Abstract
Background:
The Antibody Mediated Prevention (AMP) trials (HVTN 704/HPTN 085 & HVTN 703/HPTN 081) are the first efficacy trials to evaluate whether VRC01, a broadly neutralizing monoclonal antibody (mAb) targeting the CD4 binding site of the HIV envelope protein, prevents sexual transmission of HIV-1. HVTN 704/HPTN 085 enrolled 2,701 cisgender men and transgender (TG) individuals who have sex with men at 26 sites in Brazil, Peru, Switzerland and the United States.
Methods:
Participants were recruited and retained through early, extensive community engagement. Eligible participants were randomized 1:1:1 to 10 mg/kg or 30 mg/kg of VRC01 or saline placebo. Visits occurred monthly, with intravenous (IV) infusions every 8 weeks over 2 years, for a total of ten infusions. Participants were followed for 104 weeks after first infusion.
Results:
The median HVTN 704/HPTN 085 participant age was 28; 99% were assigned male sex; 90% identified as cisgender male, 5% as TG female and the remaining as other genders. Thirty-two percent were White, 15% Black and 57% Hispanic/Latinx. Twenty-eight percent had a sexually transmitted infection at enrollment. Over 23,000 infusions were administered with no serious IV administration complications. Overall retention and adherence to the study schedule exceeded 90%, and the drop-out rate was below 10% annually (7.3 per 100-person years) through Week 80, the last visit for the primary endpoint.
Conclusions:
HVTN 704/HPTN 085 exceeded accrual and retention expectations. With exceptional safety of IV administration and operational feasibility, it paves the way for future large-scale mAb trials for HIV prevention and/or treatment.
Keywords: VRC01, bnAb, HIV, passive immunization, AMP studies, HVTN 704/HPTN 085
INTRODUCTION
Approximately 1.7 million people acquired HIV in 2018 globally, despite the availability of multiple prevention methods1. Efforts to expand the available options have been invigorated by advances in B-cell immunology and single cell antibody cloning techniques over the past decade leading to the discovery of broadly neutralizing antibodies (bnAbs) that neutralize multiple HIV-1 variants (breadth) at various concentrations (potency) in vitro2. Reduction of simian immunodeficiency virus and simian HIV (SHIV) acquisition in nonhuman primate (NHP) models by highly potent broadly neutralizing monoclonal antibodies (mAbs) at serum concentrations achievable by intravenous (IV) or subcutaneous (SC) injection has been shown3–5. The feasibility of administering physiological doses of monoclonal antibodies (mAbs) has led to advancement in clinical trials. A fundamental scientific question remains as to whether passive transfer of HIV-1 mAbs is efficacious in preventing sexual transmission of HIV-1 in exposed individuals.
Whereas passive administration of total IgG for pre- or post-exposure prophylaxis of bacterial and viral diseases such as tetanus, hepatitis A/B, and varicella have been routine clinical practice for decades6, only palivizumab (a human mAb) has been licensed for use (prevention of respiratory syncytial virus infection)7. For HIV, select mAbs are effective in decreasing viremia in analytical treatment interruption studies of people living with HIV8,9. Highly potent CD4 binding site mAbs such as VRC01, VRC07–523 and 3BNC117 blocked HIV transmission in NHP/SHIV models and have demonstrated safety and tolerability in phase 1 clinical trials8. Moreover, a strong association exists between serum neutralization and ID50 titers required for protection in NHP/SHIV models10.
Safety and pharmacokinetics of VRC01 administered IV or SC have been evaluated in early phase trials. These data supported testing VRC01 in phase 2b efficacy trials to evaluate its effect on reducing HIV-1 acquisition. The HIV Vaccine Trials Network (HVTN) and HIV Prevention Trials Network (HPTN) partnered to conduct the Antibody Mediated Prevention (AMP) trials, HVTN 704/HPTN 085 (#NCT02716675) and HVTN 703/HPTN 081 (#NCT02568215). HVTN 703/HPTN 081 enrolled cisgender women in sub-Saharan Africa, with feasibility and enrollment results reported in a parallel manuscript. Here, we report on the design, enrollment, baseline measures, and retention of HVTN 704/HPTN 085, which was conducted in cisgender men and transgender (TG) populations in Brazil, Peru, Switzerland, and the US.
METHODS
Protocol development
Dose and administration schedule were based upon the PK and safety profile of two VRC01 phase 1 trials11–13. IV administration was selected to achieve VRC01 concentration and serum neutralizing antibody titers required to prevent HIV-1 acquisition. VRC01 PK studies indicated a plasma half-life of 15 days, with rapid decrease in plasma levels post-infusion and a slower decline over the following 8 weeks, and an estimated mean trough concentration of 6 μg/mL and 16 μg/mL for 10 mg/kg and 30 mg/kg VRC01, respectively11,12. The concentration required for protection from HIV infection is one of the secondary endpoints of the AMP trials. Based on non-human primate models, it is estimated that protection is achieved at serum antibody concentrations 50–100-fold higher than the measured IC50 of the challenge (infecting) virus5.
Participants were randomly assigned to one of three groups at a 1:1:1 ratio of VRC01 10 mg/kg, VRC01 30 mg/kg, or placebo (Figure 1A). IV administration of VRC01/placebo occurred every eight weeks for a total of 10 infusions. Enrollment was concurrent with receipt of first infusion. A minimum of 49 days was required between infusions. Visit windows were designed to allow for flexibility around the target of 56 +/− 7 days from the most recent infusion day (or target day), with an upper allowable window period of 48 days beyond the target day (i.e., up to 104 days after the most recent infusion). Week 80 was the last study visit for the primary endpoint analysis of prevention efficacy. Week 104 was the last study visit for the co-primary endpoint analysis of safety and tolerability, which accounted for the elimination tail of VRC01 and the detection of potentially suppressed/covert HIV acquisition.
Figure 1. Trial schema and CONSORT diagram.
A. Trial schedule and dosing. B. CONSORT diagram. *Total numbers reflect 2 duplicate enrollments (i.e., individuals who enrolled and were randomized twice).
Study operations and administration
HVTN704/ HPTN 085 was approved by the Institutional Review Board (IRB) at the Fred Hutchinson Cancer Research Center, which served as a central IRB for 14 US sites through agreements with those institutions. At the remaining clinical research sites (CRSs), the study was approved by the local IRBs according to in-country regulatory requirements.
Conducting the clinic visits, particularly the infusion visits, efficiently was a major challenge. A Rapid Process Improvement (RPI) workshop was conducted with a team of CRS, community, Network, and Sponsor representatives to optimize the efficiency and participant experience of infusion visits. Infusion visits in previous VRC01 phase 1 trials were >4 hours, even for 30-minute infusion times13. This was attributed in part to limited coordination between CRS pharmacies and clinics regarding study product preparation, transport, and administration, and to inefficient in-clinic visit procedures. The RPI workshop identified strategies to reduce the duration of infusion visits by over 50%, and some CRSs were thus able to accommodate over five infusion visits daily.
Infusions were administered by IV pump over 30 to 60 minutes. Globally, dedicated infusion and urgent/emergent care rooms and HIV diagnostic lab capacity was developed at CRSs, as needed. Data collection and study procedures were standardized at all CRSs in all countries by implementation of standard operating procedures.
Community engagement and recruitment
Community engagement began six months prior to study opening. Community stakeholder meetings with diverse audiences were held regionally and nationally. Recruitment and retention were considered major challenges for the AMP studies, given the 10 IV infusions and 2-year (or 104-week) duration of study participation. Print materials and animated videos were developed in multiple languages. Internet-based recruitment (through social media, Craigslist, dating websites and others), face-to-face outreach by recruiters, referrals from other participants were some of the key strategies that were utilized for recruitment14. Regional protocol-specific websites (www.ampstudy.org) were developed to enhance education of potential study participants and link them to local CRSs.
Screening and enrollment
HVTN 704/HPTN 085 included participants aged 18 through 50 years identifying as cisgender male or TG who were practicing condomless anal intercourse with one or more cisgender male or TG partner(s), or anal intercourse with two or more cisgender male or TG partners in the six months prior to randomization. Informed consent was obtained from all participants. Screening procedures included assessment of behavioral risk criteria; assessment of good general health; and willingness to commit to a two-year schedule of IV infusions, attend monthly visits for HIV testing, complete behavioral surveys, and undergo sexually transmitted infection (STI) testing at enrollment and every six months or as needed. STI testing included gonorrhea (oropharyngeal, urethral and rectal), chlamydia (urethral and rectal), and syphilis (serologic). Participants were excluded for body mass index (BMI) ≥ 40.
HIV prevention package and PrEP
Participants were offered an HIV prevention package that included risk reduction counseling, provision of condoms/lubricant, diagnosis and treatment (or referrals for treatment) of STIs, and counseling about and provision of oral pre-exposure prophylaxis (PrEP; emtricitabine/tenofovir disoproxil fumarate [FTC/TDF, brand name Truvada®]) and post-exposure prophylaxis (PEP). Multiple consultations were held with community stakeholders, site investigators, and regulatory and ethics representatives to plan PrEP access to participants.
Truvada® was not licensed for PrEP at all CRSs at trial initiation in early 2016. For US participants, an HVTN 704/HPTN 085 North America PrEP Referral Program was established through in-kind donation by Gilead Sciences in collaboration with a mail-order pharmacy. Participants in Peru had access to Truvada® through the PrEP Peru Demonstration Project. In Brazil, Truvada® was initially available through the PrEP Brasil Demonstration Project and a UNITAID project supported by the Brazilian Ministry of Health, and then through public access after approval in 2018. In Switzerland, participants accessed PrEP through a non-profit group. PrEP uptake was measured by self-report, prescriptions filled via the North America PrEP Referral Program, and dried blood spot (DBS) sampling.
Feasibility and safety monitoring
Since the AMP trials were the first proof-of-concept efficacy trials with serial IV administration of an HIV mAb, interim feasibility and safety monitoring were pre-specified in the trial design. Feasibility monitoring was completed for the first 122 enrolled participants after completion of the Week 32 visit to evaluate whether an adequate percentage of participants attended study visits and received infusions per protocol. Trial retention with receipt of the first four infusions by the Week 32 visit pooled over the three study groups had to be >80% for the trial to continue. Feasibility metrics including accrual, retention rates and data management quality were monitored throughout the study.
The trial was conducted under the oversight of the NIAID Multinational Data and Safety Monitoring Board (DSMB), which met biannually. Interim safety reports were submitted to the DSMB and the FDA. Safety, including adverse event reports blinded to treatment assignment, was monitored daily by members of the Protocol Safety Review Team (PSRT).
Social impacts
The Networks monitored the impact of trial participation in the social wellbeing of participants as a result of study involvement, including both positive (social benefit) and negative (social harm) repercussions, which were reported at any study visit.
Laboratory assays
DBS sampling for tenofovir
DBS sample collection began in July 2016 and samples were stored for assessment of quantitative concentrations of intracellular tenofovir diphosphate (TFV-DP), an anabolite of FTC/TDF. TFV-DP has a 17-day half-life in red blood cells, which translates to a 25-fold accumulation from no dosing to daily dosing. This makes TFV-DP suitable for monitoring average drug exposure over time15. Detailed testing using a calendar-based selection ensured representative sampling of participants across the visit schedule at all CRSs. This allowed prospective monitoring of FTC/TDF use during the trial to inform assessments of the trial’s ability to answer the primary study question. Prevalence of PrEP use was reported both as the estimated proportion of participant visits with highly adherent PrEP use (above the concentration of TFV-DP designated as consistent with at least four doses a week15) and the proportion of participant visits with any detectable PrEP use (concentration of TFV-DP above the lower limit of quantitation [LLOQ] for the DBS assay).
HIV testing and diagnosis
HIV diagnostic testing was scheduled every four weeks up to week 80 and at any time following report of possible exposure to HIV by a participant. The date of HIV diagnosis was defined as the specimen collection date of the first sample that led to a positive result by the HIV diagnostic algorithm. More than 57,000 HIV tests have been completed in HVTN 704/HPTN 085. All positive or indeterminate tests were evaluated by an adjudication committee prior to confirmation of HIV acquisition.
Statistical analysis
Descriptive statistics were reported for baseline participant characteristics. An inverse sampling probability estimator was used to estimate the percent person-years with detectable and effective PrEP uptake. Confidence intervals for the quantitative assessment of TFV-DP levels in DBS were calculated using a bootstrap method to account for repeated measures across study participants.
Study dropout was defined as 1) having terminated early from the study, or 2) not having a specimen collected for a least 20 weeks prior to the Week 104 visit. The dropout date was defined as the earliest of 1) the expected date of the first missed visit prior to study termination, 2) the study termination date, or 3) the date 20 weeks from the last collected specimen date. For the purpose of assessing dropout incidence, if a participant acquired HIV, follow-up time was censored at their diagnosis date. If a participant did not acquire HIV and did not drop out of the study, then follow-up time was censored at their last specimen collection date. Incidence rates of events are calculated as the number of events per 100 person-years of follow-up. For each of the AMP trials, the primary efficacy analysis in a future manuscript will assess PE defined as one minus the ratio of the cumulative incidence of the primary endpoint of HIV-1 infection at the Week 80 visit in the two mAb groups pooled versus the control group (2:1 randomization active: control).
The primary efficacy analysis will assess prevention efficacy (PE) against the primary endpoint of HIV acquisition by the Week 80 visit in the two VRC01 groups pooled versus the control group (2:1 randomization active:control16) in a future manuscript. Sample sizes were selected to provide 90% power to detect PE ≥ 60% (rejecting the null hypothesis of PE ≤ 0%)16.
Retention
Retention is defined as the number of participants who completed the visit divided by the number of participants expected for the visit plus participants who completed the visit when not expected. Visits were considered “completed” based on submission of the Infusion or Specimen Collection case report form. Visits were considered “expected” when the visit window was closed on or before the report date, subject to the additional conditions: visits were not expected for 5-day and 4-week follow-up visits if the preceding infusion visit was missed or study product was not administered at that visit; infusion schedule visits were not expected after study product discontinuation or following HIV diagnosis. Visits where the target date occurred after the termination date were not considered “expected” and were not included in the denominator. Inappropriately enrolled participants were not included in retention calculations.
Adherence
Adherence is defined as the number of participants who received an infusion divided by the number of participants who completed an infusion visit.
RESULTS
Study schema and enrollment
HVTN 704/HPTN 085 opened on March 31, 2016 and the first participant enrolled in the US on April 06, 2016; in Peru on October 13, 2016; in Switzerland on February 20, 2017; and in Brazil on April 05, 2017. The study enrolled ~900 participants in each of the three groups. Accrual occurred over ~30 months and enrollment completed on October 05, 2018, ahead of initial projections. A total of 2,701 participants enrolled at 26 CRSs: US (n=1383 or 51.2%), Peru (n=1131 or 41.9%), Brazil (n=151 or 5.6%) and Switzerland (n=36 or 1.3%) (Figure 1B). Accrual peaked at 168 participants per month and was slowed mid-trial to allow for sufficient supply of VRC01, as demand exceeded supply due to a faster than anticipated accrual rate.
Figure 1B provides the number of participants screened, randomized and enrolled for each country. The most common reasons for not enrolling in the study included physical exam findings, local lab results, medical or psychiatric history or condition (547, 45.6%); HIV test result (165, 13.8%); site assessment of participant’s availability (155, 12.9%); HIV risk criteria (76, 6.3%); and individual changed their mind (72, 6.0%) (Supplementary Tables 1&2).
Baseline characteristics
Demographics of enrolled participants were as follows: 99% were assigned male sex at birth and 90.4% identified as cisgender male, 5% as TG female, 1.1% as gender queer, 0.7% as TG male, and 0.9% as gender non-conforming (Table 1). Of the 26 participants who were assigned female sex at birth, 19 identified as TG male, 4 as gender queer, and 7 reported other gender identities. The median age was 28 years (range 18–52), and 31.5% were White, 15.1% Black/African American, 2.6% Asian, 46.6% Other (mainly reflecting the 1,128 participants from South America), and 57.2% Hispanic/Latinx. Median BMI was 25.1 (Table 1).
Table 1.
Baseline participant characteristics and risk factors by country.
| n (%) | |||||
|---|---|---|---|---|---|
| Brazil | Peru | Switzerland | US | Total | |
| Total enrolled | 151 | 1131 | 36 | 1383 | 2701 |
| Sex at birth | |||||
| Male | 151 (100.0%) | 1129 (99.8%) | 36 (100.0%) | 1359 (98.3%) | 2675 (99.0%) |
| Female | 0 (0.0%) | 2 (0.2%) | 0 (0.0%) | 24 (1.7%) | 26 (1.0%) |
| Gender identity* | |||||
| Male | 148 (98.0%) | 970 (85.8%) | 36 (100.0%) | 1289 (93.2%) | 2443 (90.4%) |
| Female | 0 (0.0%) | 38 (3.4%) | 0 (0.0%) | 6 (0.4%) | 44 (1.6%) |
| Transgender male | 0 (0.0%) | 2 (0.2%) | 0 (0.0%) | 17 (1.2%) | 19 (0.7%) |
| Transgender female | 1 (0.7%) | 102 (9.0%) | 0 (0.0%) | 33 (2.4%) | 136 (5.0%) |
| Gender queer | 1 (0.7%) | 6 (0.5%) | 0 (0.0%) | 24 (1.7%) | 31 (1.1%) |
| Gender variant or gender non-conforming | 0 (0.0%) | 6 (0.5%) | 0 (0.0%) | 19 (1.4%) | 25 (0.9%) |
| Other | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | 12 (0.9%) | 12 (0.4%) |
| Prefer not to answer | 1 (0.7%) | 7 (0.6%) | 0 (0.0%) | 5 (0.4%) | 13 (0.5%) |
| Ethnicity | |||||
| Hispanic or Latinx | 128 (84.8%) | 1130 (99.9%) | 5 (13.9%) | 282 (20.4%) | 1545 (57.2%) |
| Not Hispanic or Latinx | 23 (15.2%) | 1 (0.1%) | 31 (86.1%) | 1101 (79.6%) | 1156 (42.8%) |
| Age (years) | |||||
| 18–20 | 8 (5.3%) | 205 (18.1%) | 0 (0.0%) | 82 (5.9%) | 295 (10.9%) |
| 21–30 | 81 (53.6%) | 616 (54.5%) | 19 (52.8%) | 735 (53.1%) | 1451 (53.7%) |
| 31–40 | 50 (33.1%) | 243 (21.5%) | 12 (33.3%) | 388 (28.1%) | 693 (25.7%) |
| 41–50 | 12 (7.9%) | 66 (5.8%) | 5 (13.9%) | 178 (12.9%) | 261 (9.7%) |
| >50 | 0 (0.0%) | 1 (0.1%) | 0 (0.0%) | 0 (0.0%) | 1 (0.0%) |
| Median (min, max) | 28 (18, 49) | 26 (18, 52 | 29 (21, 50 | 29 (18, 50) | 28 (18, 52) |
| Race | |||||
| White | 55 (36.4%) | 44 (3.9%) | 33 (91.7%) | 719 (52.0%) | 851 (31.5%) |
| Black or African American | 41 (27.2%) | 10 (0/9%) | 0 (0.0%) | 358 (25.9%) | 409 (15.1%) |
| Asian | 0 (0.0%) | 2 (0.2%) | 0 (0.0%) | 67 (4.8%) | 69 (2.6%) |
| Native Hawaiian/other Pacific Islander | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | 8 (0.6%) | 8 (0.3%) |
| American Indian/Alaska Native | 0 (0.0%) | 1 (0.1%) | 0 (0.0%) | 16 (1.2%) | 17 (0.6%) |
| Other | 55 (36.4%) | 1073 (94.9%) | 3 (8.3%) | 128 (9.3%) | 1259 (46.6%) |
| Multi-racial | 0 (0.0%) | 1 (0.1%) | 0 (0.0%) | 87 (6.3%) | 88 (3.3%) |
| BMI | |||||
| <18.5 | 5 (3.3%) | 20 (1.8%) | 0 (0.0%) | 21 (1.5%) | 46 (1.7%) |
| 18.5–24.9 | 72 (47.7%) | 557 (49.2%) | 27 (75%) | 613 (44.3%) | 1269 (47%) |
| 25–29.9 | 61 (40.4%) | 442 (39.1%) | 5 (13.9%) | 445 (32.2%) | 953 (35.3%) |
| ≥30 | 13 (8.6%) | 112 (9.9%) | 4 (11.1%) | 304 (22%) | 433 (16%) |
| Median (min, max) | 24.7 (17.3, 37.1) | 24.9 (15.4, 39.6) | 23.6 (18.7, 36.7) | 25.4 (15.8, 39.9) | 25.1 (15.4, 39.9) |
| Number of sex partners in the last 2 months | |||||
| 0 | 4 (2.6%) | 26 (2.3%) | 2 (5.6%) | 99 (7.2%) | 131 (4.9%) |
| 1 | 26 (17.2%) | 105 (9.3%) | 5 (13.9%) | 256 (18.5%) | 392(14.5%) |
| 2 | 21 (13.9%) | 196 (17.3%) | 3 (8.3%) | 313 (22.6%) | 533 (19.7%) |
| 3–4 | 41 (27.2%) | 257 (22.7%) | 10 (27.8%) | 305 (22.1%) | 613 (22.7%) |
| ≥5 | 57 (37.7%) | 476 (42.1%) | 13 (36.1%) | 391 (28.3%) | 937 (34.7%) |
| Median (min, max) | 4 (0, 50) | 4 (0, 200) | 4 (0, 25) | 3 (0, 120) | 3 (1, 200) |
| Had an HIV+ partner | 24 (15.9%) | 36 (3.2%) | 3 (8.3%) | 137 (9.9%) | 200 (7.4%) |
| Unprotected receptive vaginal sex | 0 (0.0%) | 2 (0.2%) | 0 (0.0%) | 22 (1.6%) | 24 (0.9%) |
| Unprotected insertive vaginal sex | 5 (3.3%) | 207 (18.3%) | 1 (2.8%) | 64 (4.6%) | 277 (10.3%) |
| Unprotected receptive anal sex | 102 (67.5%) | 739 (65.3%) | 23 (63.9%) | 922 (66.7%) | 1786 (66.1%) |
| Unprotected insertive anal sex | 103 (68.2%) | 617 (54.6%) | 25 (69.4%) | 894 (64.6%) | 1639 (60.7%) |
| Exchange of sex for money/gifts | 10 (6.6%) | 271 (24.0%) | 2 (5.6%) | 63 (4.6%) | 346 (12.8%) |
| Alcohol use | |||||
| Never | 14 (9.3%) | 88 (7.8%) | 2 (5.6%) | 135 (9.8%) | 239 (8.8%) |
| Monthly or less | 36 (23.8%) | 424 (37.5%) | 5 (13.9%) | 207 (15.0%) | 672 (24.9%) |
| 2–4 times a month | 68 (45.0%) | 434 (38.4%) | 8 (22.2%) | 445 (32.2%) | 955 (35.4%) |
| 2–3 times a week | 29 (19.2%) | 115 (10.2%) | 16 (44.4%) | 431 (31.2%) | 591 (21.9%) |
| 4 or more times a week | 4 (2.6%) | 36 (3.2%) | 5 (13.9%) | 158 (11.4%) | 203 (7.5%) |
| Prefer not to answer | 0 (0.0%) | 12 (1.1%) | 0 (0.0%) | 5 (0.4%) | 17 (0.6%) |
| Drug use | |||||
| Amphetamine/meth/crystal meth | 6 (4.0%) | 4 (0.4%) | 3 (8.3%) | 58 (4.2%) | 71 (2.6%) |
| Cocaine, crack | 1 (0.7%) | 50 (4.4%) | 5 (13.9%) | 23 (1.7%) | 79 (2.9%) |
| Cocaine, powder | 17 (11.3%) | 76 (6.7%) | 5 (13.9%) | 133 (9.6%) | 231 (8.6%) |
| Heroin, prescription pain killer/medications | 2 (1.3%) | 53 (4.7%) | 6 (16.7%) | 63 (4.6%) | 124 (4.6%) |
| Injection drug | 5 (3.3%) | 25 (2.2%) | 2 (5.6%) | 24 (1.7%) | 56 (2.1%) |
| Marijuana | 51 (33.8%) | 153 (13.5%) | 14 (38.9%) | 638 (46.1%) | 856 (31.7%) |
| MDMA or ecstasy | 15 (9.9%) | 5 (0.4%) | 8 (22.2%) | 84 (6.1%) | 112 (4.1%) |
| Methaqualone or mandrax | 0 (0.0%) | 4 (0.4%) | 0 (0.0%) | 4 (0.3%) | 8 (0.3%) |
| Popper | 14 (9.3%) | 46 (4.1%) | 22 (61.1%) | 468 (33.8%) | 550 (20.4%) |
| Woonga/wunga | 0 (0.0%) | 2 (0.2%) | 0 (0.0%) | 0 (0.0%) | 2 (0.1%) |
Participants may self-report more than one gender identify, thus numbers and percentages may total to more than 100%.
Behaviors pertaining to sexual health and drug use were collected at baseline (Table 1). More than 1/3 of participants (34.7%) had five or more sex partners in the two months prior to enrollment, and 66.1% had unprotected receptive anal intercourse. Transactional sex ranged from 4.6% in US participants to 24% among Peruvian participants. Nearly 1/3 of participants used marijuana (31.7%), poppers (20.4%) and/or powdered cocaine (8.6%) (Table 1).
At enrollment, 28% of participants had either gonorrhea (GC, 10%), chlamydia (CT, 11%), and/or syphilis (13.6%) (Supp Table 3). Among participants with GC, oropharyngeal GC (173 of 272, 64%) and rectal GC (153 of 272, 56%) were much more prevalent than urethral infection (24 of 272, 9%). Among participants with CT, rectal CT (240 of 297, 81%) was more common than urethral CT (81 of 297, 27%).
PrEP uptake
Oral PrEP uptake was measured by self-report and quantitative assessment of TFV-DP levels in DBS. Self-reported PrEP use at enrollment was highest among US participants (414 or 29.9%), with much smaller percentages in Switzerland (2 or 5.6%), Brazil (6 or 4%) and Peru (7 or 0.6%). A higher proportion of participants reported PrEP use at any timepoint in the study: Brazil (109 or 72.2%), US (927 or 67%), Switzerland (16 or 44.4%), and Peru (62 or 5.5%). Of the 45,102 DBS samples, 2,445 were assayed for TFV-DP as of March 2019. The proportion of assayed specimens with TFV-DP above the LLOQ was 917 of 2,445, or 37.5% (95% CI: 35.0%, 40.1%), which corresponds to 40.3% person-years on detectable PrEP among HVTN 704/HPTN 085 participants (95% CI: 37.0%, 43.9%). The proportion of assayed specimens with TFV-DP above the effective use threshold was 682 of 2,445, or 27.9% (95% CI: 25.7%, 30.3%), which corresponds to 30.0% person-years on effective PrEP (95% CI: 27.0%, 33.2%). The percent person-years on detectable and effective PrEP for each country is shown in Figure 2. Overall, 19% (266 of 1383) of US participants enrolled in the PrEP referral program as of December 2018, which was 10 months after completion of US enrollment. However, the percentage of participants with active TFV-DP prescriptions among the US CRSs varied monthly, ranging from 0% to 65% (average 29%).
Figure 2. Percent person-years of PrEP uptake.
A. Overall and by country. B. PrEP uptake based on age, race and ethnicity. Detectable TFV-DP (tenofovir-diphosphate) is defined as detection at or above the lower limit of quantification. Effective TFV-DP is defined as detection of at least 700 fmol/punch TFV-DP. The height of each bar shows the estimated percent person-years of detectable or effective PrEP uptake and the vertical black lines show the 95% confidence interval. The x-axis labels indicate the population analyzed along with the number of participants contributing one or more samples used to estimate PrEP uptake.
Safety monitoring
Over 23,000 infusions were completed as of April 3, 2020. There were no major complications such as infection or thrombosis related to IV placements or IV administration of VRC01/placebo in multiple countries and clinical settings. The DSMB reviewed unblinded safety data from the trial every six months and consistently recommended continuation of the trials as designed.
Retention, dropout, and social impacts
An infusion feasibility assessment completed in January 2017 required at least 80% retention of study visits and adherence (receipt of infusion) to the first four infusions, which the trial exceeded. The total number of participants who completed each visit for the first seven infusions is shown in Table 2 and the combined retention rate across all sites was 96%. As of April 3, 2020, 1,728 participants had completed the final follow-up visit, at Week 104 for uninfected participants and 24 weeks post-diagnosis for participants who acquired HIV. As of April 3, 2020, 435 participants terminated early; the most common reasons were participant relocation (123, 34.0%), clinic unable to contact participant (80, 22.1%), participant unable to adhere to the visit schedule (68, 18.8%), and participant refusal (60, 16.6%) (Table 3). The overall annual dropout rate was less than 10%. Beneficial and negative impacts were noted in the study. Negative impacts included those to personal relationships, employment, life and health insurance and medical and dental aspects. Beneficial impacts included personal relationships, medical care, increased knowledge of HIV, and the ability to contribute to medical research.
Table 2.
Participant retention rate for first seven infusions.
| Infusion number | Retention (%) |
|---|---|
| 1 | 2701/2701 (100%) |
| 2 | 2582/2662 (97%) |
| 3 | 2510/2607 (96%) |
| 4 | 2439/2557 (95%) |
| 5 | 2387/2512 (95%) |
| 6 | 2345/2470 (95%) |
| 7 | 2304/2414 (95%) |
| Total | 17268/17923 (96%) |
Operational retention at a given visit is defined as the number of participants who completed the visit divided by the number of participants expected for the visit plus participants who completed the visit when not expected.
Table 3.
Reasons for early study termination.
| N = 362 | |
|---|---|
| Participant relocated | 123 (34.0%) |
| Unable to contact | 80 (22.1%) |
| Unable to adhere to visit schedule | 68 (18.8%) |
| Participant refused | 60 (16.6%) |
| Participant incarcerated | 8 (2.2%) |
| Investigator decision* | 6 (1.7%) |
| Inappropriate enrollment | 4 (1.1%) |
| Death | 4 (1.1%) |
| Duplicate screening/enrollment | 2 (0.6%) |
| Other | 7 (1.9%) |
1 mental health concern, 1 dual enrollment, 1 unreliable participant, 1 misconduct, 2 travel/commute.
Early termination occurred when a participant was unable to complete final scheduled study visit, which is Week 104 for those who did not acquire HIV and Week 24 for those who acquired HIV.
DISCUSSION
HVTN 704/HPTN 085 successfully reached the enrollment target of 2,701 cisgender men and TG individuals. Accrual was anticipated to be challenging, but accrual rates exceeded expectations, likely due in part to robust community engagement initiated six months prior to the trial’s opening in North America. In addition, novel strategies were developed to explain the use of an IV-administered mAb for HIV prevention, since the idea was new to communities. Animated videos of the mAb concept, advertisements in social media and dating apps, and the study websites were key elements of community engagement14.
HIV incidence in HVTN 704/HPTN 085 will be modulated by the extent of PrEP uptake and adherence by the participants, which will greatly impact the power to determine prevention efficacy. PrEP uptake dramatically increased in all four countries during the trial (e.g., 4% of participants in Brazil reported PrEP use at baseline, but 72% reported use at any timepoint during the trial), likely due to a combination of licensure status, risk reduction counseling, and facilitation of access to PrEP by the CRSs. HVTN 704/HPTN 085 was designed to accommodate up to 50% person-years of PrEP use at 90% assumed efficacy. A complete analysis of PrEP use by the trial cohort will be presented in a future manuscript. As PrEP becomes integrated into the standard of care for HIV prevention globally, a number of challenges are emerging in the design and conduct of the next generation of efficacy trials17.
In addition to accommodating the background use of PrEP in the trial design, numerous operational challenges were successfully addressed. The trial exceeded enrollment targets in spite of accrual “slowdowns” due to pre-planned safety assessments or product manufacturing considerations. Operationally, multiple checkpoints were built into the trial for a stepwise progression of feasibility and safety. Safety assessments and efficacy data will be reported in future manuscripts. Retention of trial participants and adherence to study interventions are both critical and challenging in large efficacy trials. No previous HIV prevention efficacy trials are directly comparable to HVTN 704/HPTN 085, with a rigorous schedule of monthly visits and 10 IV infusions of an investigational study product. In HVTN 505, a phase 2b vaccine trial with a duration of 24 months, the yearly rate of loss to follow-up was 6.6% (95% CI, 5.4–8.0) in the vaccine group and the trial had 12 visits compared to 25 visits in HVTN 704/HPTN 08518. Thus, HVTN 704/HPTN 085 exceeded enrollment targets and is maintaining high retention rates, with annual drop-out rates remaining below the pre-specified acceptable rate. With exceptional IV infusion safety and operational feasibility, the AMP trials are paving the way for future large-scale mAb trials for HIV-1 prevention and potentially for other infectious disease pathogens such as SARS CoV-2.
Supplementary Material
Supplementary Table 1. Reasons for screened participants not enrolling.
Supplementary Table 2. Reasons for randomized participants not enrolling.
Supplementary Table 3. Sexually transmitted infections diagnosed at enrollment (1st infusion) visit.
ACKNOWLEDGEMENTS
We thank the study participants enrolled in HVTN 704/HPTN 085 and gratefully acknowledge the participation and support of many colleagues and staff on the protocol team. At the clinical research sites, we thank the study teams (see Supplemental Material). For their roles in protocol development and study implementation, we thank Carter Bentley, PhD. We gratefully acknowledge the many colleagues at VRC/NIAID who contributed to the clinical development and manufacturing of VRC01 for this trial. For assistance with statistical programming, we thank Karan Shah and Bharathi Lakshminarayanan.
This work was supported by the National Institute of Allergy and Infectious Diseases (NIAID) U.S. Public Health Service Grants UM1 AI068614 [LOC: HIV Vaccine Trials Network], UM1 AI068635 [HVTN SDMC FHCRC], UM1 AI068618 [HVTN Laboratory Center FHCRC], and UM1AI068619 (HPTN Leadership and Operations Center). The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Sources of funding:
NIAID Award AI068614 for the HVTN Leadership and Operations Center (LOC)
NIAID Award AI068635 for the HVTN Statistical and Data Management Center (SDMC)
NIAID Award AI068618 for the HVTN Laboratory Center (LC)
NIAID Award AI068619 HPTN Leadership and Operations Center
Conflicts of Interest and Source of Funding:
PLA has received personal fees and research funds paid to his institution from Gilead Sciences.
JRM is an inventor on NIH patent for VRC01. All other authors declare no conflicts of interest.
Footnotes
- Edupuganti S et al. Feasibility and Successful Enrollment in Proof-of-Concept Trials to Assess Safety and Efficacy of a Broadly Neutralizing Monoclonal Antibody, VRC01, to Prevent HIV-1 Acquisition in Uninfected Individuals, BnAb Satellite symposium and Poster Session, HIVR4P 2018, Madrid, Spain, October 21–25, 2018.
- Edupuganti S et al. “Feasibility and Successful Enrollment in Proof-of-Concept Trials to Assess Safety and Efficacy of a Broadly Neutralizing Monoclonal Antibody, VRC01, to Prevent HIV-1 Acquisition in Uninfected Individuals. IDWeek, October 2–6, 2019, Washington, DC).
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Supplementary Table 1. Reasons for screened participants not enrolling.
Supplementary Table 2. Reasons for randomized participants not enrolling.
Supplementary Table 3. Sexually transmitted infections diagnosed at enrollment (1st infusion) visit.