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Kathleen E Squires,1 Benjamin Young,2,3 Lizette Santiago,4 Robin H Dretler,5 Sharon L Walmsley,6 Henry H Zhao,7 Gary E Pakes,8 Lisa L Ross,8 Mark S Shaefer8 On behalf of the ARIES Study Team 1Thomas Jefferson University, Philadelphia, PA, 2Apex Family Medicine and Research, Denver, CO, 3International Association of Physicians in AIDS Care, Washington DC, USA; 4HOPE Clinic and Wellness Center, San Juan, Puerto Rico; 5ID Specialists of Atlanta, Decatur, GA, USA; 6University Health Network, Toronto, ON, Canada; 7GlaxoSmithKline, 8ViiV Healthcare, Research Triangle Park, NC, USA Purpose: The 144-week results of the open-label, multicenter Atazanavir/Ritonavir Induction with Epzicom Study (ARIES) were stratified by gender to compare treatment responses.Methods: A total of 369 HIV-infected, antiretroviral-naïve subjects receiving once-daily abacavir/lamivudine + atazanavir/ritonavir (ATV/r) whose HIV-1 RNA was

Objectives HIV treatment guidelines endorse switching or simplification of antiretroviral therapy in therapy-experienced patients with suppressed viraemia; ritonavir discontinuation may also enhance tolerability and reduce long-term adverse events ( AEs). This open-label, multicentre, noninferiority study enrolled HIV-1-infected, treatment-experienced adults with confirmed HIV-1 RNA ≤ 75 HIV-1 RNA copies/mL currently receiving tenofovir/emtricitabine + atazanavir/ritonavir ( TDF/ FTC + ATV/r) for ≥ 6 months with no reported history of virological failure. Methods Participants were randomized 1:2 to continue current treatment or switch to abacavir/lamivudine + atazanavir ( ABC/3TC + ATV). Endpoints included the proportion of participants with HIV-1 RNA < 50 copies/mL by time to loss of virological response ( TLOVR), AEs, fasting lipids, and inflammatory, coagulation, bone and renal biomarkers. Results After 48 weeks, 76% (152 of 199) of ABC/3TC + ATV-treated and 79% (77 of 97) of TDF/ FTC + ATV/r-treated participants had HIV-1 RNA < 50 copies/mL ( TLOVR; P = 0.564). Other efficacy analyses yielded similar results. Rates of new grade 2-4 AEs were 45% in both groups, but an excess of hyperbilirubinaemia made the rate of treatment-emergent grade 3-4 laboratory abnormalities higher with TDF/ FTC + ATV/r (36%) compared with ABC/3TC + ATV (19%). Most fasting lipid levels remained stable over time; high-density lipoprotein ( HDL) cholesterol increased modestly in ABC/3TC + ATV-treated participants. Bone and renal biomarkers improved significantly between baseline and week 48 in participants taking ABC/3TC + ATV and were stable in participants taking TDF/ FTC + ATV/r. No significant changes occurred in any inflammatory or coagulation biomarker within or between treatment groups. Conclusions The ABC/3TC + ATV treatment-switch group had similar viral suppression rates up to 48 weeks to the TDF/ FTC + ATV/r comparator group, with lower rates of moderate- to high-grade hyperbilirubinaemia and improvements in bone and renal biomarkers. [ABSTRACT FROM AUTHOR]

APV20002 was a multicenter, international, open-label study that began in 2003 investigating the pharmacokinetics, efficacy, and safety of ritonavir-boosted fosamprenavir (FPV/r) oral solution (OS) in combination with nucleoside reverse transcriptase inhibitor-based antiretroviral therapy (ART) in participants living with HIV-1 aged 4 weeks to <2 years with a primary endpoint at Week 48 (48W). Participants in APV20002 could continue in the study post-48W until FPV OS was locally available in their countries. Children were required to discontinue after reaching >39 kg or if FPV OS had no clinical benefit. Fifty-nine participants were enrolled; 5/59 received a single FPV OS visit for pharmacokinetic determinations. Most (38/54; 70%) were antiretroviral experienced; 39/59 participants had >48 weeks on treatment, 4/39 of whom discontinued after 48 weeks due to an adverse event (AE). At 48W, 88% of participants had HIV-1 RNA <400 copies/mL by Observed analysis; the proportion with HIV-1 RNA <400 copies/mL remained high (84%-100%) through Week 684. The median CD4 + cell count was 1,235 cells/mm 3 [ n = 51] at baseline, 1,690 cells/mm 3 ( n = 41) at Week 48, and 1,280 cells/mm 3 ( n = 21) at Week 180. From baseline to Week 684, 54/59 (92%) participants had ≥1 treatment-emergent AE regardless of causality; 42/59 (71%) had a treatment-emergent grade 2-4 AE, predominantly maximum toxicity: grade 2; 21/59 (36%) and 21/59 (36%) had severe or grade 3/4 AEs. From baseline to Week 684, 14/54 (26%) participants met virologic failure (VF) criteria, 9/14 before 48W. HIV from 1/9 VFs through 48W developed treatment-emergent reduced susceptibility to FPV and 1/9 to lamivudine/emtricitabine. Post-48W, 4/5 participants with VF had phenotype results; all were still susceptible to all study drugs at VF. In conclusion, FPV OS-based ART was efficacious and generally well tolerated in this long-running pediatric study through 684 weeks of treatment, with a safety profile consistent with experience in adults and older children.

A retrospective analysis of the randomized controlled DART (Development of AntiRetroviral Therapy in Africa; ISRCTN13968779) trial in HIV-1-positive adults initiating antiretroviral therapy with co-formulated zidovudine/lamivudine plus either tenofovir, abacavir, or nevirapine was conducted to evaluate the safety of initiating standard lamivudine dosing in patients with impaired creatinine clearance (CLcr). Safety data collected through 96 weeks were analyzed after stratification by baseline CLcr (estimated using Cockcroft-Gault) of 30-49 mL/min (n = 168) versus ≥50 mL/min (n = 3,132) and treatment regimen. The Grade 3-4 adverse events (AEs) and serious AEs (for hematological, hepatic and gastrointestinal events), maximal toxicities for liver enzymes, serum creatinine and bilirubin and maximum treatment-emergent hematology toxicities were comparable for groups with baseline CLcr 30-49 versus CLcr≥50 mL/min. No new risks or trends were identified from this dataset. Substantial and similar increases in the mean creatinine clearance (>25 mL/min) were observed from baseline though Week 96 among participants who entered the trial with CLcr 30-49 mL/min, while no increase or smaller median changes in creatinine clearance (<7 mL/min) were observed for participants who entered the trial with CLcr ≥50 mL/min. Substantial increases (> 150 cells/ mm3) in mean CD4+ cells counts from baseline to Week 96 were also observed for participants who entered the trial with CLcr 30-49 mL/min and those with baseline CLcr ≥50 mL/min. Though these results are descriptive, they suggest that HIV-positive patients with CLcr of 30-49 mL/min would have similar AE risks in comparison to patients with CLcr ≥50 mL/min when initiating antiretroviral therapy delivering doses of 300 mg of lamivudine daily through 96 weeks of treatment. Overall improvements in CLcr were observed for patients with baseline CLcr 30-49 mL/min., Competing Interests: We have the following interests: LLR, ART, CCM, AC, TP, and MSS are employees of ViiV Healthcare and own stock in GlaxoSmithKline. ASW discloses receiving grant funding for the DART trial from the UK Medical Research Council, the UK Department for International Development, and the Rockefeller Foundation; receiving nonfinancial support from ViiV Healthcare, GlaxoSmithKline, Gilead Sciences, and Boehringer Ingelheim, all of which donated drugs for the DART trial; receiving funding from Gilead Sciences for teaching courses on Critical Appraisal; and receiving funding from Janssen for sitting on a Data Safety Monitoring Board. YL was an employee of PAREXEL International and owns stock in GlaxoSmithKline. DMG discloses nonfinancial support from GlaxoSmithKline, Gilead, and Boehringer Ingelheim, all of which provided drugs for the DART trial, and nonfinancial support from Gilead, ViiV Healthcare, CIPLA, and Mylan, all of which donated drugs for HIV trials outside of the submitted work. JD is an employee of and owns stock in GlaxoSmithKline. CG, PM, GM, and CMK have nothing to disclose. HG discloses receiving funds in the form of a grant from MRC/UVRI Uganda Research Unit on AIDS, during which time HG was the Unit Director and drew a salary from MRC (UK) during the conduct of the study. JH and PNM have nothing to disclose. This retrospective analysis of data through 96 weeks from the DART trial was supported by ViiV Healthcare using data provided by the DART trial sponsors, the Medical Research Council of the United Kingdom. There are no patents, products in development or marketed products to declare. This does not alter our adherence to all the PLOS ONE policies on sharing data and materials.

Background: Elbasvir/grazoprevir is a once-daily fixed-dose combination therapy for the treatment of chronic HCV infection, including HCV/HIV coinfection., Objectives: To evaluate the pharmacokinetic interaction of elbasvir and grazoprevir with raltegravir or dolutegravir., Methods: Three open-label trials in healthy adult participants were conducted. In the raltegravir trials, participants received a single dose of raltegravir 400 mg, a single dose of elbasvir 50 mg or grazoprevir 200 mg, and raltegravir with either elbasvir or grazoprevir. In the dolutegravir trial, participants received a single dose of dolutegravir 50 mg alone or co-administered with once-daily elbasvir 50 mg and grazoprevir 200 mg., Results: The raltegravir AUC0-∞ geometric mean ratio (GMR) (90% CI) was 1.02 (0.81-1.27) with elbasvir and 1.43 (0.89-2.30) with grazoprevir. Dolutegravir AUC0-∞ GMR (90% CI) was 1.16 (1.00-1.34) with elbasvir and grazoprevir. The elbasvir AUC0-∞ GMR (90% CI) was 0.81 (0.57-1.17) with raltegravir and 0.98 (0.93-1.04) with dolutegravir. The grazoprevir AUC0-24 GMR (90% CI) was 0.89 (0.72-1.09) with raltegravir and 0.81 (0.67-0.97) with dolutegravir., Conclusions: Elbasvir or grazoprevir co-administered with raltegravir or dolutegravir resulted in no clinically meaningful drug-drug interactions and was generally well tolerated. These results support the assertion that no dose adjustments for elbasvir, grazoprevir, raltegravir or dolutegravir are needed for co-administration in HCV/HIV-coinfected people., (© The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Human immunodeficiency virus (HIV)-associated neurocognitive disorders can persist in many patients despite achieving viral suppression while on antiretroviral therapy (ART). Neurocognitive function over 48 weeks was evaluated using a Cogstate test battery assessing psychomotor function, attention, learning, and working memory in 293 HIV-1-infected, ART-experienced, and virologically suppressed adults. The ASSURE study randomized participants 1:2 to remain on tenofovir/emtricitabine (TDF/FTC) and ritonavir-boosted atazanavir (ATV/r) or simplify to abacavir/lamivudine + atazanavir (ABC/3TC + ATV). Neurocognitive z-scores were computed using demographically adjusted normative data and were classified as "impaired" (defined as either a z-score ≤ - 2 or having 2 or more standardized individual test z-scores ≤ - 1); while higher scores (equaling better performance) were classified as "normal". By z-scores, 54.7% of participants had impaired neurocognition at baseline and 50.2% at week 48. There were no significant differences (p < 0.05) in the baseline-adjusted performance between treatment groups for any individual test or by z-score. Specific demographic and medical risk factors were evaluated by univariate analysis for impact on neurocognitive performance. Factors with p < 0.10 were evaluated by backwards regression analysis to identify neurocognition-correlated factors after accounting for treatment, assessment, and baseline. Four risk factors at baseline for impaired neurocognition were initially identified: lower CD4 nadir lymphocyte counts, higher Framingham risk scores, and interleukin-6 levels, and a history of psychiatric disorder not otherwise specified, however none were found to moderate the effect of treatment on neurocognition. In this aviremic, treatment-experienced population, baseline-adjusted neurocognitive function remained stable and equivalent over 48 weeks with both TDF/FTC + ATV/r-treated and in the ART-simplified ABC/3TC + ATV treatment groups.

Clinical apprenticeships, also called clinical experiences, are integral to most allied health (AH) student professional education. Clinical experiences begin the process of enculturating students into a healthcare profession where higher cognitive mastery of learned skills is supported through social interaction and scaffolding with an AH professional. In AH programs, clinical experiences for students are a necessity for programmatic accreditation; however, clinical sites have developed a range of requirements for students, which lead to a myriad of issues. These requirements may include drug screens, criminal background checks, and HIPAA training prior to a student beginning their clinical experience. Because of differing interpretation of policy, there is variability of requirements imposed on students before beginning these clinical experiences. This variability can create a financial burden on the student, who likely pays out-of-pocket for criminal background checks, vaccines, or drug screens. It also creates an administrative burden for clinical coordinators, who must know what each of the hundreds of clinical sites require, and they must follow up with each site to determine if these requirements have changed. Some strategies exist that may help clinical coordinators to manage clinical site requirements for student placement.

Pre-existing HIV drug resistance can jeopardize first-line antiretroviral therapy (ART) success. Changes in the prevalence of drug resistance-associated mutations (DRMs) were analyzed from HIV-infected, ART-naive, U.S. individuals seeking ART treatment from 2000 to 2009. HIV DRM data from 3,829 ART-naive subjects were analyzed by year of sample collection using International Antiviral Society-United States (IAS-USA) and World Health Organization (WHO) "surveillance" DRM definitions; minor IAS-USA-defined DRMs were excluded. IAS-USA DRM prevalence between 2000 and 2009 was 14%, beginning with 8% in 2000 and 13% in 2009. The greatest incidence was observed in 2007 (17%). Overall, IAS-USA-defined non-nucleoside reverse transcriptase inhibitor (NNRTI) DRMs were 9.5%; nucleoside reverse transcriptase inhibitor (NRTI): 4%, and major protease inhibitor (PI): 3%. The most frequently detected IAS-USA-defined DRMs by class were NNRTI: K103N/S (4%), NRTI: M41L (1.5%), and PI: L90M (1%). Overall, WHO-defined DRM prevalence was 13% (5% in 2000; 13% in 2009). By class, NNRTI prevalence was 6%, NRTI: 6%, and PI: 3.2%. The most frequent WHO-defined DRMs were NRTI: codon T215 (3.0%), NNRTI: K103N/S (4%), and PI: L90 (1%). WHO-defined NNRTI DRMs declined significantly (p = .0412) from 2007 to 2009. The overall prevalence of HIV-1 containing major IAS-USA or WHO-defined DRMs to ≥2 or ≥3 classes was 2% and <1%, respectively. The prevalence of HIV-1 with WHO-defined dual- or triple-class resistance significantly declined (p = .0461) from 2008 (4%) to 2009 (<1%). In this U.S. cohort, the prevalence of HIV-1 DRMs increased from 2000 onward, peaked between 2005 and 2007, and then declined between 2008 and 2009; the detection of WHO-defined dual- or triple-class DRM similarly decreased from 2008 to 2009.

Introduction: Doravirine, a non-nucleoside reverse-transcriptase inhibitor in development for the treatment of patients with human immunodeficiency virus-1 infection, has potential to be used concomitantly in antiretroviral therapy with dolutegravir, an integrase strand transfer inhibitor. The pharmacokinetic interactions between these drugs were therefore assessed., Methods: Oral formulations of doravirine and dolutegravir were dosed both individually and concomitantly once daily in healthy adults. Twelve subjects (six were male), 23-42 years of age, were enrolled and 11 completed this phase I, open-label, three-period, fixed-sequence study per protocol; one subject was discontinued for a positive cotinine test at admission to period 2. In period 1, dolutegravir 50 mg was administered for 7 days. After a 7-day washout, doravirine 200 mg was dosed for 7 days in period 2, followed (without washout) by both doravirine and dolutegravir simultaneously for 7 days in period 3. Plasma samples were taken to determine dolutegravir and doravirine concentrations., Results: The steady-state concentration 24 h post-dose (C 24 ) of dolutegravir was not substantially altered by co-administration of doravirine multiple doses; area under the plasma concentration-time curve from dosing to 24 h post-dose (AUC 0-24 ), maximum concentration (C max ), and C 24 geometric mean ratios were 1.36, 1.43, and 1.27, respectively. The pharmacokinetics of doravirine was not affected by multiple doses of dolutegravir (geometric mean ratios: 1.00, 0.98, and 1.06 for AUC 0-24 , C 24 , and C max , respectively). Both drugs were generally well tolerated., Conclusion: The results of this study demonstrate that concomitant administration of doravirine and dolutegravir in healthy subjects causes no clinically significant alteration in the pharmacokinetic and safety profiles of the two drugs, thereby supporting further evaluation of co-administration of these agents for human immunodeficiency virus-1 treatment.

Background: The presence of the HLA-B*57:01 allele in HIV-infected subjects is associated with a higher risk of abacavir-associated hypersensitivity reaction (ABC HSR). HLA-B*57:01 allele prevalence varies in different populations, but HLA-B*57:01 testing with immunological confirmation has had a negative predictive value for ABC HSR between 97 and 100%., Methods: In the ASSURE study (EPZ113734), the HLA-B*57:01 prevalence in virologically suppressed, antiretroviral treatment-experienced, HIV-infected subjects from the United States, including Puerto Rico, was assessed., Results: Three hundred eighty-five subjects were screened; 13 were HLA-B*57:01 positive and 372 were negative. Only HLA-B*57:01-negative, abacavir-naive subjects were eligible to enroll into the ASSURE trial. Eleven of the 13 subjects who possessed the HLA-B*57:01 allele were white, the other 2 were African-American. There was no geographic clustering of HLA-B*57:01-positive subjects, and the incidence correlated roughly with those states with the greatest numbers of subjects screened. Similarly, there was no statistically significant correlation between subjects who possessed or lacked the allele and age, gender, ethnicity or CD4+ T-cell numbers. The incidence of ABC HSR following abacavir initiation was also evaluated. Only 1 of 199 HLA-B*57:01-negative subjects (an African-American male) randomized to receive abacavir-containing treatment developed symptoms consistent with suspected ABC HSR; ABC HSR was not immunologically confirmed., Conclusions: These findings confirm the utility of HLA-B*57:01 allele testing to reduce the frequency of ABC HSR. The prevalence of HLA-B*57:01 positivity was higher in white than in African-American subjects. In HLA-B*57:01-negative subjects, suspected ABC HSR is very rare, but should lead to discontinuation of abacavir when ABC HSR cannot be definitively excluded from the differential diagnosis., Trial Registration: The ASSURE (EPZ113734) study was registered on ClinicalTrials.gov registration on April 8th 2010 and the registration number is NCT01102972.

Background: Daclatasvir (DCV) is an NS5A replication complex inhibitor recently approved for chronic hepatitis C virus treatment., Methods: To assess drug interactions between the HIV integrase strand transfer inhibitor dolutegravir (DTG) and DCV, subjects were randomized into 1 of 2 sequences in an open-label, 3-period, crossover study. Subjects received either DTG 50 mg once daily or DCV 60 mg once daily for 5 days in periods 1 and 2 and DTG 50 mg plus DCV 60 mg once daily for 5 days in period 3, with no washout between periods 2 and 3. Between periods 1 and 2, there was a washout period of at least 7 days., Results: The geometric least-squares mean ratios (90 % confidence intervals) of DCV area under the concentration-time curve over a dosing interval (AUC0-τ), maximum observed concentration (Cmax), and concentration at the end of the dosing interval (Cτ) were 0.978 (0.831-1.15), 1.03 (0.843-1.25), and 1.06 (0.876-1.29), respectively, when DCV was administered with DTG compared with DCV alone. Compared with DTG alone, coadministration of DTG with DCV increased DTG AUC0-τ, Cmax, and Cτ by approximately 33, 29, and 45 %, respectively., Conclusions: DCV plasma exposure was not meaningfully affected by DTG. Coadministration of DTG with DCV resulted in slight increases in DTG AUC0-τ, Cmax, and Cτ. Accumulated safety and tolerability data in humans receiving DTG to date suggests this effect is not considered clinically significant. DTG and DCV can be coadministered without dose adjustment., Trial Registration: Registered on March 6, 2014 with ClinicalTrials.gov; registration number: NCT02082808 and as Study ID: 201102 on the ViiV Clinical Study Registry.

Postsecondary education institutions have enjoyed increased access to student populations with the advent of online programs. Diploma mills have also been able to proliferate in this newly realized and ever expanding academic market. In response, the US Department of Education implemented new regulations in 2010 that require institutions to adhere to state authorization requirements to continue eligibility to receive Title IV funding. The regulations were challenged in federal court and the regulations were rescinded, due to a failure to properly vet the regulations. The Department of Education has drafted and vetted a new set of regulations that have yet to be implemented. State authorization has left institutions scrambling to find a pragmatic solution to conform to the regulations, which has led to the creation of the State Authorization Reciprocity Agreements. These agreements permit states to acknowledge the accreditation merit of institutions from other states and satisfy federal requirements. It will likely be several years before the full effect of state authorization and online education will be realized.

Treatment-emergent mutations and drug resistance were analyzed in virus from HIV-infected children meeting virologic failure (VF) criteria over 48 weeks following treatment with unboosted fosamprenavir or fosamprenavir/ritonavir-containing regimens in studies APV20002 and APV29005. Both antiretroviral therapy (ART)-naïve and ART-experienced patients were enrolled. Patients met VF criteria by either failing to suppress HIV-RNA to <400 copies/mL through week 24 or after confirmed viral rebound (≥400 copies/mL) anytime through week 48. Viral isolates were analyzed for treatment-emergent mutations or reduced drug susceptibility. Through week 48, 25/109 (23%) of APV29005 and 9/54 (17%) APV20002 study patients met VF. VF was more common in ART-experienced patients (68% and 78%, respectively). Major or minor treatment-emergent mutations were detected at VF in virus from 3 patients receiving unboosted fosamprenavir-containing regimens and in virus from 10 patients receiving fosamprenavir/ritonavir-containing regimens across the two studies. Major protease inhibitor mutations and the reverse transcriptase mutation M184V were detected at VF in virus from 4 and 5 patients, respectively, across both studies. Reduced drug susceptibility to any drug emerged in virus from 9 patients at VF, although reduced fosamprenavir susceptibility emerged in virus from only 4 patients (2 ART-naïve and 2 ART-experienced). No cross-resistance to the protease inhibitor darunavir was observed. In conclusion, given the high proportion of ART-experienced children (71%) in these two studies, the overall incidence of children meeting VF criteria through 48 weeks was relatively low (21%) and development of fosamprenavir reduced drug susceptibility at VF was uncommon, further supporting the use of fosamprenavir-containing ART regimens in HIV-infected children.

Objective: Simplification of antiretroviral therapy in patients with suppressed viremia may minimize long-term adverse effects. The study's primary objective was to determine whether abacavir/lamivudine + atazanavir (ABC/3TC+ATV) was virologically non-inferior to tenofovir/emtricitabine + atazanavir/ritonavir (TDF/FTC+ATV/r) over 24 weeks in a population of virologically suppressed, HIV-1 infected patients., Design: This open-label, multicenter, non-inferiority study enrolled antiretroviral experienced, HIV-infected adults currently receiving a regimen of TDF/FTC+ATV/r for ≥ 6 months with no history of virologic failure and whose HIV-1 RNA had been ≤ 75 copies/mL on 2 consecutive measurements including screening. Patients were randomized 1 ∶ 2 to continue current treatment or simplify to ABC/3TC+ATV., Methods: The primary endpoint was the proportion of patients with HIV-RNA<50 copies/mL at Week 24 by the Time to Loss of Virologic Response (TLOVR) algorithm. Secondary endpoints included alternative measures of efficacy, adverse events (AEs), and fasting lipids. Exploratory endpoints included inflammatory, coagulation, bone, and renal biomarkers., Results: After 24 weeks, ABC/3TC+ATV (n = 199) was non-inferior to TDF/FTC+ATV/r (n = 97) by both the primary analysis (87% in both groups) and all secondary efficacy analyses. Rates of grade 2-4 AEs were similar between the two groups (40% vs 37%, respectively), but an excess of hyperbilirubinemia made the rate of grade 3-4 laboratory abnormalities higher in the TDF/FTC+ATV/r group (30%) compared with the ABC/3TC+ATV group (13%). Lipid levels were stable except for HDL cholesterol, which increased significantly in the ABC/3TC+ATV group. Bone and renal biomarkers improved significantly between baseline and Week 24 in patients taking ABC/3TC+ATV, and the difference between groups was significant at Week 24. No significant changes occurred in any inflammatory or coagulation biomarker within or between treatment groups., Conclusions: After 24 weeks, simplification to ABC/3TC+ATV from TDF/FTC+ATV/r maintained viral suppression was well-tolerated, and led to improvements in bone and renal biomarkers and HDL cholesterol., Trial Registration: ClinicalTrials.gov NCT01102972 GlaxoSmithKline Clinical Study Register #113734.

Factors that contribute to the transmission of human immunodeficiency virus type 1 (HIV-1), especially drug-resistant HIV-1 variants remain a significant public health concern. In-depth phylogenetic analyses of viral sequences obtained in the screening phase from antiretroviral-naïve HIV-infected patients seeking enrollment in EPZ108859, a large open-label study in the USA, Canada and Puerto Rico (ClinicalTrials.gov NCT00440947) were examined for insights into the roles of drug resistance and epidemiological factors that could impact disease dissemination. Viral transmission clusters (VTCs) were initially predicted from a phylogenetic analysis of population level HIV-1 pol sequences obtained from 690 antiretroviral-naïve subjects in 2007. Subsequently, the predicted VTCs were tested for robustness by ultra deep sequencing (UDS) using pyrosequencing technology and further phylogenetic analyses. The demographic characteristics of clustered and non-clustered subjects were then compared. From 690 subjects, 69 were assigned to 1 of 30 VTCs, each containing 2 to 5 subjects. Race composition of VTCs were significantly more likely to be white (72% vs. 60%; p = 0.04). VTCs had fewer reverse transcriptase and major PI resistance mutations (9% vs. 24%; p = 0.002) than non-clustered sequences. Both men-who-have-sex-with-men (MSM) (68% vs. 48%; p = 0.001) and Canadians (29% vs. 14%; p = 0.03) were significantly more frequent in VTCs than non-clustered sequences. Of the 515 subjects who initiated antiretroviral therapy, 33 experienced confirmed virologic failure through 144 weeks while only 3/33 were from VTCs. Fewer VTCs subjects (as compared to those with non-clustering virus) had HIV-1 with resistance-associated mutations or experienced virologic failure during the course of the study. Our analysis shows specific geographical and drug resistance trends that correlate well with transmission clusters defined by HIV sequences of similarity. Furthermore, our study demonstrates the utility of molecular and epidemiological analysis of VTCs for identifying population-specific risks associated with HIV-1 transmission and developing effective local healthcare strategies.

Background: Pharmacokinetics, safety and antiviral activity of fosamprenavir (FPV) with ritonavir (RTV) twice daily were evaluated in HIV-1-infected infants and children 4 weeks to <2 years over 48 weeks., Methods: Results from intensive pharmacokinetic sampling of subjects enrolled in single dose visits was used to determine individualized dosing for the first 6-10 subjects in each of 2 cohorts (4 weeks to <6 months, 6 months to <2 years); steady state pharmacokinetic data were then used to select the dosage regimen for the remaining subjects recruited to the cohort. Intensive pharmacokinetic sampling was performed at week 2 or 8; predose samples were collected every 4-12 weeks thereafter. Safety and plasma HIV-1 RNA were monitored every 4-12 weeks., Results: Fifty-nine subjects received study medication. FPV 45 mg/kg boosted with RTV 7 to 10 mg/kg BID achieved average plasma amprenavir area under curve(0-τ) values 26% to 28% lower and Cmax similar to historical adult data for FPV/RTV 700/100 mg BID; amprenavir Cτ values were lower in the subjects <6 months of age. At week 48, 35 of 54 (65%) subjects had achieved plasma HIV-1 RNA <400 copies/mL and 33 of 54 (61%) had plasma HIV-1 RNA values <50 copies/mL. The most common adverse events were diarrhea, upper respiratory tract infection, gastroenteritis and otitis media., Conclusions: Final FPV/RTV dosing regimens achieved plasma amprenavir exposures comparable with those from regimens approved in adults, with the exception of trough exposures in the <6-month-old infants. The FPV/RTV regimens led to viral suppression in 61% of patients and were generally well tolerated.

Propensity for developing coronary heart disease (CHD) is linked with Framingham-defined cardiovascular risk factors and elevated inflammatory biomarkers. Cardiovascular risk and inflammatory biomarkers were evaluated in ARIES, a Phase IIIb/IV clinical trial in which 515 antiretroviral-naive HIV-infected subjects initially received abacavir/lamivudine + atazanavir/ritonavir for 36 weeks. Subjects who were virologically suppressed by week 30 were randomized 1:1 at week 36 to either maintain or discontinue ritonavir for an additional 108 weeks. Framingham 10-year CHD risk scores (FRS) and risk category of <6% or ≥6%, lipoprotein-associated phospholipase A(2) (Lp-PLA(2)), interleukin-6 (IL-6), and high-sensitivity C-reactive protein (hsCRP) were assessed at baseline, week 84, and week 144. Biomarkers were stratified by FRS category. When ritonavir-boosted/nonboosted treatment groups were combined, median hsCRP did not change significantly between baseline (1.6 mg/liter) and week 144 (1.4 mg/liter) in subjects with FRS <6% (p=0.535) or with FRS ≥6% (1.9 mg/liter vs. 2.0 mg/liter, respectively; p=0.102). Median IL-6 was similar for subjects with FRS <6% (p=0.267) at baseline (1.6 pg/ml) and week 144 (1.4 pg/ml) and for FRS ≥6% (2.0 pg/ml vs. 2.2 pg/ml, respectively; p=0.099). Median Lp-PLA(2) decreased significantly (p<0.001) between baseline (197 nmol/min/ml) and week 144 (168 nmol/min/ml) in subjects with FRS <6% and with FRS ≥6% (238 nmol/min/ml vs. 175 nmol/min/ml, respectively; p<0.001). In conclusion, in antiretroviral-naive subjects treated with abacavir-based therapy for 144 weeks, median inflammatory biomarker levels for hsCRP and IL-6 generally remained stable with no significant difference between baseline and week 144 for subjects with either FRS <6% or FRS ≥6%. Lp-PLA(2) median values declined significantly over 144 weeks for subjects in either FRS stratum.

Background: The open-label study ARIES (ClinicalTrials.gov NCT00440947) utilized a ritonavir (/r)-boosted protease inhibitor treatment simplification strategy. Antiretroviral-naïve subjects received abacavir/lamivudine (ABC/3TC) + atazanavir/ ritonavir (ATV/r) from baseline through randomization at week 36, then maintained or discontinued ritonavir for an additional 108 weeks. Non-inferiority of the unboosted regimen was demonstrated at week 84. In this optional extension phase, virologic suppression and adverse events were assessed through week 144., Methods: Patients were randomized at week 36 if they had confirmed HIV RNA <50 copies/mL by week 30 and no previous virologic failure (VF; defined as failure to achieve HIV RNA <400 copies/mL or confirmed rebound after achieving HIV RNA ≥400 copies/mL). Three hundred sixty-nine subjects who completed 84 weeks in ARIES participated in the extension phase and maintained their randomized regimen for an additional 60 weeks post randomization., Results: At week 144, 146/189 (77%) versus 132/180 (73%) subjects in the unboosted ATV and ATV/r groups, respectively, maintained HIV RNA <50 copies/mL. Post randomization (weeks 36-144), treatment-related grade 2-4 adverse events were more common in the ATV/r-treated (23%) compared to the ATV-treated (13%) group; the most frequently reported was increased serum bilirubin (6% of ATV-treated subjects vs 14 % of ATV/r-treated subjects). During the extension phase, 3% (11/369) of subjects met protocol-defined VF (5 ATV-treated and 6 ATV/ r-treated subjects); one ATV/r-treated subject had treatment-emergent major viral resistance-associated mutations. The median change in fasting triglycerides from baseline to week 144 was significantly different (P=.001) in the ATV-treated (-8.5 mg/dL) compared to the ATV/r-treated (28.5 mg/dL) groups., Conclusions: These long-term study results demonstrate that ATV in combination with ABC/3TC is a potent, well-tolerated regimen in patients who have achieved initial suppression on a ritonavir-boosted regimen.

Detection of drug resistance is critical for determining antiretroviral treatment options. Ultradeep pyrosequencing (UDPS; 454 Life Sciences) is capable of detecting virus variant subpopulations with much greater sensitivity than population sequencing, which typically has a detection limit around 20%. UDPS of the HIV-1 reverse transcriptase (RT) (amino acids 56-120) was performed to detect the key mutations K65R and L74V associated with tenofovir and abacavir use. Plasma specimens from subjects with persistent rebound viremia following suppression on tenofovir (n = 8) or abacavir (n = 9)-based therapy were studied. Samples from a subject treated with zidovudine/lamivudine/efavirenz with a similar loss of virologic response served as a control. HIV-1 plasma RNA was ≥3.68 log(10) copies/ml at all time points sequenced. The median number of UDPS sequences analyzed/time point was 33,246. Among the eight tenofovir-treated subjects, three showed high-frequency (>20%) RT K65R at the time of failure, whereas one showed low-frequency (<20%) L74V; no low-frequency K65R was detected in these subjects. Among the nine abacavir-treated subjects, three showed low-frequency K65R; no L74V was detected in these patients. No K65R or L74V was detected in the samples from the control subject. At failure, other RT mutations were detected, including low-frequency NNRTI-resistant species detected at ≥1 time point in nine subjects; the key NNRTI mutation K103N, however, was always observed at >20% frequency. Although UDPS is useful in the detection of low-frequency subpopulations with transmitted resistance in antiviral-naive patients, it may have less utility in treatment-experienced patients with persistent viremia on therapy.

Background: Treatment simplification strategies involving induction with a ritonavir (RTV)-boosted (/r) protease inhibitor regimen followed by simplification (without RTV) are appealing because they may offer sustained virologic suppression while minimizing potential long-term adverse effects associated with RTV., Methods: This open-label, randomized, noninferiority study enrolled 515 antiretroviral therapy-naive patients to receive abacavir/lamivudine plus atazanavir/RTV (ATV/r) followed by randomization at week 36 (N = 419) to maintain or discontinue RTV for an additional 48 weeks. Eligibility for randomization required confirmed HIV RNA level below 50 copies/ml and no virologic failure. Protocol-defined virologic failure after week 36 was confirmed rebound of HIV RNA level at least 400 copies/ml. The primary endpoint was the proportion of patients with HIV RNA level below 50 copies/ml at week 84 (time to loss of virologic response). This study is registered with ClinicalTrials.gov number NCT00440947., Results: At week 84, noninferiority of ATV to ATV/r (95% confidence interval around the treatment difference -1.75 to 12.48%) was demonstrated with 181 of 210 (86%) patients in the ATV group and 169 of 209 (81%) in the ATV/r group maintaining HIV RNA level below 50 copies/ml. During the randomized phase (weeks 36-84), 10 versus 14% of patients in the ATV and ATV/r arms, respectively, experienced a drug-related grades 2-4 adverse event with hyperbilirubinemia being the most frequently reported (4 versus 10%). The overall rate of protocol-defined virologic failure was 2%; no patient had virus that developed a major protease inhibitor mutation., Conclusion: ATV in combination with abacavir/lamivudine is a potent and well tolerated regimen in patients who have achieved initial suppression on an induction regimen and represents a viable treatment simplification strategy.

Population genotyping (PG) can underestimate resistance if resistance-containing low abundance variants go undetected. PG and clonal analysis (CA) results were compared in virologic failures (VFs) from a 48-week clinical trial that evaluated once-daily fosamprenavir/ritonavir (FPV/r) 1400 mg/100 mg or atazanavir/ritonavir (ATV/r) 300 mg/100 mg, each combined with tenofovir/emtricitabine, in antiretroviral-naive patients. VF was defined as confirmed HIV-1 RNA > or =400 copies/ml at > or =24 weeks or viral rebound >400 copies/ml any time following viral suppression. All patients had baseline PG. One hundred and six patients enrolled (53/arm). Baseline resistance mutations were more prevalent in patients receiving FPV/r (10/53) than ATV/r (3/53). Seven patients (7%) were VFs-four on FPV/r and three on ATV/r. In the four FPV/r-treated VFs, baseline HIV TAMs combinations and/or PI mutations were detected in one by PG at VF (RT: L210W + T215C; PR: M46I + L76V) and three others by CA alone (RT: L210W + T215Y; RT: M41L; RT: K65R + K70R; PR: I47V); all four had study drug-associated mutations (CA detecting more HIV-1 resistance mutations than PG). In the three ATV/r VFs, no baseline drug-associated mutations were detected by PG; for one patient CA detected RT: K65R; PR: I84V. Phylogenetic analysis revealed tight clustering for FPV/r-treated VFs with highly related clones, whereas HIV-1 from ATV/r-treated VFs had no outgrowth from baseline of low abundance resistance-containing variants. In conclusion, low-abundance HIV resistance-containing variants were detected in baseline samples from patients with VF. The archived viruses that reemerged under selection pressure and acquired additional mutations were found primarily in patients in the FPV/r arm. Despite this and a baseline resistance imbalance between the two arms, FPV/r and ATV/r provided similar virologic suppression through 48 weeks; however, these findings highlight the necessity for the development of quick and inexpensive methods for detection of minority species to better guide therapy selection.

Purpose: The ARIES study assessed safety and efficacy of an induction regimen with atazanavir/ritonavir (ATV/RTV) + abacavir/lamivudine (ABC/3TC) followed by simplification to ATV + ABC/3TC in antiretroviral-naïve patients., Methods: This report includes a noncomparative analysis of all patients in the induction phase of the ARIES study through 36 weeks (clinicaltrials.gov: NCT00440947). This open-label study included 515 antiretroviral-naïve,HLA-B*5701-negative patients receiving a regimen of ATV 300 mg, RTV 100 mg, and ABC/3TC 600 mg/300 mg once daily for 36 weeks; eligible patients were then randomized to continue the induction regimen or simplify to ATV 400 mg plus ABC/3TC 600 mg/300 mg once daily., Results: Eighty-six percent (442/515) of patients completed 36 weeks on study; 80% (410/515) achieved HIV RNA <50 copies/mL (84% and 76% of patients with baseline HIV RNA of < and >or=100,000 copies/mL achieved this endpoint). Virologic failure (VF) was uncommon (3%); treatment-emergent major protease inhibitor and nucleoside reverse transcriptase inhibitor mutations were detected in 0/15 and 4/15 patients, respectively. Median CD4+ cell increase was 171 (range, -176 to 718) cells/mm(3). Hyperbilirubinemia (13%), diarrhea (4%), nausea (2%), and rash (2%) were the most frequent drug-related Grade 2-4 adverse events. Few adverse events (3%) led to study discontinuation., Conclusions: Induction with ATV/RTV + ABC/3TC once daily provides an efficacious and well-tolerated regimen for the initial treatment of HIV.

Background: HIV clonal genotypic analysis (CG) was used to investigate whether a more sensitive analysis method would detect additional low-abundance mutations compared with population genotyping (PG) in antiretroviral-naive patients who experienced virological failure (VF) during treatment with abacavir/lamivudine/zidovudine and tenofovir., Methods: HIV was analysed by PG and CG (771 baseline and 657 VF clones) from subjects with VF (confirmed HIV RNA > or = 400 copies/mL at 24-48 weeks)., Results: Fourteen of 123 subjects (11%) met VF criteria; their median baseline HIV RNA was 5.4 log(10) copies/mL, and 4.0 log(10) copies/mL at VF. By baseline PG, 2/14 had HIV-1 with nucleoside reverse transcriptase inhibitor (NRTI) or non-NRTI mutations. By baseline CG, 9/14 had HIV-1 with NNRTI and/or NRTI mutations; 7/9 had study drug-associated mutations. By PG at VF, 10/14 had selected for resistance mutations [2, K65R; 1, M184V; and 7, thymidine analogue mutations (TAMs) +/- M184V]. By CG at VF, for subjects with TAMs, T215F was more commonly detected (5/14 samples) than T215Y (2/14). For one subject who selected K65R at VF, both K65R-containing clones and TAM-containing clones (both T215A and T215F) were observed independently but not conjunctively in the same clone in a post-VF sample., Conclusions: The majority of subjects with VF had major and minor mutations detected at VF; CG detected additional low-abundance variants at baseline and VF that could have influenced mutation selection pathways. Both PG and CG data suggest TAMs, not K65R selection, are the preferred resistance route, biased towards 215F selection. No HIV clone contained both K65R and T215F/Y mutations, suggesting in vivo antagonism between the two mutations. The once-daily zidovudine usage and high baseline viraemia may also have contributed to rapid selection of HIV with multiple mutations in VFs.

Objectives: to examine the impact of downward social comparison and the "known partner is a safe partner" heuristic on college students' sexual decisions., Participants: One hundred-eighty heterosexual or bisexual undergraduate college students., Methods: participants read dating vignettes that varied on perspective and familiarity and then rated the likelihood the couple would engage in sexual intercourse and use a condom., Results: there were no differences in rated likelihood based on familiarity, suggesting that the students did not view the 2 partner types as significantly different. Students rated the likelihood of sexual intercourse lower and condom use higher when the vignette was presented from the second person perspective., Conclusions: the students' use of downward social comparison is consistent with the "better than average effect," suggesting that the students perceive their own behavior as safe. The implication is that safer sex messages might be most effective if they focus on what students will gain by practicing safer sex behaviors, not just avoidance of a risk behavior.

The long-term efficacy of once-daily (qd) fosamprenavir (FPV) 1400 mg boosted by ritonavir 100 mg (FPV/r100) has not been evaluated previously. A 96-week open-label, randomized, multicenter study compared the efficacy/safety of FPV/r100 with FPV 1400 mg boosted by ritonavir 200 mg qd (FPV/r200), plus abacavir/lamivudine 600 mg/300 mg qd, in antiretroviral-naive, HIV-infected patients with viral load (VL)> or =1000 copies/ml. Primary endpoints were proportion of patients achieving VL <400 copies/ml or discontinuing for drug-related reasons. In the intent-to-treat:exposed (ITT-E) population, missing = failure (M = F), and observed approaches were used to assess between-arm differences in VL responses by Cochran-Mantel-Haenszel test and CD4(+) count by Wilcoxon rank-sum test. One hundred and fifteen (115) patients enrolled, with 58 on FPV/r100 (median VL 4.7 log(10) copies/ml; CD4(+) count 259 cells/mm(3)) and 57 on FPV/r200 (median VL 4.9 log(10) copies/ml; CD4(+) count 179 cells/mm(3)). Fewer FPV/r100-treated patients discontinued treatment prematurely (12 vs. 24) and experienced virologic failure (5 vs. 8, none developing major protease inhibitor resistance mutations). At week 96, more FPV/r100-treated patients had VL <400 copies/ml [ITT-E,M = F: 78% (45/58) vs. 53% (30/57), p = 0.006; observed: 98% (45/46) vs. 94% (30/32)] and VL<50 copies/ml [ITT-E,M = F: 66% (38/58) vs. 53% (30/57); observed: 83% (38/46) vs. 94% (30/32)]. The FPV/r100 and FPV/r200 arms were similar at week 96 regarding median change from baseline in CD4(+) count (+265 vs. +260 cells/mm(3)) and total cholesterol (+33 vs. +35 mg/dl), and in total-cholesterol:HDL-cholesterol ratio (4.0 vs. 4.1) and type/frequency of treatment-related grade 2-4 adverse events, although FPV/r100 was associated with a lower elevation in triglycerides (+27 vs. +48 mg/dl). In conclusion, through 96 weeks, FPV/r100 was more effective and prompted less elevation in triglycerides than FPV/r200.

Thymidine-sparing triple-nucleoside regimens have exhibited poor virologic response despite apparent phenotypic susceptibility to 2 of 3 regimen components at early time points. Phenotypic resistance masking by wild-type virus may explain this discrepancy.Consistent with this notion were (1) the presence of low level nucleoside reverse-transcriptase inhibitor-resistant human immunodeficiency virus in subjects receiving failing first-line regimens consisting of tenofovir (TDF), abacavir (ABC), and lamivudine (3TC); (2) lower fold resistance associated with mixtures versus mutants in a clinical-isolate database; and (3) dose dependent changes in susceptibility to ABC, 3TC, TDF, and didanosine on titration of K65R and/or M184V with wild-type virus. These findings underscore the limitations of stand-alone phenotypic susceptibility measures and emphasize the importance of complementary and/or more sensitive techniques.

Background: The purpose of this study was to determine if bulb syringe irrigators are a potential source for bacterial contamination in patients with chronic rhinosinusitis., Methods: Standard 3-oz bulb syringe irrigators (n = 24) were each flushed with the following solutions twice daily: A (n = 8), sterile isotonic saline; B (n = 8), prepared hypertonic saline (3 tsp table salt/L of sterile water); and C (n = 8), prepared baking soda/saline (1 tsp table salt + 1 tsp baking soda/L of commercial sterile water). Syringes were stored on a residential bathroom counter, and two from each group were harvested for culture weekly for 4 weeks., Results: There was no growth from syringes irrigated with any of the three solutions after the first 7 days of irrigation. After the entire 4-week study period, potential pathogens were recovered from 6/8 (75%) bulbs from group A, 0/8 bulbs from group B, and 1/8 bulbs (12.5%) from group C. All positive cultures revealed growth by 1-2 days postinoculation (p = 0.002). The organism recovered from syringes in group A was Pseudomonas fluorescens in all six specimens. The one positive culture in group C represented a single colony of Gram-positive cocci., Conclusion: Under realistic conditions, bulb syringes are susceptible to contamination with potential bacterial pathogens, particularly when using unbuffered isotonic saline.

Background: Once-daily (QD) ritonavir 100 mg-boosted fosamprenavir 1400 mg (FPV/r100) or atazanavir 300 mg (ATV/r100), plus tenofovir/emtricitabine (TDF/FTC) 300 mg/200 mg, have not been compared as initial antiretroviral treatment. To address this data gap, we conducted an open-label, multicenter 48-week study (ALERT) in 106 antiretroviral-naïve, HIV-infected patients (median HIV-1 RNA 4.9 log10 copies/mL; CD4+ count 191 cells/mm3) randomly assigned to the FPV/r100 or ATV/r100 regimens., Results: At baseline, the FPV/r100 or ATV/r100 arms were well-matched for HIV-1 RNA (median, 4.9 log10 copies/mL [both]), CD4+ count (mean, 176 vs 205 cells/mm3). At week 48, intent-to-treat: missing/discontinuation = failure analysis showed similar responses to FPV/r100 and ATV/r100 (HIV-1 RNA < 50 copies/mL: 75% (40/53) vs 83% (44/53), p = 0.34 [Cochran-Mantel-Haenszel test]); mean CD4+ count change-from-baseline: +170 vs +183 cells/mm3, p = 0.398 [Wilcoxon rank sum test]). Fasting total/LDL/HDL-cholesterol changes-from-baseline were also similar, although week 48 median fasting triglycerides were higher with FPV/r100 (150 vs 131 mg/dL). FPV/r100-treated patients experienced fewer treatment-related grade 2-4 adverse events (15% vs 57%), with differences driven by ATV-related hyperbilirubinemia. Three patients discontinued TDF/FTC because their GFR decreased to <50 mL/min., Conclusion: The all-QD regimens of FPV/r100 and ATV/r100, plus TDF/FTC, provided similar virologic, CD4+ response, and fasting total/LDL/HDL-cholesterol changes through 48 weeks. Fewer FPV/r100-treated patients experienced treatment-related grade 2-4 adverse events.

In vitro, the reverse transcriptase mutation K65R can simultaneously reduce drug susceptibility, replicative capacity and restrict HIV-1 replication. Here, we assessed the effect of tenofovir discontinuation for a patient receiving antiretroviral therapy whose HIV-1 had a dominant K65R/M184V genotype. Although limited by the single-case nature, the data support a hypothesis that there is no HIV viral RNA or CD4+ T-cell count benefit of taking tenofovir for experienced patients with genotypic evidence of K65R/M184V.

Background: Axillary hyperhidrosis is a chronic condition characterized by excess axillary perspiration. This results in considerable patient morbidity, with no consistently efficacious medical or surgical treatment method described in the literature., Methods: All cases of axillary hyperhidrosis over a 5-year period were reviewed retrospectively. Data were gathered by a chart review and telephone interview. Inclusion criteria included primary hyperhidrosis, failed conservative therapy, no prior surgical therapy, surgical management using a new arthroscopic shaver technique (R.L.B.-S.), and 6 months of postoperative follow-up. The technique used was consistent between surgeons. Sweating severity was assessed using a subjective numerical rating scale ranging from 1 to 10. Patient demographics, symptom history, results, and complications were analyzed., Results: Average follow-up for 50 patients meeting the inclusion criteria was 28 months. The subjective severity scale demonstrated severity of 9.8 of 10 preoperatively and 2.3 of 10 postoperatively. Three patients (6 percent) reported mild recurrence of symptoms (4.6 of 10), which was not severe enough to seek further treatment. The average follow-up of those patients was 18.5 months. An overall subjective satisfaction of 96 percent was found, with a treatment success rate of 94 percent. Complications were minimal and self-limiting. The average time away from employment was 3.9 days and the average surgical operating room time was 46 minutes., Conclusions: The authors' new arthroscopic shaver technique is efficacious, with no significant morbidity, a 96 percent satisfaction rate, a subjectively measured 75 percent reduction of sweat, and a recurrence rate of only 6 percent. For cases of primary hyperhidrosis affecting the axilla not amenable to conservative treatment, the authors recommend an arthroscopic shaver technique as the first-line treatment of choice.

The impact of drug resistance-associated mutations on subsequent antiretroviral therapy is an important consideration in managing treatment-experienced, HIV-1-infected patients. Lamivudine (3TC) and emtricitabine (FTC) are structurally related nucleoside reverse transcriptase inhibitors (NRTIs) approved for use in HIV-1-infected individuals. To evaluate whether susceptibility differences exist between lamivudine and emtricitabine, the phenotypic impact of common NRTI resistance-associated mutations was compared in HIV-1 from patient samples with paired FTC and 3TC susceptibility results. FTC phenotypic susceptibility was more greatly impacted than 3TC susceptibility in the presence of thymidine analogue mutations (TAMs), as the mean fold-change values were higher for FTC than for 3TC in groups of samples containing TAMs (P < 0.001 for 6 of 7 groups). For samples with K65R, L74I/V, or Q151M mutations, the phenotypic impact was similar, as the mean fold-change was not significantly different between drugs. Although the long-term clinical significance of these differences is unclear, they may suggest differential efficacy in some patients with prior NRTI experience, especially those with HIV harboring TAMs.

Superimposing serial radiographs is an easy method for assessing growth changes or treatment progress. Conventional films could be superimposed manually over a light box. The layering and variable-opacity features of digital imaging software can be used to superimpose digital images on your computer screen. Digital imaging software can be used to compare digital radiographs to identify growth patterns or treatment progress.

Objectives: Lipoatrophy is an important manifestation of the lipodystrophy syndrome and is particularly associated with stavudine exposure. Increased apoptosis has been suggested as a possible mechanism of lipoatrophy. We assessed the degree and reversibility of adipocyte apoptosis in patients with lipoatrophy before and 48 weeks after substituting abacavir or zidovudine for stavudine., Methods: Apoptotic adipocytes were identified using terminal transferase dUTP nick end labeling and quantified using video image analysis., Results: Fat biopsy specimens were obtained from patients before (n = 15) and 48 weeks after (n = 10) switching from stavudine and from 20 HIV-uninfected controls. More apoptotic cells were seen in fat samples from patients with lipoatrophy treated with stavudine than in specimens from controls (P < 0.0001). Forty-eight weeks after switching from stavudine to abacavir or zidovudine, there was a reduction in apoptotic cells per unit area (P = 0.01) and as a proportion of all adipocytes present (P = 0.02) in patient biopsy specimens. Levels of adipocyte apoptosis in the 48-week biopsy specimens were no longer significantly different from those seen in control biopsy specimens (P > 0.1)., Conclusions: Increased apoptosis is present in fat samples from patients with lipoatrophy treated with stavudine. This improves toward normal within 48 weeks of switching from stavudine to abacavir or zidovudine, suggesting a causative role for stavudine in this process.

Objective: To determine if stavudine (alpha4T)-associated mitochondrial toxicity could be reversed by substitution with another nucleoside reverse transcriptase inhibitor. As apoptosis and dysfunction of electron transport chain (ETC) activities may underlie mitochondrial toxicity, these parameters were also evaluated., Design: The 16 participants (on d4T for >3 years; with lipoatrophy and/or hyperlactatemia) substituted abacavir or zidovudine for stavudine in their antiretroviral regimen. Key parameters including dual-energy X-ray absorptiometry (DEXA) scans, fat apoptosis, mitochondrial DNA (mtDNA) content in peripheral blood mononuclear cells (PBMC), skeletal muscle and fat, as well as skeletal muscle mitochondrial ETC activities were evaluated at study entry and at 48 weeks after the substitution., Methods: Quantitative PCR was used to evaluate mtDNA levels and the presence of deletions/rearrangements; CLIA-validated methods for ETC activities; terminal deoxynucleotidyl transferase dUTP-digoxigenin nick-end labeling assays to evaluate adipocyte apoptosis; and DEXA scans to measure changes in body fat., Results: MtDNA was depleted at study entry in muscle, adipose tissue and PBMC but levels rebounded with respective mean increases of 141%, 146%, and 369% at week 48. Corresponding fat improvements were noted with DEXA increases of 21%, 11%, and 16% in arm, leg, and trunk, respectively. Quantitative adipocyte apoptosis were significantly increased at baseline (P < 0.01 versus HIV-negative controls), with a significant reduction at week 48 (P < 0.05 versus baseline). Mean values for seven mitochondrial enzyme activities assays at entry indicated substantial loss of function (48% to 85% of controls) with significant improvement of complex I activity by week 48., Conclusions: Substitution of stavudine with abacavir or zidovudine improves mitochondrial indices and fat apoptosis in the setting of lipoatrophy.

Background: Few data are available concerning the impact of antiretroviral resistance in response to antiviral therapy in children. We evaluated the development of antiretroviral genotypic resistance and clinical outcome in a subgroup of children involved in a prospective antiretroviral therapy trial (Pediatric AIDS Clinical Trials Group Protocol 152)., Design: We studied 26 matched case/control pairs. A case was defined as having clinical disease progression during the study period; controls did not have disease progression. Cases and controls were matched by age and CD4+ cell count at baseline. Matched pairs received treatment with zidovudine (9 pairs), didanosine (12 pairs) or combined therapy (5 pairs). Multiple codons of the reverse transcriptase coding region (41, 67, 70, 74, 151, 184, 210, 215 and 219) were analyzed. Patients were evaluated for CD4+ cell count, HIV-1 viral load and HIV-1 biologic phenotype at baseline and clinical endpoint., Results: The presence of mutations associated with resistance after nucleoside antiretroviral therapy (P = 0.039) and syncytium-inducing phenotype (P = 0.031), were significantly associated with increased risk of clinical disease progression. The mean difference in HIV-1 RNA levels between cases and their matched controls after nucleoside antiretroviral therapy was 0.77 log10 copies/ml higher for cases (P = 0.003). The median difference between cases and controls for CD4+ cell count after nucleoside antiretroviral therapy was 349 cells/mm3 lower for cases (P < 0.001)., Conclusions: In this small prospective study of HIV-infected children, mutations in the reverse transcriptase coding region, syncytium-inducing viral phenotype, higher HIV-1 RNA load and lower CD4+ cell count were significantly correlated with increased risk of HIV clinical disease progression.

A post hoc analysis of safety data from study protocol NZT40012 assessed the incidence of conditions defined by the Centers for Disease Control and Prevention in 86 zidovudine-naïve, antiretroviral-experienced patients with HIV-1 infection who responded poorly (plasma HIV-1 RNA > 1000 copies/mL) despite at least 4 months' treatment with stavudine-containing regimens. Peripheral neuropathy occurred in 21%; other conditions were seen less frequently (candidiasis [13%], herpes zoster [12%], diarrhea lasting > 1 month [9%], Pneumocystis carinii pneumonia [9%], and wasting syndrome [8%]). The incidence of peripheral neuropathy rose significantly with the number of drugs comprising treatment regimens (> or = 4 vs 1-3; P = .013) and tended to be higher in patients with longer exposure to stavudine (29% with > or = 24 months' exposure vs 13% with < 24 months). Because peripheral neuropathy was observed with such high frequency, vigilance for signs and symptoms of this condition appears warranted if stavudine-containing regimens are to be continued.

Objective: The authors examined brain activity associated with the internal monitoring of performance to test the hypothesis that error-related activity in the anterior cingulate cortex is impaired in patients with schizophrenia., Method: Seventeen patients with schizophrenia and 16 healthy comparison subjects underwent event-related functional magnetic resonance imaging during a continuous performance task; stimulus degradation was used to increase error rates., Results: Comparison subjects, but not schizophrenic patients, showed error-related activity in the anterior cingulate cortex, and this difference in brain activity was significantly different across the two groups. Patients also showed less slowing of reaction time after error commission., Conclusions: Lower error-related activity in the anterior cingulate cortex and less performance adjustment after error commission are consistent with the hypothesis that disturbances in anterior cingulate cortex function are related to a specific alteration in an evaluative component of executive functioning-the internal monitoring of performance.

This open-label, multicenter, single-arm clinical trial assessed the 48-week efficacy of a twice-daily triple nucleoside reverse-transcriptase inhibitor regimen containing a lamivudine (150 mg)-zidovudine (300 mg) combination tablet (COM) and abacavir (ABC; 300 mg) in 87 antiretroviral therapy-experienced, protease inhibitor-naive patients infected with human immunodeficiency virus type 1 (HIV-1). At baseline, the median plasma HIV-1 RNA level was 3.10 log(10) copies/mL, and the median CD4 cell count was 506 cells/mm(3). An intent-to-treat&rcolon;observed analysis showed that, at weeks 24 and 48 of treatment, HIV-1 RNA level was <400 copies/mL in 48 (76%) of 63 and 45 (82%) of 55 patients, respectively, and <50 copies/mL in 37 (59%) of 63 and 31 (56%) of 55 patients, respectively. Previous zidovudine or lamivudine use and presence at baseline of the M184V reverse-transcriptase mutation did not impact virologic response. Median CD4 cell counts were maintained above baseline throughout the study. COM plus ABC was generally well tolerated.

Although a rare diagnosis, with few reports in the literature, calcific myonecrosis is a diagnosis that must be entertained in individuals presenting with expanding masses in the muscle compartments occurring years after an initial injury. The authors report a previously healthy 66-year-old man with an expanding right lower extremity mass felt initially to be an abscess. Despite presumably appropriate antimicrobial therapy, the lesion continued to expand, causing pain and loss of function. The patient subsequently underwent extensive debridement and free muscle flap transfer with an excellent outcome. This patient serves to remind us that, although calcific myonecrosis is an uncommonly encountered condition, it must be maintained in the differential diagnosis of an expanding muscle compartment mass.

Adélie penguin (Pygoscelis adeliae) males and females, nesting in Antarctica, alternate attendance at the nest with absences of many days to forage at sea. We investigated the importance of tactile input from egg and chicks on prolactin levels by observing nest attendance patterns and obtaining blood samples (1) during the first nest exchange of the incubation stage, (2) from birds whose incubation period was artificially increased or decreased by about 10 days, and (3) from birds whose nests had failed. Prolactin levels in females after 8 to 11 days of absence from the breeding colony did not differ from those in incubating males and did not change after females resumed incubation. Moving eggs between nests resulted in nests in which chicks hatched after about 26, 36 (normal), or 46 days. Duration of incubation did not affect prolactin levels in the parents measured during incubation, at the pip stage, hatch stage, or early brood stage. Adults first left their chicks unguarded on about the same calendar date, regardless of chick age. However, chicks from long incubation nests averaged 8 days younger when they were left unguarded than chicks from control or short-incubation nests. In females, there was no effect of nest failure on prolactin levels. In males, prolactin levels were slightly lower after nest failure than in males tending nests. Testosterone was significantly higher in males after nest failure than in males still tending nests. Prolactin is elevated in Adélie penguins as part of the program of cyclical hormonal changes that accompany the lengthy reproductive season and is relatively independent of tactile input. Sustained prolactin secretion is probably required for the maintenance of parental behavior in offshore feeding species that must be absent from the nest for many days at a time., (Copyright 2000 Academic Press.)