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Safety and tolerability of injectable Rilpivirine LA in HPTN 076: A phase 2 HIV pre-exposure prophylaxis study in women

BACKGROUND: Daily oral TDF/FTC is protective against HIV infection when used for pre-exposure prophylaxis (PrEP). However, daily adherence to oral PrEP is difficult for many; therefore, finding alternative PrEP strategies remains a priority. HPTN 076 evaluated the long-acting injectable form of rilp...

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Autores principales: Bekker, L.G., Li, S., Pathak, S., Tolley, E.E., Marzinke, M.A., Justman, J.E., Mgodi, N.M., Chirenje, M., Swaminathan, S., Adeyeye, A., Farrior, J., Hendrix, C.W., Piwowar-Manning, E., Richardson, P., Eshelman, S.H., Redinger, H., Williams, P., Sista, N.D.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7139112/
https://www.ncbi.nlm.nih.gov/pubmed/32280940
http://dx.doi.org/10.1016/j.eclinm.2020.100303
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author Bekker, L.G.
Li, S.
Pathak, S.
Tolley, E.E.
Marzinke, M.A.
Justman, J.E.
Mgodi, N.M.
Chirenje, M.
Swaminathan, S.
Adeyeye, A.
Farrior, J.
Hendrix, C.W.
Piwowar-Manning, E.
Richardson, P.
Eshelman, S.H.
Redinger, H.
Williams, P.
Sista, N.D.
author_facet Bekker, L.G.
Li, S.
Pathak, S.
Tolley, E.E.
Marzinke, M.A.
Justman, J.E.
Mgodi, N.M.
Chirenje, M.
Swaminathan, S.
Adeyeye, A.
Farrior, J.
Hendrix, C.W.
Piwowar-Manning, E.
Richardson, P.
Eshelman, S.H.
Redinger, H.
Williams, P.
Sista, N.D.
author_sort Bekker, L.G.
collection PubMed
description BACKGROUND: Daily oral TDF/FTC is protective against HIV infection when used for pre-exposure prophylaxis (PrEP). However, daily adherence to oral PrEP is difficult for many; therefore, finding alternative PrEP strategies remains a priority. HPTN 076 evaluated the long-acting injectable form of rilpivirine (RPV), known as RPV LA for safety, pharmacokinetics and acceptability. METHODS: HPTN 076 (NTC 02165202) was a phase 2, double-blind, 2:1 randomized trial comparing the safety of 1200mg RPV LA (LA) to placebo (P). The study included a 28-day oral run-in phase of daily, self- administered oral RPV (25 mg), with directly observed oral dosing about six times. Of 136 enrolled sexually active, HIV-uninfected, low HIV-risk African (100) and US (36) adult women, injectable product was administered in two gluteal, intramuscular (IM) injections once every eight weeks to 122 participants following the oral run-in phase. A maximum of six injection time points occurred over a 48-week period. Acceptability, safety, tolerability and pharmacokinetic (PK) data were collected throughout the study. This paper includes primary endpoint data collected up to the week 52 post enrollment. FINDINGS: The median age of the enrolled population was 31 years (IQR: 25,38), median weight 75 kg (IQR: 64, 89), median body mass index (BMI) 30 (IQR: 27, 35), 46% married, 94% Black and 60% unemployed. A total of 122 (80 LA, 42 P) women received at least one injection and 98 (64 LA, 34 P) received all six injections. During the injection phase, three women withdrew from the study (2 LA, 1 P) and 16 women discontinued study product (10 LA, 6 P). Fourteen women (11 LA and 3 P) discontinued oral study product and did not enter the injection phase. Study product discontinuations were not significantly different between the two arms throughout. Of the product discontinuations in the injection phase, 8% in LA and 5% in P arm were due to adverse events (AEs), including one randomized to the P arm with prolonged QTc interval on EKG. The proportion of women who experienced Grade 2 or higher AEs during the injection phase as the primary outcome was not significantly different between the two arms [73.8%, 95% CI: (63.2%, 82.1%) for LA and 73.8%, 95% CI: (58.9%, 84.7%), p>0.99]. Transient Grade ≥2 liver abnormalities occurred in 14% of women in the LA arm compared with 12% in P arm. Three LA women (4%) developed Grade 3 injection site reactions compared with none in P arm. In participants who received at least 1 injection, the geometric mean of overall RPV trough concentrations (C(trough)) was 62.2 ng/mL. In participants who received all six injections, the geometric mean of C(Trough) through the injection phase and after the last injection were 72.8 ng/mL and 100.9 ng/mL, respectively. At week 52 (eight weeks after last injection), the geometric mean of RPV C(trough) was 75.0 ng/mL. At the last injection visit (Week 44), 80 % of women who answered acceptability questions strongly agreed that they would think about using- and 68% that they would definitely use a PrEP injectable in the future. INTERPRETATION: RPV LA IM injections every eight weeks in African and US women were safe and acceptable. Overall, despite more injection site reactions and pain in the participants receiving RPV LA the injections were well tolerated. Data from this study support the further development of injectable PrEP agents.
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spelling pubmed-71391122020-04-10 Safety and tolerability of injectable Rilpivirine LA in HPTN 076: A phase 2 HIV pre-exposure prophylaxis study in women Bekker, L.G. Li, S. Pathak, S. Tolley, E.E. Marzinke, M.A. Justman, J.E. Mgodi, N.M. Chirenje, M. Swaminathan, S. Adeyeye, A. Farrior, J. Hendrix, C.W. Piwowar-Manning, E. Richardson, P. Eshelman, S.H. Redinger, H. Williams, P. Sista, N.D. EClinicalMedicine Research paper BACKGROUND: Daily oral TDF/FTC is protective against HIV infection when used for pre-exposure prophylaxis (PrEP). However, daily adherence to oral PrEP is difficult for many; therefore, finding alternative PrEP strategies remains a priority. HPTN 076 evaluated the long-acting injectable form of rilpivirine (RPV), known as RPV LA for safety, pharmacokinetics and acceptability. METHODS: HPTN 076 (NTC 02165202) was a phase 2, double-blind, 2:1 randomized trial comparing the safety of 1200mg RPV LA (LA) to placebo (P). The study included a 28-day oral run-in phase of daily, self- administered oral RPV (25 mg), with directly observed oral dosing about six times. Of 136 enrolled sexually active, HIV-uninfected, low HIV-risk African (100) and US (36) adult women, injectable product was administered in two gluteal, intramuscular (IM) injections once every eight weeks to 122 participants following the oral run-in phase. A maximum of six injection time points occurred over a 48-week period. Acceptability, safety, tolerability and pharmacokinetic (PK) data were collected throughout the study. This paper includes primary endpoint data collected up to the week 52 post enrollment. FINDINGS: The median age of the enrolled population was 31 years (IQR: 25,38), median weight 75 kg (IQR: 64, 89), median body mass index (BMI) 30 (IQR: 27, 35), 46% married, 94% Black and 60% unemployed. A total of 122 (80 LA, 42 P) women received at least one injection and 98 (64 LA, 34 P) received all six injections. During the injection phase, three women withdrew from the study (2 LA, 1 P) and 16 women discontinued study product (10 LA, 6 P). Fourteen women (11 LA and 3 P) discontinued oral study product and did not enter the injection phase. Study product discontinuations were not significantly different between the two arms throughout. Of the product discontinuations in the injection phase, 8% in LA and 5% in P arm were due to adverse events (AEs), including one randomized to the P arm with prolonged QTc interval on EKG. The proportion of women who experienced Grade 2 or higher AEs during the injection phase as the primary outcome was not significantly different between the two arms [73.8%, 95% CI: (63.2%, 82.1%) for LA and 73.8%, 95% CI: (58.9%, 84.7%), p>0.99]. Transient Grade ≥2 liver abnormalities occurred in 14% of women in the LA arm compared with 12% in P arm. Three LA women (4%) developed Grade 3 injection site reactions compared with none in P arm. In participants who received at least 1 injection, the geometric mean of overall RPV trough concentrations (C(trough)) was 62.2 ng/mL. In participants who received all six injections, the geometric mean of C(Trough) through the injection phase and after the last injection were 72.8 ng/mL and 100.9 ng/mL, respectively. At week 52 (eight weeks after last injection), the geometric mean of RPV C(trough) was 75.0 ng/mL. At the last injection visit (Week 44), 80 % of women who answered acceptability questions strongly agreed that they would think about using- and 68% that they would definitely use a PrEP injectable in the future. INTERPRETATION: RPV LA IM injections every eight weeks in African and US women were safe and acceptable. Overall, despite more injection site reactions and pain in the participants receiving RPV LA the injections were well tolerated. Data from this study support the further development of injectable PrEP agents. Elsevier 2020-04-06 /pmc/articles/PMC7139112/ /pubmed/32280940 http://dx.doi.org/10.1016/j.eclinm.2020.100303 Text en © 2020 Published by Elsevier Ltd. http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Research paper
Bekker, L.G.
Li, S.
Pathak, S.
Tolley, E.E.
Marzinke, M.A.
Justman, J.E.
Mgodi, N.M.
Chirenje, M.
Swaminathan, S.
Adeyeye, A.
Farrior, J.
Hendrix, C.W.
Piwowar-Manning, E.
Richardson, P.
Eshelman, S.H.
Redinger, H.
Williams, P.
Sista, N.D.
Safety and tolerability of injectable Rilpivirine LA in HPTN 076: A phase 2 HIV pre-exposure prophylaxis study in women
title Safety and tolerability of injectable Rilpivirine LA in HPTN 076: A phase 2 HIV pre-exposure prophylaxis study in women
title_full Safety and tolerability of injectable Rilpivirine LA in HPTN 076: A phase 2 HIV pre-exposure prophylaxis study in women
title_fullStr Safety and tolerability of injectable Rilpivirine LA in HPTN 076: A phase 2 HIV pre-exposure prophylaxis study in women
title_full_unstemmed Safety and tolerability of injectable Rilpivirine LA in HPTN 076: A phase 2 HIV pre-exposure prophylaxis study in women
title_short Safety and tolerability of injectable Rilpivirine LA in HPTN 076: A phase 2 HIV pre-exposure prophylaxis study in women
title_sort safety and tolerability of injectable rilpivirine la in hptn 076: a phase 2 hiv pre-exposure prophylaxis study in women
topic Research paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7139112/
https://www.ncbi.nlm.nih.gov/pubmed/32280940
http://dx.doi.org/10.1016/j.eclinm.2020.100303
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