Clinical Trial Details
— Status: Not yet recruiting
Administrative data
NCT number |
NCT05515770 |
Other study ID # |
59166522.7.1001.5262 |
Secondary ID |
|
Status |
Not yet recruiting |
Phase |
Phase 3
|
First received |
|
Last updated |
|
Start date |
September 20, 2022 |
Est. completion date |
February 2026 |
Study information
Verified date |
August 2022 |
Source |
Evandro Chagas National Institute of Infectious Disease |
Contact |
Thiago Torres, Pharm D, PhD |
Phone |
+55213865-9573 |
Email |
thiago.torres[@]ini.fiocruz.br |
Is FDA regulated |
No |
Health authority |
|
Study type |
Interventional
|
Clinical Trial Summary
Although CAB LA PrEP has been proven efficacious in blinded randomized controlled clinical
trials, additional research is needed to evaluate effectiveness in real world settings as
well as to identify effective implementation strategies. The proposed implementation study
will assess the safety and effectiveness of open label CAB LA PrEP when offered at public
health facilities to cisgender men and transgender or gender non-binary individuals who have
sex with persons assigned male at birth. The study will also evaluate two nested
implementation strategies, an mHealth education and decision support tool and a WhatsApp
injection appointment reminder. The study will also assess overall facilitators and barriers
to integrating CAB LA into existing oral PrEP services.
Description:
HIV Pre-Exposure Prophylaxis in Latin America: Results from randomized clinical trials and
observational studies have proven that oral tenofovir disoproxil fumarate-based pre-exposure
prophylaxis (PrEP) is protective against HIV acquisition. This protection has been confirmed
to be both effective and safe across all types of exposures, sexes and gender identities, and
dosing regimens. PrEP is now recommended as part of the standard prevention regimen by the
World Health Organization (WHO) for individuals at substantial risk of HIV infection.
Increasing PrEP access is a priority in Latin America, where several countries have recorded
a rising HIV infection incidence, particularly among men who have sex with men (MSM).
In 2020, there were an estimated 930,000 people in Brazil living with HIV (PLWH). Recent
studies estimate an HIV prevalence among Brazilian MSM reaching approximately 23% and rates
among transgender women (TGW) surpassing 30% in some cities. Young MSM are among the few
populations with increasing numbers of new HIV infections in Brazil, where HIV incidence has
stabilized in overall population. PrEP in Brazil is freely available through the national
Public Health System. As of May 2022, there were 424 healthcare centers across all Brazilian
states providing PrEP to approximately 343,000 individuals. Although over 80% of current PrEP
users in Brazil are MSM, PrEP utilization remains well below the 2018 estimate of 66,120
Brazilian MSM aged 15-64 years who were eligible for and willing to use PrEP. This number is
likely to be even higher with 2021 population estimates. Among more than 57,000 individuals
that initiated PrEP in Brazil, approximately 43% discontinued its use. PrEP discontinuation
was common among MSM (~40%) and TGW (over 50%).
Tenofovir-based oral PrEP has been effective in dramatically reducing population-level HIV
incidence in multiple districts, including London, San Francisco, New South Wales, and in
rural Kenya and Ugand. Despite these successes, PrEP has not decreased HIV incidence equally,
particularly among the most at-risk populations (women, youth, racial and ethnic minority
MSM, and TGW), due to user adherence challenges. PrEP Brasil, the Brazilian daily oral PrEP
demonstration study, identified that 74% of overall participants had protective drug levels.
Nevertheless, young participants and TGW had decreasing rates of protective drug
concentrations throughout the study. In addition, data from the ImPrEP study, the largest
PrEP demonstration study in Latin America with the goal of evaluating the feasibility of
same-day PrEP implementation to MSM and transgender women in the context of the Public Health
Systems of Brazil, Mexico, and Peru, identified lower PrEP adherence among transgender woman
and individuals younger than 24 years of age.
To realize PrEP benefits, individuals need to both initiate PrEP and remain on PrEP during
periods at-risk. In multiple studies, reasons for stopping or never initiating PrEP include,
in addition to challenges accessing the medication, low self-perceived risk, concerns about
medication side effects or a desire not to take a daily pill, stigma, or competing life
events. Long-acting PrEP agents have the potential to address some of these concerns by
providing consistent protection through infrequent, discrete administration, avoiding relying
on adherence to a daily oral regimen and the need for disclosure with sex partners and
acquaintances.
Long Acting Cabotegravir for Prevention: Long-acting injectable cabotegravir (CAB-LA) is a
novel integrase strand-transfer inhibitor (INSTI). Two large randomized controlled trials
(RCTs), known as HIV Prevention Trials Network (HPTN) Study 083 and HPTN Study 084, have
demonstrated the effectiveness of injectable cabotegravir when compared to oral
tenofovir-disoproxil-fumarate/emtricitabine (TDF/FTC) PrEP.
HPTN 083 was a double-blind double-dummy RCT which assessed the effectiveness of every-8-week
dosing of cabotegravir for PrEP compared to oral TDF/FTC PrEP among cisgender men and TGW at
43 sites in the United States, Latin America, Asia, and Africa using a non-inferiority study
design. Overall, 4,566 participants, of whom 12.5% were TGW, were assigned 1:1 to injectable
cabotegravir given every 8 weeks or daily oral TDF/FTC PrEP and were followed for 153 weeks
during the blinded phase of the study. The blinded portion of the study was stopped early for
efficacy, with injectable cabotegravir demonstrating statistical superiority over TDF/FTC
with a hazard ratio (HR) of 0.34 for HIV incidence when compared to TDF/FTC [95% confidence
interval (CI)=0.18-0.62]. Evidence of post-enrollment HIV infection was identified in 51
participants, with only 12 of the cases occurring in the cabotegravir group. When examining
sub-groups, the magnitude and direction of the effectiveness of cabotegravir was preserved
among populations who have historically experienced greater adherence challenges with TDF/FTC
PrEP, including among youth, TGW, and U.S. Black participants.
Updated results including incident HIV infections for the Year 1 unblinded period show 11 new
incident HIV infections in the CAB arm and 31 in the TDF/FTC arm, maintaining a HR of 0.34,
with incidence rates in both arms showing more than 1 ½ fold higher in the unblinded period
compared to the blinded period, with no new safety concerns identified. PrEP adherence
declined in both arms over time. In the TDF/FTC arm, adherence decreased from 73% in the
blinded period to 59% the Year 1 unblinded period. In the CAB arm, injection "coverage"
declined from 91.5% during the blinded study period to 79.9% during the Year 1 unblinded
period.
An important characteristic of ARV-based PrEP regimens is how long the drug persists after
final administration (i.e., the tail phase of the drug). It was initially thought that the
pharmacokinetic tail could create a period of vulnerability in persons who acquire HIV
infection, allowing for emergence of drug-resistant strains (33,34). However, based on the
current data, it seems very unlikely that this is a period of vulnerability as no incident
infections have happened during the pharmacological tail period in the HTPN 083 trial.
Rare breakthrough infections were observed in HPTN 083, but detection of HIV infection in
participants who received CAB PrEP was often delayed using standard HIV testing algorithms.
Integrase strand transfer inhibitor (INSTI) resistance-associated mutations (RAMs) were
detected in 5 CAB-exposed participants with HIV infection (GenoSure PRIME assay, viral load
[VL] ≥500 c/mL); 2 other participants did not have genotyping results since all VLs were <500
c/mL. In all 7 participants, detection of infection at study sites using rapid tests and
antigen/antibody tests was delayed (median 60 days; range 35-117) and all 7 participants
received CAB-LA injections after HIV infection had occurred. The use of a single-genome
sequencing (SGS) INSTI genotyping assay detected INSTI RAMs in 6/7 participants. The use of
an RNA assay with a limit of detection (LOD) of 30 copies/mL detected infection before a
major INSTI RAM was detected (4 cases) or before additional major INSTI RAMs accumulated (2
cases). In the last case, this could not be assessed since SGS was not successful before the
first site-positive visit. Consistent with newly released CDC guidelines, earlier detection
of HIV infection using an HIV RNA assay in the setting of CAB-LA PrEP would allow for earlier
antiretroviral therapy (ART) initiation which may reduce the risk of INSTI resistance. The
impact of different HIV testing strategies on INSTI resistance in real-world settings is
unclear making implementation science projects critical.
Using a similar superiority study design, HPTN 084 enrolled HIV negative cisgender women at
risk for HIV infection at 20 sites in 7 countries in sub-Saharan Africa including South
Africa, Botswana, Eswatini, Zimbabwe, Malawi, Kenya and Uganda. Overall, 3,223 cisgender
women were enrolled, with 57% of participants 18-25 years old. There were 40 confirmed HIV
infections observed over 3892 person-years of follow up. The overall HIV incidence among all
study participants was 1%, suggesting that both products were highly effective in preventing
HIV in this population. Four infections were detected in the CAB arm which is equivalent to
an incidence of 0.2%, and 36 infections were detected in participants assigned to TDF/FTC
which is equivalent to an incidence of 1.85%. No differences in treatment effects were
observed in pre-specified sub-group analyses exploring effects by age, BMI, and contraceptive
use.
Data from 083 and 084 supported the US Food and Drug Administration regulatory approval of
CAB-LA for HIV prevention on December 20, 2021. Subsequently, national regulatory approval
for CAB-LA PrEP has been sought in numerous countries, including Brazil.
The ImPrEP Study: ImPrEP is a UNITAID funded, multi-country PrEP implementation project. It
is a collaboration between the Oswaldo Cruz Foundation (Fiocruz) and Ministries of Health
from Brazil, Peru, and Mexico. One of the ImPrEP components has been a multi-site
prospective, open-label demonstration study to assess uptake, acceptability, and feasibility
of same-day, daily TDF/FTC oral PrEP among MSM and TGW at substantial risk for HIV
acquisition. A total of 28 sites conducted the study, 14 sites in Brazil, 4 in Mexico, and 10
in Peru. Overall, a total of 9,509 participants were enrolled with 26% being young (18-24
years), 73% were non-white, and over 640 (5.6%) participants were TGW. Overall, 68% of
participants had long-term engagement; however, younger, less educated participants, TGW and
sex workers were significantly less likely to reach long-term engagement.
Although HIV incidence during the study was relatively low (0.82/100 person-years), it was
higher among non-white, younger (18-24 years) and TGW participants. These disproportionately
worse outcomes highlight that PrEP agents not requiring daily or planned oral dosing could
increase effective PrEP use among these most vulnerable populations. It is reassuring that
injectable cabotegravir has demonstrated comparable effectiveness among youth, Black MSM, and
TGW in clinical trials. However, advantages in bypassing daily adherence behavior may not be
realized if individuals cannot access injectable PrEP or do not return for repeat injections.
Additional data from injectable PrEP service delivery in real-world settings will be needed
to support roll-out and national program decisions to include CAB LA PrEP as part of
prevention services.
Person-centered HIV Prevention: At the core of person-centered HIV prevention is the
acknowledgement that people are best placed to decide which prevention methods are right for
them and that their preference may change over the course of their life. Person-centered care
emphasizes meeting an individual's sexual preferences, needs, and goals, using
person-centered counseling approaches, such as shared decision-making. In a counseling visit
utilizing shared decision-making, the individual is recognized as the expert regarding their
lived experience, life situations, needs, and preferences for sexual health prevention and
care. The conclusion of such a counseling conversation may include patients choosing not to
use a prevention method or discontinuation of a more effective method for a less effective
method (or no method at all). Central to a people-centered approach to HIV prevention is
effectively communicating information about the advantages and disadvantages of available
methods and about product characteristics to facilitate informed decision making. A
people-centered approach also supports adherence, once an HIV prevention method has been
chosen, in ways which will be experienced as supportive and useful by the method user.
Implementation Research is Needed to Prepare for Scale-up of CAB-LA PrEP: Now that the
efficacy of CAB-LA PrEP has been proven in large clinical trials, implementation studies must
explore how to best integrate its delivery into existing PrEP services in 'real world'
settings. Implementation studies provide crucial information about how interventions, proven
efficacious under randomized clinical trial conditions, can be optimized for delivery within
routine service contexts. Implementation research provides an opportunity to identify
implementation barriers and to maximize the feasibility and acceptability of intervention
delivery as well as intervention effectiveness.
The investigators are proposing a CAB-LA implementation-effectiveness research study (hybrid
Type 2) that leverages the impact of the current ImPrEP project in Brazil to generate
critical evidence about the feasibility, acceptability, and effectiveness of incorporating
CAB-LA PrEP into existing services for oral PrEP. This implementation project is fully
grounded in the principles of people-centered care, with a focus on respect for participant's
preference and expressed needs. Study results will inform global guideline recommendations,
regional and national policy development, and program implementation guidance for Brazil and
other low and middle-income countries (LMIC).
In the field of contraception, increased availability of method options and informed
decision-making about method choice has improved uptake and persistence of the contraceptive
methods used. It is likely that expanding method options for HIV prevention will similarly
improve uptake and persistence. However, informed decision-making requires user understanding
of how methods must be used, potential side effects, and effectiveness. Although health
worker counseling plays a crucial role in providing patients with information about different
methods, mobile health (mHealth) has great potential to provide valuable additional
educational support. For example, decision support tools have been shown to be both
acceptable and effective in guiding women's contraceptive decisions. The investigators will
develop and test a similar mHealth education and decision support tool for use in MSM,
non-binary and transgender populations.
Adherence to the CAB LA injection schedule (at 1 month for a second dose, and every 2 months
thereafter) will be crucial to preventing HIV acquisition. Although the results of HPTN 083
and 084 demonstrated that overall, participants had better adherence to clinic visits for
their CAB LA injections than for daily oral PrEP, additional support for maintaining
adherence to the CAB LA injection clinic visits is needed for some users. In a randomized
controlled trial, interactive short message service (SMS)-based support improved daily oral
PrEP persistence (80% vs. 57% at 36 weeks, p<0.01) when compared to standard of care among
diverse young MSM at risk for HIV acquisition in the US. In the current study, The
investigators will test the impact of WhatsApp appointment reminders on participant adherence
and continuation of CAB-LA PrEP.
Finally, this implementation research study will include an exploration of the best,
acceptable HIV testing strategy and algorithm for use with CAB LA PrEP. A key challenge with
the implementation of injectable cabotegravir as PrEP is its impact on diagnosis of
breakthrough HIV infections. Detection of HIV infection at study sites was delayed in
participants in both HPTN 083 and 084, illustrating the challenge of using conventional
testing approaches to screen for HIV infection in studies using potent, long-acting PrEP
agents. With CAB-LA, the result of delayed diagnosis may contribute to the development of
resistance associated mutations that would be expected to confer reduced susceptibility to
integrase inhibitors. The use of an HIV RNA assay for screening could possibly detect these
infections earlier, prompting earlier ART initiation and preventing emergence of HIV
resistance. Nevertheless, viral load (VL) testing is expensive and could cause implementation
of cabotegravir-based PrEP to remain limited in LMICs should these testing requirements be
adopted by regulatory agencies and guideline panels. Early detection of HIV infection and
prompt ART initiation could improve clinical outcomes in persons who become infected despite
CAB-LA prophylaxis. In addition to HIV rapid tests this study will incorporate the use of
point-of-care VL testing with GeneXpert for VL to identify HIV infection not detectable with
the HIV rapid tests at enrollment. The use of this technology will enable participants to
receive VL results and, if negative, receive a same-day CAB LA injection. The use of
non-INSTI ART to treat people who acquire HIV while taking injectable CAB may be an option.