricitabine/tenofovir DF (n=269)
Web-based randomization. Follow-up: 3 times monthly for up to 24 months.
Primary endpoint: HIV infection in the first 12 months.
Baseline characteristics:
Age: 35 years.
White: 81%.
No current relationship: 54%.
Full-time employment: 72%.
Recreational drug use in the last 90 days: 70%.
*McCormack S, Dunn D. Pragmatic Open-Label Randomised Trial of Preexposure
Prophylaxis: The PROUD Study. 22nd CROI, 2015, Abstract 22LB.
PROUD Study: Results
– 86% reduction (P=0.0002)
– Number needed to treat to
prevent 1 infection: 13
• Preliminary analysis found that
risk behaviors were similar
between the 2 arms
.
*McCormack S, Dunn D. Pragmatic Open-Label Randomised Trial of Preexposure
Prophylaxis: The PROUD Study. 22nd CROI, 2015, Abstract 22LB.
8.9
(6.0-12.7)
HIV Incidence
(per 100-person-years)
• Significantly fewer new HIV
infections with immediate
versus deferred PrEP (3 versus
19 cases)
HIV Incidence
86%
Reduction
(P=0.0002)
1.3
(0.4-3.0)
Deferred
Immediate
(n=269)
(n=276)
Question 3
What are the benefits and risks associated with using
pre-exposure prophylaxis broadly (to the population) and
individually (to this patient)?
PrEP Safety: Generally Well tolerated
 Start-up syndrome
 1-18.5% with nausea, vomiting ± dizziness
 Renal safety
 0.2% Grade 2-4 elevations in creatinine among 5469 participants randomized
to TDF/FTC
 Bone safety
 0.4 to 1.5% loss of BMD across several bone groups
 Return towards baseline over time in adults
 Not associated with increased fracture risk
*Grant RM, Lama JR, Anderson PL, McMahan V, Liu AY, Vargas L, et al. Preexposure
Chemoprophylaxis for HIV Prevention in Men Who Have Sex with Men. N Engl J Med.
2010;363:2587-2599.
*Baeten JM, Donnell D, Ndase P, Mugo NR, Campbell JD, Wangisi J, et al. Antiretroviral Prophylaxis
for HIV Prevention in Heterosexual Men and Women. N Engl J Med. 2012;367:399-410.
*Thigpen MC, Kebaabetswe PM, Paxton LA, Smith DK, Rose CE, Segolodi TM, et al. Antiretroviral
preexposure prophylaxis for HIV transmission in Botswana. N Engl J Med. 2012;367:423-434.
*Van Damme L, Corneli A, Ahmed K, Agot K, Lombaard J, Kapiga S, et al. Preexposure Prophylaxis
for HIV Infection among African Women. N Engl J Med. 2012;367:411-422.
*Marrazzo JM, Ramjee G, Richardson BA, Gomez K, Mgodi N, Nair G, et al. Tenofovir-based preexposure prophylaxis
for HIV infection among African women. N Engl J Med. 2015;372:509-518.
*Solomon MM, Lama JR, Glidden DV, Mulligan K, McMahan V, Liu AY, et al. Changes in renal function associated with
oral emtricitabine/tenofovir disoproxil fumarate use for HIV pre-exposure prophylaxis. AIDS 2014;28:851-859.
*Liu AY, Vittinghoff E, Sellmeyer DE, Irvin R, Mulligan K, Mayer K, et al. Bone mineral density in HIV-negative men
participating in a tenofovir pre-exposure prophylaxis randomized clinical trial in San Francisco. PLoS One.
2011;6:e23688.
*Kasonde M, Niska RW, Rose C, Henderson FL, Segolodi TM, Turner K, et al. Bone mineral density changes among
HIV-uninfected young adults in a randomised trial of pre-exposure prophylaxis with tenofovir-emtricitabine or
placebo in Botswana. PLoS One. 2014;9:e90111.
Detailed Sexual Health Assessment
The Centers for Disease Control and Prevention (CDC) has
developed a simple categorization of sexual history
questions to help focus on key issues.
http://www.cdc.gov/lgbthealth/
*Taking routine histories of sexual health: A system-wide approach for health centers. August 2014.
Available from: http://www.lgbthealtheducation.org/wp-content/uploads/COM827_SexualHistoryToolkit_August2014_v7.pdf
Algorithm for Taking Sexual Histories
www.lgbthealtheducation.org
Set the Stage



Bring up the sexual history as part of the overall history
Explain that you ask these questions of all patients
Ensure confidentiality
Begin with Three Screening Questions
1. Have you been sexually active in the last year?
2. Do you have sex with men, women, or both?
3. How many people have you had sex with in the last year?
Multiple Partners,
New Partner
Long-term
Monogamous Partner
Not Sexually Active
*Taking routine histories of sexual health: A system-wide approach for health centers. August 2014. Available from: http://www.lgbthealtheducation.org/wpcontent/uploads/COM827_SexualHistoryToolkit_August2014_v7.pdf
Purview paradox: contradictory beliefs about who
should prescribe PrEP
HIV providers:
PrEP best prescribed
By PCP
Primary care
providers:
PrEP meds are too
complicated
*Krakower D, Ware N, Mitty JA, Maloney K, Mayer KH. HIV providers' perceived
barriers and facilitators to implementing pre-exposure prophylaxis in care
settings: a qualitative study. AIDS Behav. 2014;18:1712-1721.
*Smith DK, Pals SL, Herbst JH, Shinde S, Carey JW. Development of a clinical screening index
predictive of incident HIV infection among men who have sex with men in the United States. J
Acquir Immune Defic Syndr. 2012;60:421-427.
PrEP in an HIV Serodiscordant Relationship
• Partner risk assessment
-Is partner highly adherent to HAART?
-What is partner risk for other STDs?
-Is partner stably virologically suppressed?
• Patient risk assessment
-What is his sex pattern with outside partners?
-Oral only, condomless anal, or….?
Substance use during sex and ability to negotiate
• Patient interest in using PrEP
Does he understand the importance of adherence and
engagement in care?
Howard Libman, MD
would counsel against using PrEP in this case.
I acknowledge that PrEP is highly effective and
am pleased that it is available as an option for
HIV prevention.
Factors Affecting HIV Sexual Transmissibility
•
•
•
•
•
Type of sexual behaviors
Use of condoms
Sexually transmitted diseases (e.g., HSV, syphilis)
HIV plasma viral load
Circumcision (acquisition from female partner)
Interventions for HIV Prevention
• Decrease source of infection
- Barrier protection
- STD diagnosis and treatment
- Blood product screening
- Antiretroviral therapy of infected persons
• Decrease host susceptibility to infection
- Barrier protection
- STD diagnosis and treatment
- PEP and PrEP
- Topical microbicides
- Circumcision
• Alter risk-taking behavior
- Individual, couples, and community-based interventions
*Mayer KH, Venkatesh KK. Antiretroviral therapy as HIV prevention: status and prospects. Am J Public
Health. 2010;100:1867-1876.
Behavioral interventions reduce high risk sexual activity
among men who have sex with men
• Systematic review of 44 studies evaluating 58
interventions with 18,585 participants with varying
formats (community, small group, individual)
• 40 studies with behavioral interventions measured
against minimal to no HIV prevention intervention
reduced occasions of or partners for unprotected
anal sex by 27% (95% CI, 0.15-0.37)
*Johnson WD, Diaz RM, Flanders WD, Goodman M, Hill AN, Holtgrave D, et al. Behavioral
interventions can reduce unprotected sex among men who have sex with men. Cochrane
Database Syst Rev. 2008;16:CD001230.
Condoms are effective in preventing HIV transmission
• For inclusion, studies had to have: 1) data concerning sexually
active HIV serodiscordant heterosexual couples; 2) a
longitudinal study design; 3) HIV status determined by serology;
and 4) contain condom usage information on cohort of “always”
or “never” condom users
• There were 13 cohorts of “always” condom users that yielded a
homogeneous HIV incidence estimate of 1.14 (95% CI, 0.562.04) per 100 person-years; there were 10 cohorts of “never”
condom users that were heterogeneous
• Overall, the proportionate reduction in HIV seroconversion with
condom use was approximately 80%
*Weller S, Davis K. Condom effectiveness in reducing heterosexual HIV transmission. Cochrane
Database Syst Rev. 2002;CD003255.
QUESTIONS TO DISCUSSANTS
What is the risk that this patient will contract HIV
infection from his husband? From unknown contacts?
The risk from his husband is very low without PrEP.
The risk from occasional oral sex outside of his marital
relationship is also quite low.
Suppressive antiretroviral regimens are
associated with low seminal viral levels
• Cross-sectional cohort study of 119 HIV-infected subjects
divided into three groups according to treatment status
• Blood and semen were collected concurrently
• All subjects taking NNRTIs (n=36, mean treatment of 33
months ± 14) or PIs (n=45, mean treatment of 31 months ±
25) had plasma viral load < 50 copies/mL and seminal viral
load < 250 copies/mL
• In untreated subjects (n=38), plasma and seminal viral loads
were positively correlated (p=0.002)
*Chan DJ, Ray JE, McNally L, Batterham M, Smith DE. Correlation between HIV-1 RNA load in blood
and seminal plasma depending on antiretroviral treatment status, regimen and penetration of
semen by antiretroviral drugs. Curr HIV Res. 2008;6:477-484.
Suppressive antiretroviral regimens are
associated with low seminal viral levels
• Evaluate impact of a first-line LPV/rtv alone or ZDV, 3TC, and
LPV/rtv on HIV shedding in the genital tract
• HIV-infected men enrolled in Monark randomized trial were
eligible for study after completing 48 weeks of treatment
• Ten patients were included: 5 of them received lopinavir/
ritonavir monotherapy and 5 received a triple combination
• At week 48, all patients had plasma viral loads <1.7 log10
copies/mL, and all had undetectable seminal viral levels
(<2.3 log10 copies/mL)
*Ghosn J, Chaix ML, Peytavin G, Bresson JL, Galimand J, Girard PM, et al. Absence of HIV-1 shedding in
male genital tract after 1 year of first-line lopinavir/ritonavir alone or in combination with
zidovudine/lamivudine. J Antimicrob Chemother. 2008;61:1344-1347.
Effective treatment of HIV infection is associated with significant
reduction in the risk of transmission to serodiscordant partners
• One randomized controlled trial and 9 observational studies
• HIV transmission rate ratio for the single controlled trial was
0.04 (95% CI, 0.00-0.27). All index partners in this study had
CD4 cell counts at baseline of 350-550/µL
• Summary rate ratio for nine observational studies was 0.58
(95% CI, 0.35-0.96)
• Among couples in which the infected partner had ≥350 CD4
cells/µL, estimated rate ratio was 0.12 (95% CI, 0.01-1.99)
*Anglemyer A, Rutherford GW, Horvath T, Baggaley RC, Egger M, Siegfried N. Antiretroviral therapy for
prevention of HIV transmission in HIV- discordant couples. Cochrane Database Syst Rev. 2013;CD009153.
*From the New England Journal of Medicine, Cohen MS, Chen YQ, McCauley M, Gamble T, Hosseinipour MC, Kumarasamy N, et al,
Prevention of HIV-1 Infection with Early Antiretroviral Therapy, Vol. 365, pp. 493-505. © 2011 Massachusetts Medical Society.
Reprinted with permission from Massachusetts Medical Society.
Estimated Per-Act Probability of Sexually
Acquiring HIV from Infected Source
•
•
•
•
•
•
Receptive anal intercourse
Insertive anal intercourse
Receptive penile-vaginal intercourse
Insertive penile-vaginal intercourse
Receptive oral intercourse
Insertive oral intercourse
138/10,000
11/10,000
8/10,000
4/10,000
lower
lower
*Adapted from Centers for Disease Control and Prevention. HIV Transmission Risk. July 2014.
http://www.cdc.gov/hiv/policies/law/risk.html
*Patel P, Borkowf CB, Brooks JT, Lasry A, Lansky A, Mermin J. Estimating per-act HIV transmission risk: a systematic review.
AIDS. 2014;28:1509-1519.
*Baggaley RF, White RG, Boily MC. Systematic review of orogenital HIV-1 transmission probabilities. Int J Epidemiol.
2008;37:1255-1265.
Risk of HIV Transmission with Oral Sex
*del Romero J, Marincovich B, Castilla J, García S, Campo J, Hernando V, et al. Evaluating the risk of HIV
transmission through unprotected orogenital sex. AIDS. 2002;16:1296-1297.
QUESTIONS TO DISCUSSANTS
Does pre-exposure prophylaxis lower that risk, and by
how much?
PrEP reduces the relative risk by 75% or more, but its
absolute risk reduction in this patient is of debatable
clinical significance.
Overview of Major PrEP Trials
Clinical Trial
Participants
Medication(s)
mITT Efficacy
% (CI)
Adjusted for
Adherence
% (CI)
Bangkok TDF
Injection drug
users
TDF
49 (18-90)
74 (17-94)
Partners PrEP
Heterosexual
discordant
couples
TDF
67 (44-81)
86 (67-94)
TDF/FTC
75 (55-87)
90 (58-98)
TDF2
Heterosexual
men/women
TDF/FTC
63 (21-83)
85 (NS)
iPrEx
Men who have
sex with men
TDF/FTC
44 (15-63)
92 (40-99)
Fem-PrEP
Heterosexual
women
TDF/FTC
NS
VOICE
Heterosexual
women
TDF
TDF/FTC
NS
NS
*Adapted from Centers for Disease Control and Prevention (CDC). Preexposure prophylaxis for the prevention of HIV infection in the United States - 2014. Atlanta (GA): Centers for Disease
Control and Prevention (CDC); 2014.
Examples of Absolute HIV Risk Without and With PrEP
Sexual Activity Risk Per
Exposure
Annual Risk
Without PrEP
Annual Risk
With PrEP
Annual Risk
Reduction
Receptive Anal
Intercourse
1/100
41%
12%
29%
Receptive
Vaginal
Intercourse
1/1000
5.1%
1.3%
3.8%
Oral
Intercourse
1/10,000
0.52%
0.13%
0.39%
Assumes one sexual act per week and the absence of any other factors that would
affect the risk of transmission
Relative versus Absolute Risk
Estimated absolute risk of transmission per sexual encounter with patient’s husband
of 138/10,000
If the patient and his husband were having sexual relations once per week…
Cumulative one-year risk would be:
0.515 x 0.04 (96% risk reduction in serodiscordant couples with partner who has
suppressed VL) = 2.06% without PrEP
2.06% x 0.25 (75% risk reduction from PrEP) = 0.52% on PrEP
Number of Patients Needed to Treat to Prevent One Infection = 65
By comparison, regular condom use would reduce relative risk by 80% or cumulative
risk to 0.41%
If the patient and his husband were having sexual relations 3 times/week…
Cumulative one-year risk would be:
0.886 x 0.04 (96% risk reduction in serodiscordant couples with partner who has
suppressed VL) = 3.54% without PrEP
3.54% x 0.25 (75% risk reduction from PrEP) = 0.89% on PrEP
Number of Patients Need to Treat to Prevent One Infection = 38
By comparison, regular condom use would reduce relative risk by 80% or cumulative
risk to 0.71%
HIV transmission is a low frequency,
high impact event.
Is reduction in the one-year risk from 2.06% to 0.52%
clinically significant?
QUESTIONS TO DISCUSSANTS
What are the benefits and risks associated with using preexposure prophylaxis broadly (to the population) and individually
(to this patient)?
If PrEP is reserved for patients at highest risk, it provides health
benefits to the individual and population.
If PrEP is used indiscriminately, there is an increased individual
risk of drug side effects, long-term toxicities, and potentially
other unintended consequences, as well as increased cost to
society as a whole.
Questions about Incorporating
PrEP into Clinical Practice
• Selection of patients
– How should patients at highest risk be identified?
– Need validated HIV transmission risk calculator
• Sending “mixed messages”
– Will PrEP disinhibiting in some patients?
– This could inadvertently increase risk of transmission
– This could also increase the risk of other STDs
• Drug toxicities
– How common are renal dysfunction (TDF) and accelerated bone loss (TDF) when
TDF/FTC is used for prevention?
– Need longer experience than that afforded by clinical trials
• Medication adherence
– How adherent will patients on PrEP be in clinical practice?
– Lack of adherence could increase risk of transmission
Questions about Incorporating
PrEP into Clinical Practice
• Viral resistance
– How often will viral resistance in acquired infection develop?
– Not a concern on short-term basis; long-term data are not available
• Relationship to other approaches to prevention
– How should we think of PrEP in relation to other HIV prevention options?
• Cost of therapy, monitoring, and office visits
–
–
–
–
Will PrEP be affordable on a population scale?
TDF/FTC currently is $6,000 to $16,000/year
There are additional charges for laboratory testing/clinic visits
Will insurers continue to cover the costs?
Physicians behave very much like humans
(non-evidence-based commentary)
• We are cognizant of the limited time that we have to spend
with patients in the ambulatory setting
• We are averse to dealing with content areas about which we
may not be comfortable and/or knowledgeable (e.g., sexual
and drug use behaviors)
• We are generally better at treatment than prevention
• We usually favor medications over other interventions
• We want to feel as if we are providing “cutting edge,” stateof-the-art care
Sexual risk-reduction counseling in primary care can be effective
in the prevention of STDs
*O'Conner EA, Lin JS, Burda BU, Henderson JT, Walsh ES, Whitlock EP. Behavioral sexual risk-reduction counseling in primary care to prevent sexually transmitted infections:
a systematic review for the U.S. Preventive Services Task Force. Ann Intern Med. 2014;161:874-883.
USPSTF Systematic Review
• 31 trials included with over 70,000 subjects
• Most targeted persons at increased risk for STDs
• High-intensity (> 2 hours) interventions reduced STD
incidence in adults (OR, 0.70 [95% CI, 0.56-0.87]) and
adolescents (OR, 0.38 [95% CI, 0.24-0.60]); lower intensity
ones were not as effective
• Successful interventions generally provided information
about STDs; help in identifying personal risk; training in
behavior change processes, such as problem solving, decision
making, and goal-setting; training in communication about
condom use and safe sex; and practicing condom use
*O'Conner EA, Lin JS, Burda BU, Henderson JT, Walsh ES, Whitlock EP. Behavioral sexual risk-reduction counseling in primary care to prevent sexually transmitted infections: a
systematic review for the U.S. Preventive Services Task Force. Ann Intern Med. 2014;161:874-883.
Conclusions
• Suppressive antiretroviral regimens are generally associated with
undetectable seminal viral levels
• Effective treatment of HIV infection is associated with a 96% reduction
in the risk of transmission to serodiscordant partners
• This patient is at minimal risk of acquiring HIV infection from his
husband despite the fact that his sexual behavior would traditionally
be viewed as “high risk”
• PrEP would reduce this patient’s risk of acquiring HIV infection by 75%
or more, but, because the likelihood of contracting it from his husband
is very low at baseline, the absolute risk reduction is of debatable
clinical significance
• There are other effective interventions to prevent HIV transmission
Conclusions
• For this patient, consideration should be given to a behavioral approach
to promote regular condom use, which has minimal cost and provides
comparable benefits to PrEP, as well as counseling him to avoid outside
relationships
• While the risk associated with giving PrEP to this patient is small, using
it in instances when it is unlikely to provide substantial clinical benefit
increases the risk of side effects, toxicities, potentially other unintended
consequences, and the cost of care to society as a whole
• The approach to HIV prevention should individualized based upon the
specifics of each case
• Physicians need to be better educated about all options, and resources
to provide effective behavioral counseling should be readily accessible
in the primary care setting
We would like to thank…
Our Patient, Mr. X
Howard Libman, MD & Kenneth Mayer, MD
Risa Burns, MD, MPH
Eileen Reynolds, MD
Deborah Cotton, MD, MPH Gerald Smetana, MD
Last Minute Productions
BIDMC Media Services
Lizzie Williamson
© 2015 American College of Physicians
The information contained herein should never be
used as a substitute for clinical judgment.