Transcript VIREAD™ (tenofovir disoproxil fumarate)

Incidence of Genital Ulcers and HSV + genital
ulcers in trial of HSV-2 suppression to prevent
HIV acquisition
Jorge Sánchez MD MPH
XVII International AIDS conference
Mexico City
August 7th, 2008
Interactions: HSV-2 and HIV
HIV
HSV-2
Effect of HIV on HSV-2
Effect of HSV-2 on HIV
• Alters clinical presentation &
frequency of HSV-2 shedding
• Longer duration of lesions (CD4
<200)
•  HSV-2 acquisition &
transmission
•  HIV acquisition
•  HIV levels in plasma &
genital tract
•  HIV transmission
HSV-2 increases HIV susceptibility
• Epidemiologic Data
• Longitudinal studies which adjusted for age & sexual behavior (n=18)
• Prevalent HSV-2 infection and HIV acquisition:
• Men
• Women
• MSM
RR 2.7 (95% CI 1.9-3.9)
RR 3.1 (95% 1.7-5.6)
RR 1.7 (95% CI 1.2-2.4)
• 38-69% of new HIV infections in ♀ & 8-49% in ♂ due to prevalent HSV-2
(Freeman AIDS 2006)
• Biologic Plausibility
• HSV-2 causes macro- & microscopic ulcerations
• HSV-2 reactivation is frequent: 20% of days HSV PCR+ in HIV-negative
persons (Mark ISSTDR 2007)
•  cervical CD4 T cells & immature dendritic cells in HSV-2 seropositive
women (Rebbapragada AIDS 2007)
Translating epidemiology and
biology to Proof of Concept trials
• Use antiviral therapy as a ‘probe’ to evaluate:
• HSV-2 and Increased HIV Susceptibility
• London School of Hygiene & Trop Medicine Trial in Tanzania
• HIV Prevention Trials Network (HPTN 039) trial in US, Peru, & Africa
• HSV-2 and Increased HIV Infectiousness
• 6 pilot studies
• 1 large multi-center trial (Partners in Prevention) in Africa
• HSV-2 and HIV Disease Progression
• Partners in Prevention trial
• Rakai, Uganda trial
• Ultimately best intervention is to prevent HSV-2
acquisition through an HSV vaccine
HPTN 039: HSV-2 suppressive therapy to prevent
HIV acquisition
Harare, Zimbabwe
Lusaka, Zambia
Johannesburg, So Africa
HIV- HSV-2+
heterosexual women
and
HIV- HSV-2+ MSM
Lima, Iquitos, Pucallpa: Peru
Seattle, San Francisco, NYC
Randomize
Acyclovir 400 mg bid
Matching Placebo bid
Both arms received episodic ACV for GUD & risk reduction counseling
1° endpoint: HIV infection
HPTN 039
Assumptions & Analyses
•
Sample size assumptions: 50% effect size;90% power; 3.5% HIV incidence in
placebo arm
•
Primary analysis: Intent-to-treat
•
Risk estimates adjust for gender, age, GUD at enrollment & # of sex partner in
last 12 months at entry
•
Additional analyses adjust for sexual behavior during the study as timedependent covariates
•
Adherence measured by monthly pill count (& used self-report, when pill bottles
not returned)
•
GUD definition based on exam (enrollment, quarterly in all pts, and monthly if
report symptoms)
HPTN 039
Study Design
11731 assessed for eligibility
8454 ineligible
3277 randomized
1637 assigned to
intervention
1640 assigned to
control
8 HIV +
3 duplicate
45 HSV-2 -
13 HIV +
2 duplicate
34 HSV-2 1581 included in
analysis
1591 included in
analysis
HPTN 039
Entry criteria
•
Age of informed consent (>18 yrs all but Zambia, >16 yrs)
•
HIV negative
•
HSV-2 seropositive
• Focus EIA index value > 3.4; confirmed with UW HSV Western blot
•
Behavioral criteria
• Women from southern Africa:
• >1 episode of unprotected vaginal sex in past 6 months
• MSM from U.S. and Peru:
• > 1 episode of anal intercourse in past 6 months & not mutually
monogamous with HIV- man
HPTN 039 Study Drug Adherence
Based on Pill Count & Self-Report
% doses taken of doses dispensed (by pill count)
94%*
Maximum doses missed in a row ≥ 6 doses
4.4%
% bottles not dispensed due to pregnancy
4.8%
Open label episodic HSV treatment since last visit
3.2%
*87% ‘true adherence’ for ITT analysis where each randomized participant counts
HPTN 039: Demographic & behavioral
characteristics at enrollment, N=3172
Women
N =1358
Peru MSM N
=1355
U.S. MSM
N = 459
31
28
40
76%
61%
16%
# SP, past year (median)
1
10
6
# SP, past month (median)
1
2
1
# sex acts past 3 months
24
6
6
Any unprotected vaginal sex, past 3
months
90%
-
-
Any unprotected receptive anal sex,
past 3 months
-
56%
33%
Any unprotected insertive anal sex,
past 3 months
-
21%
40%
Age (median)
Secondary education or less
HPTN 039: Time to HIV by study arm
Overall HR 1.16 (95% CI 0.83-1.62); p=0.39
Riesgo Relativo de ulcera genital
Riesgo Relativo de Ulceras Genitales, Aciclovir
vs. Placebo, p<0.001 para todas las sedes
GENERAL
US
PERU
AFRICA
Sedes de Estudio
En general, 37% de reducción en la incidencia de ulcera genital en el grupo de Aciclovir
Diferencias significativas en la reducción de las ulceras genitales por región (p=0.01)
Episodios de ulceras genitales por brazo
N° de personas
Porcentaje de participante con ulcera genital
Ulcera Genital durante el estudio
Aciclovir
Placebo
Numero de recurrencias de ulceras genitales durante el estudio
Association between self-report GUD and GUD
on exam
GUD on exam
Self-report No
GUD
Yes
Total
No
14965 (97.66%)
359 (2.34%)
15324 (89.05%)
Yes
749
1136 (60.27%)
1885 (10.95%)
Total
15714
* P < 0.001
Based on GEE model
(39.73%)
1885
OR
[95% CI]
62.4 [52.95, 73.58] *
Frecuency of HSV 2 detection in Genital
Ulcers
Aciclovir
Placebo
N = 729 hisopos N=1258 hisopos
VHS-2* PCR +
246 (33.7%)
688 (54.7%)**
Negativo
473 (64.9%)
552 (43.9%)
Inhibido
8 (1.1%)
16 (1.2%)
Solo 2 muestras positivas para VHS-1 ADN
** p <0.001
Porcentaje
Cantidad de VHS DNA detectado (log10) entre episodios
positivos de ulceras genitales herpéticas por región
Numero de copias de VHS DNA PCR (log10)
RR for Aggregate GUD as a function of
quarterly adherence
AFRICA
RR CI95%
PERU
OR CI95%
US
OR CI95%
OVERALL
OR CI95%
Adherence Low
adherence :
Acyclovir vs
Placebo
0.63 [0.37, 1.08]
**
0.37 [0.18, 0.74]
0.18 [0.07, 0.44]*
0.41 [0.27, 0.62] *
Adherence High
adherence:
Acyclovir vs
Placebo
0.401 [0.3, 0.53] *
0.30 [0.19, 0.45] *
0.36 [0.21, 0.60] *
0.33 [0.26, 0.42] *
Age increase 1 yr
0.97 [0.95, 0.99] *
0.97 [0.95, 0.99] *
0.97 [0.95, 0.99] *
0.97[0.96, 0.98] *
* P < 0.001
Based on GEE model
** P > 0.05
Low adherence=90-105%, High adherence=>105%
test for effect modification by level of adherence is not significant
RR for HSV 2 + GUD as a function of
quarterly adherence
RR for Aggregate GUD as a function of quarterly adherence
AFRICA
RR CI95%
PERU
OR CI95%
US
OR CI95%
OVERALL
OR CI95%
Adherence Low adherence
: Acyclovir vs Placebo
0.63 [0.37, 1.08] **
0.37 [0.18, 0.74]
0.18 [0.07,
0.44]*
0.41 [0.27, 0.62] *
Adherence High
adherence: Acyclovir vs
Placebo
0.401 [0.3, 0.53] *
0.30 [0.19, 0.45] *
0.36 [0.21, 0.60]
*
0.33 [0.26, 0.42] *
Age increase 1 yr
0.97 [0.95, 0.99] *
0.97 [0.95, 0.99] *
0.97 [0.95, 0.99]
*
0.97[0.96, 0.98] *
* P < 0.001
Based on GEE model
** P > 0.05
Low adherence %, High adherence=90-105%
Test for effect modification by level of adherence is not significant
Conclusions
• Acyclovir 400 mg bid did not reduce risk of HIV
acquisition among high-risk HSV-2 seropositive MSM
and women. Acyclovir 400 mg bid was safe and welltolerated; largest trial ever of HSV-2 suppression
• Adherence to study drug was excellent
o 94% of dispensed doses taken, 87% expected doses taken
• Suppressive acyclovir led to a significant reduction in
incidence of genital ulcers
o  47% overall GUD,  63% HSV+ GUD
• Higher than expected prevalence, non-specificity and
site variability in GUD diagnosis among women
Possible Interpretations
•
HSV-2 is a risk marker, not a risk factor for HIV
o Unlikely to be only confounding, given plethora of epidemiologic data
•
Concept is right but intervention isn’t potent enough
– HSV in Africa responds less well to acyclovir; less effect on HSV+ GUD than in
prior trials
o Acyclovir pharmacokinetics or susceptibility a factor?
o Adherence overestimated?
o Different natural history of HSV in African women?
o Other etiologies of GUD in African women?
•
We have underestimated HSV-2
– More frequent reactivation, persistent genital immune response
o Need better virologic and/or immunologic tools
Acknowledgements
♦
♦
♦
♦
Study Participants
HPTN 039 Protocol team and staff
HIV Prevention Trials Network (HPTN)
Sponsored by NIAID, NIDA, NIMH, NICHD,
and OAR under Cooperative Agreement #
U01 AI068619
Association between Perianal or Penile ulcers and
circumcision
Compare
Perianal Ulcer/
Circumcision
OR CI95%
P value
Penile Ulcer /
Circumcision
OR CI95%
P value
Circumcision:
0.62 [0.33, 1.16]
0.134
0.80 [0.38, 1.69]
0.561
Age increase 1 yr
0.97 [0.95, 0.99]
0.003
0.96 [0.95, 0.98]
< 0.001
Based on GEE model, adjusted for region and time in study
Effect of sexual role on association between penile
ulcer and circumcision
Compare
OR
CI95%
P-value
Acyclovir vs Placebo
0.417
[0.29, 0.59
< 0.001
Receptive: Circumcision yes vs no
2.87
[1.23,
6.66]
0.0014
Versatile: Circumcision yes vs no
1.14
[0.46,
2.81]
0.779
Insertive: Circumcision yes vs no
0.55
[0.28,
1.07]
0.079
Unknown: Circumcision yes vs no
0.23
[0.07,
0.67]
0.007
Age increase 1 yr
0.97
[0.95,
0.98]
< 0.001
Time increase 1 yr
0.93
[0.91,
0.96]
< 0.001
Based on GEE model, adjusted for region and time in
study
Acyclovir as a ‘probe’ for HSV-HIV
synergy
• Targets an enzyme only present in herpes viruses (thymidine
kinase), not in human cells or other viruses
• Shortens duration of genital ulcers in episodic therapy
• If taken daily (eg acyclovir 400 mg twice daily), reduces
shedding of herpes virus (HSV-2 ) by 80-90%
• Does not have specific activity against HIV virus
• Very safe and well-tolerated; rare to have any side effects
• Resistance is rare (3%) and only occurs in the setting of ‘drug
pressure’ in immunocompromised persons
• Related antivirals (valacyclovir & famciclovir) have similar
spectrum of activity, modestly longer half-life, not yet generic