Evaluating group-sequential non-inferiority clinical trials following interim stopping: The HIV Prevention Trials Network 083 trial.

BACKGROUND/AIMS: The HIV Prevention Trials Network 083 trial was a group-sequential non-inferiority trial designed to compare HIV incidence under a novel experimental regimen for HIV prevention, long-acting injectable cabotegravir, with an active-control regimen of daily oral tenofovir disoproxil fumarate/emtricitabine (brand name Truvada). In March of 2020, just as the trial had completed enrollment, the COVID-19 pandemic threatened to prevent trial participants from attending study visits and obtaining study medication, motivating the study team to update the interim monitoring plan. The Data and Safety Monitoring Board subsequently stopped the trial at the first interim review due to strong early evidence of efficacy. METHODS: Here we describe some unique aspects of the trial's design, monitoring, analysis, and interpretation. We illustrate the importance of computing point estimates, confidence intervals, and p values based on the sampling distribution induced by sequential monitoring. RESULTS: Accurate analysis, decision-making and interpretation of trial results rely on pre-specification of a stopping boundary, including the scale on which the stopping rule will be implemented, the specific test statistics to be calculated, and how the boundary will be adjusted if the available information fraction at interim review is different from planned. After appropriate adjustment for the sampling distribution and overrun, the HIV Prevention Trials Network 083 trial provided strong evidence that the experimental regimen was superior to the active control. CONCLUSIONS: For the HIV Prevention Trials Network 083 trial, the difference between corrected inferential statistics and naive results was quite small-as will often be the case-nevertheless, it is appropriate to report and publish the most accurate and unbiased statistical results.

A scalable, integrated intervention to engage people who inject drugs in HIV care and medication-assisted treatment (HPTN 074): a randomised, controlled phase 3 feasibility and efficacy study.

BACKGROUND: People who inject drugs (PWID) have a high incidence of HIV, little access to antiretroviral therapy (ART) and medication-assisted treatment (MAT), and high mortality. We aimed to assess the feasibility of a future controlled trial based on the incidence of HIV, enrolment, retention, and uptake of the intervention, and the efficacy of an integrated and flexible intervention on ART use, viral suppression, and MAT use. METHODS: This randomised, controlled vanguard study was run in Kyiv, Ukraine (one community site), Thai Nguyen, Vietnam (two district health centre sites), and Jakarta, Indonesia (one hospital site). PWID who were HIV infected (index participants) and non-infected injection partners were recruited as PWID network units and were eligible for screening if they were aged 18-45 years (updated to 18-60 years 8 months into study), and active injection drug users. Further eligibility criteria for index participants included a viral load of 1000 copies per mL or higher, willingness and ability to recruit at least one injection partner who would be willing to participate. Index participants were randomly assigned via a computer generated sequence accessed through a secure web portal (3:1) to standard of care or intervention, stratified by site. Masking of assignment was not possible due to the nature of intervention. The intervention comprised systems navigation, psychosocial counselling, and ART at any CD4 count. Local ART and MAT services were used. Participants were followed up for 12-24 months. The primary objective was to assess the feasibility of a future randomised controlled trial. To achieve this aim we looked at the following endpoints: HIV incidence among injection partners in the standard of care group, and enrolment and retention of HIV-infected PWID and their injection partners and the uptake of the integrated intervention. The study was also designed to assess the feasibility, barriers, and uptake of the integrated intervention. Endpoints were assessed in a modified intention-to-treat popualtion after exclusion of ineligible participants. This trial is registered on ClinicalTrials.gov, NCT02935296, and is active but not recruiting new participants. FINDINGS: Between Feb 5, 2015, and June 3, 2016, 3343 potential index participants were screened, of whom 502 (15%) were eligible and enrolled. 1171 injection partners were referred, and 806 (69%) were eligible and enrolled. Index participants were randomly assigned to intervention (126 [25%]) and standard of care (376 [75%]) groups. At week 52, most living index participants (389 [86%] of 451) and partners (567 [80%] of 710) were retained, and self-reported ART use was higher among index participants in the intervention group than those in the standard of care group (probability ratio [PR] 1·7, 95% CI 1·4-1·9). Viral suppression was also higher in the intervention group than in the standard of care group (PR 1·7, 95% CI 1·3-2·2). Index participants in the intervention group reported more MAT use at 52 weeks than those in the standard of care group (PR 1·7, 95% CI 1·3-2·2). Seven incident HIV infections occurred, and all in injection partners in the standard of care group (intervention incidence 0·0 per 100 person-years, 95% CI 0·0-1·7; standard of care incidence 1·0 per 100 person-years, 95% CI 0·4-2·1; incidence rate difference -1·0 per 100 person-years, 95% CI -2·1 to 1·1). No severe adverse events due to the intervention were recorded. INTERPRETATION: This vanguard study provides evidence that a flexible, scalable intervention increases ART and MAT use and reduces mortality among PWID. The low incidence of HIV in both groups impedes a future randomised, controlled trial, but given the strength of the effect of the intervention, its implementation among HIV-infected PWID should be considered. FUNDING: US National Institutes of Health.

Social Network Factors as Correlates and Predictors of High Depressive Symptoms Among Black Men Who Have Sex with Men in HPTN 061.

Depression is linked to a range of poor HIV-related health outcomes. Minorities and men who have sex with men (MSM), suffer from high rates of depression. The current study examined the relationship between depressive symptoms and social network characteristics among community-recruited Black MSM in HPTN 061 from 6 US cities. A social network inventory was administer at baseline and depression was assessed with the CES-D at baseline, 6, and 12-months. At baseline, which included 1167 HIV negative and 348 HIV positive participants, size of emotional, financial, and medical support networks were significantly associated with fewer depressive symptoms. In longitudinal mixed models, size of emotional, financial, and medical support networks were significantly associated with fewer depressive symptoms as was the number of network members seen weekly. In the multivariate analyses, size of medical appointment network remained statistically significant (aOR 0.89, CI 0.81-0.98). These findings highlight the importance of network support of medical care on depression and suggest the value of support mobilization.

Efficacy and safety of long-acting cabotegravir compared with daily oral tenofovir disoproxil fumarate plus emtricitabine to prevent HIV infection in cisgender men and transgender women who have sex with men 1 year after study unblinding: a secondary analysis of the phase 2b and 3 HPTN 083 randomised controlled trial.

BACKGROUND: Injectable cabotegravir was superior to daily oral tenofovir disoproxil fumarate plus emtricitabine for HIV prevention in two clinical trials. Both trials had the primary aim of establishing the HIV prevention efficacy of long-acting injectable cabotegravir pre-exposure prophylaxis (PrEP) compared with tenofovir disoproxil fumarate plus emtricitabine daily oral PrEP. Long-acting PrEP was associated with diagnostic delays and integrase strand-transfer inhibitor (INSTI) resistance. This report presents findings from the first unblinded year of the HIV Prevention Trials Network (HPTN) 083 study. METHODS: The HPTN 083 randomised controlled trial enrolled HIV-uninfected cisgender men and transgender women at elevated HIV risk who have sex with men, from 43 clinical research sites in Africa, Asia, Latin America, and the USA. Inclusion criteria included: a negative HIV serological test at the screening and study entry, undetectable HIV RNA levels within 14 days of study entry, age 18 years or older, overall good health as determined by clinical and laboratory evaluations, and a creatinine clearance of 60 mL/min or higher. Participants were randomly allocated to receive long-acting injectable cabotegravir or daily oral tenofovir disoproxil fumarate plus emtricitabine PrEP. After study unblinding, participants remained on their original regimen awaiting an extension study. HIV infections were characterised retrospectively at a central laboratory. Here we report the secondary analysis of efficacy and safety for the first unblinded year. The primary outcome was incident HIV infection. Efficacy analyses were done on the modified intention-to-treat population using a Cox regression model. Adverse events were compared across treatment groups and time periods (blinded vs unblinded). This trial is registered with ClinicalTrials.gov, NCT02720094. FINDINGS: Of the 4488 participants who contributed person-time to the blinded analysis, 3290 contributed person-time to the first unblinded year analysis between May 15, 2020, and May 14, 2021. Updated HIV incidence in the blinded phase was 0·41 per 100 person-years for long-acting injectable cabotegravir PrEP and 1·29 per 100 person-years for daily oral tenofovir disoproxil fumarate plus emtricitabine PrEP (hazard ratio [HR] 0·31 [95% CI 0·17-0·58], p=0·0003). HIV incidence in the first unblinded year was 0·82 per 100 person-years for long-acting PrEP and 2·27 per 100 person-years for daily oral PrEP (HR 0·35 [0·18-0·69], p=0·002). Adherence to both study products decreased after study unblinding. Additional infections in the long-acting PrEP group included two with on-time injections; three with one or more delayed injections; two detected with long-acting PrEP reinitiation; and 11 more than 6 months after their last injection. Infection within 6 months of cabotegravir exposure was associated with diagnostic delays and INSTI resistance. Adverse events were generally consistent with previous reports; incident hypertension in the long-acting PrEP group requires further investigation. INTERPRETATION: Long-acting injectable cabotegravir PrEP retained high efficacy for HIV prevention in men and transgender women who have sex with men during the first year of open-label follow-up, with a near-identical HR for HIV risk reduction between long-acting injectable cabotegravir and daily oral tenofovir disoproxil fumarate plus emtricitabine PrEP during the first year after unblinding compared with the blinded period. Extended follow-up further defined the risk period for diagnostic delays and emergence of INSTI resistance. FUNDING: Division of AIDS at the National Institute of Allergy and Infectious Diseases, ViiV Healthcare, and Gilead Sciences.

Engaging People Who Inject Drugs Living With HIV in Antiretroviral Treatment and Medication for Opioid Use Disorder: Extended Follow-up of HIV Prevention Trials Network (HPTN) 074.

BACKGROUND: People who inject drugs (PWID) living with HIV experience inadequate access to antiretroviral treatment (ART) and medication for opioid use disorders (MOUD). HPTN 074 showed that an integrated intervention increased ART use and viral suppression over 52 weeks. To examine durability of ART, MOUD, and HIV viral suppression, participants could re-enroll for an extended follow-up period, during which standard-of-care (SOC) participants in need of support were offered the intervention. METHODS: Participants were recruited from Ukraine, Indonesia and Vietnam and randomly allocated 3:1 to SOC or intervention. Eligibility criteria included: HIV-positive; active injection drug use; 18-60 years of age; ≥1 HIV-uninfected injection partner; and viral load ≥1,000 copies/mL. Re-enrollment was offered to all available intervention and SOC arm participants, and SOC participants in need of support (off-ART or off-MOUD) were offered the intervention. RESULTS: The intervention continuation group re-enrolled 89 participants, and from week 52 to 104, viral suppression (<40 copies/mL) declined from 41% to 29% (estimated 9.4% decrease per year, 95% CI -17.0%; -1.8%). The in need of support group re-enrolled 94 participants and had increased ART (re-enrollment: 55%, week 26: 69%) and MOUD (re-enrollment: 16%, week 26: 25%) use, and viral suppression (re-enrollment: 40%, week 26: 49%). CONCLUSIONS: Viral suppression declined in year 2 for those who initially received the HPTN 074 intervention and improved maintenance support is warranted. Viral suppression and MOUD increased among in need participants who received intervention during the study extension. Continued efforts are needed for widespread implementation of this scalable, integrated intervention.

Longitudinal assessment of cognitive changes associated with adjuvant treatment for breast cancer: impact of age and cognitive reserve.

PURPOSE: To examine the impact of age and cognitive reserve on cognitive functioning in patients with breast cancer who are receiving adjuvant treatments. PATIENTS AND METHODS: Patients with breast cancer exposed to chemotherapy (n = 60; mean age, 51.7 years) were evaluated with a battery of neuropsychological and psychological tests before treatment and at 1, 6, and 18 months after treatment. Patients not exposed to chemotherapy (n = 72; mean age, 56.6 years) and healthy controls (n = 45; mean age, 52.9 years) were assessed at matched intervals. RESULTS: Mixed-effects modeling revealed significant effects for the Processing Speed and Verbal Ability domains. For Processing Speed, a three-way interaction among treatment group, age, and baseline cognitive reserve (P < .001) revealed that older patients with lower baseline cognitive reserve who were exposed to chemotherapy had lower performance on Processing Speed compared with patients not exposed to chemotherapy (P = .003) and controls (P < .001). A significant group by time interaction for Verbal Ability (P = .01) suggested that the healthy controls and no chemotherapy groups improved over time. The chemotherapy group failed to improve at 1 month after treatment but improved during the last two follow-up assessments. Exploratory analyses suggested a negative effect of tamoxifen on Processing Speed (P = .036) and Verbal Memory (P = .05) in the no-chemotherapy group. CONCLUSION: These data demonstrated that age and pretreatment cognitive reserve were related to post-treatment decline in Processing Speed in women exposed to chemotherapy and that chemotherapy had a short-term impact on Verbal Ability. Exploratory analysis of the impact of tamoxifen suggests that this pattern of results may be due to a combination of chemotherapy and tamoxifen.

Cognitive function in breast cancer patients prior to adjuvant treatment.

PURPOSE: To compare the neuropsychological functioning of breast cancer patients with invasive cancer and noninvasive cancer prior to adjuvant treatment. PATIENTS AND METHODS: Breast cancer patients (N = 132) with invasive (Stages 1-3, N = 110, age = 54.1 +/- 8.1) or noninvasive (Stage 0, N = 22, age = 55.8 +/- 8.0) disease completed a battery of neuropsychological and psychological instruments following surgery but prior to initiation of chemotherapy, radiation or hormonal therapy. Matched healthy controls (N = 45, age = 52.9 +/- 10.0) completed the same battery of instruments. For the patients, data on menstrual status, type of surgery, time of general anesthesia, CBC and platelets, nutritional status (B12 and folate), and thyroid function were collected. RESULTS: Comparison of mean neuropsychological test scores revealed that all groups scored within the normal range; however, patients with Stage 1-3 cancer scored significantly lower than healthy controls on the Reaction Time domain (p = 0.005). Using a definition of lower than expected cognitive performance that corrected for misclassification error, Stage 1-3 patients were significantly (p = 0.002) more likely to be classified as having lower than expected overall cognitive performance (22%) as compared to Stage 0 patients (0%) and healthy controls (4%). No differences were observed between patients classified as having lower than expected cognitive performance compared to those classified as normal performance on measures of depression, anxiety, fatigue, menstrual status, surgery/anesthesia or any of the blood work parameters. CONCLUSION: Patients with Stage 1-3 breast cancer were more likely to be classified as having lower than expected cognitive performance prior to adjuvant treatment as compared to Stage 0 patients and healthy controls, although correction for misclassification error produced a lower rate than previously reported.

Differences in the work-up and treatment of conditions associated with low back pain by patient gender and ethnic background.

STUDY DESIGN: Retrospective review comparing physician workup of degenerative lumbosacral pathologies between different genders and ethnic groups. OBJECTIVES: To investigate whether patient ethnicity and gender influence the workup and treatment of degenerative spinal pathologies. SUMMARY OF BACKGROUND DATA: Data from numerous studies suggest that patient gender and ethnicity play a role in medical decision-making, with white males receiving more frequent interventions than women and minorities. METHODS: Patients enrolled for an "initial visit" in the National Spine Network database with lumbosacral level degenerative diagnosis were reviewed. Variables included patient gender, ethnicity, age, duration of symptoms, patient-graded severity of symptoms, radicular symptom pattern, and work status. RESULTS: We identified 5690 patients with degenerative lumbosacral pathologies. Although females were more likely than males to have imaging tests ordered, male (18.5%) patients were significantly more likely to have surgery recommended than female (16.3%) patients (P < 0.031). Nonwhite females were 52% less likely to have surgery offered at initial visit, as compared to white males (P < 0.005). More imaging tests were ordered or reviewed among whites (76.6%) than among any other ethnic group (P = 0.162). White (18.3%) and Asian (22.5%) patients were significantly more likely to have surgery recommended or prescribed than black (11.1%) and Hispanic (14.5) patients (P < 0.0001). CONCLUSIONS: This study suggests that ethnicity and gender affect the workup and surgical management of degenerative spinal disorders. However, it should be noted that there are a number of confounding factors not identified in the database, including managed care and insurance status and cultural differences, which may affect both test ordering and treatment recommendations. Further study of bias in clinical decision-making is indicated to assure equal delivery of quality care.

Impact of neck and arm pain on overall health status.

STUDY DESIGN: A prospective, multicenter, cross-sectional analysis of data from the National Spine Network database. OBJECTIVES: To compare the relative impact of radicular and axial symptoms associated with disease of the cervical spine on general health as measured by the SF-36 Health Survey, and to compare the impact of these symptoms among patients of varying age and symptom duration. BACKGROUND: Degenerative disorders of the cervical spine can cause debilitating symptoms of neck and arm pain. Physicians generally treat radiculopathy more aggressively than axial neck pain alone, although it has never been shown that the presence of radiculopathy leads to a greater impairment of physical and mental function. MATERIALS AND METHODS: SF-36 Health Survey data were collected from all consenting patients seen within the National Spine Network. Patients with symptoms referable to the cervical spine (as per their physician) were included (n = 1,809). SF-36 scores for all eight scales (bodily pain (BP), vitality (VT), general health (GH), mental health (MH), physical function (PF), role physical (RP), role emotional (RE), and social function (SF), and two summary scales (Physical Component Summary [PCS] and Mental Component Summary [MCS]) were calculated. Age/gender normative scores were subtracted from the scale scores to produce a negative "impact" score, which reflected how far below normal health status these patients were. Patients were grouped according to location of symptoms (axial only, radicular only, or axial and radicular), age (younger than 40, 40 to 60, and older than 60 years), and symptom duration (acute: <6 wk; subacute: 6 wk-6 mo; and chronic: >6 mo). SF-36 scores were compared between all groups using analysis of variance and multiple comparisons with Bonferroni adjustment. RESULTS: Patients who presented with both axial and radicular symptoms had the lowest SF-36 scores relative to age and gender norms. These scores were significantly lower than those for patients with only axial or only radicular symptoms across all eight subscales (P < 0.05- P < 0.0001). Scores for patients with only axial pain were significantly lower than for patients with only radicular pain for VT (P < 0.04) and GH (P < 0.004). Patients younger than 40 and those between ages 40 to 60 years were significantly more impacted by their symptoms than patients older than 60 years for all eight scales (P < 0.01). PCS scores were similar for acute, subacute, and chronic groups, whereas MCS scores were significantly worse for patients with chronic pain. CONCLUSIONS: Combined neck and arm pain were much more disabling than either symptom alone. Younger patients (younger than 40 or 40-60) were more affected by these symptoms than patients older than 60 years. In addition, as symptom duration increased, a negative impact on mental health was observed, although chronic symptoms did not affect physical health. This study suggests that patients with a significant component of axial pain in conjunction with cervical radiculopathy should be considered the most affected of all patients with cervical spondylosis. Given the evidence that the treatment methods at the disposal of physicians are effective, this study suggests that prompt treatment of these patients may help avoid the harmful effects of chronic symptoms on mental functioning, especially among younger patients who were found to be more impacted by the symptoms.