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 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 (Ctrough) was 62.2 ng/mL. In participants who received all six injections, the geometric mean of CTrough 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 Ctrough 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.

Penicillin resistance and other predictors of mortality in pneumococcal bacteremia in a population with high human immunodeficiency virus seroprevalence.

Rates of invasive disease caused by penicillin-resistant pneumococci are rising. Previous reports have found no association between resistant pneumococci and increased mortality. To evaluate the impact of penicillin resistance and other variables on mortality, we retrospectively studied all cases of pneumococcal bacteremia identified by our microbiology laboratory from 1 January 1992 through 31 December 1996. There were 462 cases of pneumococcal bacteremia in 432 patients. The mean age was 35 years; 55% of the cases occurred in male patients, 58% were in black patients, and 40% were in Hispanic patients. One-half of the cases occurred in patients with documented human immunodeficiency virus (HIV) infection. Penicillin resistance was first noted in 1994 and increased yearly, accounting for 17% of 1996 isolates. Of all resistant isolates, 65% were resistant to penicillin at a high level. The overall mortality was 17%. On multivariate analysis, high-level penicillin resistance, older age, severe disease, multilobar infiltrates and/or effusion(s) on chest roentgenogram, and Hispanic ethnicity were independent predictors of mortality in pneumococcal bacteremia. In HIV-infected patients, a CD4 cell count below the median just missed statistical significance. This is the first report demonstrating penicillin resistance as an independent predictor of mortality among patients with pneumococcal bacteremia.

Factors influencing time to sputum conversion among patients with smear-positive pulmonary tuberculosis.

For hospitalized patients with smear-positive pulmonary or laryngeal tuberculosis, the Centers for Disease Control and Prevention recommends that three consecutive sputum samples be negative for acid-fast bacilli (AFB) before respiratory isolation is discontinued. Limited data are available to predict the length of time to obtain three negative sputum smears and cultures and to determine factors associated with a prolonged interval before sputum smear and culture conversion, especially among patients infected with human immunodeficiency virus (HIV). For 100 consecutive patients with smear-positive pulmonary tuberculosis, the mean and median numbers of days from the initiation of appropriate therapy to the first of three consecutive negative smears were calculated, and associated risk factors were determined. The mean number of days before the first of three consecutive negative sputum smears was 33 days; the median was 23 days. On stepwise multiple regression analysis, cavitary disease, numerous AFB on the initial smear, and no prior history of tuberculosis were the factors independently associated with an increased number of days for both smear and culture conversion. HIV does not prolong the period of infectiousness.