Last data update: May 06, 2024. (Total: 46732 publications since 2009)
Records 1-5 (of 5 Records) |
Query Trace: Spreen W[original query] |
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Sexually transmitted infections and depot medroxyprogesterone acetate do not impact protection from SHIV acquisition by long-acting cabotegravir in macaques
Vishwanathan SA , Zhao C , Luthra R , Khalil GK , Morris MM , Dinh C , Gary MJ , Mitchell J , Spreen WR , Pereira LE , Heneine W , García-Lerma JG , McNicholl JM . AIDS 2021 36 (2) 169-176 OBJECTIVE: We had previously shown that long-acting cabotegravir (CAB-LA) injections fully protected macaques from vaginal simian HIV (SHIV) infection. Here, we reassessed CAB-LA efficacy in the presence of depot medroxyprogesterone acetate and multiple sexually transmitted infections (STI) that are known to increase HIV susceptibility in women. DESIGN: Two macaque models of increasing vaginal STI severity were used for efficacy assessment. METHODS: The first study (n = 11) used a double STI model that had repeated exposures to two vaginal STI, Chlamydia trachomatis (CT) and Trichomonas vaginalis (TV). Six animals were CAB-LA treated and 5 were controls. The second study (n = 9) included a triple STI model with repeated exposures to CT, TV and syphilis, and the contraceptive, depot medroxyprogesterone acetate (DMPA). Six animals were CAB-LA treated and three were controls. All animals received up to 14 vaginal SHIV challenges. A survival analysis was performed to compare the number of SHIV challenges to infection in the drug-treated group compared to untreated controls over time. RESULTS: All 6 CAB-LA treated animals in both models, the double STI or the triple STI-DMPA model, remained protected after 14 SHIV vaginal challenges while the untreated animals became SHIV-infected after a median of 2 challenges (log-rank p < 0.001) or 1 challenge (log-rank p = 0.002), respectively. Both models recapitulated human STI disease, with vaginal discharge, ulcers and seroconversion. CONCLUSION: In these high and sustained susceptibility models spanning more than 3 months, CAB-LA maintained complete efficacy, demonstrating robustness of the CAB-LA dose used in clinical trials, and suggesting its insensitivity to multiple STIs and DMPA. |
Cabotegravir for HIV prevention in cisgender men and transgender women
Landovitz RJ , Donnell D , Clement ME , Hanscom B , Cottle L , Coelho L , Cabello R , Chariyalertsak S , Dunne EF , Frank I , Gallardo-Cartagena JA , Gaur AH , Gonzales P , Tran HV , Hinojosa JC , Kallas EG , Kelley CF , Losso MH , Madruga JV , Middelkoop K , Phanuphak N , Santos B , Sued O , Valencia Huamaní J , Overton ET , Swaminathan S , Del Rio C , Gulick RM , Richardson P , Sullivan P , Piwowar-Manning E , Marzinke M , Hendrix C , Li M , Wang Z , Marrazzo J , Daar E , Asmelash A , Brown TT , Anderson P , Eshleman SH , Bryan M , Blanchette C , Lucas J , Psaros C , Safren S , Sugarman J , Scott H , Eron JJ , Fields SD , Sista ND , Gomez-Feliciano K , Jennings A , Kofron RM , Holtz TH , Shin K , Rooney JF , Smith KY , Spreen W , Margolis D , Rinehart A , Adeyeye A , Cohen MS , McCauley M , Grinsztejn B . N Engl J Med 2021 385 (7) 595-608 BACKGROUND: Safe and effective long-acting injectable agents for preexposure prophylaxis (PrEP) for human immunodeficiency virus (HIV) infection are needed to increase the options for preventing HIV infection. METHODS: We conducted a randomized, double-blind, double-dummy, noninferiority trial to compare long-acting injectable cabotegravir (CAB-LA, an integrase strand-transfer inhibitor [INSTI]) at a dose of 600 mg, given intramuscularly every 8 weeks, with daily oral tenofovir disoproxil fumarate-emtricitabine (TDF-FTC) for the prevention of HIV infection in at-risk cisgender men who have sex with men (MSM) and in at-risk transgender women who have sex with men. Participants were randomly assigned (1:1) to receive one of the two regimens and were followed for 153 weeks. HIV testing and safety evaluations were performed. The primary end point was incident HIV infection. RESULTS: The intention-to-treat population included 4566 participants who underwent randomization; 570 (12.5%) identified as transgender women, and the median age was 26 years (interquartile range, 22 to 32). The trial was stopped early for efficacy on review of the results of the first preplanned interim end-point analysis. Among 1698 participants from the United States, 845 (49.8%) identified as Black. Incident HIV infection occurred in 52 participants: 13 in the cabotegravir group (incidence, 0.41 per 100 person-years) and 39 in the TDF-FTC group (incidence, 1.22 per 100 person-years) (hazard ratio, 0.34; 95% confidence interval, 0.18 to 0.62). The effect was consistent across prespecified subgroups. Injection-site reactions were reported in 81.4% of the participants in the cabotegravir group and in 31.3% of those in the TDF-FTC group. In the participants in whom HIV infection was diagnosed after exposure to CAB-LA, INSTI resistance and delays in the detection of HIV infection were noted. No safety concerns were identified. CONCLUSIONS: CAB-LA was superior to daily oral TDF-FTC in preventing HIV infection among MSM and transgender women. Strategies are needed to prevent INSTI resistance in cases of CAB-LA PrEP failure. (Funded by the National Institute of Allergy and Infectious Diseases and others; HPTN 083 ClinicalTrials.gov number, NCT02720094.). |
Cabotegravir long-acting protects macaques against repeated penile SHIV exposures
Dobard C , Makarova N , Nishiura K , Dinh C , Holder A , Sterling M , Lipscomb J , Mitchell J , Deyounks F , Garber D , Khalil G , Spreen W , Heneine W , Garcia-Lerma JG . J Infect Dis 2020 222 (3) 391-395 We used a novel penile simian HIV (SHIV) transmission model to investigate if cabotegravir long-acting (CAB LA) prevents penile SHIV acquisition in macaques. Twenty-two macaques were exposed to SHIV via the foreskin and urethra once-weekly for 12 weeks. Of these, six received human-equivalent doses of CAB LA, six received oral FTC/TDF, and 10 were untreated. The efficacy of CAB LA was high (94.4% [95%CI=58.2%-99.3%]) and similar to that seen with oral FTC/TDF (94.0% [95%CI=55.1%-99.2%]). The high efficacy of CAB LA in the penile transmission model supports extending the clinical advancement of CAB LA PrEP to heterosexual men. |
Drug resistance emergence in macaques administered cabotegravir long-acting for pre-exposure prophylaxis during acute SHIV infection
Radzio-Basu J , Council O , Cong ME , Ruone S , Newton A , Wei X , Mitchell J , Ellis S , Petropoulos CJ , Huang W , Spreen W , Heneine W , Garcia-Lerma JG . Nat Commun 2019 10 (1) 2005 A long-acting injectable formulation of the HIV integrase inhibitor cabotegravir (CAB-LA) is currently in clinical development for PrEP. Although the long plasma half-life of CAB-LA is an important attribute for PrEP, it also raises concerns about drug resistance emergence if someone becomes infected with HIV, or if PrEP is initiated during undiagnosed acute infection. Here we use a macaque model of SHIV infection to model risks of drug resistance to CAB-LA PrEP. Six macaques infected with SHIV received CAB-LA before seroconversion. We show integrase mutations G118R, E92G/Q, or G140R in plasma from 3/6 macaques as early as day 57, and identify G118R and E92Q in viruses from vaginal and rectal fluids. G118R and G140R confer > 800-fold resistance to CAB and cross-resistance to all licensed integrase inhibitors. Our results emphasize the need for appropriate HIV testing strategies before and possibly shortly after initiating CAB LA PrEP to exclude acute infection. |
The long-acting integrase inhibitor GSK744 protects macaques from repeated intravaginal SHIV challenge
Radzio J , Spreen W , Yueh YL , Mitchell J , Jenkins L , Garcia-Lerma JG , Heneine W . Sci Transl Med 2015 7 (270) 270ra5 Daily preexposure prophylaxis (PrEP) with Truvada is a proven HIV prevention strategy; however, its effectiveness is limited by low adherence. Antiretroviral drug formulations that require infrequent dosing may increase adherence and thus PrEP effectiveness. We investigated whether monthly injections of a long-acting formulation of the HIV integrase inhibitor GSK1265744 (GSK744 LA) prevented simian/human immunodeficiency virus (SHIV) infection by vaginal challenge in macaques. Female pigtail macaques (n = 12) were exposed to intravaginal inoculations of SHIV twice a week for up to 11 weeks. Half of the animals received a GSK744 LA injection every 4 weeks, and half received placebo. GSK744 LA, at plasma concentrations achievable with quarterly injections in humans, protected all six macaques from infection. Placebo controls were all infected after a median of 4 (range, 2 to 20) vaginal challenges with SHIV. Efficacy was related to high and sustained vaginal and plasma drug concentrations that remained above the protein-adjusted 90% inhibitory concentration during the dosing cycles. These data support advancement of GSK744 LA as a potential PrEP candidate for women. |
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