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Single Injected Dose of Long-Acting Rilpivirine Inhibits HIV in Rectal Tissue

January 25, 2017

A single intramuscular dose of long-acting rilpivirine (Edurant) significantly lowered HIV-1 p24 antigen in rectal tissue but not in vaginal or cervical tissue in a study of 36 healthy, HIV-negative volunteers. The single dose caused no grade 3 or 4 adverse events.

Rilpivirine, a nonnucleoside reverse transcriptase inhibitor licensed for treatment of chronic HIV infection, has been formulated as a long-acting injectable agent for HIV prevention. In humanized BLT mice, injected long-acting rilpivirine prevented HIV infection after vaginal challenge. Initial phase 1 studies of long-acting rilpivirine, with or without the integrase inhibitor cabotegravir, established the safety and acceptability of this agent in humans.

A new phase 1 trial in healthy volunteers aimed to assess the safety, pharmacokinetics and ex vivo activity of long-acting rilpivirine in rectal and genital tract tissue. This single-center, open-label U.S. trial recruited HIV-negative volunteers 18 to 45 years old and assigned them alternately to a single intramuscular dose of 1200 or 600 mg of long-acting rilpivirine. Before and at regular intervals after rilpivirine administration, volunteers gave plasma samples, genital and rectal fluid samples and rectal, cervical and vaginal biopsy samples. No volunteers had used antiretrovirals for HIV prevention and none had condomless insertive or receptive anal intercourse within six months of screening.

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The study enrolled 12 men and 24 women; half in each group received a single dose of 1200 mg and half received 600 mg. Eight participants (22%) were black, and three were (8%) Hispanic. Age averaged 29.2 years. Dosage arms did not differ significantly in these demographic variables. All participants completed the study.

Of the 204 adverse events recorded, 200 (98%) were grade 1 or 2. None of the grade 3 or 4 adverse events could be attributed to rilpivirine. Rates of grade 2 or worse adverse events did not differ significantly by dose in women or men. Thirty-two of 36 participants (89%) had injection site reactions, and 28 participants (78%) had a prolonged QT interval. No QT values recorded exceeded the U.S. Food and Drug Administration definition of QT interval prolongation. Self-reported anxiety was significantly lower in women than men (P = .04). On a scale of 1 to 10, likelihood of using long-acting rilpivirine (assuming good protection against HIV) averaged 6.83.

In plasma samples collected 28 days after dosing, geometric mean rilpivirine concentrations with 1200 mg were 53 ng/mL in women and 43 ng/mL in men; with 600 mg geometric means were 28 ng/mL in women and 17 ng/mL in men. All geometric mean concentrations were higher than the 12.2 ng/mL protein binding-corrected effective concentration predicted to suppress 90% of wild-type HIV-1 (EC90). All women receiving the 1200-mg dose had rilpivirine concentrations above the EC90 for up to 98 days. Among women receiving the 600-mg dose, 92% had a rilpivirine concentration above the EC90 by day 42. Among men, rilpivirine plasma concentrations remained above the EC90 for up to 14 days with the 600-mg dose and for up to 84 days with the 1200-mg dose.

Among women, rilpivirine tissue-to-plasma ratios were 1.5- to 2.5-fold higher in rectal tissue (1.10 to 1.53) than in vaginal tissue (0.61 to 0.72) or cervical tissue (0.50 to 0.71). Rilpivirine concentrations in rectal tissue were similar in men and women and correlated strongly with paired plasma concentrations (r2 = 0.795 in women and 0.812 in men).

Ex vivo analysis identified a dose effect for change in amount of HIV-1 p24 antigen after 14 days of incubation in rectal issue (P = .04) but not in cervical tissue (P = .55) or vaginal tissue (P = .07). HIV-1 p24 suppression in rectal tissue persisted for 112 days with either rilpivirine dose, but p24 levels returned to baseline values by day 168 with the 1200-mg dose and day 140 with the 600-mg dose.

The researchers believe their findings "confirm rilpivirine as a long-acting formulation but raise questions about the compartmental pharmacokinetic profile and whether there might be differential levels of protection associated with rectal and vaginal transmission of HIV-1 infection." They caution that subtherapeutic rilpivirine levels toward the end of a long dosing interval could allow emergence of nonnucleoside-resistant HIV-1 in people who become infected. The researchers add that an ongoing study of long-acting rilpivirine in the United States, South Africa and Zimbabwe will reveal more about longer-term safety and acceptability and about whether this agent should advance to efficacy trials for prevention of HIV infection.

Mark Mascolini writes about HIV infection.


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