Summary Background High plasma HIV-1 RNA concentrations are associated with increased risk of HIV-1 transmission. Initiation of antiretroviral therapy (ART) reduces plasma HIV-1 concentrations. We ...aimed to assess the effect of ART use by patients infected with HIV-1 on risk of transmission to their uninfected partners. Methods Participants in our prospective cohort analysis were from a randomised placebo-controlled trial that enrolled heterosexual African adults who were seropositive for both HIV-1 and herpes simplex virus type 2, and their HIV-1 seronegative partners. At enrolment, HIV-1 infected participants had CD4 counts of 250 cells per μL or greater and did not meet national guidelines for ART initiation; during 24 months of follow-up, CD4 counts were measured every 6 months and ART was initiated in accordance with national guidelines. Uninfected partners were tested for HIV-1 every 3 months. The primary outcome was genetically-linked HIV-1 transmission within the study partnership. We assessed rates of HIV-1 transmission by ART status of infected participants. Findings 3381 couples were eligible for analysis. 349 (10%) participants with HIV-1 initiated ART during the study, at a median CD4 cell count of 198 (IQR 161–265) cells per μL. Only one of 103 genetically-linked HIV-1 transmissions was from an infected participant who had started ART, corresponding to transmission rates of 0·37 (95% CI 0·09–2·04) per 100 person-years in those who had initiated treatment and 2·24 (1·84–2·72) per 100 person-years in those who had not—a 92% reduction (adjusted incidence rate ratio 0·08, 95% CI 0·00–0·57, p=0·004). In participants not on ART, the highest HIV-1 transmission rate (8·79 per 100 person-years) was from those with CD4 cell counts lower than 200 cells per μL. In couples in whom the untreated HIV-1 infected partner had a CD4 cell count greater than 200 cells per μL, 66 (70%) of 94 transmissions occurred when plasma HIV-1 concentrations exceeded 50 000 copies per mL. Interpretation Low CD4 cell counts and high plasma HIV-1 concentrations might guide use of ART to achieve an HIV-1 prevention benefit. Provision of ART to HIV-1 infected patients could be an effective strategy to achieve population-level reductions in HIV-1 transmission. Funding Bill & Melinda Gates Foundation; US National Institutes of Health.
Summary Background Scarce data are available to assess sexual behaviour of individuals using antiretroviral pre-exposure prophylaxis for HIV prevention. Increased sexual risk taking by individuals ...using effective HIV prevention strategies, like pre-exposure prophylaxis, could offset the benefits of HIV prevention. We studied whether the use of pre-exposure prophylaxis in HIV-uninfected men and women in HIV-serodiscordant couples was associated with increased sexual risk behaviour. Methods We undertook a longitudinal analysis of data from the Partners PrEP Study, a double-blind, randomised, placebo-controlled trial of daily oral pre-exposure prophylaxis among HIV-uninfected partners of heterosexual HIV-serodiscordant couples (n=3163, ≥18 years of age). Efficacy for HIV prevention was publicly reported in July 2011, and participants continued monthly follow-up thereafter. We used regression analyses to compare the frequency of sex—unprotected by a condom—during the 12 months after compared with the 12 months before July 2011, to assess whether knowledge of pre-exposure prophylaxis efficacy for HIV prevention caused increased sexual risk behaviour. Results We analysed 56 132 person-months from 3024 HIV-uninfected individuals (64% male). The average frequency of unprotected sex with the HIV-infected study partner was 59 per 100 person-months before unmasking versus 53 after unmasking; we recorded no immediate change (p=0·66) or change over time (p=0·25) after July, 2011. We identified a significant increase in unprotected sex with outside partners after July, 2011, but the effect was small (average of 6·8 unprotected sex acts per year vs 6·2 acts in a predicted counterfactual scenario had patients remained masked, p=0·04). Compared with before July, 2011, we noted no significant increase in incident sexually transmitted infections or pregnancy after July, 2011. Interpretation Pre-exposure prophylaxis, provided as part of a comprehensive prevention package, might not result in substantial changes in risk-taking sexual behaviour by heterosexual couples. Funding The Bill & Melinda Gates Foundation and the US National Institute of Mental Health.
Summary Background Antiretroviral pre-exposure prophylaxis (PrEP), with daily oral tenofovir disoproxil fumarate or tenofovir disoproxil fumarate in combination with emtricitabine, has been shown to ...be efficacious for HIV-1 prevention. Although the use of more than one antiretroviral agent is essential for effective HIV-1 treatment, more than one agent might not be required for effective prophylaxis. We assessed the efficacy of single-agent tenofovir disoproxil fumarate relative to combination emtricitabine plus tenofovir disoproxil fumarate as PrEP. Methods We did a randomised, double-blind, placebo-controlled three-group phase 3 trial of daily oral tenofovir disoproxil fumarate and emtricitabine plus tenofovir disoproxil fumarate PrEP in HIV-1 uninfected individuals in heterosexual HIV-1 serodiscordant couples from Kenya and Uganda. After an interim review, the trial's placebo group was discontinued and thereafter the active groups were continued, and participants initially randomly assigned to placebo were offered rerandomisation in a 1:1 ratio to tenofovir disoproxil fumarate or emtricitabine plus tenofovir disoproxil fumarate as PrEP. The primary endpoints were HIV-1 seroconversion and safety. This trial is registered with ClinicalTrials.gov , number NCT00557245. Findings 4410 (99·6%) of 4427 couples received tenofovir disoproxil fumarate or emtricitabine plus tenofovir disoproxil fumarate and were followed up for HIV-1 acquisition. Of 52 incident HIV-1 infections, 31 occurred in individuals assigned tenofovir disoproxil fumarate (incidence 0·71 cases per 100 person-years) and 21 were in those assigned emtricitabine plus tenofovir disoproxil fumarate (0·48 cases per 100 person-years); HIV-1 incidence in the placebo group until discontinuation was two cases per 100 person-years. HIV-1 prevention efficacy with emtricitabine plus tenofovir disoproxil fumarate was not significantly different from that of tenofovir disoproxil fumarate alone (hazard ratio HR 0·67, 95% CI 0·39–1·17; p=0·16). Detection of tenofovir in plasma samples, compared with no detection and as measured in seroconverters and a subset of non-seroconverters, was associated with an 85% relative risk reduction in HIV-1 acquisition for the tenofovir disoproxil fumarate group (HR 0·15, 95% CI 0·06–0·37; p<0·0001) and 93% for the emtricitabine plus tenofovir disoproxil fumarate group (0·07, 0·02–0·23; p<0·0001). No significant differences were noted in the frequency of deaths, serious adverse events, or serum creatinine and phosphorus abnormalities between the two groups. Interpretation These results do not rule out the potential for a slight difference in HIV-1 protection with tenofovir disoproxil fumarate compared with emtricitabine plus tenofovir disoproxil fumarate, but show that once-daily oral tenofovir disoproxil fumarate or emtricitabine plus tenofovir disoproxil fumarate regimens both provide high protection against HIV-1 acquisition in heterosexual men and women. Funding Bill & Melinda Gates Foundation and US National Institutes of Health.
Summary Background Most people infected with HIV-1 are dually infected with herpes simplex virus type 2. Daily suppression of this herpes virus reduces plasma HIV-1 concentrations, but whether it ...delays HIV-1 disease progression is unknown. We investigated the effect of aciclovir on HIV-1 progression. Methods In a trial with 14 sites in southern Africa and east Africa, 3381 heterosexual people who were dually infected with herpes simplex virus type 2 and HIV-1 were randomly assigned in a 1:1 ratio to aciclovir 400 mg orally twice daily or placebo, and were followed up for up to 24 months. Eligible participants had CD4 cell counts of 250 cells per μL or higher and were not taking antiretroviral therapy. We used block randomisation, and patients and investigators were masked to treatment allocation. Effect of aciclovir on HIV-1 disease progression was defined by a primary composite endpoint of first occurrence of CD4 cell counts of fewer than 200 cells per μL, antiretroviral therapy initiation, or non-trauma related death. As an exploratory analysis, we assessed the endpoint of CD4 falling to <350 cells per μL. Analysis was by intention to treat. The trial is registered with ClinicalTrials.gov , number NCT00194519. Findings At enrolment, the median CD4 cell count was 462 cells per μL and median HIV-1 plasma RNA was 4·1 log10 copies per μL. Aciclovir reduced risk of HIV-1 disease progression by 16%; 284 participants assigned aciclovir versus 324 assigned placebo reached the primary endpoint (hazard ratio HR 0·84, 95% CI 0·71–0·98, p=0·03). In those with CD4 counts ≥350 cells per μL, aciclovir delayed risk of CD4 cell counts falling to <350 cells per μL by 19% (0·81, 0·71–0·93, p=0·002) Interpretation The role of suppression of herpes simplex virus type 2 in reduction of HIV-1 disease progression before initiation of antiretroviral therapy warrants consideration. Funding Bill & Melinda Gates Foundation.
Summary Background Poly(ADP-ribose) polymerase (PARP) inhibitors have activity in ovarian carcinomas with homologous recombination deficiency. Along with BRCA1 and BRCA2 (BRCA) mutations genomic loss ...of heterozygosity (LOH) might also represent homologous recombination deficiency. In ARIEL2, we assessed the ability of tumour genomic LOH, quantified with a next-generation sequencing assay, to predict response to rucaparib, an oral PARP inhibitor. Methods ARIEL2 is an international, multicentre, two-part, phase 2, open-label study done at 49 hospitals and cancer centres in Australia, Canada, France, Spain, the UK, and the USA. In ARIEL2 Part 1, patients with recurrent, platinum-sensitive, high-grade ovarian carcinoma were classified into one of three predefined homologous recombination deficiency subgroups on the basis of tumour mutational analysis: BRCA mutant (deleterious germline or somatic), BRCA wild-type and LOH high (LOH high group), or BRCA wild-type and LOH low (LOH low group). We prespecified a cutoff of 14% or more genomic LOH for LOH high. Patients began treatment with oral rucaparib at 600 mg twice per day for continuous 28 day cycles until disease progression or any other reason for discontinuation. The primary endpoint was progression-free survival. All patients treated with at least one dose of rucaparib were included in the safety analyses and all treated patients who were classified were included in the primary endpoint analysis. This trial is registered with ClinicalTrials.gov , number NCT01891344 . Enrolment into ARIEL2 Part 1 is complete, although an extension (Part 2) is ongoing. Findings 256 patients were screened and 206 were enrolled between Oct 30, 2013, and Dec 19, 2014. At the data cutoff date (Jan 18, 2016), 204 patients had received rucaparib, with 28 patients remaining in the study. 192 patients could be classified into one of the three predefined homologous recombination deficiency subgroups: BRCA mutant (n=40), LOH high (n=82), or LOH low (n=70). Tumours from 12 patients were established as BRCA wild-type, but could not be classified for LOH, because of insufficient neoplastic nuclei in the sample. The median duration of treatment for the 204 patients was 5·7 months (IQR 2·8–10·1). 24 patients in the BRCA mutant subgroup, 56 patients in the LOH high subgroup, and 59 patients in the LOH low subgroup had disease progression or died. Median progression-free survival after rucaparib treatment was 12·8 months (95% CI 9·0–14·7) in the BRCA mutant subgroup, 5·7 months (5·3–7·6) in the LOH high subgroup, and 5·2 months (3·6–5·5) in the LOH low subgroup. Progression-free survival was significantly longer in the BRCA mutant (hazard ratio 0·27, 95% CI 0·16–0·44, p<0·0001) and LOH high (0·62, 0·42–0·90, p=0·011) subgroups compared with the LOH low subgroup. The most common grade 3 or worse treatment-emergent adverse events were anaemia or decreased haemoglobin (45 22% patients), and elevations in alanine aminotransferase or aspartate aminotransferase (25 12%). Common serious adverse events included small intestinal obstruction (10 5% of 204 patients), malignant neoplasm progression (10 5%), and anaemia (nine 4%). Three patients died during the study (two because of disease progression and one because of sepsis and disease progression). No treatment-related deaths occurred. Interpretation In patients with BRCA mutant or BRCA wild-type and LOH high platinum-sensitive ovarian carcinomas treated with rucaparib, progression-free survival was longer than in patients with BRCA wild-type LOH low carcinomas. Our results suggest that assessment of tumour LOH can be used to identify patients with BRCA wild-type platinum-sensitive ovarian cancers who might benefit from rucaparib. These results extend the potential usefulness of PARP inhibitors in the treatment setting beyond BRCA mutant tumours. Funding Clovis Oncology, US Department of Defense Ovarian Cancer Research Program, Stand Up To Cancer—Ovarian Cancer Research Fund Alliance—National Ovarian Cancer Coalition Dream Team Translational Research Grant, and V Foundation Translational Award.
Background Although preoperative chemotherapy (cisplatin-etoposide) and radiotherapy, followed by surgical resection, is considered a standard of care for superior sulcus cancers, treatment is ...rigorous and relapse limits long-term survival. The Southwest Oncology Group-Intergroup Trial S0220 was designed to incorporate an active systemic agent, docetaxel, as consolidation therapy. Methods Patients with histologically proven and radiologically defined T3 to 4, N0 to 1, M0 superior sulcus non-small cell lung cancer underwent induction therapy with cisplatin-etoposide, concurrently with thoracic radiotherapy at 45 Gy. Nonprogressing patients underwent surgical resection within 7 weeks. Consolidation consisted of docetaxel every 3 weeks for 3 doses. The accrual goal was 45 eligible patients. The primary objective was feasibility. Results Of 46 patients registered, 44 were eligible and assessable; 38 (86%) completed induction, 29 (66%) underwent surgical resection, and 20 (45% of eligible, 69% surgical, and 91% of those initiating consolidation therapy) completed consolidation docetaxel; 28 of 29 (97%) underwent a complete (R0) resection; 2 (7%) died of adult respiratory distress syndrome. In resected patients, 21 of 29 (72%) had a pathologic complete or nearly complete response. The known site of first recurrence was local in 2, local-systemic in 1, and systemic in 10, with 7 in the brain only. The 3-year progression-free survival was 56%, and 3-year overall survival was 61%. Conclusions Although trimodality therapy provides excellent R0 and local control, only 66% of patients underwent surgical resection and only 45% completed the treatment regimen. Even in this subset, distant recurrence continues to be a major problem, particularly brain-only relapse. Future strategies to improve treatment outcomes in this patient population must increase the effectiveness of systemic therapy and reduce the incidence of brain-only metastases.
Objective We sought to characterize the relationship between serum 25-hydroxy vitamin D (25-OH D) levels and implantation and clinical pregnancy rates in women who undergo a euploid blastocyst embryo ...transfer. Study Design This retrospective cohort study, conducted in an academic setting, included 529 cycles in which comprehensive chromosome screening was performed as part of routine infertility care with an autologous transfer of 1 or 2 euploid blastocysts. After excluding repeat cycles there were 517 unique cycles representing 517 women for evaluation. Vitamin D levels from serum samples obtained on the day of ovulation trigger in the fresh in vitro fertilization cycle were analyzed. The primary outcome was ongoing pregnancy rate as defined by sonographic presence of fetal heart rate at >8 weeks’ gestation. Results For the population as a whole, serum vitamin D ranges and pregnancy outcomes did not correlate. Furthermore, pregnancy rates did not differ when comparing women in different strata of vitamin D levels (<20, 20-29.9, and ≥30 ng/mL). No meaningful breakpoint for vitamin D levels and ongoing pregnancy rate was identified using receiver operating characteristic analysis with the resultant line possessing an area under the curve of 0.502. Multivariate logistic regression controlling for age, transfer order, race, season, and body mass index did not yield a different result. The study was powered to detect an 18% difference in ongoing pregnancy rates between patients grouped by the 3 vitamin D ranges. Conclusion In women undergoing euploid embryo transfer, vitamin D status was unrelated to pregnancy outcomes. Measuring serum 25-OH vitamin D levels does not predict the likelihood that euploid blastocysts will implant. These results may not apply to women who do not undergo extended embryo culture, blastocyst biopsy for comprehensive chromosome screening, and euploid embryo transfer.
CONTEXT Universal screening for mental health problems and suicide risk is at
the forefront of the national agenda for youth suicide prevention, yet no
study has directly addressed the potential harm ...of suicide screening. OBJECTIVE To examine whether asking about suicidal ideation or behavior during
a screening program creates distress or increases suicidal ideation among
high school students generally or among high-risk students reporting depressive
symptoms, substance use problems, or suicide attempts. DESIGN, SETTING, AND PARTICIPANTS A randomized controlled study conducted within the context of a 2-day
screening strategy. Participants were 2342 students in 6 high schools in New
York State in 2002-2004. Classes were randomized to an experimental group
(n = 1172), which received the first survey with suicide questions,
or to a control group (n = 1170), which did not receive suicide
questions. MAIN OUTCOME MEASURES Distress measured at the end of the first survey and at the beginning
of the second survey 2 days after the first measured on the Profile of Mood
States adolescent version (POMS-A) instrument. Suicidal ideation assessed
in the second survey. RESULTS Experimental and control groups did not differ on distress levels immediately
after the first survey (mean SD POMS-A score, 5.5 9.7 in the experimental
group and 5.1 10.0 in the control group; P = .66)
or 2 days later (mean SD POMS-A score, 4.3 9.0 in the experimental group
and 3.9 9.4 in the control group; P = .41),
nor did rates of depressive feelings differ (13.3% and 11.0%, respectively; P = .19). Students exposed to suicide questions
were no more likely to report suicidal ideation after the survey than unexposed
students (4.7% and 3.9%, respectively; P = .49).
High-risk students (defined as those with depression symptoms, substance use
problems, or any previous suicide attempt) in the experimental group were
neither more suicidal nor distressed than high-risk youth in the control group;
on the contrary, depressed students and previous suicide attempters in the
experimental group appeared less distressed (P = .01)
and suicidal (P = .02), respectively, than
high-risk control students. CONCLUSIONS No evidence of iatrogenic effects of suicide screening emerged. Screening
in high schools is a safe component of youth suicide prevention efforts.
The benefit of adding androgen deprivation therapy (ADT) to dose-escalated radiation therapy (RT) for men with intermediate-risk prostate cancer is unclear; therefore, we assessed the impact of ...adding ADT to dose-escalated RT on freedom from failure (FFF).
Three groups of men treated with intensity modulated RT or 3-dimensional conformal RT (75.6-78 Gy) from 1993-2008 for prostate cancer were categorized as (1) 326 intermediate-risk patients treated with RT alone, (2) 218 intermediate-risk patients treated with RT and ≤6 months of ADT, and (3) 274 low-risk patients treated with definitive RT. Median follow-up was 58 months. Recursive partitioning analysis based on FFF using Gleason score (GS), T stage, and pretreatment PSA concentration was applied to the intermediate-risk patients treated with RT alone. The Kaplan-Meier method was used to estimate 5-year FFF.
Based on recursive partitioning analysis, intermediate-risk patients treated with RT alone were divided into 3 prognostic groups: (1) 188 favorable patients: GS 6, ≤T2b or GS 3+4, ≤T1c; (2) 71 marginal patients: GS 3+4, T2a-b; and (3) 68 unfavorable patients: GS 4+3 or T2c disease. Hazard ratios (HR) for recurrence in each group were 1.0, 2.1, and 4.6, respectively. When intermediate-risk patients treated with RT alone were compared to intermediate-risk patients treated with RT and ADT, the greatest benefit from ADT was seen for the unfavorable intermediate-risk patients (FFF, 74% vs 94%, respectively; P=.005). Favorable intermediate-risk patients had no significant benefit from the addition of ADT to RT (FFF, 94% vs 95%, respectively; P=.85), and FFF for favorable intermediate-risk patients treated with RT alone approached that of low-risk patients treated with RT alone (98%).
Patients with favorable intermediate-risk prostate cancer did not benefit from the addition of ADT to dose-escalated RT, and their FFF was nearly as good as patients with low-risk disease. In patients with GS 4+3 or T2c disease, the addition of ADT to dose-escalated RT did improve FFF.
Abstract Context As endorsed by the palliative care “Measuring What Matters” initiative, capturing patients' direct assessment of their care is essential for ongoing quality reporting and ...improvement. Fostering an environment where seriously ill patients feel heard and understood is of crucial importance to modern health care. Objectives To describe the development and performance of a self-report field measure for seriously ill patients to report how well they feel heard and understood in the hospital environment. Methods As part of a larger ongoing cohort study of inpatient palliative care, we developed and administered the following point-of-care item: “Over the past two days, how much have you felt heard and understood by the doctors, nurses and hospital staff?” (completely, quite a bit, moderately, slightly, not at all). Participants completed the measure before and the day after palliative care consultation. For the postconsultation version, we changed the time frame from “past two days” to “today.” Results One hundred sixty patients with advanced cancer completed the preconsultation assessment, and 87% of them completed the postconsultation version. Responses encompassed full use of the ordinal scale, did not exhibit ceiling or floor effects, and showed improvement from preassessment to postassessment. The item was quick to administer and easy for patients to complete. Conclusion The “Heard & Understood” item is a promising self-report quality measure for the inpatient palliative care setting.
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