Jason Brunetta

Switching from tenofovir disoproxil fumarate to tenofovir alafenamide in antiretroviral regimens for virologically suppressed adults with HIV-1 infection: a randomised, active-controlled, multicentre, open-label, phase 3, non-inferiority study

BACKGROUND Antiretroviral regimens containing tenofovir disoproxil fumarate have been associated with renal toxicity and reduced bone mineral density. Tenofovir alafenamide is a novel tenofovir prodrug that reduces tenofovir plasma concentrations by 90%, thereby decreasing off-target side-effects. We aimed to assess whether efficacy, safety, and tolerability were non-inferior in patients switched to a regimen containing tenofovir alafenamide versus in those remaining on one containing tenofovir disoproxil fumarate. METHODS In this randomised, actively controlled, multicentre, open-label, non-inferiority trial, we recruited HIV-1-infected adults from Gilead clinical studies at 168 sites in 19 countries. Patients were virologically suppressed (HIV-1 RNA <50 copies per mL) with an estimated glomerular filtration rate of 50 mL per min or greater, and were taking one of four tenofovir disoproxil fumarate-containing regimens for at least 96 weeks before enrolment. With use of a third-party computer-generated sequence, patients were randomly assigned (2:1) to receive a once-a-day single-tablet containing elvitegravir 150 mg, cobicistat 150 mg, emtricitabine 200 mg, and tenofovir alafenamide 10 mg (tenofovir alafenamide group) or to carry on taking one of four previous tenofovir disoproxil fumarate-containing regimens (tenofovir disoproxil fumarate group) for 96 weeks. Randomisation was stratified by previous treatment regimen in blocks of six. Patients and treating physicians were not masked to the assigned study regimen; outcome assessors were masked until database lock. The primary endpoint was the proportion of patients who received at least one dose of study drug who had undetectable viral load (HIV-1 RNA <50 copies per mL) at week 48. The non-inferiority margin was 12%. This study was registered with ClinicalTrials.gov, number NCT01815736. FINDINGS Between April 12, 2013 and April 3, 2014, we enrolled 1443 patients. 959 patients were randomly assigned to the tenofovir alafenamide group and 477 to the tenofovir disoproxil fumarate group. Viral suppression at week 48 was noted in 932 (97%) patients assigned to the tenofovir alafenamide group and in 444 (93%) assigned to the tenofovir disoproxil fumarate group (adjusted difference 4·1%, 95% CI 1·6-6·7), with virological failure noted in ten and six patients, respectively. The number of adverse events was similar between the two groups, but study drug-related adverse events were more common in the tenofovir alafenamide group (204 patients [21%] vs 76 [16%]). Hip and spine bone mineral density and glomerular filtration were each significantly improved in patients in the tenofovir alafenamide group compared with those in the tenofovir disoproxil fumarate group. INTERPRETATION Switching to a tenofovir alafenamide-containing regimen from one containing tenofovir disoproxil fumarate was non-inferior for maintenance of viral suppression and led to improved bone mineral density and renal function. Longer term follow-up is needed to better understand the clinical impact of these changes. FUNDING Gilead Sciences.

Gemini: a noninferiority study of saquinavir/ritonavir versus lopinavir/ritonavir as initial HIV-1 therapy in adults.

Introduction:Direct comparison of the efficacy and safety of different agents is needed to guide selection of optimal treatment regimens for therapy-naive HIV-1-infected patients. Methods:Gemini was a 48-week, multicenter, open-label, noninferiority trial in treatment-naive HIV-1-infected adults randomized to either saquinavir/ritonavir (SQV/r) 1000 mg/100 mg twice a day or lopinavir/ritonavir (LPV/r) 400 mg/100 mg twice a day, each with emtricitabine/tenofovir 200 mg/300 mg every day. Results:A similar proportion of participants in the SQV/r (n = 167) and LPV/r (n = 170) arms had HIV-1 RNA levels <50 copies per milliliter at week 48: 64.7% vs 63.5% and estimated difference in proportion for noninferiority: 1.14%, 96% confidence interval: −9.6 to11.9 (P < 0.012), confirming that SQV/r was noninferior to LPV/r treatment. There were no significant differences in week 48 CD4 counts between arms. The rate and severity of adverse events were similar in both groups. There were no significant differences in the median change from baseline between arms in plasma lipids except for triglyceride levels, which were significantly higher in the LPV/r at week 48. Conclusions:In treatment-naive, HIV-1-infected patients, SQV/r treatment was noninferior in virologic suppression at 48 weeks to LPV/r treatment and offered a better triglyceride profile.

Evaluation of brief screening tools for neurocognitive impairment in HIV/AIDS: a systematic review of the literature

Objective(s):To systematically review literature on brief screening tools used to detect and differentiate between normal cognition and neurocognitive impairment and HIV-associated neurocognitive disorders (HANDs) in adult populations of persons with HIV. Design:A formal systematic review. Methods:We searched six electronic databases in 2011 and contacted experts to identify relevant studies published through May 2012. We selected empirical studies that focused on evaluating brief screening tools (<20 min) for neurocognitive impairment in persons with HIV. Two reviewers independently reviewed retrieved literature for potential relevance and methodological quality. Meta-analyses were completed on screening tools that had sufficient data. Results:Fifty-one studies met inclusion criteria; we focused on 31 studies that compared brief screening tools with reference tests. Within these 31 studies, 39 tools were evaluated and 67% used a comprehensive neuropsychological battery as a reference. The majority of these studies evaluated HIV-associated dementia (HAD). Meta-analyses demonstrated that the HIV Dementia Scale (HDS) has poor pooled sensitivity (0.48) and the International HIV Dementia Scale (IHDS) has moderate pooled sensitivity (0.62) in detecting a range of cognitive impairment. Five newer screening tools had relatively good sensitivities (>0.70); however, none of the tools differentiated HAND conditions well enough to suggest broader use. There were significant methodological shortcomings noted in most studies. Conclusion:HDS and IHDS perform well to screen for HAD but poorly for milder HAND conditions. Further investigation, with improved methodology, is required to understand the utility of newer screening tools for HAND; further tools may need to be developed for milder HAND conditions.

Effect of raltegravir intensification on HIV proviral DNA in the blood and gut mucosa of men on long-term therapy: a randomized controlled trial.

Background:Highly active antiretroviral therapy (HAART) dramatically reduces plasma HIV-1 viremia. However, despite completely suppressive HAART, it has been suggested that low-levels of viral replication may persist in the gut mucosa and elsewhere in individuals on long-term HAART. Objective:We conducted a double-blind randomized, placebo-controlled trial evaluating whether intensification of HAART in long-term virologically suppressed individuals with raltegravir is associated with a reduction in the level of proviral HIV-1 DNA in CD4+ T cells in blood and the sigmoid colon (gut). Methods:Long-term (>4 years) virologically suppressed HIV-infected individuals on standard HAART were randomized 1 : 1 in a double-blind fashion to receive raltegravir (400 mg twice/day) or placebo for 48 weeks. After week 48, all participants were treated with raltegravir to week 96. Blood and sigmoid biopsies were sampled and the frequency of CD4+ T cells carrying HIV-1 proviral DNA was determined. Results:Twenty-four study patients were recruited. At 48 weeks, no difference was apparent between participants receiving raltegravir or placebo in blood HIV-1 proviral levels (P = 0.62), CD4+ T-cell counts (P = 0.25) and gut proviral loads (P = 0.74). Similarly, prolonged raltegravir intensification up to week 96 had no further effect on both blood and gut HIV-1 proviral loads and blood CD4+ T-cell counts. Conclusion:In long-term virologically suppressed patients on standard HAART, intensification with raltegravir did not result in further decay of CD4+ T cells carrying HIV-1 proviral DNA in either the blood or gut after 48 or 96 weeks of therapy, or in any increase in CD4+ T-cell counts.

Brief Report: Efficacy and Safety of Switching to a Single-Tablet Regimen of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide in HIV-1/Hepatitis B-Coinfected Adults.

Abstract:Coformulated elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide (E/C/F/TAF) has high efficacy and improved renal and bone safety in multiple phase 3 trials; TAF single agent is being studied in 2 phase 3 trials in patients with chronic hepatitis B. We report the results of an open-label, noncomparative switch study evaluating the efficacy and safety of E/C/F/TAF in HIV/hepatitis B virus (HBV)–coinfected adults. At 48 weeks, 91.7% of the 72 participants maintained or achieved virologic suppression (HIV-1 RNA <50 copies/mL; HBV DNA <29 IU/mL). Seroconversion occurred in 2.9% of hepatitis B surface antigen–positive participants and in 3.3% of HBV e antigen–positive participants; 40% of those with abnormal alanine aminotransferase normalized. E/C/F/TAF was associated with improved renal function and reduced bone turnover. These data support the use of E/C/F/TAF in treating HIV/HBV coinfection.

Community-Associated Methicillin-Resistant Staphylococcus aureus Infections in Men Who Have Sex With Men: A Case Series

BACKGROUND The purpose of the present study was to describe the clinical characteristics and management of community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) infections among a cohort of men who have sex with men. PATIENTS AND METHODS A retrospective chart review was conducted of patients with culture-proven MRSA at Maple Leaf Medical Clinic (Toronto, Ontario) between November 2004 and December 2005. Cases were identified by individual physicians and by queries in the clinical management system. A standard data collection form was used to record patient demographics, potential risk factors for MRSA and course of illness. When available, antimicrobial sensitivities were recorded. DNA fingerprinting using pulsed-field gel electrophoresis, and genetic analysis for SCCmec typing and detection of the Panton-Valentine leukocidin cytotoxin were performed on six available isolates. RESULTS Seventeen patients with MRSA infection were identified, 12 (71%) of whom were HIV-positive. The most common clinical presentation was abscess (35%), followed by furuncle (17%), folliculitis (17%), cellulitis (17%) and sinusitis (12%). The majority of MRSA isolates were resistant to ciprofloxacin (92%) and levofloxacin (77%). All isolates were susceptible to trimethoprim-sulfamethoxazole, rifampin, linezolid, gentamicin and clindamycin, while the majority were susceptible to tetracycline (80%). All six isolates tested were SCCmec type IVa-positive and Panton-Valentine leukocidin-positive, and had fingerprint patterns consistent with the CMRSA-10 (USA300) clone. CONCLUSION The present study describes the clinical presentation and management of CA-MRSA infections occurring in Toronto among men who have sex with men. The infections appear to have been caused by CMRSA-10, which has caused the majority of CA-MRSA outbreaks elsewhere.

Pharmacokinetics of maraviroc, raltegravir, darunavir, and etravirine in the semen of HIV-infected men.

To the Editors: Research examining the pharmacokinetic profile of antiretrovirals in the male genital tract is important for both the purposes of characterizing the disposition of these drugs within this compartment and informing subsequent research aimed at ascertaining their effectiveness for interrupting the sexual transmission of human immunodeficiency virus (HIV). We therefore undertook a study to characterize the pharmacokinetic disposition of maraviroc, raltegravir, darunavir, and etravirine over a 12-hour dosing interval in the semen of HIV-infected men. We prospectively recruited 10 HIV-infected men aged

Long-term efficacy and safety of polyalkylimide gel for the treatment of HIV-associated lipoatrophy.

18 years who had been receiving maravirocand raltegravir-based combination antiretroviral therapy (cART) for a minimum of 90 days, of whom 8 were receiving concomitant therapy with darunavir and etravirine. Additional eligibility criteria included having an undetectable viral load (,50 copies per milliliter) for a minimum of 1 month, ability to provide written informed consent, and no active illness or comorbidity, including acute renal or hepatic disease. We excluded patients who were nonadherent to their prescribed cART regimen, were receiving concomitant therapy with a nonantiretroviral inducer of CYP3A4 and who were expected to have difficulty adhering to the study protocol for any reason. We obtained written informed consent from all the participants of the study. We used a staggered sampling approach in which semen samples were produced by participants over several days at different sampling times relative to the morning dose of antiretrovirals. Specifically, semen samples were collected 30 minutes to 1 hour before the morning dose ofmedication (day1), and then at hours 1, 2, 4, 8, and 12 postdrug ingestion on days 2–6. We collected corresponding blood samples within 1 hour of the semen sample. Semen and blood samples were centrifuged without delay, and isolated seminal and blood plasma were aliquoted and stored at −80°C until analyzed. Antiretroviral drug concentrations were determined by a validated high-performance liquid chromatography (HPLC) coupled to the tandem mass spectrometry (LC– MS/MS) method. Specifically, before analysis, protein was removed from the samples by precipitation with 0.1% acetic acid in methanol followed by centrifugation at 2000g for 5 minutes. One hundred microliters of a 2000 ng/mL of internal standard, 6,7-dimethyl-2,3-di (2-pyridyl)quinoxaline (Aldrich, Milwaukee, WI), were added to 250 mL of supernatant, and the concentrations of maraviroc, darunavir, raltegravir, and etravirine were determined by LC–MS/MS. The gradient mobile phase system with a run time of 8 minutes consisted of 3 mobile phases: 5 mM ammonium acetate, pH 4.15 with 5% methanol; pure methanol; 0.1% acetic acid. A Hewlett Packard-1100 HPLC system (Agilent Technologies, Wilmington, DE) consisting of a Supelco (Supelcosil ABZ1Plus) 15 cm · 4.6 mm, 3 mm C18 column (Supelco, Bellefonte, PA) coupled to a PE Sciex API-2000 LC– MS/MS triple quadruple mass spectrometer (AB/MDS/Sciex, Concord, ON, Canada) equipped with a turbo ion spray source was used. Analyst software version 4.11 (AB/MDS/Sciex) was used as the system controller and integrator. All the solvents and chemicals were obtained from Sigma (Oakville, ON, Canada) and were of HPLC grade. We used noncompartmental analyses to determine the pharmacokinetic parameters of maraviroc, raltegravir, darunavir, and etravirine in seminal and blood plasma. Specifically, for each drug, we used the exact sample collection and data observation times to determine the maximum concentration (Cmax), minimum concentration (Cmin), time to maximum concentration (Tmax), and area under the curve by using the trapezoidal rule from 0 to 12 hours (AUC0–12 h) in both compartments. We used published estimates of antiretroviral protein binding in seminal plasma and in vitro unbound EC90 for HIV-1 to facilitate interpretation of our results. We also determined the coefficient of variation (CV) of SP:BP ratios for each drug. Finally, we summarized baseline characteristics of the participants using medians and interquartile range (IQR) for continuous variables and proportions for categorical variables (Sigmastat 3.5). We obtained ethics approval for this study from Institutional Review Board Services and the Ottawa Hospital Research Ethics Board. The median age and baseline CD4+ cell count of the 10 participants were 51 years (IQR 46–57 years) and 335 cells per cubic millimeter (IQR 218–348 cells per cubic millimeter). Virologic suppression to ,50 copies per milliliter had been maintained for a median of 10 months (IQR 2.5–10.5 months) at the time of Supported by an unrestricted research grant from Pfizer Inc. The sponsors had no role in the design and conduct of the study; in the collection, analysis, and interpretation of the data; or in the preparation, review, or approval of the manuscript. The opinions, results, and conclusions reported in this article are those of the authors and are independent from the funding source. Tony Antoniou is supported by a postdoctoral fellowship from the Ontario HIV Treatment Network. M. Loutfy receives salary support from the Canadian Institutes for Health Research. During the past 3 years, T. Antoniou has received an unrestricted research grant from Merck for different studies. M. Loutfy has received unrestricted research grants for other projects from, and has acted as a speaker and advisor for, Abbott Canada, Merck Frosst, Pfizer, Bristol-Myers Squibb, Tibotec, Boehringer Ingelheim, and GlaxoSmithKline. C. Kovacs has been on advisory boards and/or received unrestricted research funds from Merck, Bristol-Myers-Squibb, Pfizer, Viiv, Abbott, and Gilead. J. Brunetta has received honoraria for consulting and advisory work from Abbott, ViiV, Tibotec, Merck, Eli Lilly, and Gilead. G. Smith has received speaker fees and advisory board fees from Merck, Abbott, Viiv, and Tibotec/Jansen. C. la Porte has received grants or research support from, or served as a consultant, advisor, or speaker for Abbott Laboratories, Bristol-Myers Squibb, Merck, Roche, Boehringer Ingelheim, Pfizer, and Tibotec and is currently employed at Janssen-Cilag BV, Tilburg, The Netherlands. All other authors declare (1) no support from any company for the submitted work; (2) no relationships with any companies that might have an interest in the submitted work in the previous 3 years; (3) their spouses, partners, or children have no financial relationships that may be relevant to the submitted work; and (4) no nonfinancial interests that may be relevant to the submitted work. Presented at the 13th International Workshop on Clinical Pharmacology of HIV Therapy, April 16–18, 2012, Barcelona, Spain (abstract P24). Letters to the Editor J Acquir Immune Defic Syndr Volume 62, Number 2, February 1, 2013

Prevalence of Sexually Transmitted Viral and Bacterial Infections in HIV-Positive and HIV-Negative Men Who Have Sex with Men in Toronto

Abstract The long-term safety and efficacy of products used in the correction of HIV-associated facial lipoatrophy (FLA) are largely unknown. The purpose of this study was to describe the long-term efficacy and safety of polyalkylimide gel (PAIG) in the treatment of HIV-associated FLA. In this open-label, randomized, single-center study, 31 HIV-positive individuals (median age 48 years (interquartile ranges (IQR) 45, 55, 97% male) with FLA were randomized to immediate (week 0 and six) or delayed (week 12 and 18) PAIG injections. Week 96 endpoints included change in FLA severity scores (FLSS) (five-point scale), proportion of patients with adverse events, and changes in quality of life, depression and anxiety using validated surveys. Results at week 96 were available for 28 patients. Adverse events, including swelling, redness, bruising and pain, were mild, and resolved after a median of three days following the injection. At week 96, median changes in physician and patient FLSS scores were −2 (IQR −3, −1; p<0.001 vs. baseline) and −2 (IQR −2, −1; p<0.001 vs. baseline), respectively. Physician and patient FLSS scores were not significantly different between the groups at week 96. Significant improvements in patients anxiety (p<0.001), depression (p<0.001) and mental health (p=0.01) were observed from baseline to week 96. In conclusion, treatment with PAIG was associated with sustained improvements in both the physical and psychological components of FLA through 96 weeks of follow-up.

Herpes Simplex Virus Type 2 Coinfection Does Not Accelerate CD4 Count Decline in Untreated HIV Infection

Background Hepatitis B (HBV), hepatitis C (HCV) and other sexually transmitted infections (STIs) have been associated with HIV transmission risk and disease progression among gay men and other men who have sex with men (MSM), but the frequency and distribution of STIs in this community in Canada has not been extensively studied. Methods We recruited MSM living with and without HIV from a large primary care clinic in Toronto. Participants completed a detailed socio-behavioural questionnaire using ACASI and provided blood for syphilis, HIV, HBV and HCV, herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2), and human cytomegalovirus (CMV) serology, urine for chlamydia and gonorrhea, and a self-collected anal swab for human papillomavirus (HPV) molecular diagnostics. Prevalences were expressed as a proportion and compared using chi-square. Results 442 MSM were recruited, 294 living with HIV and 148 without. Active syphilis (11.0% vs. 3.4%), ever HBV (49.4% vs. 19.1%), HCV (10.4% vs. 3.4%), HSV-2 (55.9% vs. 38.2%), CMV (98.3% vs. 80.3%) and high-risk (HR) anal HPV (67.6% vs. 51.7%) infections were significantly more common in men living with HIV. Chlamydia and gonorrhea were infrequent in both groups. Regardless of HIV infection status, age and number of lifetime male sexual partners were associated with HBV infection and lifetime injection drug use with HCV infection. Conclusions Syphilis and viral infections, including HBV, HCV, HSV-2, CMV, and HR-HPV, were common in this clinic-based population of MSM in Toronto and more frequent among MSM living with HIV. This argues for the implementation of routine screening, vaccine-based prevention, and education programs in this high-risk population.