Design challenges facing clinical trials of the effectiveness of new HIV prevention technologies

Recent successes of antiretroviral pre-exposure prophylaxis (PrEP) in preventing HIV infection have raised questions whether further placebo controlled trials of new HIV-prevention technologies are ethically justifiable. A trial with active agent(s) in the comparator group can be designed either as a superiority or non-inferiority trial. In a non-inferiority trial the hypothesis tested is that the intervention is not inferior to, by a predefined clinically relevant amount, or at least as effective as, the comparator. Non-inferiority trials pose challenges in data interpretation.Firstly it is possible to show equivalence of two non-effective interventions. If the active comparator intervention is ineffective, the new intervention would be shown to be non-inferior to this inactive intervention, while neither intervention is superior to placebo or no intervention. The second challenge is that any effect that dilutes the true efficacy of an intervention in a trial, such as non-adherence, loss to follow-up or protocol violations, makes it easier for the two interventions to be declared equivalent. Non-differential low adherence is unlikely to lead to the conclusion that an inferior intervention is non-inferior. However, differential adherence between study arms, which is more likely in non-blinded trials, is likely to bias the results and lead to incorrect conclusions. Investigators conducting non-inferiority trials will have to pay special attention to supporting, measuring and maintaining high adherence. The goal in future non-inferiority trials should be to maintain similar levels of high adherence in all study arms, but at a minimum to reduce the likelihood of differential adherence across study arms

Determinants of optimal adherence over time to antiretroviral therapy amongst HIV positive adults in South Africa : a longitudinal study.

Highly active antiretroviral therapy (HAART) requires strict adherence to achieve optimal clinical and survival benefits. A study was done to explore the factors affecting HAART adherence among HIV positive adults by reviewing routinely collected patient information in the Centre for the AIDS Programme of Research in South Africa’s (CAPRISA) AIDS Treatment Programme. Records of 688 patients enrolled between 2004 and 2006 were analysed. Patients were considered adherent if they had taken at least 95% of their prescribed drugs. Generalized estimating equations were used to analyse the data. The results showed that HAART adherence increased over time, however, the rate of increase differed by some of the socio-demographic and behavioural characteristics of the patients. For instance, HAART adherence increased in both urban and rural treatment sites over time, but the rate of increase was higher in the rural site. This helped identify sub-populations, such as the urban population, that required ongoing adherence counseling

Impact of home-based HIV testing services on progress toward the UNAIDS 90-90-90 targets in a hyperendemic area of South Africa.

CAPRISA, 2019.Abstract available in PDF

Anaemia in Acute HIV-1 Subtype C Infection

BACKGROUND: The high prevalence of anaemia and the increased morbidity and mortality associated with anaemia during AIDS has been well described yet there has been little information about anaemia and changes in haemoglobin levels during acute and early HIV-1 infection. METHODS: HIV-negative women (n = 245) were enrolled into an observational cohort as part of the Centre for the AIDS Programme of Research in South Africa (CAPRISA) Acute Infection Study. Acute infection was diagnosed following a positive HIV RNA PCR in the absence of antibodies, or detection of HIV-1 antibodies within 3 months of a previously negative antibody test. Haemotologic parameters were assessed before infection and at regular intervals in the first twelve months of HIV infection. RESULTS: Fifty-seven participants with acute HIV infection were identified at a median of 14.5 days post-infection (range 10-81) and were enrolled in the CAPRISA Acute Infection cohort at a median of 41 days post-infection (range 15-104). Mean haemoglobin prior to HIV-1 infection was 12.7 g/dL, with a mean decline of 0.46 g/dL following infection. The prevalence of anaemia increased from 25.0% prior to HIV-1 infection to 52.6% at 3 months post-infection, 61.1% at 6 months post-infection, and 51.4% at 12 months post-infection. CONCLUSIONS: Haematologic derangements and anaemia with a trend towards iron deficiency are common with acute HIV-1 subtype C infection in this small cohort. The negative impact of anaemia concurrent with established HIV infection upon morbidity and mortality has been well documented but the prognostic potential and long-term effects of anaemia during acute HIV-1 infection remain unknown

Evaluacija inovativno digitalno kontroliranog Er:YAG lasera u liječenju leukoplakije - probno istraživanje

The use of lasers for treatment of oral leukoplakia has gained a lot of interest in the past years, however, data on the use of Er:YAG laser are scarce. The aim of this study was to compare the efficacy of Er:YAG laser and 1% topical isotretinoin in the treatment of 27 oral leukoplakia patients. Er:YAG laser (LightWalker AT, Fotona, Slovenia) was used in 27 patients with 27 leukoplakia lesions. Postoperative pain was assessed by use of visual analog scale (VAS), and the impact of laser treatment on the quality of life was assessed by the OHIP-14 questionnaire (Croatian version). Control group consisted of the same 27 patients previously treated with 1% topical isotretionin three times a day during the period of one year. No improvement in the size of leukoplakia lesions was observed after treatment with topical isotretinoin. There were significant differences between men and women according to leukoplakia localization, number of laser sessions and VAS (p<0.05). At follow-up after six months and one year, there was no recurrence of lesions. Er:YAG laser is a successful treatment for oral leukoplakia. Topical isotretionin treatment is unsuccessful in patients with oral leukoplakia.Posljednjih godina postoji veliko zanimanje za upotrebu lasera u liječenju oralne leukoplakije, ali su podatci o upotrebi Er:YAG lasera malobrojni. Cilj ovoga istraživanja bio je usporediti učinak Er:YAG lasera i 1%-tnog topikalnog izotretinoina u liječenju 27 bolesnika s oralnom leukoplakijom. Er:YAG laser (LightWalker AT, Fotona, Slovenia) je korišten u 27 bolesnika s 27 leukoplakičnih lezija. Poslijeoperacijska bol je određena uz pomoć vizualne analogne ljestvice (visual analog scale, VAS), a utjecaj na kvalitetu života mjeren je pomoću upitnika OHIP-14 (hrvatska verzija). Kontrolna skupina se sastojala od istih 27 bolesnika koji su prije toga liječeni 1%-tnim topikalnim izotretioninom tri puta na dan tijekom tri mjeseca. Nije bilo poboljšanja u veličini lezija leukoplakije nakon topikalno primijenjenog izotretinoina. Utvrđene su značajne razlike između muškaraca i žena s obzirom na lokalizaciju leukoplakije, broj laserskih zahvata i rezultata VAS (p<0,05). Šest mjeseci i godinu dana od laserskog zahvata nije bilo recidiva oralne leukoplakije. Er:YAG laser je uspješna terapija u liječenju oralne leukoplakije. Topikalna primjena izotretionina nije uspješna u liječenju oralne leukoplakije

The safety of combined triple drug therapy with ivermectin, diethylcarbamazine and albendazole in the neglected tropical diseases co-endemic setting of Fiji: A cluster randomised trial

Lymphatic filariasis has remained endemic in Fiji despite repeated mass drug administration using the well-established and safe combination of diethylcarbamazine and albendazole (DA) since 2002. In certain settings the addition of ivermectin to this combination (IDA) remains a safe strategy and is more efficacious. However, the safety has yet to be described in scabies and soil-transmitted helminth endemic settings like Fiji. Villages of Rotuma and Gau islands were randomised to either DA or IDA. Residents received weight-based treatment unblinded with standard exclusions. Participants were actively found and asked by a nurse about their health daily for the first two days and then asked to seek review for the next five days if unwell. Anyone with severe symptoms were reviewed by a doctor and any serious adverse event was reported to the Medical Monitor and Data Safety Monitoring Board. Of 3612 enrolled and eligible participants, 1216 were randomised to DA and 2396 to IDA. Age and sex in both groups were representative of the population. Over 99% (3598) of participants completed 7 days follow-up. Adverse events were reported by 600 participants (16.7%), distributed equally between treatment groups, with most graded as mild (93.2%). There were three serious adverse events, all judged not attributable to treatment by an independent medical monitor. Fatigue was the most common symptom reported by 8.5%, with headache, dizziness, nausea and arthralgia being the next four most common symptoms. Adverse events were more likely in participants with microfilaremia (43.2% versus 15.7%), but adverse event frequency was not related to the presence of scabies or soil-transmitted helminth infection. IDA has comparable safety to DA with the same frequency of adverse events experienced following community mass drug administration. The presence of co-endemic infections did not increase adverse events. IDA can be used in community programs where preventative chemotherapy is needed for control of lymphatic filariasis and other neglected tropical diseases

Associations of retinal microvascular caliber with large arterial function and structure: A population-based study of 11 to 12 year-olds and midlife adults

Objective We examined associations between retinal microvascular and large arterial phenotypes to explore relationships between the micro- and macro-vasculature in childhood and midlife. Methods Participants were 1288 children (11-12 years, 50.9% female) and 1264 adults (mean age 44 years, 87.6% female) in a cross-sectional population-based study. Exposures were retinal arteriolar and venular caliber quantified from retinal images. Outcomes included arterial function (pulse wave velocity; carotid arterial elasticity) and structure (carotid intima-media thickness). Multivariable regression models were performed adjusting for age, sex, and family socioeconomic position. Results In children, one standard deviation wider arteriolar caliber was associated with slower pulse wave velocity (-0.15 SD, 95% CI -0.21, -0.09) and higher elasticity (0.13 SD, 95% CI 0.06, 0.20); per SD wider venular caliber was associated with faster pulse wave velocity (0.09 SD, 95% CI 0.03, 0.15) and lower elasticity (-0.07 SD, 95% CI -0.13, -0.01). The size of adult associations was approximately double. Wider arteriolar caliber was associated with smaller carotid intima-media thickness (-0.09 SD, 95% CI -0.16, -0.03) in adults but not children. Venular caliber and carotid intima-media thickness showed little evidence of association. Conclusions Narrower retinal arterioles and wider venules are associated with large arterial function as early as mid-childhood. Associations strengthen by midlife and also extend to arterial structure, although effect sizes remain small.</p

Inflammatory diet and preclinical cardiovascular phenotypes in 11–12 year-olds and mid-life adults: A cross-sectional population-based study

Background and aims: Pro-inflammatory diet may be a modifiable risk factor for cardiovascular disease. We examine associations of two inflammatory diet scores with preclinical cardiovascular phenotypes at two life course stages.Methods: Participants: 1771 children (49% girls) aged 11–12 years and 1793 parents (87% mothers, mean age 43.7 (standard deviation 5.2) years) in the Child Health CheckPoint Study. Measures: 23 items in the Australian National Secondary Students' Diet and Activity (NaSSDA) survey were used to derive two inflammatory diet scores based on: 1) published evidence of associations with C-reactive protein (literature-derived score), and 2) empirical associations with CheckPoint's inflammatory biomarker (glycoprotein acetyls, GlycA-derived score). Cardiovascular phenotypes assessed vascular structure (carotid intima-media thickness, retinal vessel calibre) and function (pulse wave velocity, blood pressure). Analyses: Linear regression models were conducted, adjusted for age, sex, socioeconomic position and child pubertal status, plus a sensitivity analysis also including BMI (z-score for children).Results: In adults, both inflammatory diet scores showed small associations with adverse cardiovascular function and microvascular structure. Per standard deviation higher GlycA-derived diet score, pulse wave velocity was 0.17  m/s faster (95% CI 0.11 to 0.22), mean arterial pressure was 1.85  mmHg (1.34–2.37) higher, and retinal arteriolar calibre was 1.29 μm narrower (−2.10 to −0.49). Adding BMI to models attenuated associations towards null. There was little evidence of associations in children.Conclusions: Our findings support cumulative adverse effects of a pro-inflammatory diet on preclinical cardiovascular phenotypes across the life course. Associations evident by mid-life were not present in childhood, when preventive measures should be instituted.</p

Protocol for a cluster-randomised non-inferiority trial of one versus two doses of ivermectin for the control of scabies using a mass drug administration strategy (the RISE study).

INTRODUCTION: Scabies is a significant contributor to global morbidity, affecting approximately 200 million people at any time. Scabies is endemic in many resource-limited tropical settings. Bacterial skin infection (impetigo) frequently complicates scabies infestation in these settings. Community-wide ivermectin-based mass drug administration (MDA) is an effective control strategy for scabies in island settings, with a single round of MDA reducing population prevalence by around 90%. However, current two-dose regimens present a number of barriers to programmatic MDA implementation. We designed the Regimens of Ivermectin for Scabies Elimination (RISE) trial to investigate whether one-dose MDA may be as effective as two-dose MDA in controlling scabies in high-prevalence settings. METHODS AND ANALYSIS: RISE is a cluster-randomised non-inferiority trial. The study will be conducted in 20 isolated villages in Western Province of Solomon Islands where population prevalence of scabies is approximately 20%. Villages will be randomly allocated to receive either one dose or two doses of ivermectin-based MDA in a 1:1 ratio. The primary objective of the study is to determine if ivermectin-based MDA with one dose is as effective as MDA with two doses in reducing the prevalence of scabies after 12 months. Secondary objectives include the effect of ivermectin-based MDA on impetigo prevalence after 12 and 24 months, the prevalence of scabies at 24 months after the intervention, the impact on presentation to health facilities with scabies and impetigo, and the safety of one-dose and two-dose MDA. ETHICS AND DISSEMINATION: This trial has been approved by the ethics review committees of the Solomon Islands and the Royal Children's Hospital, Australia. Results will be disseminated in peer-reviewed publications and in meetings with the Solomon Islands Ministry of Health and Medical Services and participating communities. TRIAL REGISTRATION DETAILS: Australian New Zealand Clinical Trials Registry: ACTRN12618001086257. Date registered: 28 June 2018

Early clinical markers of overweight/obesity onset and resolution by adolescence

Objectives: We examined how combinations of clinical indicators at various ages predict overweight/obesity development, as well as resolution, by 10–11 and 14–15 years of age.Methods: Data were derived from Birth (N = 3469) and Kinder (N = 3276) cohorts of the Longitudinal Study of Australian Children, followed from ages 2–3 and 4–5 years, respectively. Every two years, 25 potential obesity-relevant clinical indicators were quantified. Overweight/obesity was defined using International Obesity Taskforce cutpoints at 10–11 years and 14–15 years.Results: In both cohorts, three factors predicted both development and resolution of overweight/obesity in multivariable models. Among normal weight children, increased odds of developing overweight/obesity were associated with higher child (odd ratio (OR) 1.67–3.35 across different study waves) and maternal (OR 1.05–1.09) BMI, and inversely with higher maternal education (OR 0.60–0.62, when assessed at age 2–7 years). Lower odds of resolving existing overweight/obesity were related with higher child (OR 0.51–0.79) and maternal (OR 0.89–0.95) BMI, and inversely with higher maternal education (OR 1.62–1.92, when assessed at age 2–5 years). The prevalence of overweight/obesity at the age of 14–15 years was 13% among children with none of these risk factors at age 6–7 years, compared with 71% among those with all 3 risk factors (P Conclusions: From early childhood onwards, child and maternal BMI and maternal education predict overweight/obesity onset and resolution by adolescence. A simple risk score, easily available to child health clinicians, could help target treatment or prevention.</p