Safety, tolerability, and pharmacokinetics of long-acting injectable cabotegravir in low-risk HIV-uninfected individuals: HPTN 077, a phase 2a randomized controlled trial

Raphael J. Landovitz, Sue Li, Beatriz Grinsztejn, Halima Dawood, Albert Y. Liu, Manya Magnus, Mina C. Hosseinipour, Ravindre Panchia, Leslie Cottle, Gordon Chau, Paul Richardson, Mark A Marzinke, Craig Hendrix, Susan Eshleman, Yinfeng Zhang, Elizabeth Tolley, Jeremy Sugarman, Ryan Kofron, Adeola Adeyeye, David BurnsAlex R. Rinehart, David Margolis, William R. Spreen, Myron S. Cohen, Marybeth McCauley, Joseph J. Eron

Research output: Contribution to journalArticle

Abstract

Background: Cabotegravir (CAB) is a novel strand-transfer integrase inhibitor being developed for HIV treatment and prevention. CAB is formulated both as an immediate-release oral tablet for daily administration and as a long-acting injectable suspension (long-acting CAB [CAB LA]) for intramuscular (IM) administration, which delivers prolonged plasma exposure to the drug after IM injection. HIV Prevention Trials Network study 077 (HPTN 077) evaluated the safety, tolerability, and pharmacokinetics of CAB LA in HIV-uninfected males and females at 8 sites in Brazil, Malawi, South Africa, and the United States. Methods and findings: HPTN 077 was a double-blind, placebo-controlled phase 2a trial. Healthy individuals age 18–65 years at low HIV risk were randomized (3:1) to receive CAB or placebo (PBO). In the initial oral phase, participants received 1 daily oral tablet (CAB or PBO) for 4 weeks. Those without safety concerns in the oral phase continued and received injections in the injection phase (Cohort 1: 3 injections of CAB LA 800 mg or 0.9% saline as PBO IM every 12 weeks for 3 injection cycles; Cohort 2: CAB LA 600 mg or PBO IM for 5 injection cycles; the first 2 injections in Cohort 2 were separated by 4 weeks, the rest by 8 weeks). The primary analysis included weeks 5 to 41 of study participation, encompassing the injection phase. The cohorts were enrolled sequentially. Primary outcomes were safety and tolerability. Secondary outcomes included pharmacokinetics and events occurring during the oral and injection phases. Between February 9, 2015, and May 27, 2016, the study screened 443 individuals and enrolled 110 participants in Cohort 1 and 89 eligible participants in Cohort 2. Participant population characteristics were as follows: 66% female at birth; median age 31 years; 27% non-Hispanic white, 41% non-Hispanic black, 24% Hispanic/Latino, 3% Asian, and 6% mixed/other; and 6 transgender men and 1 transgender woman. Twenty-two (11%) participants discontinued the oral study product; 6 of these were for clinical or laboratory adverse events (AEs). Of those who received at least 1 CAB LA injection, 80% of Cohort 1 and 92% of Cohort 2 participants completed all injections; injection course completion rates were not different from those in the PBO arm. Injection site reactions (ISRs) were common (92% of Cohort 1 and 88% of Cohort 2 participants who received CAB LA reported any ISR). ISRs were mostly Grade 1 (mild) to Grade 2 (moderate), and 1 ISR event (Cohort 1) led to product discontinuation. Grade 2 or higher ISRs were the only AEs reported more commonly among CAB LA recipients than PBO recipients. Two Grade 3 (severe) ISRs occurred in CAB recipients, 1 in each cohort, but did not lead to product discontinuation in either case. Seven incident sexually transmitted infections were diagnosed in 6 participants. One HIV infection occurred in a participant 48 weeks after last injection of CAB LA: CAB was not detectable in plasma both at the time of first reactive HIV test and at the study visit 12 weeks prior to the first reactive test. Participants in Cohort 2 (unlike Cohort 1) consistently met prespecified pharmacokinetic targets of at least 95% of participants maintaining CAB trough concentrations above PA-IC90, and 80% maintaining trough concentrations above 4× PA-IC90. Study limitations include a modest sample size, a short course of injections, and a low-risk study population. Conclusions: In this study, CAB LA was well tolerated at the doses and dosing intervals used. ISRs were common, but infrequently led to product discontinuation. CAB LA 600 mg every 8 weeks met pharmacokinetic targets for both male and female study participants. The safety and pharmacokinetic results observed support the further development of CAB LA, and efficacy studies of CAB LA for HIV treatment and prevention are in progress. Trial registration: ClinicalTrials.gov Registry: ClinicalTrials.gov Trial number: NCT02178800.

Original languageEnglish (US)
Article numbere1002690
JournalPLoS Medicine
Volume15
Issue number11
DOIs
StatePublished - Nov 1 2018

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Randomized Controlled Trials
Pharmacokinetics
HIV
Safety
Injections
Placebos
Transgender Persons
Intramuscular Injections
Hispanic Americans
Tablets
Integrase Inhibitors
Malawi
Population Characteristics
Sexually Transmitted Diseases
South Africa
Sample Size
HIV Infections
Brazil
Registries
Suspensions

ASJC Scopus subject areas

  • Medicine(all)

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Safety, tolerability, and pharmacokinetics of long-acting injectable cabotegravir in low-risk HIV-uninfected individuals : HPTN 077, a phase 2a randomized controlled trial. / Landovitz, Raphael J.; Li, Sue; Grinsztejn, Beatriz; Dawood, Halima; Liu, Albert Y.; Magnus, Manya; Hosseinipour, Mina C.; Panchia, Ravindre; Cottle, Leslie; Chau, Gordon; Richardson, Paul; Marzinke, Mark A; Hendrix, Craig; Eshleman, Susan; Zhang, Yinfeng; Tolley, Elizabeth; Sugarman, Jeremy; Kofron, Ryan; Adeyeye, Adeola; Burns, David; Rinehart, Alex R.; Margolis, David; Spreen, William R.; Cohen, Myron S.; McCauley, Marybeth; Eron, Joseph J.

In: PLoS Medicine, Vol. 15, No. 11, e1002690, 01.11.2018.

Research output: Contribution to journalArticle

Landovitz, RJ, Li, S, Grinsztejn, B, Dawood, H, Liu, AY, Magnus, M, Hosseinipour, MC, Panchia, R, Cottle, L, Chau, G, Richardson, P, Marzinke, MA, Hendrix, C, Eshleman, S, Zhang, Y, Tolley, E, Sugarman, J, Kofron, R, Adeyeye, A, Burns, D, Rinehart, AR, Margolis, D, Spreen, WR, Cohen, MS, McCauley, M & Eron, JJ 2018, 'Safety, tolerability, and pharmacokinetics of long-acting injectable cabotegravir in low-risk HIV-uninfected individuals: HPTN 077, a phase 2a randomized controlled trial', PLoS Medicine, vol. 15, no. 11, e1002690. https://doi.org/10.1371/journal.pmed.1002690
Landovitz, Raphael J. ; Li, Sue ; Grinsztejn, Beatriz ; Dawood, Halima ; Liu, Albert Y. ; Magnus, Manya ; Hosseinipour, Mina C. ; Panchia, Ravindre ; Cottle, Leslie ; Chau, Gordon ; Richardson, Paul ; Marzinke, Mark A ; Hendrix, Craig ; Eshleman, Susan ; Zhang, Yinfeng ; Tolley, Elizabeth ; Sugarman, Jeremy ; Kofron, Ryan ; Adeyeye, Adeola ; Burns, David ; Rinehart, Alex R. ; Margolis, David ; Spreen, William R. ; Cohen, Myron S. ; McCauley, Marybeth ; Eron, Joseph J. / Safety, tolerability, and pharmacokinetics of long-acting injectable cabotegravir in low-risk HIV-uninfected individuals : HPTN 077, a phase 2a randomized controlled trial. In: PLoS Medicine. 2018 ; Vol. 15, No. 11.
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title = "Safety, tolerability, and pharmacokinetics of long-acting injectable cabotegravir in low-risk HIV-uninfected individuals: HPTN 077, a phase 2a randomized controlled trial",
abstract = "Background: Cabotegravir (CAB) is a novel strand-transfer integrase inhibitor being developed for HIV treatment and prevention. CAB is formulated both as an immediate-release oral tablet for daily administration and as a long-acting injectable suspension (long-acting CAB [CAB LA]) for intramuscular (IM) administration, which delivers prolonged plasma exposure to the drug after IM injection. HIV Prevention Trials Network study 077 (HPTN 077) evaluated the safety, tolerability, and pharmacokinetics of CAB LA in HIV-uninfected males and females at 8 sites in Brazil, Malawi, South Africa, and the United States. Methods and findings: HPTN 077 was a double-blind, placebo-controlled phase 2a trial. Healthy individuals age 18–65 years at low HIV risk were randomized (3:1) to receive CAB or placebo (PBO). In the initial oral phase, participants received 1 daily oral tablet (CAB or PBO) for 4 weeks. Those without safety concerns in the oral phase continued and received injections in the injection phase (Cohort 1: 3 injections of CAB LA 800 mg or 0.9{\%} saline as PBO IM every 12 weeks for 3 injection cycles; Cohort 2: CAB LA 600 mg or PBO IM for 5 injection cycles; the first 2 injections in Cohort 2 were separated by 4 weeks, the rest by 8 weeks). The primary analysis included weeks 5 to 41 of study participation, encompassing the injection phase. The cohorts were enrolled sequentially. Primary outcomes were safety and tolerability. Secondary outcomes included pharmacokinetics and events occurring during the oral and injection phases. Between February 9, 2015, and May 27, 2016, the study screened 443 individuals and enrolled 110 participants in Cohort 1 and 89 eligible participants in Cohort 2. Participant population characteristics were as follows: 66{\%} female at birth; median age 31 years; 27{\%} non-Hispanic white, 41{\%} non-Hispanic black, 24{\%} Hispanic/Latino, 3{\%} Asian, and 6{\%} mixed/other; and 6 transgender men and 1 transgender woman. Twenty-two (11{\%}) participants discontinued the oral study product; 6 of these were for clinical or laboratory adverse events (AEs). Of those who received at least 1 CAB LA injection, 80{\%} of Cohort 1 and 92{\%} of Cohort 2 participants completed all injections; injection course completion rates were not different from those in the PBO arm. Injection site reactions (ISRs) were common (92{\%} of Cohort 1 and 88{\%} of Cohort 2 participants who received CAB LA reported any ISR). ISRs were mostly Grade 1 (mild) to Grade 2 (moderate), and 1 ISR event (Cohort 1) led to product discontinuation. Grade 2 or higher ISRs were the only AEs reported more commonly among CAB LA recipients than PBO recipients. Two Grade 3 (severe) ISRs occurred in CAB recipients, 1 in each cohort, but did not lead to product discontinuation in either case. Seven incident sexually transmitted infections were diagnosed in 6 participants. One HIV infection occurred in a participant 48 weeks after last injection of CAB LA: CAB was not detectable in plasma both at the time of first reactive HIV test and at the study visit 12 weeks prior to the first reactive test. Participants in Cohort 2 (unlike Cohort 1) consistently met prespecified pharmacokinetic targets of at least 95{\%} of participants maintaining CAB trough concentrations above PA-IC90, and 80{\%} maintaining trough concentrations above 4× PA-IC90. Study limitations include a modest sample size, a short course of injections, and a low-risk study population. Conclusions: In this study, CAB LA was well tolerated at the doses and dosing intervals used. ISRs were common, but infrequently led to product discontinuation. CAB LA 600 mg every 8 weeks met pharmacokinetic targets for both male and female study participants. The safety and pharmacokinetic results observed support the further development of CAB LA, and efficacy studies of CAB LA for HIV treatment and prevention are in progress. Trial registration: ClinicalTrials.gov Registry: ClinicalTrials.gov Trial number: NCT02178800.",
author = "Landovitz, {Raphael J.} and Sue Li and Beatriz Grinsztejn and Halima Dawood and Liu, {Albert Y.} and Manya Magnus and Hosseinipour, {Mina C.} and Ravindre Panchia and Leslie Cottle and Gordon Chau and Paul Richardson and Marzinke, {Mark A} and Craig Hendrix and Susan Eshleman and Yinfeng Zhang and Elizabeth Tolley and Jeremy Sugarman and Ryan Kofron and Adeola Adeyeye and David Burns and Rinehart, {Alex R.} and David Margolis and Spreen, {William R.} and Cohen, {Myron S.} and Marybeth McCauley and Eron, {Joseph J.}",
year = "2018",
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language = "English (US)",
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TY - JOUR

T1 - Safety, tolerability, and pharmacokinetics of long-acting injectable cabotegravir in low-risk HIV-uninfected individuals

T2 - HPTN 077, a phase 2a randomized controlled trial

AU - Landovitz, Raphael J.

AU - Li, Sue

AU - Grinsztejn, Beatriz

AU - Dawood, Halima

AU - Liu, Albert Y.

AU - Magnus, Manya

AU - Hosseinipour, Mina C.

AU - Panchia, Ravindre

AU - Cottle, Leslie

AU - Chau, Gordon

AU - Richardson, Paul

AU - Marzinke, Mark A

AU - Hendrix, Craig

AU - Eshleman, Susan

AU - Zhang, Yinfeng

AU - Tolley, Elizabeth

AU - Sugarman, Jeremy

AU - Kofron, Ryan

AU - Adeyeye, Adeola

AU - Burns, David

AU - Rinehart, Alex R.

AU - Margolis, David

AU - Spreen, William R.

AU - Cohen, Myron S.

AU - McCauley, Marybeth

AU - Eron, Joseph J.

PY - 2018/11/1

Y1 - 2018/11/1

N2 - Background: Cabotegravir (CAB) is a novel strand-transfer integrase inhibitor being developed for HIV treatment and prevention. CAB is formulated both as an immediate-release oral tablet for daily administration and as a long-acting injectable suspension (long-acting CAB [CAB LA]) for intramuscular (IM) administration, which delivers prolonged plasma exposure to the drug after IM injection. HIV Prevention Trials Network study 077 (HPTN 077) evaluated the safety, tolerability, and pharmacokinetics of CAB LA in HIV-uninfected males and females at 8 sites in Brazil, Malawi, South Africa, and the United States. Methods and findings: HPTN 077 was a double-blind, placebo-controlled phase 2a trial. Healthy individuals age 18–65 years at low HIV risk were randomized (3:1) to receive CAB or placebo (PBO). In the initial oral phase, participants received 1 daily oral tablet (CAB or PBO) for 4 weeks. Those without safety concerns in the oral phase continued and received injections in the injection phase (Cohort 1: 3 injections of CAB LA 800 mg or 0.9% saline as PBO IM every 12 weeks for 3 injection cycles; Cohort 2: CAB LA 600 mg or PBO IM for 5 injection cycles; the first 2 injections in Cohort 2 were separated by 4 weeks, the rest by 8 weeks). The primary analysis included weeks 5 to 41 of study participation, encompassing the injection phase. The cohorts were enrolled sequentially. Primary outcomes were safety and tolerability. Secondary outcomes included pharmacokinetics and events occurring during the oral and injection phases. Between February 9, 2015, and May 27, 2016, the study screened 443 individuals and enrolled 110 participants in Cohort 1 and 89 eligible participants in Cohort 2. Participant population characteristics were as follows: 66% female at birth; median age 31 years; 27% non-Hispanic white, 41% non-Hispanic black, 24% Hispanic/Latino, 3% Asian, and 6% mixed/other; and 6 transgender men and 1 transgender woman. Twenty-two (11%) participants discontinued the oral study product; 6 of these were for clinical or laboratory adverse events (AEs). Of those who received at least 1 CAB LA injection, 80% of Cohort 1 and 92% of Cohort 2 participants completed all injections; injection course completion rates were not different from those in the PBO arm. Injection site reactions (ISRs) were common (92% of Cohort 1 and 88% of Cohort 2 participants who received CAB LA reported any ISR). ISRs were mostly Grade 1 (mild) to Grade 2 (moderate), and 1 ISR event (Cohort 1) led to product discontinuation. Grade 2 or higher ISRs were the only AEs reported more commonly among CAB LA recipients than PBO recipients. Two Grade 3 (severe) ISRs occurred in CAB recipients, 1 in each cohort, but did not lead to product discontinuation in either case. Seven incident sexually transmitted infections were diagnosed in 6 participants. One HIV infection occurred in a participant 48 weeks after last injection of CAB LA: CAB was not detectable in plasma both at the time of first reactive HIV test and at the study visit 12 weeks prior to the first reactive test. Participants in Cohort 2 (unlike Cohort 1) consistently met prespecified pharmacokinetic targets of at least 95% of participants maintaining CAB trough concentrations above PA-IC90, and 80% maintaining trough concentrations above 4× PA-IC90. Study limitations include a modest sample size, a short course of injections, and a low-risk study population. Conclusions: In this study, CAB LA was well tolerated at the doses and dosing intervals used. ISRs were common, but infrequently led to product discontinuation. CAB LA 600 mg every 8 weeks met pharmacokinetic targets for both male and female study participants. The safety and pharmacokinetic results observed support the further development of CAB LA, and efficacy studies of CAB LA for HIV treatment and prevention are in progress. Trial registration: ClinicalTrials.gov Registry: ClinicalTrials.gov Trial number: NCT02178800.

AB - Background: Cabotegravir (CAB) is a novel strand-transfer integrase inhibitor being developed for HIV treatment and prevention. CAB is formulated both as an immediate-release oral tablet for daily administration and as a long-acting injectable suspension (long-acting CAB [CAB LA]) for intramuscular (IM) administration, which delivers prolonged plasma exposure to the drug after IM injection. HIV Prevention Trials Network study 077 (HPTN 077) evaluated the safety, tolerability, and pharmacokinetics of CAB LA in HIV-uninfected males and females at 8 sites in Brazil, Malawi, South Africa, and the United States. Methods and findings: HPTN 077 was a double-blind, placebo-controlled phase 2a trial. Healthy individuals age 18–65 years at low HIV risk were randomized (3:1) to receive CAB or placebo (PBO). In the initial oral phase, participants received 1 daily oral tablet (CAB or PBO) for 4 weeks. Those without safety concerns in the oral phase continued and received injections in the injection phase (Cohort 1: 3 injections of CAB LA 800 mg or 0.9% saline as PBO IM every 12 weeks for 3 injection cycles; Cohort 2: CAB LA 600 mg or PBO IM for 5 injection cycles; the first 2 injections in Cohort 2 were separated by 4 weeks, the rest by 8 weeks). The primary analysis included weeks 5 to 41 of study participation, encompassing the injection phase. The cohorts were enrolled sequentially. Primary outcomes were safety and tolerability. Secondary outcomes included pharmacokinetics and events occurring during the oral and injection phases. Between February 9, 2015, and May 27, 2016, the study screened 443 individuals and enrolled 110 participants in Cohort 1 and 89 eligible participants in Cohort 2. Participant population characteristics were as follows: 66% female at birth; median age 31 years; 27% non-Hispanic white, 41% non-Hispanic black, 24% Hispanic/Latino, 3% Asian, and 6% mixed/other; and 6 transgender men and 1 transgender woman. Twenty-two (11%) participants discontinued the oral study product; 6 of these were for clinical or laboratory adverse events (AEs). Of those who received at least 1 CAB LA injection, 80% of Cohort 1 and 92% of Cohort 2 participants completed all injections; injection course completion rates were not different from those in the PBO arm. Injection site reactions (ISRs) were common (92% of Cohort 1 and 88% of Cohort 2 participants who received CAB LA reported any ISR). ISRs were mostly Grade 1 (mild) to Grade 2 (moderate), and 1 ISR event (Cohort 1) led to product discontinuation. Grade 2 or higher ISRs were the only AEs reported more commonly among CAB LA recipients than PBO recipients. Two Grade 3 (severe) ISRs occurred in CAB recipients, 1 in each cohort, but did not lead to product discontinuation in either case. Seven incident sexually transmitted infections were diagnosed in 6 participants. One HIV infection occurred in a participant 48 weeks after last injection of CAB LA: CAB was not detectable in plasma both at the time of first reactive HIV test and at the study visit 12 weeks prior to the first reactive test. Participants in Cohort 2 (unlike Cohort 1) consistently met prespecified pharmacokinetic targets of at least 95% of participants maintaining CAB trough concentrations above PA-IC90, and 80% maintaining trough concentrations above 4× PA-IC90. Study limitations include a modest sample size, a short course of injections, and a low-risk study population. Conclusions: In this study, CAB LA was well tolerated at the doses and dosing intervals used. ISRs were common, but infrequently led to product discontinuation. CAB LA 600 mg every 8 weeks met pharmacokinetic targets for both male and female study participants. The safety and pharmacokinetic results observed support the further development of CAB LA, and efficacy studies of CAB LA for HIV treatment and prevention are in progress. Trial registration: ClinicalTrials.gov Registry: ClinicalTrials.gov Trial number: NCT02178800.

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