Clinical Trial Details
— Status: Completed
Administrative data
NCT number |
NCT04965662 |
Other study ID # |
JF006-3170 |
Secondary ID |
|
Status |
Completed |
Phase |
Phase 4
|
First received |
|
Last updated |
|
Start date |
January 1, 2018 |
Est. completion date |
March 16, 2021 |
Study information
Verified date |
July 2021 |
Source |
Guy's and St Thomas' NHS Foundation Trust |
Contact |
n/a |
Is FDA regulated |
No |
Health authority |
|
Study type |
Interventional
|
Clinical Trial Summary
The study is looking at a new way to reduce the risk of catching HIV. Post-exposure
Prophylaxis for sexual exposure (PEPSE) is where a month of HIV drugs can be given to reduce
the chance of getting HIV, after a risk. To improve its use the Investigators want to see
whether providing a 5-day course of PEPSE for people to keep at home (HOME PEPSE) will lead
to it being taken much quicker than having to get it from sexual health clinics or A&E. The
HOME PEPSE packs contain HIV tablets that are used in routine HIV care. However the type of
HIV drugs are slightly different to those currently used in PEPSE and the Investigators hope
that they will have fewer side effects. HOME PEP consists of Truvada and Maraviroc.
140 gay men who are at high risk of getting HIV will be randomised to one of two groups.
Group A will receive HOME PEPSE immediately and group B will receive HOME PEPSE after 48
weeks on the study.
Description:
HIV causes significant morbidity and the estimated lifetime cost of one HIV transmission is
£0.5-1 million. Despite enormous prevention efforts, transmission rates in the UK remain
stable. The population most at risk of acquiring HIV in the UK are men who have sex with men
(MSM), who are estimated to number over 500,000 (3.6% of the male population). The estimated
prevalence of HIV among MSM aged between 15 and 44 years old is approximately 5%.
In 2013 the highest ever number of new HIV diagnoses (3,000) among MSM was reported and 85%
of these were estimated to have been acquired in the UK.
This is supported by a concomitant increase in reported high risk behaviours such as
condomless anal sex, from 24.3% to 36.5% of the cohort surveyed in London gyms in 1998 and
2008 respectively. In London, approximately 80% MSM are HIV negative: however high-risk sex
continues in the presence of an increasing pool of HIV infected individuals. As such
effective HIV prevention interventions are urgently needed to keep such individuals
uninfected.
Despite sustained education and public health messages high levels of condomless sex among
MSM are reported. HIV prevention tools include condoms, Post-Exposure Prophylaxis following
Sexual Exposure (PEPSE), HIV pre-exposure prophylaxis (PrEP), HIV testing to reduce the
undiagnosed fraction, antiretroviral treatment (ART) -as-prevention and circumcision.
Clinical trials are underway to evaluate the efficacy and cost effectiveness of these
approaches.
PEPSE is a key component of HIV prevention. A prospective randomised-controlled trial to
determine the efficacy of PEPSE has been precluded due to the high number of participants
that would be required for such a study. A case-control study conducted in healthcare workers
suggested that the use of zidovudine (AZT) for post exposure prophylaxis after percutaneous
exposure to HIV-infected blood was associated with a significant (OR 0.19 (95% CI 0.06-0.52)
decrease in the risk of HIV transmission. In addition, mother to child transmission studies
where only the neonate received ART have demonstrated a protective effect.
The efficacy of PEPSE is dependent upon the following key factors:
1. Speed of uptake from sexual exposure :
The time from exposure to initiation of PEPSE is critical for efficacy. Once HIV crosses
a mucosal barrier it may take up to 48-72 hours before HIV can be detected within
regional lymph nodes and up to five days before HIV can be detected in blood. Initiation
of ART has been shown to reduce dissemination and replication of virus in all tissues if
initiated early after inoculation in an animal model.
Animal models mimicking sexual exposure either vaginally or rectally also show
protective benefits of the use of ART and demonstrate that time to initiation and
duration of PEPSE influence outcome of PEPSE, with delays and shorter courses reducing
effectiveness (Tsai J Virol 1998). For example, a phase I/II clinical trial using PMPA
(Tenofovir) administered subcutaneously for PEPSE demonstrated that simian
immunodeficiency virus (SIV) infection was prevented following an intravenous
inoculation in 100% of macaques if administered within 24 hours and continued for 28
days. As either the time to initiation of PEP was increased or the duration of PEPSE was
reduced then the number of macaques protected declined.
Following rectal SIV challenge however, PEPSE offers no protection if taken >24 hours
post exposure, with most protection occurring within a 2 hour exposure timeframe. This
is of enormous concern for those practicing unprotected receptive anal sex, which is the
highest risk sex act for HIV transmission. In the UK, the median time to first PEPSE
dose is 24 hours; this unsatisfactory duration has been attributed to the fact that most
exposures to HIV occur outside routine clinic hours and a lack of knowledge of where to
access PEPSE out-of-hours. Learning from the emergency contraception model women
provided with an advance provision of emergency contraception use it to a greater extent
and more rapidly after condomless vaginal sex without engaging in increased sexual
risk-taking behaviour compared to standard of care.
2. Uptake following sexual exposure. In the Gay Mens survey, 1.7% of gay men reported ever
using PEPSE despite 94% reporting at least one sexual partner sex in the preceding year.
Approaches to increase PEPSE uptake are therefore required.
3. Adherence
The British Society for Sexual Health and HIV (BASHH) guidelines for PEPSE recommend Truvada
and Kaletra for 28 days and the indications for its use are shown in table 1. It is well
recognized that ritonavir-boosted protease inhibitors including Kaletra are commonly
associated with gastrointestinal side effects and elevations in lipids (Kaletra Spc). Kaletra
inhibits cytochrome p450 CYP3A and therefore has many drug-drug interactions. Within the
ABT-730 study 37% patients experienced grade 3 or 4 adverse events and laboratory
abnormalities in the BD Kaletra arm.
As delayed initiation and non-completion of PEPSE due to side effect are likely to reduce
efficacy, it is important to explore regimens that is likely to be better tolerated and ways
in which PEPSE could be taken sooner after exposure. Maraviroc (MVC), a CCR5 antagonist has
been shown to be an effective antiretroviral agent in the MOTIVATE and MERIT studies. In
MERIT the percentage of patients achieving HIV-1 RNA <50 copies/mL was comparable to those
receiving efavirenz where they had CCR5-tropic virus at baseline. Maraviroc does not inhibit
any of the major P450 enzymes at clinically relevant concentrations (CYP1A2, CYP2B6, CYP2C8,
CYP2C9, CYP2C19, CYP2D6 and CYP3A4). Maraviroc appears to have fewer drug-drug interactions
than Kaletra and the frequency of grade 3 or 4 adverse events was low (20%) in the MERIT
study. Maraviroc acts pre-integration which may have theoretical advantages for PEPSE/PrEP
against HIV. Animal data demonstrates that the use of a CCR5 inhibitor reduced the likelihood
of macaques acquiring SIV following vaginal exposure. Maraviroc has also been demonstrated to
penetrate the male and female genital tract well and achieve high rectal tissue
concentrations which may be beneficial for PEP or PrEP. In the event of failure of MVC based
PEPSE, it is unlikely treatment options will be affected. Maraviroc is given for HIV
treatment twice daily, however safety data supports once daily use and may confer advantages
in adherence. Trials evaluating the safety of Maraviroc (MVC) as PEPSE are currently underway
in the UK and Spain.
Overall, the cost of PEPSE is minimal in comparison to an HIV transmission and may provide
potential cost saving and adherence benefits over daily PrEP. The Investigators propose
reducing the time from HIV exposure to first dose of PEPSE in high risk individuals by
providing HOME PEPSE (a 5-day pack of PEPSE to be kept at home by the individual in case of
need). By removing traditional logistical barriers to PEPSE use, this approach aims to
improve the appropriate and immediate access of PEPSE, reduce attendance at A & E, reduce
time to first dose (and hence increase efficacy) and further empower individuals to prevent
HIV acquisition. If a positive preventative effect is shown then this approach will be
evaluated in a large randomised controlled study, rolled out to other NHS providers and is
likely to lead to a revision of the UK PEPSE guidelines. Maraviroc lends itself well to
episodic, HOME provision PEPSE - it is stable over a long period of time, has fewer drug-drug
interactions than protease inhibitors and is well tolerated.
The Investigators hypothesize that advanced provision of PEPSE using Truvada/Maraviroc 600mg
OD, so called "HOME" PEPSE to high HIV risk individuals will improve the speed and
appropriate uptake of PEPSE and be extremely well tolerated.
140 men who have sex with men and who are at high risk of getting HIV will be randomised to
one of two groups. Everyone will be seen at 12 weekly intervals for a sexual behaviour
questionnaire and sexual health screen. A more detailed questionnaire will be given at week 0
, week 48 and week 72.
Group A will receive HOME PEPSE immediately and finish the study at week 48. Anyone starting
HOME PEPSE will be advised to come to clinic as soon as possible to be assessed for the need
for a 28 day PEP course. As starting HOME PEPSE (or standard PEPSE for Arm B) is dependant on
participant risk behaviour, HOME PEPSE could not be taken at all during the trial or could be
taken multiple times. Therefore how many time certain standard of care/research procedures
occur during this trial, such as phlebotomy, is dependant on how many times participants take
PEPSE.
Group B will receive HOME PEPSE after 48 weeks on the study and finish the study at week 72.
For the first 48 weeks, people in this group will be able to get PEPSE from the normal places
i.e. an A&E department or a sexual health clinic. If people do start PEPSE they will be
advised to contact the research team so that they can record this and complete a short
questionnaire summarizing what happened.
At 48 weeks, everyone will receive a HOME PEPSE pack and have a urine test and blood test to
test the kidneys and liver. They will then be followed up for a further 6 months.