Facilitating Next-Generation Pre-Exposure Prophylaxis Clinical Trials Using HIV Recent Infection Assays: A Consensus Statement from the Forum HIV Prevention Trial Design Project.

Standard-of-care HIV pre-exposure prophylaxis (PrEP) is highly efficacious, but uptake of and persistence on a daily oral pill is low in many settings. Evaluation of alternate PrEP products will require innovation to avoid the unpractically large sample sizes in noninferiority trials. We propose estimating HIV incidence in people not on PrEP as an external counterfactual to which on-PrEP incidence in trial subjects can be compared. HIV recent infection testing algorithms (RITAs), such as the limiting antigen avidity assay plus viral load used on specimens from untreated HIV positive people identified during screening, is one possible approach. Its feasibility is partly dependent on the sample size needed to ensure adequate power, which is impacted by RITA performance, the number of recent infections identified, the expected efficacy of the intervention, and other factors. Screening sample sizes to support detection of an 80% reduction in incidence for 3 key populations are more modest, and comparable to the number of participants in recent phase III PrEP trials. Sample sizes would be significantly larger in populations with lower incidence, where the false recency rate is higher or if PrEP efficacy is expected to be lower. Our proposed counterfactual approach appears to be feasible, offers high statistical power, and is nearly contemporaneous with the on-PrEP population. It will be important to monitor the performance of this approach during new product development for HIV prevention. If successful, it could be a model for preventive HIV vaccines and prevention of other infectious diseases.

The effect of pumpless extracorporeal CO2 removal on regional perfusion of the brain in experimental acute lung injury.

BACKGROUND: Lung-protective mechanical ventilation with low tidal volumes (V(T)) is often associated with hypercapnia (HC), which may be unacceptable in patients with brain injury. CO2 removal using a percutaneous extracorporeal lung assist (pECLA) enables normocapnia despite low V(T), but its effects on regional cerebral blood flow (rCBF) remain ambiguous. We hypothesized that reversal of HC by pECLA impairs rCBF in a porcine lung injury model. METHODS: Lung injury was induced in 9 anesthetized pigs by hydrochloric acid aspiration. rCBF and systemic hemodynamics were measured by colored microsphere technique and transpulmonary-thermodilution during a randomized sequence of 4 experimental situations: pECLA shunt-on (1) with HC and (2) without HC, pECLA shunt-off (3) with HC and (4) without HC. RESULTS: HC increased rCBF (P<0.05). CO2 removal with pECLA resulting in normocapnia, decreased rCBF to levels comparable to those without pECLA and normocapnia. HC resulted in increased cardiac output (+25.5%). Cardiac output was highest during HC with pECLA shunt (+44.9%). During pECLA with CO2 removal, cardiac output (+38.1%) decreased compared with pECLA without CO2 removal, but stayed higher than during normocapnia/no pECLA shunt (P<0.05). CONCLUSIONS: In this animal model, mechanical ventilation with low V(T) was associated with HC and increased rCBF. CO2 removal by pECLA restored normocapnia, reduced rCBF to levels of normocapnia, but required a higher systemic blood flow for the perfusion of the pECLA device. If these results could be transferred to patients, extracorporeal CO2 removal might be an option for treatment of combined lung and brain injury in condition of a sufficient cardiac flow reserve.

The counteraction of opioid-induced ventilatory depression by the serotonin 1A-agonist 8-OH-DPAT does not antagonize antinociception in rats in situ and in vivo.

BACKGROUND: Spontaneous breathing during mechanical ventilation is gaining increasing importance during intensive care but is depressed by narcotics, such as opioids. Serotonin 1A-receptor (5-HT(1A)-R) agonists have been shown to antagonize opioid-induced ventilatory depression, but both enhancement and attenuation of nociceptive reflexes have been found with different experimental models. To clarify contradictory findings, we simultaneously determined dose-response functions of the standard 5-HT(1A)-R-agonist 8-OH-DPAT and two different opioids for spontaneous ventilation and nociception. Two hypotheses were tested: 1) 8-OH-DPAT at a dose to stimulate spontaneous breathing does not activate nociceptive reflexes. 2) 8-OH-DPAT does not diminish opioid-induced antinociception. METHODS: (A) A dose-response relationship of 8-OH-DPAT, spontaneous phrenic nerve activity and a nociceptive C-fiber reflex (CFR) were established simultaneously in an in situ perfused, nonanesthetized, rat brainstem-spinal cord preparation. (B) Fentanyl was administered in situ to investigate the interaction with 8-OH-DPAT on phrenic nerve activity and nociceptive CFR. Additional experiments involved the selective 5-HT(1A)-R-antagonist WAY 100 635 to exclude effects of receptors other than 5-HT(1A)-R. (C) The effects of 8-OH-DPAT on spontaneous ventilation and nociceptive tail-flick reflex with and without morphine were verified in in vivo anesthetized rats. RESULTS: Low-dose 8-OH-DPAT (0.001 and 0.01 microM in situ, 0.1 microg/kg in vivo) enhanced nociceptive reflexes but did not activate spontaneous ventilation. On the contrary, high doses of 8-OH-DPAT (1 microM in situ and 10-100 microg/kg in vivo) stimulated ventilation, whereas nociceptive CFR amplitude in situ returned to baseline and tail-flick reflex was depressed in vivo. Opioid-induced ventilatory depression was antagonized by 8-OH-DPAT (1 microM in situ, and 10 microg/kg in vivo), whereas antinociception sustained. Selective 5-HT(1A)-R-antagonist WAY 100 635 (1 microM) prevented the effects of 8-OH-DPAT in situ. CONCLUSION: 5-HT(1A)-R-agonist 8-OH-DPAT activates spontaneous breathing without diminishing opioid-induced antinociception in rats.

Effects of spinal anaesthesia versus epidural anaesthesia for caesarean section on postoperative analgesic consumption and postoperative pain.

BACKGROUND AND OBJECTIVE: Regional anaesthesia is commonly used for elective caesarean section. The aim of this study was to investigate whether there is a positive effect of either spinal or epidural anaesthesia on postoperative analgesic requirements and pain relief. METHODS: The analgesic effect of either spinal or epidural induction of perispinal anaesthesia have been compared in 132 women (ASA I or II) scheduled for elective caesarean section, all having epidural catheterization for perioperative anaesthesia and postoperative analgesia. The patients were randomized into two groups. To achieve a sensory block height to the level of the sixth thoracic dermatome, the parturients received isobaric bupivacaine 0.5% and 5 microg sufentanil intrathecally or ropivacaine 0.75% and 10 microg sufentanil epidurally. For postoperative analgesia, all patients used patient-controlled epidural analgesia at identical settings [bolus of ropivacaine 0.133% (11-15 mg according to patient's height), lock-out time 1 h]. Intraoperative and postoperative pain was recorded using a visual analogue pain score as well as analgesic requirements over the first 24 h after surgery. RESULTS: One hundred and twenty-five patients completed the study. There were no differences in patient-controlled epidural analgesic requirements between groups. During surgery, the pain score on a visual analogue scale was more intense with epidural anaesthesia than with spinal anaesthesia (P < 0.05). For the whole 24 h observation period, the area under the curve for pain was lower with spinal anaesthesia (P < 0.0005). At almost all postoperative time points, visual analogue scale scores at rest and during mobilization were lower with spinal anaesthesia (P < 0.05), which was accompanied by less motor blockade and lower frequency of adverse effects. More patients with epidural anaesthesia received supplemental analgesic medication. CONCLUSION: In parturients undergoing elective caesarean section, postoperative use of epidural ropivacaine via patient-controlled epidural analgesia is similar after spinal and epidural anaesthesia. Spinal anaesthesia is, however, accompanied with less postoperative pain, use of additional analgesics and side-effects.