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Safety and tolerability of vaginal tenofovir gel (TFV) in HIV-uninfected and HIV-infected women (HPTN 050)
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K H Mayer1, L Maslankowski2, W El-Sadr3, J Justman4, B Masse5, C Hendrix6, J Rooney7, A Kwiecien8, L Soto-Torres9
1Miriam Hospital/Brown University, Providence, United States; 2University of Pennsylvania, Philadelphia, United States; 3Harlem Hospital, New York City, United States; 4Bronx-Lebanon Hospital, New York City, United States; 5University of Washington, Seattle, United States; 6Johns Hopkins University, Baltimore, United States; 7Gilead Pharmaceuticals, Foster City, United States; 8Family Health International, Arlington, United States; 9NIAID, Bethesda, United States
Ken Mayer reported the results of this study in an oral abstract at the Intl AIDS Conference in Bangkok (July 2004). One of the most compelling needs in HIV both globally in the USA is to find an effective microbicide that prevent HIV sexual transmission. The results from this study are a first step in making progress towards perhaps tenofovir gel providing an answer to this problem.
The purpose of this study was to determine if use of the gel is acceptable to men & women, to assess local & systemic toxicity, and to determine the highest tolerated combination of either 0.3% or 1% tenofovir gel (TFV) applied once or twice daily for two weeks in low-risk, sexually abstinent and active HIV(-) and then in abstinent and active HIV (+) women. TFV gel pharmacokinetics (PK) and effects on genital HIV shedding were also studied.
Safety labs and pelvic exams were completed at screening, enrollment, Day 2-3, Day 7 and Day 14 visits with colposcopy at enrollment and at Day 14. PK samples were collected after the first product application and on Day 13. Adverse events (AE) were graded based on NIH criteria.
RATIONALE FOR THE USE OF TOPICAL TENOFOVIR (PMPA, brand name Viread)
--PMPA is an adenosine nucleoside monophosphate (nucleotide) RTI
--Subcutaneous injection of 20-30 mg/kg of PMPA once daily for 4 weeks before or after intravenous SIV challenge protected 25/25 rhesus macaques (Tsai, 1995)
--Intravaginal application of 1% or 10% PMPA gel before or after vaginal SIV challenge also protected 100% of macaques (Miller, 1996)
--Animal toxicology studies of vaginal PMPA demonstrated a good safety profile.
The author's conclusions:
--no life-threatening AEs or deaths
--rare severe AEs (1 possibly product-related)
--most AEs were mild and confined to the genital tract]
--only one severe colposcopic finding
--about half of women tested had low, but detectable serum Tenofovir levels
--Tenofovir gel is acceptable to women
--Tenofovir vaginal gel used 1% BID was well-tolerated in abstinent and sexually active HIV(-) and HIV(+) women, with limited systemic absorption and with no clinically significant systemic toxicity detected and with possible beneficial effects on vaginal microflora
--extended safety and effectiveness studies are warranted, based on these initial data.
STUDY AND RESULTS
HPTN 050 -- PHASE I TRIAL
--open-label, dose and frequency ranging, safety and acceptability trial of 0.3% and 1,0% Tenofovir (PMPA) vaginal gel with a PK component.
--14 days of product use
--sexually abstinent and sexually active HIV-negative & HIV-positive women were enrolled in study
--sites: New York, Philadelphia, Providence, RI
PRIMARY STUDY OBJECTIVES
--to assess the local toxicity of Tenofovir vaginal gel on vulvar and cervicovaginal mucosa in low risk, HIV- & HIV+ women
--to assess the systemic toxicity of tenofovir vaginal gel
--to describe systemic pharmacokinetics (PK) of Tenofovir vaginal gel in a subset of women
SECONDARY STUDY OBJECTIVES
--to assess the acceptability of, and adherence to, a short-term regimen of Tenofovir vaginal gel in low-risk, HIV- women & in HIV+ women and their male sexual partners (active cohorts)
--to examine qualitative aspects of acceptability and adherence, as a pilot for substantive qualitative and quantitative assessments and study burden in future studies
EXPLORATORY OBJECTIVES
--to measure the occurrence of cervicovaginal shedding of HIV
--to assess the genotypic resistance patterns of HIV in genital secretions and blood samples from the HIV-infected female participants
--to measure vaginal flora characteristics, and to descriptively examine changes in these characteristics
COHORT PROGRESSION
A1- Sexually abstinent HIV- 0.3% QD (n=12)
A2- Sexually abstinent HIV- 1.0% QD (n=12)
A3- Sexually abstinent HIV- 0.3% BID (n=12)
A4- Sexually abstinent HIV- 1.0% BID (n=12)
B- Sexually active- HPDF (n=12)*
C- Sexually abstinent HIV+ HPDF (n=12)
D- Sexually Active HIV+ HPDF (n=12)*
HPDF=Highest Practical Daily Frequency 1.0% BID
PK done on 6 women from cohorts A2, B, C, D
*male partners are enrolled.
HPTN 050 INCLUSION CRITERIA
--18 to 45 yrs old
--regular menstryual cycle, or amenorrheic due to long acting progestins
--sexually active cohorts: mutually monogamous male artner
HIV+ Cohorts:
--CD4 cell count of at least 200
--HIV plasma RNA <10,000 if on HAART and
--stable ART or
--HIV plasma RNA <55,000 if treatment naïve
HPTN 050: EXCLUSION CRITERIA
--post-menausal or have had a hysterectomy
--pregnant or breast feeding
--grade 3 liver, renal, or hematologic abnormality
--antibiotic treatment <14 days prior to enrollment
--abnormal PAP smear
--genital ulcer or other deep epithelial disruption
--intermenstrual bleeding within 3 months prior to enrollment
--STD in 6 months prior to enrollment
HPTN 050
--full medical history & physical exam on screening
--safety labs, pelvic exams on screening, enrollment, day 2-3, day 7 & day 14 using DAIDS Toxicity Tables
--Colposcopy at enrollment, day 14
--enrollment completed at 16 Jan 2004 (n=84)
PK PROTOCOL & VIROLOGY
Enrollment and day 13
PK measurements
--0.5, 1, 2, 4, 6, 8, 12 hours post-dosing
--day 14 (24 hr post-day 13 dose)
Resistance Testing
--plasma & CVL tested at day 14
--Roche Amplicor, version 15
CVL RNA extracted by Boom Method
--PVL & CVL >500 c/ml: Viroseq Genotyping Assays run by Susan Eshleman, JHU
HPTN 050: ACCEPTABILITY RESULTS
ACCEPTABILITY MEASUREMENT:
Quantitative
--behavioral assessment measuring history of vaginal product use
--follow-up acceptability measuring vehicle-, application-, and use-associated factors
Qualitative
--Female Participants: focus groups
--Male Sexual Partners: individual interviews
HPTN 050 PARTICIPANTS
Demographics (n=84):
--mean age: 36.5
Race:
--African-American/Black: 45%^
--White: 35%
--Asian: 2%
--Other: 18%
--Latino: 19%
Employed: 34%
Student: 17%
HPTN 050 ADVERSE EVENTS
--no life-threatening AEs or deaths were reported
--92% had at least one AE; 87% had a mild AE; 40% had at least one moderate AE; generally limited duration
--70% had a genital tract AE; 32% a GI symptom
--1 severe AE (possibly drug related): lower abdominal cramping
--3 severe AEs (not drug related): bronchitis, hyperglycemia, suicidal ideation
--1 participant terminated product use due to a moderate AE of vulvar ulceration (probably related)
THE MOST COMMON ADVERSE EVENTS WERE:
Genital pruritis (itching): 23%
Genital erythema (redness of skin): 18%
Applicator site bruising: 17%
Applicator site erythema: 17%
Vaginal discharge: 15%
Irregular menses: 13%
Metrorrhagia (bleeding from uerus): 11%
Gel concentration, sexual activity, and HIV status were not associated with a specific AE pattern.
HPTN 050 COLPOSCOPY DATA
--50% developed at least one new pelvic exam or colposcopic finding while on study gel
--erythema was the most common colposcopy finding
--1 woman had a severe colposcopic finding (defined as deep epithelial disruption)- finding occurred 9 days after last dose and pt had similar ulcerations on other parts of body associated with eczema exacerbation
HPTN 050 PHARMACOKINETICS
--women on oral Tenofovir were excluded
--lower limit of quantification: 2.99 ng/ml
--14 of 25 (56%) women with PK data had low but detectable serum Tenofovir levels
--Cmax 3,0-25.8 ng/ml; these levels are below the Cmin following daily oral Tenofovir DF dosing (50 ng/ml)
HPTN: 050: VIROLOGY
--HIV was detected in the plasma of 13/24 HIV+ women dat Day 0 and 12/24 at Day 14, but in CVL of only 2 women at Day ) & none at Day 14
--no new resistance mutations evolved in plasma or CVL after 14 days of TFV gel use
--no pt had high level TFV mutations e.g. K65R
--3 women had plasma mutations associated with low level TFV resistance at Days 0 and 14 (M41L, L210M, +/- T215 I/Y), but 2 also had M184V, which would increase TFV susceptibility
HPTN 050: VAGINAL MICROFLORA
--29 women had Asymptomatic Bacterial Vaginosis at Enrollment (Nugent's criteria)
--BV resolved in 14 of these women (48%)
--1 of 39 women without BV at enrollment developed BV after 14 days of gel use
--5% of women developed vaginal candidiasis after product use
HPTN 050: ADHERENCE
--non-adherence was defined as 3 or more days of missed product use (out of 14 days)
--74 (91%) of 81 women who completed the trial were adherent to gel use
--3 women terminated early from the vstudy
--1 woman was lost to follow-up; 2 women refused further participation
--none were associated with AEs
HPTN 050: ACCEPTABILITY RESULTS
"If you had reasons to be worried about getting or passing HIV and this gel were available, how likely would you be to use the gel?"
| Women | Men | | n=79 | n=21 | | Would definitely or probably use it | 94% | 81% | | Would definitely or probably NOT use it | 6% | 19% |
HPTN 050 ACCEPTABILITY RESULTS
Reactions to gel's characteristics
| Women | Men | | n=79 | n=21 | | Liked a lot or somewhat the gel's ... | | | | --color | 94% | 76% | | --smell | 82% | 71% | | --consistency | 75% | 67% | | OVERALL LIKED GEL | 78% | 76% |
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