Randomized Trial of BCG Vaccine to Protect against Covid-19 in Health Care Workers.

BACKGROUND: The bacille Calmette-Guérin (BCG) vaccine has immunomodulatory "off-target" effects that have been hypothesized to protect against coronavirus disease 2019 (Covid-19). METHODS: In this international, double-blind, placebo-controlled trial, we randomly assigned health care workers to receive the BCG-Denmark vaccine or saline placebo and followed them for 12 months. Symptomatic Covid-19 and severe Covid-19, the primary outcomes, were assessed at 6 months; the primary analyses involved the modified intention-to-treat population, which was restricted to participants with a negative test for severe acute respiratory syndrome coronavirus 2 at baseline. RESULTS: A total of 3988 participants underwent randomization; recruitment ceased before the planned sample size was reached owing to the availability of Covid-19 vaccines. The modified intention-to-treat population included 84.9% of the participants who underwent randomization: 1703 in the BCG group and 1683 in the placebo group. The estimated risk of symptomatic Covid-19 by 6 months was 14.7% in the BCG group and 12.3% in the placebo group (risk difference, 2.4 percentage points; 95% confidence interval [CI], -0.7 to 5.5; P = 0.13). The risk of severe Covid-19 by 6 months was 7.6% in the BCG group and 6.5% in the placebo group (risk difference, 1.1 percentage points; 95% CI, -1.2 to 3.5; P = 0.34); the majority of participants who met the trial definition of severe Covid-19 were not hospitalized but were unable to work for at least 3 consecutive days. In supplementary and sensitivity analyses that used less conservative censoring rules, the risk differences were similar but the confidence intervals were narrower. There were five hospitalizations due to Covid-19 in each group (including one death in the placebo group). The hazard ratio for any Covid-19 episode in the BCG group as compared with the placebo group was 1.23 (95% CI, 0.96 to 1.59). No safety concerns were identified. CONCLUSIONS: Vaccination with BCG-Denmark did not result in a lower risk of Covid-19 among health care workers than placebo. (Funded by the Bill and Melinda Gates Foundation and others; BRACE ClinicalTrials.gov number, NCT04327206.).

Borrowing information across patient subgroups in clinical trials, with application to a paediatric trial.

BACKGROUND: Clinical trial investigators may need to evaluate treatment effects in a specific subgroup (or subgroups) of participants in addition to reporting results of the entire study population. Such subgroups lack power to detect a treatment effect, but there may be strong justification for borrowing information from a larger patient group within the same trial, while allowing for differences between populations. Our aim was to develop methods for eliciting expert opinions about differences in treatment effect between patient populations, and to incorporate these opinions into a Bayesian analysis. METHODS: We used an interaction parameter to model the relationship between underlying treatment effects in two subgroups. Elicitation was used to obtain clinical opinions on the likely values of the interaction parameter, since this parameter is poorly informed by the data. Feedback was provided to experts to communicate how uncertainty about the interaction parameter corresponds with relative weights allocated to subgroups in the Bayesian analysis. The impact on the planned analysis was then determined. RESULTS: The methods were applied to an ongoing non-inferiority trial designed to compare antiretroviral therapy regimens in 707 children living with HIV and weighing ≥ 14 kg, with an additional group of 85 younger children weighing < 14 kg in whom the treatment effect will be estimated separately. Expert clinical opinion was elicited and demonstrated that substantial borrowing is supported. Clinical experts chose on average to allocate a relative weight of 78% (reduced from 90% based on sample size) to data from children weighing ≥ 14 kg in a Bayesian analysis of the children weighing < 14 kg. The total effective sample size in the Bayesian analysis was 386 children, providing 84% predictive power to exclude a difference of more than 10% between arms, whereas the 85 younger children weighing < 14 kg provided only 20% power in a standalone frequentist analysis. CONCLUSIONS: Borrowing information from a larger subgroup or subgroups can facilitate estimation of treatment effects in small subgroups within a clinical trial, leading to improved power and precision. Informative prior distributions for interaction parameters are required to inform the degree of borrowing and can be informed by expert opinion. We demonstrated accessible methods for obtaining opinions.

ODYSSEY clinical trial design: a randomised global study to evaluate the efficacy and safety of dolutegravir-based antiretroviral therapy in HIV-positive children, with nested pharmacokinetic sub-studies to evaluate pragmatic WHO-weight-band based dolutegravir dosing.

BACKGROUND: Dolutegravir (DTG)-based antiretroviral therapy (ART) is highly effective and well-tolerated in adults and is rapidly being adopted globally. We describe the design of the ODYSSEY trial which evaluates the efficacy and safety of DTG-based ART compared with standard-of-care in children and adolescents. The ODYSSEY trial includes nested pharmacokinetic (PK) sub-studies which evaluated pragmatic World Health Organization (WHO) weight-band-based DTG dosing and opened recruitment to children < 14 kg while dosing was in development. METHODS: ODYSSEY (Once-daily DTG based ART in Young people vS. Standard thErapY) is an open-label, randomised, non-inferiority, basket trial comparing the efficacy and safety of DTG + 2 nucleos(t) ides (NRTIs) versus standard-of-care (SOC) in HIV-infected children < 18 years starting first-line ART (ODYSSEY A) or switching to second-line ART (ODYSSEY B). The primary endpoint is clinical or virological failure by 96 weeks. RESULTS: Between September 2016 and June 2018, 707 children weighing ≥14 kg were enrolled; including 311 ART-naïve children and 396 children starting second-line. 47% of children were enrolled in Uganda, 21% Zimbabwe, 20% South Africa, 9% Thailand, 4% Europe. 362 (51%) participants were male; median age [range] at enrolment was 12.2 years [2.9-18.0]. 82 (12%) children weighed 14 to < 20 kg, 135 (19%) 20 to < 25 kg, 206 (29%) 25 to < 35 kg, 284 (40%) ≥35 kg. 128 (18%) had WHO stage 3 and 60 (8%) WHO stage 4 disease. Challenges encountered include: (i) running the trial across high- to low-income countries with differing frequencies of standard-of-care viral load monitoring; (ii) evaluating pragmatic DTG dosing in PK sub-studies alongside FDA- and EMA-approved dosing and subsequently transitioning participants to new recommended doses; (iii) delays in dosing information for children weighing 3 to < 14 kg and rapid recruitment of ART-naïve older/heavier children, which led to capping recruitment of participants weighing ≥35 kg in ODYSSEY A and extending recruitment (above 700) to allow for ≥60 additional children weighing between 3 to < 14 kg with associated PK; (iv) a safety alert associated with DTG use during pregnancy, which required a review of the safety plan for adolescent girls. CONCLUSIONS: By employing a basket design, to include ART-naïve and -experienced children, and nested PK sub-studies, the ODYSSEY trial efficiently evaluates multiple scientific questions regarding dosing and effectiveness of DTG-based ART in children. TRIAL REGISTRATION: NCT, NCT02259127 , registered 7th October 2014; EUDRACT, 2014-002632-14, registered 18th June 2014 ( https://www.clinicaltrialsregister.eu/ctr-search/trial/2014-002632-14/ES ); ISRCTN, ISRCTN91737921 , registered 4th October 2014.

Patterns of Drug Use and Drug-related Hospital Admissions in HIV-Positive and -Negative Gay and Bisexual Men.

We aimed to compare rates of illicit drug-related hospitalisations in HIV-negative (HIV-ve) (n = 1325) and HIV-positive (HIV+ve) (n = 557) gay and bisexual men (GBM) with rates seen in the general male population and to examine the association between self-reported illicit drug use and drug-related hospitalisation. Participants were asked how often they used a range of illicit drugs in the previous 6 months at annual interviews. Drug-related hospital admissions were defined as hospital admissions for mental or behavioural disorders due to illicit drug use (ICD 10: F11-16, F18, F19), drug poisoning (T40-T45, T50) or toxic effect of gases (T53, T59, T65). Drug-related hospitalisations were 4.8 times higher in the HIV-ve cohort [SIR 4.75 (95 % CI 3.30-6.91)] and 3.5 times higher in the HIV+ve cohort [SIR 3.51 (1.92-5.88)] compared with the general population. Periods of weekly drug use [IRR 1.86 (1.01-3.46)], poly-drug use [IRR 2.17 (1.07-4.38)] and cannabis use [low use-IRR 1.95 (1.01-3.77), high use-IRR 2.58 (1.29-5.16)] were associated with drug-related hospitalisation in both cohorts, as was being a consistently high meth/amphetamine user throughout follow-up [IRR 3.24 (1.07-9.83)] and being an inconsistent or consistent injecting drug user throughout follow-up [IRR 3.94 (1.61-9.66), IRR 4.43(1.04-18.76), respectively]. Other risk factors for drug-related hospitalisation indicated the likelihood of comorbid drug and mental health issues in GBM hospitalised for drug use.

Impact of vaccine platform and BCG vaccination on antibody responses to COVID-19 vaccination.

Multiple factors, including vaccine platform and prior vaccinations, influence vaccine responses. We compared antibody responses to CoronaVac (Sinovac) and ChAdOx1-S (AstraZeneca-Oxford) vaccination in 874 healthcare workers in Brazil. As participants were randomised to BCG vaccination or placebo in the preceding 0-6 months as part of the BCG vaccination to reduce the impact of COVID-19 in healthcare workers (BRACE) trial, we also investigated the influence of recent BCG vaccination on antibody responses to these COVID-19 vaccines. Twenty-eight days after the second dose of each vaccine, ChAdOx1-S induced a stronger anti-spike IgG response than CoronaVac vaccination. Recent BCG vaccination did not impact IgG antibody responses to ChAdOx1-S or CoronaVac.

Bacillus Calmette-Guérin vaccination for protection against recurrent herpes labialis: a nested randomised controlled trial.

Background: Recurrences of herpes simplex virus (HSV) in the orofacial region (herpes labialis or cold sores) impact quality-of-life. We aimed to study whether the bacille Calmette-Guérin (BCG) vaccine can attenuate cold sore recurrences through off-target immunomodulatory effects. Methods: In this nested randomised controlled trial within the multicentre, phase 3 BRACE trial, 6828 healthcare workers were randomised in 36 sites in Australia, the Netherlands, Spain, the United Kingdom and Brazil, to receive BCG-Denmark or no BCG (1:1 ratio using a web-based procedure) and followed for 12 months with 3-monthly questionnaires. Exclusion criteria included contraindication to BCG vaccine or previous vaccination with BCG within the past year, any other live-attenuated vaccine within the last month, or any COVID-specific vaccine. The intervention group received one intradermal dose of 0.1 mL of BCG-Denmark corresponding to 2-8 x 105 colony forming units of Mycobacterium bovis, Danish strain 1331. The primary outcome was the difference in restricted mean survival time (i.e., time to first cold-sore recurrence), in participants with frequent recurrent herpes labialis (≥4 recurrences/year), analysed by intention-to-treat. Secondary outcomes addressed additional questions, including analyses in other sub-populations. Adverse events were monitored closely during the first 3 months and were reported in all participants who received one dose of study drug according to intervention received. The BRACE trial is registered with ClinicalTrials.gov, NCT04327206. Findings: Between March 30, 2020 and February 18, 2021, 84 individuals with frequent recurrent cold sores were randomly assigned to BCG (n = 38) or control (n = 46). The average time to first cold-sore recurrence was 1.55 months longer in the BCG group (95% CI 0.27-2.82, p = 0.02) than the control group (hazard ratio 0.54, 95% CI 0.32-0.91; intention-to-treat). The beneficial effect of BCG was greater in the as-treated population (difference 1.91 months, 95% CI 0.69-3.12, p = 0.003; hazard ratio 0.45, 95% CI 0.26-0.76). In prespecified subgroup analyses, only sex modified the treatment effect (interaction p = 0.007), with benefit restricted to males. Over 12 months, a greater proportion of participants in the BCG group compared with the control group reported a decrease in duration (61% vs 21%), severity (74% vs 21%), frequency (55% vs 21%), and impact on quality of life (42% vs 15%) of cold sore recurrences. In participants who had ever had a cold sore, there was also a decrease in self-reported burden of recurrences in the BCG group. In participants who had never had a cold sore, there was an increased risk of a first episode in the BCG group (risk difference 1.4%; 95% CI 0.3-2.6%, p = 0.02). There were no safety concerns. Interpretation: BCG-Denmark vaccination had a beneficial effect on herpes labialis, particularly in males with frequent recurrences, but may increase the risk of a first cold sore. Funding: Bill & Melinda Gates Foundation, the Minderoo Foundation, Sarah and Lachlan Murdoch, the Royal Children's Hospital Foundation, Health Services Union NSW, the Peter Sowerby Foundation, SA Health, the Insurance Advisernet Foundation, the NAB Foundation, the Calvert-Jones Foundation, the Modara Pines Charitable Foundation, the UHG Foundation Pty Ltd, Epworth Healthcare, and individual donors.

Dolutegravir dosing for children with HIV weighing less than 20 kg: pharmacokinetic and safety substudies nested in the open-label, multicentre, randomised, non-inferiority ODYSSEY trial.

BACKGROUND: Dolutegravir-based antiretroviral therapy is a preferred first-line treatment for adults and children living with HIV; however, very little pharmacokinetic data for dolutegravir use are available in young children. We therefore aimed to evaluate dolutegravir dosing and safety in children weighing 3 kg to less than 20 kg by assessing pharmacokinetic parameters and safety data in children taking dolutegravir within the ODYSSEY trial. METHODS: We did pharmacokinetic substudies nested within the open-label, multicentre, randomised, non-inferiority ODYSSEY trial. We enrolled children from seven research centres in South Africa, Uganda, and Zimbabwe. Children weighing 3 kg to less than 14 kg received 5 mg dispersible tablets of dolutegravir according to WHO weight bands: 5 mg for children weighing 3 kg to less than 6 kg and younger than 6 months, 10 mg for children weighing 3 kg to less than 6 kg and aged 6 months or older, 15 mg for children weighing 6 kg to less than 10 kg, and 20 mg for children weighing 10 kg to less than 14 kg. Children weighing 14 kg to less than 20 kg received a 25 mg film-coated tablet once per day early in the trial or 25 mg dispersible tablets (five 5 mg tablets once per day) later in the trial. A minimum of eight children per weight band or dose was targeted for 24 h pharmacokinetic profiling at steady state. The primary pharmacokinetic parameter was the trough concentration 24 h after observed dolutegravir intake (Ctrough). Pharmacokinetic targets were based on adult dolutegravir Ctrough and the 90% effective concentration (EC90; ie, 0·32 mg/L). Safety was evaluated in eligible children consenting to pharmacokinetic substudies. FINDINGS: Between May 25, 2017, and Aug 15, 2019, we enrolled 72 children aged between 3 months and 11 years. 71 children were included in the safety population and 55 (76%) of 72 children contributed 65 evaluable pharmacokinetic profiles. Geometric mean Ctrough in children on dispersible tablets in weight bands between 3 kg and less than 20 kg ranged between 0·53-0·87 mg/L, comparable to the adult geometric mean Ctrough of 0·83 mg/L. Variability was high with coefficient of variation percentages ranging between 50% and 150% compared with 26% in adults. Ctrough below EC90 was observed in four (31%) of 13 children weighing 6 kg to less than 10 kg taking 15 mg dispersible tablets, and four (21%) of 19 weighing 14 kg to less than 20 kg taking 25 mg film-coated tablets. The lowest geometric mean Ctrough of 0·44 mg/L was observed in children weighing 14 kg to less than 20 kg on 25 mg film-coated tablets. Exposures were 1·7-2·0 times higher on 25 mg dispersible tablets versus 25 mg film-coated tablets. 19 (27%) of 71 children had 29 reportable grade 3 or higher adverse events (13 serious adverse events, including two deaths), none of which were related to dolutegravir. INTERPRETATION: Weight-band dosing of paediatric dolutegravir dispersible tablets provides appropriate drug exposure in most children weighing 3 kg to less than 20 kg, with no safety signal. 25 mg film-coated tablets did not achieve pharmacokinetic parameters in children weighing 14 kg to less than 20 kg, which were comparable to adults, suggesting dosing with dispersible tablets is preferable or a higher film-coated tablet dose is required. FUNDING: Paediatric European Network for Treatment of AIDS Foundation, ViiV Healthcare, and UK Medical Research Council.

Simplified dolutegravir dosing for children with HIV weighing 20 kg or more: pharmacokinetic and safety substudies of the multicentre, randomised ODYSSEY trial.

BACKGROUND: Paediatric dolutegravir doses approved by stringent regulatory authorities (SRAs) for children weighing 20 kg to less than 40 kg until recently required 25 mg and 10 mg film-coated tablets. These tablets are not readily available in low-resource settings where the burden of HIV is highest. We did nested pharmacokinetic substudies in patients enrolled in the ODYSSEY-trial to evaluate simplified dosing in children with HIV. METHODS: We did pharmacokinetic and safety substudies within the open-label, multicentre, randomised ODYSSEY trial (NCT02259127) of children with HIV starting treatment in four research centres in Uganda and Zimbabwe. Eligible children were randomised to dolutegravir in ODYSSEY and weighed 20 kg to less than 40 kg. In children weighing 20 kg to less than 25 kg, we assessed dolutegravir's pharmacokinetics in children given once daily 25 mg film-coated tablets (approved by the SRAs at the time of the study) in part one of the study, and 50 mg film-coated tablets (adult dose) or 30 mg dispersible tablets in part two of the study. In children weighing 25 kg to less than 40 kg, we also assessed dolutegravir pharmacokinetics within-subject on film-coated tablet doses of 25 mg or 35 mg once daily, which were approved by the SRAs for the children's weight band; then switched to 50 mg film-coated tablets once daily. Steady-state 24 h dolutegravir plasma concentration-time pharmacokinetic profiling was done in all enrolled children at baseline and 1, 2, 3, 4, 6, and 24 h after observed dolutegravir intake. Target dolutegravir trough concentrations (Ctrough) were based on reference adult pharmacokinetic data and safety was evaluated in all children in the corresponding weight bands who consented to pharmacokinetic studies and received the studied doses. FINDINGS: Between Sept 22, 2016, and May 31, 2018, we enrolled 62 black-African children aged from 6 years to younger than 18 years (84 pharmacokinetic-profiles). In children weighing 20 kg to less than 25 kg taking 25 mg film-coated tablets, the geometric mean (GM) Ctrough (coefficient of variation) was 0·32 mg/L (94%), which was 61% lower than the GM Ctrough of 0·83 mg/L (26%) in fasted adults on dolutegravir 50 mg once-daily; in children weighing 25 kg to less than 30 kg taking 25 mg film-coated tablets, the GM Ctrough was 0·39 mg/L (48%), which was 54% lower than the GM Ctrough in fasted adults; and in those 30 kg to less than 40 kg taking 35 mg film-coated tablets the GM Ctrough was 0·46 mg/L (63%), which was 45% lower than the GM Ctrough in fasted adults. On 50 mg film-coated tablets or 30 mg dispersible tablets, Ctrough was close to the adult reference (with similar estimates on the two formulations in children in the 20 to <25 kg weight band), with total exposure (area under the concentration-time curve from 0 h to 24 h) in between reference values in adults dosed once and twice daily, where safety data are reassuring, although maximum concentrations were higher in children weighing 20 kg to less than 25 kg than in the twice-daily adult reference. Over a 24-week follow-up period in 47 children on 30 mg dispersible tablets or 50 mg film-coated tablets, none of the three reported adverse events (cryptococcal meningitis, asymptomatic anaemia, and asymptomatic neutropenia) were considered related to dolutegravir. INTERPRETATION: Adult dolutegravir 50 mg film-coated tablets given once daily provide appropriate pharmacokinetic profiles in children weighing 20 kg or more, with no safety signal, allowing simplified practical dosing and rapid access to dolutegravir. These results informed the WHO 2019 dolutegravir paediatric dosing guidelines and have led to US Food and Drug Administration approval of adult dosing down to 20 kg. FUNDING: Paediatric European Network for Treatment of AIDS Foundation, ViiV Healthcare, UK Medical Research Council.

Multi-arm, multi-stage randomised controlled trials for evaluating therapeutic HIV cure interventions.

The evaluation of immune-based approaches to achieve an antiretroviral therapy free remission of HIV infection requires proven efficacy through antiretroviral therapy interruption placebo-controlled trials. This approach is not without risk to participants and innovative trial designs need to be developed that minimise the number of participants treated with placebo and ineffective candidates. Multi-arm, multi-stage (MAMS) trial designs can be used in this context to accelerate the development of an immune-based therapeutic agent for HIV cure. Issues related to implementing a MAMS design within the planned EHVA T01 trial are considered here. EHVA T01 is a multicentre, MAMS, double-blind, phase 1 and 2 trial that aims to evaluate the effect of immune interventions on viral control in HIV-1 infected participants following analytic treatment interruption. The application of a MAMS design increases the likelihood that the EHVA T01 trial will identify a successful treatment and minimises the number of participants undergoing analytical treatment interruptions who have been treated with futile agents. The use of a MAMS design is a promising strategy to evaluate complex immune-based approaches aimed at curing HIV-infection, particularly relevant to the pipeline with multiple agents requiring examination.

Metabolic profiles of individuals switched to second-line antiretroviral therapy after failing standard first-line therapy for treatment of HIV-1 infection in a randomized, controlled trial.

BACKGROUND: To investigate metabolic changes associated with second-line antiretroviral therapy (ART) following virological failure of first-line ART. METHODS: SECOND-LINE was an open-label randomized controlled trial. Participants were randomized 1:1 to receive ritonavir-boosted lopinavir (LPV/r) with 2-3 nucleoside/nucleotide reverse transcriptase inhibitors (N[t]RTI group) or raltegravir (RAL group). 210 participants had a dual energy X-ray absorptiometry (DXA)-scan at baseline, week 48 and 96. We categorized participants according to second-line ART backbone: thymidine analogue (ta-NRTI) + lamivudine/emtricitabine (3[F]TC; ta-NRTI group); tenofovir (TDF)+3(F)TC (TDF group); TDF+ta-NRTI ±3(F)TC (TDF+ta-NRTI group); RAL. Changes in fasted total cholesterol (TC), low-density lipoprotein (LDL)-cholesterol, high-density lipoprotein (HDL)-cholesterol, TC/HDL-cholesterol ratio, triglycerides and glucose from baseline to week 96 were examined. We explored the association between metabolic and DXA-assessed soft-tissue changes. Linear regression methods were used. RESULTS: We analysed 454 participants. Participants in RAL group had greater TC increases, TC (adjusted mean difference [aMD]=0.65, 95% CI 0.33, 0.96), LDL-c (aMD=0.38, 95% CI 0.15, 0.61) and glucose (aMD=0.47, 95% CI -0.01, 0.92) compared to TDF group, and had greater increases in TC (aMD=0.65, 95% CI 0.28, 1.03), HDL-c (aMD=0.12, 95% CI 0.02, 0.23) and LDL-c (aMD=0.41, 95% CI 0.13, 0.69) compared to TDF+ta-NRTI group. TC/HDL ratio and triglycerides increased in all groups without significant differences between groups. A 1 kg increase in trunk fat mass was associated with an increase in TC. CONCLUSIONS: We observed metabolic changes of limited clinical significance in the relatively young population enrolled in this study. However, the metabolic changes observed may have greater clinical significance in older people living with HIV or those with other concomitant cardiovascular risks.

Weekends-off efavirenz-based antiretroviral therapy in HIV-infected children, adolescents and young adults (BREATHER): Extended follow-up results of a randomised, open-label, non-inferiority trial.

BACKGROUND: Weekends off antiretroviral therapy (ART) may help engage HIV-1-infected young people facing lifelong treatment. BREATHER showed short cycle therapy (SCT; 5 days on, 2 days off ART) was non-inferior to continuous therapy (CT) over 48 weeks. Planned follow-up was extended to 144 weeks, maintaining original randomisation. METHODS: BREATHER was an open-label, non-inferiority trial. Participants aged 8-24yrs with virological suppression on efavirenz-based first-line ART were randomised 1:1, stratified by age and African/non-African sites, to remain on CT or change to SCT. The Kaplan-Meier method was used to estimate the proportion of participants with viral rebound (confirmed VL≥50 copies/mL) under intent-to-treat at 48 weeks (primary outcome), and in extended follow-up at 96, 144, and 192 weeks. SCT participants returned to CT following viral rebound, 3 VL blips or discontinuation of efavirenz. FINDINGS: Of 199 participants (99 SCT, 100 CT), 97 per arm consented to extended follow-up. Median follow-up was 185.3 weeks (IQR 160.9-216.1). 69 (70%) SCT participants remained on SCT at last follow-up. 105 (53%) were male, baseline median age 14 years (IQR 12-18), median CD4 count 735 cells/µL (IQR 576-968). 16 SCT and 16 CT participants had confirmed VL≥50 copies/mL by the end of extended follow-up (HR 1.00, 95% CI 0.50-2.00). Estimated difference in percentage with viral rebound (SCT minus CT) by week 144 was 1.9% (90% CI -6.6-10.4; p = 0.72) and was similar in a per-protocol analysis. There were no significant differences between arms in proportions of participants with grade 3/4 adverse events (18 SCT vs 16 CT participants; p = 0.71) or ART-related adverse events (10 vs 12; p = 0.82). 20 versus 8 serious adverse events (SAEs) were reported in 16 SCT versus 4 CT participants, respectively (p = 0.005 comparing proportions between groups; incidence rate ratio 2.49, 95%CI 0.71-8.66, p = 0.15). 75% of SAEs (15 SCT, 6 CT) were hospitalisations for a wide range of conditions. 3 SCT and 6 CT participants switched to second-line ART following viral failure (p = 0.50). CONCLUSIONS: Sustainable non-inferiority of virological suppression in young people was shown for SCT versus CT over median 3.6 years. Standard-dose efavirenz-based SCT is a viable option for virologically suppressed HIV-1 infected young people on first-line ART with 3-monthly VL monitoring. TRIAL REGISTRATION: EudraCT 2009-012947-40 ISRCTN 97755073 ClinicalTrials.gov NCT01641016.

Body composition and metabolic outcomes after 96 weeks of treatment with ritonavir-boosted lopinavir plus either nucleoside or nucleotide reverse transcriptase inhibitors or raltegravir in patients with HIV with virological failure of a standard first-line antiretroviral therapy regimen: a substudy of the randomised, open-label, non-inferiority SECOND-LINE study.

BACKGROUND: Lipoatrophy is one of the most feared complications associated with the use of nucleoside or nucleotide reverse transcriptase inhibitors (N[t]RTIs). We aimed to assess soft-tissue changes in participants with HIV who had virological failure of a first-line antiretroviral (ART) regimen containing a non-nucleoside reverse transcriptase inhibitor plus two N(t)RTIs and were randomly assigned to receive a second-line regimen containing a boosted protease inhibitor given with either N(t)RTIs or raltegravir. METHODS: Of the 37 sites that participated in the randomised, open-label, non-inferiority SECOND-LINE study, eight sites from five countries (Argentina, India, Malaysia, South Africa, and Thailand) participated in the body composition substudy. All sites had a dual energy x-ray absorptiometry (DXA) scanner and all participants enrolled in SECOND-LINE were eligible for inclusion in the substudy. Participants were randomly assigned (1:1), via a computer-generated allocation schedule, to receive either ritonavir-boosted lopinavir plus raltegravir (raltegravir group) or ritonavir-boosted lopinavir plus two or three N(t)RTIs (N[t]RTI group). Randomisation was stratified by site and screening HIV-1 RNA. Participants and investigators were not masked to group assignment, but allocation was concealed until after interventions were assigned. DXA scans were done at weeks 0, 48, and 96. The primary endpoint was mean percentage and absolute change in peripheral limb fat from baseline to week 96. We did intention-to-treat analyses of available data. This substudy is registered with ClinicalTrials.gov, number NCT01513122. FINDINGS: Between Aug 1, 2010, and July 10, 2011, we recruited 211 participants into the substudy. The intention-to-treat population comprised 102 participants in the N(t)RTI group and 108 participants in the raltegravir group, of whom 91 and 105 participants, respectively, reached 96 weeks. Mean percentage change in limb fat from baseline to week 96 was 16·8% (SD 32·6) in the N(t)RTI group and 28·0% (37·6) in the raltegravir group (mean difference 10·2%, 95% CI 0·1-20·4; p=0·048). Mean absolute change was 1·04 kg (SD 2·29) in the N(t)RTI group and 1·81 kg (2·50) in the raltegravir group (mean difference 0·6, 95% CI -0·1 to 1·3; p=0·10). INTERPRETATION: Our findings suggest that for people with virological failure of a first-line regimen containing efavirenz plus tenofovir and lamivudine or emtricitabine, the WHO-recommended switch to a ritonavir-boosted protease inhibitor plus zidovudine (a thymidine analogue nucleoside reverse transcriptase inhibitor) and lamivudine might come at the cost of peripheral lipoatrophy. Further study could help to define specific groups of people who might benefit from a switch to an N(t)RTI-sparing second-line ART regimen. FUNDING: The Kirby Institute and the Australian National Health and Medical Research Council.

Poor record linkage sensitivity biased outcomes in a linked cohort analysis.

OBJECTIVES: To examine the validity of deterministic compared to probabilistic record linkage in the ascertainment of hospitalizations in two linked cohorts. STUDY DESIGN AND SETTING: HIV-negative (HIV-ve) (n = 1,325) and HIV-positive (HIV+ve) gay and bisexual men (n = 557) recruited in Sydney, Australia, were probabilistically and deterministically linked to a statewide hospital registry (July 2000-June 2012). RESULTS: Using probabilistic linkage as the reference standard, deterministic linkage had higher specificity but much lower sensitivity [34.67% (95% confidence interval: 33.44, 35.92)]. A disproportionate number of links missed were individuals with poorer socioeconomic and health indicators, including HIV status. Risk of hospitalization compared to the general male population [HIV+ve standardized incidence ratio (SIR) = 1.45 (1.33-1.59); HIV-ve SIR = 0.72 (0.67-0.78)] was significantly underestimated when deterministic linkage was used [HIV+ve SIR = 0.46 (0.37-0.58); HIV-ve SIR = 0.29 (0.24-0.35)]. The impact of linkage strategy on the calculation of incidence rate ratios (IRRs) was less, but a greater discrepancy in IRRs was seen for diagnostic categories where event rates were low or where the sensitivity of the deterministic linkage was differential between the two cohorts. CONCLUSION: Linkage without proven high sensitivity and specificity should be carefully considered. In circumstances of undetermined sensitivity, SIRs should not be calculated as the extent of underestimation is unknown. The comparison of linked events within or between cohorts is more robust to linkage misclassification; however, selection bias does affect estimates and should be considered before linkage.

Hospitalization for Anxiety and Mood Disorders in HIV-Infected and -Uninfected Gay and Bisexual Men.

BACKGROUND: Prevalence of anxiety and mood disorders (AMDs) in HIV-infected individuals has varied widely because of the variety of measurements used and differences in risk factor profiles between different populations. We aimed to examine the relationship between HIV status and hospitalization for AMDs in gay and bisexual men (GBM). DESIGN AND METHODS: HIV-infected (n = 557) and HIV-uninfected (n = 1325) GBM recruited in Sydney, Australia were probabilistically linked to their hospital admissions and death notifications (2000-2012). Random-effects Poisson models were used to assess HIV risk factors for hospitalization. Cox regression methods were used to assess risk factors for mortality. RESULTS: We observed 300 hospitalizations for AMDs in 15.3% of HIV-infected and 181 in 5.4% of HIV-uninfected participants. Being infected with HIV was associated with a 2.5-fold increase in risk of hospitalization for AMDs in GBM. Other risk factors in the HIV-infected cohort included previous hospitalization for HIV-related dementia, a more recent HIV diagnosis, and a CD4 T-cell count above 350 cells per cubic millimeter. Being hospitalized for an AMD was associated with a 5.5-fold increased risk of mortality; this association did not differ by HIV status. An association between substance use and mortality was observed in individuals hospitalized for AMDs. CONCLUSIONS: There is a need to provide more effective strategies to identify and treat AMDs in HIV-infected GBM. This research highlights the importance of further examination of the effects of substance use, neurocognitive decline, and AMDs on the health of HIV-infected individuals.

Antiretroviral Resistance After First-Line Antiretroviral Therapy Failure in Diverse HIV-1 Subtypes in the SECOND-LINE Study.

We investigate mutations and correlates according to HIV-1 subtype after virological failure (VF) of standard first-line antiretroviral therapy (ART) (non-nucleoside/nucleotide reverse transcriptase inhibitor [NNRTI] +2 nucleoside/nucleotide reverse transcriptase inhibitor [N(t)RTI]). SECOND-LINE study participants were assessed at baseline for HIV-1 subtype, demographics, HIV-1 history, ART exposure, viral load (VL), CD4(+) count, and genotypic ART resistance. We used backward stepwise multivariate regression (MVR) to assess associations between baseline variables and presence of ≥3 N(t)RTI mutations, ≥1 NNRTI mutation, ≥3 thymidine analog-N(t)RTI [ta-N(t)RTI] mutations (TAMs), the K65/K70 mutation, and predicted etravirine (ETV)/rilpivirine (RPV) activity. The inclusion p-value for MVR was p < .2. The exclusion p-value from stepwise elimination was p > .05. Of 541 participants, 491 (91%) had successfully characterized baseline viral isolates. Subtype distribution: B (n = 123, 25%), C (n = 202, 41%), CRF01_AE (n = 109, 22%), G (n = 25, 5%), and CRF02_AG (n = 27, 5%). Baseline CD4(+) 200-394 cells/mm(3) were associated with <3 N(t)RTI mutations (OR = 0.47; 95% CI 0.29-0.77; p = .003), absence of the K65/K70 mutation (OR = 0.43; 95% CI 0.26-0.73; p = .002), and higher ETV sensitivity (OR = 0.52; 95% CI 0.35-0.78; p = .002). Recent tenofovir (TDF) use was associated with K65/K70 mutations (OR = 8.91; 95% CI 5.00-15.85; p < .001). Subtype CRF01_AE was associated with ≥3 N(t)RTI mutations (OR = 2.34; 95% CI 1.31-4.17; p = .004) and higher RPV resistance (OR = 2.13; 95% CI 1.30-3.49; p = .003), and subtype C was associated with <3 TAMs (OR = 0.45; 95% CI 0.21-0.99; p = .015). Subtypes CRF01_AE (OR = 2.46; 95% CI 1.26-4.78; p = .008) and G (OR = 4.77; 95% CI 1.44-15.76; p = .01) were associated with K65/K70 mutations. Higher VL at confirmed first-line VF was associated with ≥3 N(t)RTI mutations (OR = 1.39; 95% CI 1.07-1.78; p = .013) and ≥3 TAMs (OR = 1.62; 95% CI 1.15-2.29; p = .006). The associations of first-line resistance mutations across the HIV-1 subtypes in this study are consistent with knowledge derived from subtype B, with some exceptions. Patterns of resistance after failure of a first-line ta-N(t)RTI regimen support using TDF in N(t)RTI-containing second-line regimens, or using N(t)RTI-sparing regimens.

Baseline HIV-1 resistance, virological outcomes, and emergent resistance in the SECOND-LINE trial: an exploratory analysis.

BACKGROUND: WHO-recommended second-line antiretroviral therapy (ART) of a pharmacologically enhanced (boosted) protease inhibitor plus nucleoside or nucleotide reverse transcriptase inhibitors (NtRTIs) might be compromised by resistance. Results of the 96 week SECOND-LINE randomised trial showed that NtRTI-sparing ART with ritonavir-boosted lopinavir and raltegravir (raltegravir-group) provided non-inferior efficacy to ritonavir-boosted lopinavir and two or three NtRTIs (NtRTI-group) in participants with virological failure composed of a first-line regimen of a non-nucleoside reverse transcriptase inhibitor plus two NtRTIs. We report the relation of baseline virological resistance with virological failure and emergent resistance on study. METHODS: As part of the randomised open-label SECOND-LINE trial, second-line ART NtRTI selection was made by either genotype (local laboratory) or algorithm. Genotypic resistance for the entire cohort at baseline was assessed on stored samples at a central laboratory. Virological failure was defined as plasma viral load greater than 200 copies per mL. Baseline viral isolates were assigned genotypic sensitivity scores (GSSs) by use of the Stanford HIV Database version 6.3.1: a global GSS (gGSS), defined as the combined GSS for lamivudine or emtricitabine, abacavir, zidovudine, stavudine, didanosine, and tenofovir and a specific GSS (sGSS) defined as the GSS for the ART regimen initiated by a specific participant. Emergent resistance was reported on samples with a viral load greater than 500 copies per mL. We used multivariate logistic regression with backward elimination to assess predictors of virological failure and emergent resistance. FINDINGS: From April 19, 2010, to July 22, 2013, 271 patients were included in the NtRTI group and and 270 in the raltegravir group. In the NtRTI group 215 had available baseline sequence data, and 240 had viral load measurements at 96 weeks; in the raltegravir group 236 had baseline sequence data and 255 had viral load measurements at 96 weeks. Median (IQR) gGSS was 3.0 (1.3-4.3) in the NtRTI group and 3.0 (1.0-4.3) in the raltegravir group. The median sGSS in the NtRTI group was 1.0 (0.5-1.8). Multivariate analysis showed significant associations between virological failure and less than complete adherence at week 4 (odds ratio [OR] 2.18, 95%CI 1.07-4.47; p=0·03) and week 48 (2.49, 1.09-5.69; p=0.03), baseline plasma viral load greater than 100,000 copies per mL (3.43, 1.70-6.94; p=0.0006), baseline gGSS >4.25 (4.73, 1.94-11.6; p=0.0007), and being Hispanic (3.13, 1.21-8.13; p=0.02) or African (3.49, 1.68-7.28; p=0.0008) rather than Asian. We observed emergent major mutations in one (1%) of 129 participants for protease (both groups), eight (13%) of 64 for reverse transcriptase (NtRTI group) and 16 (20%) of 79 for integrase. Emergent resistance was associated with the raltegravir group (OR 2.47, 95% CI 1.02-5.99; p=0.05), baseline log10 viral load (1.83, 1.12-2.97; p=0.02), and absence of the Lys65Arg (K65R) or Lys70Glu (K70E) mutation at baseline (3.18, 1.12-9.02; p=0.03). INTERPRETATION: Poor adherence was a major determinant of virological failure in people on second-line ART. In settings with limited resources, investment in optimisation of adherence rather than implementation of drug resistance testing might be advisable. FUNDING: University of New South Wales Australia, Merck, AbbVie, and the Foundation for AIDS Research.

Early antiretroviral therapy with raltegravir generates sustained reductions in HIV reservoirs but not lower T-cell activation levels.

OBJECTIVE: The initiation of antiretroviral therapy (ART) during primary infection may offer clinical benefits for HIV-infected individuals by reducing HIV DNA reservoir size and chronic T-cell activation. Current evidence for the advantages of early ART, however, are mostly derived from cross-sectional studies, with the long-term benefits yet to be ascertained. DESIGN/METHODS: We conducted an open-label, nonrandomized study, monitoring for 3 years: plasma viral load (pVL), T-cell phenotypes, and peripheral CD4(+) T-cell associated total, integrated and 2-long terminal repeat HIV DNA species. The study included 16 treatment-naive individuals initiating ART with raltegravir and Truvada during either primary (PHI, n = 8) or chronic (CHI, n = 8) HIV infection. RESULTS: ART initiated during PHI compared with CHI generated significant reductions of peripheral CD4(+) T-cell HIV DNA reservoirs that were sustained for 3 years of therapy. Median log10 HIV DNA copies/10(6) CD4(+) T cells at the final visit: total; CHI = 3.23 > PHI = 2.72, P < 0.01; integrated; CHI = 2.64 > PHI = 1.77, P < 0.01. Similar trends were observed for pVL, however, did not reach significance: log10 HIV RNA copies/ml plasma at the final visit: CHI = 1.3 ≥ PHI = 0.39, P = 0.08. Both cohorts displayed similar and elevated levels of CD38/HLA-DR coexpression on CD4(+) and CD8(+) T cells relative to uninfected healthy controls. CONCLUSION: The reduction in HIV DNA reservoirs generated by the early initiation of ART was sustained for 3 years of therapy. Although the PHI cohort trended to lower levels of pVL, and pVL was associated with CD8(+) T-cell activation, no differences in T-cell activation were observed between the PHI and CHI groups.

Raltegravir non-inferior to nucleoside based regimens in second-line therapy with lopinavir/ritonavir over 96 weeks: a randomised open label study for the treatment of HIV-1 infection.

OBJECTIVE: To determine the durability over 96 weeks of safety and efficacy of lopinavir/ritonavir (LPV/r) and raltegravir (RAL) which was demonstrated to have non-inferior efficacy relative to a regimen of LPV/r with nucleoside/nucleotide reverse transcriptase inhibitors (N(t)RTIs) (Control) in primary analysis at 48 weeks. DESIGN: Open label, centrally randomised trial. SETTING: Recruitment was from 37 primary and secondary care sites from Africa, Asia, Australia, Europe and Latin America. SUBJECTS: 541 HIV-1 infected adults virologically failing first-line non-NRTI + 2N(t)RTI, with no previous exposure to protease inhibitors or integrase strand transfer inhibitors were analysed, 425 completed 96 weeks follow up on randomised therapy. INTERVENTION: Randomisation was 1:1 to Control or RAL. MAIN OUTCOME MEASURES: Differences between the proportion of participants with plasma HIV-1 RNA (VL) <200 copies/mL by intention to treat were compared with a non-inferiority margin of -12%. Differences in biochemical, haematological and metabolic changes were assessed using T-tests. RESULTS: VL <200 copies/mL at 96 weeks was: RAL 80.4%, Control 76.0% (difference: 4.4 [95%CI -2.6, 11.3]) and met non-inferiority criteria. The RAL arm had a significantly higher mean change (difference Control-RAL; 95%CI) in haemoglobin (-2.9; -5.7, -1.1), total lymphocytes (-0.2; -0.3, -0.0), total cholesterol (-0.5; -0.8, -0.3), HDL cholesterol (-0.1; -0.1, -0.0) and LDL cholesterol (-0.3; -0.5, -0.2). CONCLUSION: At 96 weeks, both RAL and Control maintained efficacy greater than 75% and continued to demonstrate similar safety profiles. These results support the use of a combination LPV/r and RAL regimen as an option following failure of 1st line NNRTI + 2N(t)RTIs. TRIAL REGISTRATION: ClinicalTrials.gov NCT00931463.

A new method for assessing how sensitivity and specificity of linkage studies affects estimation.

BACKGROUND: While the importance of record linkage is widely recognised, few studies have attempted to quantify how linkage errors may have impacted on their own findings and outcomes. Even where authors of linkage studies have attempted to estimate sensitivity and specificity based on subjects with known status, the effects of false negatives and positives on event rates and estimates of effect are not often described. METHODS: We present quantification of the effect of sensitivity and specificity of the linkage process on event rates and incidence, as well as the resultant effect on relative risks. Formulae to estimate the true number of events and estimated relative risk adjusted for given linkage sensitivity and specificity are then derived and applied to data from a prisoner mortality study. The implications of false positive and false negative matches are also discussed. DISCUSSION: Comparisons of the effect of sensitivity and specificity on incidence and relative risks indicate that it is more important for linkages to be highly specific than sensitive, particularly if true incidence rates are low. We would recommend that, where possible, some quantitative estimates of the sensitivity and specificity of the linkage process be performed, allowing the effect of these quantities on observed results to be assessed.

HIV lipodystrophy in participants randomised to lopinavir/ritonavir (LPV/r) +2-3 nucleoside/nucleotide reverse transcriptase inhibitors (N(t)RTI) or LPV/r + raltegravir as second-line antiretroviral therapy.

OBJECTIVE: To compare changes over 48 weeks in body fat, lipids, Metabolic Syndrome and cardiovascular disease risk between patients randomised 1:1 to lopinavir/ritonavir (r/LPV) plus raltegravir (RAL) compared to r/LPV plus 2-3 nucleoside/nucleotide reverse transcriptase inhibitors (N(t)RTIs) as second-line therapy. METHODS: Participants were HIV-1 positive (>16 years) failing first-line treatment (2 consecutive HIV RNA >500 copies/mL) of NNRTI +2N(t)RTI. Whole body dual energy x-ray absorptiometry was performed at baseline and week 48. Data were obtained to calculate the Metabolic Syndrome and Framingham cardiovascular disease (CVD) risk score. Linear regression was used to compare mean differences between arms. Logistic regression compared incidence of metabolic syndrome. Associations between percent limb fat changes at 48 weeks with baseline variables were assessed by backward stepwise multivariate linear regression. Analyses were adjusted for gender, body mass index and smoking status. RESULTS: 210 participants were randomised. The mean (95% CI) increase in limb fat over 48 weeks was 15.7% (5.3, 25.9) or 0.9 kg (0.2, 1.5) in the r/LPV+N(t)RTI arm and 21.1% (11.1, 31,1) or 1.3 kg (0.7, 1.9) in the r/LPV+RAL arm, with no significant difference between treatment arms (-5.4% [-0.4 kg], p>0.1). Increases in total body fat mass (kg) and trunk fat mass (kg) were also similar between groups. Total:HDL cholesterol ratio was significantly higher in the RAL arm (mean difference -0.4 (1.4); p = 0.03), there were no other differences in lipid parameters between treatment arms. There were no statistically significant differences in CVD risk or incidence of Metabolic Syndrome between the two treatment arms. The baseline predictors of increased limb fat were high viral load, high insulin and participant's not taking lipid lowering treatment. CONCLUSION: In patients switching to second line therapy, r/LPV combined with RAL demonstrated similar improvements in limb fat as an N(t)RTI + r/LPV regimen, but a worse total:HDL cholesterol ratio over 48 weeks. TRIAL REGISTRATION: This clinical trial is registered on Clinicaltrials.gov, registry number NCT00931463 http://clinicaltrials.gov/ ct2/show/NCT00931463?term = NCT00931463&rank = 1.