PRO 140, a monoclonal antibody targeting CCR5, as a long-acting, single-agent maintenance therapy for HIV-1 infection.

Background PRO 140 is a humanized monoclonal antibody targeting CCR5 with potent antiviral activity in patients with CCR5-tropic HIV-1 infection. In phase 2b studies, we evaluated the long-term efficacy, safety, and tolerability of PRO 140 monotherapy in maintaining viral suppression for over 24 months in patients who were stable on combination antiretroviral therapy on entry into the trials. Methods and Results Forty-one adult patients, infected exclusively with CCR5-tropic HIV-1 with viral loads <50 copies/mL, were switched from daily oral combination ART regimens to weekly PRO 140 monotherapy for 12 weeks. Participants who completed 12 weeks of treatment without experiencing virologic rebound were allowed to self-administer PRO 140 as a 350 mg subcutaneous injection weekly, for up to an additional 160 weeks. Participants were monitored bi-weekly for one year, and every four weeks thereafter for virologic rebound. PRO 140 provided virologic suppression in 23/41 (56.1%) participants for 12 weeks and was well tolerated. Ten (10) participants are currently ongoing, of which nine participants have completed more than two years of monotherapy treatment (47-129 weeks). Participants experiencing virologic rebound achieved full viral suppression upon re-initiation of oral combination ART regimen. Anti-PRO 140 antibodies were not detected in any patient, and no drug-related major adverse events or treatment discontinuations were reported. Conclusions PRO 140 has a potential to address an unmet need for a long-acting, single-agent, maintenance regimen for HIV infection in selected patients. Studies are underway to determine host and/or virologic factors that may predict treatment success on PRO 140 monotherapy. Moreover, it has sufficient potency for a prolonged period of monotherapy that it would be an excellent component of a multi long-acting drug combination.

Mortality and long-term functional outcome associated with intracranial pressure after traumatic brain injury.

PURPOSE: Elevated intracranial pressure (ICP) has been associated with increased mortality in patients with severe traumatic brain injury (TBI). We have examined whether raised ICP is independently associated with mortality, functional status and neuropsychological functioning in adult TBI patients. METHODS: Data from a randomized trial of 499 participants were secondarily analyzed. The primary endpoints were mortality and a composite measure of functional status and neuropsychological function (memory, speed of information processing, executive function) over a 6-month period. The area under the curve of the ICP profile (average ICP) during the first 48 h of monitoring was the main predictor of interest. Multivariable regression was used to adjust for a priori defined confounders: age, Glasgow Coma Score, Abbreviated Injury Scale-head and hypoxia. RESULTS: Of the participants, 365 patients had complete 48-h ICP data. The overall 6-month mortality was 18 %. The adjusted odds ratio of mortality comparing 10-mmHg increases in average ICP was 3.12 (95 % confidence interval 1.79, 5.44; p < 0.01). Overall, higher average ICP was associated with decreased functional status and neuropsychological functioning (p < 0.01). Importantly, among survivors, increasing average ICP was not independently associated with worse performance on neuropsychological testing (p = 0.46). CONCLUSIONS: Average ICP in the first 48 h of monitoring was an independent predictor of mortality and of a composite endpoint of functional and neuropsychological outcome at the 6-month follow-up in moderate or severe TBI patients. However, there was no association between average ICP and neuropsychological functioning among survivors.