HIGH-FREQUENCY failure of combination antiretroviral therapy in paediatric HIV infection is associated with unmet maternal needs causing maternal NON-ADHERENCE.

BACKGROUND: Early combination antiretroviral therapy (cART) reduces the size of the viral reservoir in paediatric and adult HIV infection. Very early-treated children may have higher cure/remission potential. METHODS: In an observational study of 151 in utero (IU)-infected infants in KwaZulu-Natal, South Africa, whose treatment adhered strictly to national guidelines, 76 infants diagnosed via point-of-care (PoC) testing initiated cART at a median of 26 h (IQR 18-38) and 75 infants diagnosed via standard-of-care (SoC) laboratory-based testing initiated cART at 10 days (IQR 8-13). We analysed mortality, time to suppression of viraemia, and maintenance of aviraemia over the first 2 years of life. FINDINGS: Baseline plasma viral loads were low (median 8000 copies per mL), with 12% of infants having undetectable viraemia pre-cART initiation. However, barely one-third (37%) of children achieved suppression of viraemia by 6 months that was maintained to >12 months. 24% had died or were lost to follow up by 6 months. Infant mortality was 9.3%. The high-frequency virological failure in IU-infected infants was associated not with transmitted or acquired drug-resistant mutations but with cART non-adherence (plasma cART undetectable/subtherapeutic, p<0.0001) and with concurrent maternal cART failure (OR 15.0, 95%CI 5.6-39.6; p<0.0001). High-frequency virological failure was observed in PoC- and SoC-tested groups of children. INTERPRETATION: The success of early infant testing and cART initiation strategies is severely limited by subsequent cART non-adherence in HIV-infected children. Although there are practical challenges to administering paediatric cART formulations, these are overcome by mothers who themselves are cART-adherent. These findings point to the ongoing obligation to address the unmet needs of the mothers. Eliminating the particular barriers preventing adequate treatment for these vulnerable women and infants need to be prioritised in order to achieve durable suppression of viraemia on cART, let alone HIV cure/remission, in HIV-infected children. FUNDING: Wellcome Trust, National Institutes of Health.

Increasing Diagnostic Uncertainties in Children With In Utero HIV Infection.

We present a case of an in utero HIV-infected child, who on day 1 of life had a positive whole blood total nucleic acid test but viral load <20 RNA copies/mL. Dried blood spot total nucleic acid testing was negative on day 1, 10 and at 3 months, while on ART prophylaxis then positive at 5 months after prophylaxis ended. Retrospective peripheral blood mononuclear cells HIV DNA testing from day 1 of life was positive, confirming in utero infection.

Multiple-dose ponezumab for mild-to-moderate Alzheimer's disease: Safety and efficacy.

INTRODUCTION: Multiple intravenous doses of ponezumab, an anti-amyloid antibody, were evaluated in subjects with mild-to-moderate Alzheimer's disease (AD). METHODS: In part A, 77 subjects were randomized to ponezumab 0.1, 0.5, or 1 mg/kg (75 treated) and 26 to placebo (24 treated). In part B, 63 subjects were randomized and treated with ponezumab 3 or 8.5 mg/kg and 32 with placebo. Subjects received 10 infusions over 18 months and were followed for 6 months thereafter. RESULTS: Ponezumab was generally safe and well tolerated. Most common adverse events were fall (16.7% ponezumab, 21.4% placebo), headache (13.8%, 21.4%), and cerebral microhemorrhage (13.8%, 19.6%). Plasma ponezumab increased dose-dependently with limited accumulation. Cerebrospinal fluid penetration was low. Plasma Aß1-x and Aß1-40 showed robust increases, but cerebrospinal fluid biomarkers showed no dose response. Ponezumab had no effects on cognitive/functional outcomes or brain volume. CONCLUSIONS: Multiple-dose ponezumab was generally safe, but not efficacious, in mild-to-moderate AD.

Emergence of anti-conflict effects of zolpidem in rhesus monkeys following extended post-injection intervals.

RATIONALE: Zolpidem is a hypnotic drug that binds to γ-aminobutyric acid type A receptors but lacks consistently demonstrable anxiolytic efficacy. METHODS: Rhesus monkeys (N = 4) were trained under a multiple schedule in which food-maintained responding was programmed (18-response fixed ratio) for a 5-min period, followed by a 5-min period in which the food-maintained responding was suppressed by response-contingent electric shock (20-response fixed ratio). Doses of zolpidem (range = 0.03 to 1.0 mg/kg, i.v.) were administered 5 min before the session, and responding was re-assessed at three additional 20-min intervals. A similar experiment also was carried out with the non-selective benzodiazepine, triazolam, over a dose range of 0.001 to 0.1 mg/kg, i.v. RESULTS: Zolpidem did not engender a significant increase in average rates of suppressed responding at earlier time points; however, rates of non-suppressed responding were robustly decreased. At 45- and 65-min post-injection, zolpidem treatment resulted in a dose-dependent increase in rates of suppressed responding. In contrast, the non-selective benzodiazepine triazolam increased rates of suppressed responding in a dose-dependent manner at all four time points, although decreases in non-suppressed responding were less at the later time points. CONCLUSIONS: These findings suggest that zolpidem has anxiolytic-like effects, but only >25 min after i.v. injection in this rhesus monkey conflict model. It was hypothesized that time-dependent effects on the response rate-suppressing properties of zolpidem become tolerant (i.e., acute tolerance). Because anxiolytic-like effects remain stable throughout the session, the absence of rate-decreasing effects may "unmask" anti-conflict effects.

Retrograde effects of triazolam and zolpidem on sleep-dependent motor learning in humans.

Drugs that act as allosteric activators at the benzodiazepine site of the gamma-aminobutyric acid (GABA(A)) receptor complex are used commonly to treat insomnia but relatively little is known of how such use affects learning and memory. Although anterograde effects on memory acquisition have been shown, possible retrograde effects on consolidation are more relevant when such agents are administered at bedtime. We tested the effects of two GABA(A) allosteric activators on sleep-dependent motor skill memory consolidation in 12 healthy male subjects. Subjects slept in a sleep laboratory for four consecutive nights (one accommodation night followed by three experimental nights). Placebo, triazolam 0.375 mg, and zolpidem 10 mg were given to each subject in counterbalanced order on the experimental nights. Polysomnographic (PSG) sleep measurement and sleep-dependent motor learning were assessed at each condition. Triazolam was associated with longer total sleep time and increased Stage 2 sleep. Both zolpidem and triazolam were associated with increased latency to rapid eye movement (REM) sleep. Overnight motor learning correlated with total sleep time in the placebo condition but not in the triazolam or zolpidem conditions. A statistically significant impairment in motor performance occurred overnight in the triazolam condition only. Triazolam, given in sufficient doses to prolong sleep in healthy people, affected overnight motor learning adversely. Zolpidem, in a dose sufficient to prolong REM onset latency but without other effects on PSG-measured sleep, degraded the relationship between total sleep time and overnight motor learning. These data indicate that non-selective or alpha1-preferring benzodiazepine site allosteric activators can interfere with sleep-dependent memory consolidation.