Sofosbuvir plus ribavirin for the treatment of chronic genotype 4 hepatitis C virus infection in patients of Egyptian ancestry.

BACKGROUND & AIMS: We conducted an open-label phase 2 study to assess the efficacy and safety of the oral nucleotide polymerase inhibitor sofosbuvir in combination with ribavirin in patients of Egyptian ancestry, chronically infected with genotype 4 hepatitis C virus (HCV). METHODS: Treatment-naive and previously treated patients with genotype 4 HCV were randomly allocated in a 1:1 ratio to receive sofosbuvir 400mg and weight-based ribavirin, for 12 or 24 weeks. The primary efficacy endpoint was the proportion of patients with sustained virologic response (HCV RNA <25IU/ml) 12 weeks after cessation of therapy (SVR12). RESULTS: Thirty treatment-naive and thirty previously treated patients were enrolled and treated for 12 weeks (n=31) or 24 weeks (n=29). Overall, 23% of patients had cirrhosis and 38% had diabetes. 14% of treatment-naive patients were interferon ineligible and 63% of treatment-experienced patients had prior non-response. SVR12 was achieved by 68% of patients (95% CI, 49-83%) in the 12-week group, and by 93% of patients (95% CI, 77-99%) in the 24-week group. The most common adverse events were headache, insomnia, and fatigue. No patient discontinued treatment due to an adverse event. CONCLUSIONS: The findings from the present study suggest that 24 weeks of sofosbuvir plus ribavirin is an efficacious and well tolerated treatment in patients with HCV genotype 4 infection.

Ergonomic evaluation of masons laying concrete masonry units and autoclaved aerated concrete.

Masons working with concrete masonry unit block have high rates of work-related musculoskeletal disorders to the low back and shoulders associated with repetitively lifting and buttering heavy block. A new material, autoclaved aerated concrete, may reduce the risk of shoulder and back injury but, ergonomic evaluation is needed. This study evaluated shoulder exposure parameters, low back stress, and worker perceptions in two groups of journey level masons, one using CMU and the other using AAC block. Results indicate that for the left arm AAC masons spent significantly more time than CMU masons in static (38.2% versus 31.1%, respectively), and less time in slow motions (48.2% versus 52.2%, respectively) and faster motions (13.6% versus 16.7%, respectively) (p<0.05). CMU masons had significantly greater shoulder and low back pain (p=0.009) and they held block significantly longer than AAC masons (p<0.001). Low back compressive forces were high for both materials. Masons handling AAC demonstrated less left upper extremity stress but both materials were estimated to be hazardous to the low back.

Prospective study of topical testosterone gel (AndroGel) versus intramuscular testosterone in testosterone-deficient HIV-infected men.

PURPOSE: Testosterone replacement therapy via deep intramuscular injections causes extraphysiologic variations in serum testosterone concentrations. A topical transdermal testosterone gel formulation (AndroGel(R)) provides sustained physiologic concentrations of serum testosterone. The objective of this open-label switch study was to compare pharmacokinetics, safety, tolerability, and efficacy of delivery of daily testosterone gel versus intramuscular testosterone injection every 1 or 2 weeks in hypogonadal human immunodeficiency virus (HIV)-infected men. METHOD: Patients received intramuscular testosterone (100-200 mg/wk) for 8 weeks, then switched to daily topical testosterone gel (5-10 g gel/day) for 8 weeks. Study endpoints included free serum testosterone concentrations and quality-of-life scores. RESULTS: Thirty patients (average age, 45 years) were recruited; 24 completed the study. Mean peak free testosterone concentrations with intramuscular testosterone and testosterone gel were 42 pg/mL and 23 pg/mL, respectively, and mean peaktrough fluctuations in free testosterone were 26.7 +/- 12.8 pg/mL and 2.7 +/- 10.7 pg/mL, respectively (p < .001). Quality-of-life scores indicated more improved physical and emotional well-being with gel versus intramuscular testosterone. No significant changes in laboratory parameters or lean body mass were noted. CONCLUSION: Daily testosterone gel produced stable testosterone concentrations and improved quality of life compared with intermittent intramuscular testosterone injections.

Evidence of ongoing immune reconstitution in subjects with sustained viral suppression following 6 years of lopinavir-ritonavir treatment.

BACKGROUND: We evaluated the immunologic impact of highly active antiretroviral therapy in subjects who maintained human immunodeficiency virus type 1 (HIV-1) suppression through 6 years of receiving a lopinavir-ritonavir-based regimen. METHODS: A total of 100 antiretroviral-naive subjects with any CD4+ T cell count initiated therapy with lopinavir-ritonavir, stavudine, and lamivudine. Sixty-three subjects who remained in the study for 6 years were assessed. Laboratory measurements included plasma HIV-1 RNA levels, multiparameter flow cytometry of immune cells, and markers of maturation and activation. RESULTS: After 6 years, 62 of 63 subjects had plasma HIV-1 RNA levels <50 copies/mL. The mean increase in CD4+ T cell count was 528 cells/microL (P<.001), and 81% of subjects had CD4+ T cell counts >500 cells/microL, compared with 21% of subjects at baseline. The mean ratio of CD4+ T cell count to CD8+ T cell count increased from 0.38 at baseline to 0.96 at year 6 (P<.001). The percentage of subjects with cell counts below the lower limit of normal at year 6, compared with at baseline, was significantly decreased for total T cells, B cells, and natural killer cells. At year 6, the median CD4+ T cell activation level was 3.4%, and the median CD8+ T cell activation level was 5.8%. CONCLUSIONS: The receipt of a lopinavir-ritonavir-based regimen resulted in ongoing immune reconstitution through 6 years of therapy in a cohort of HIV-1-infected, antiretroviral-naive subjects with suppressed HIV-1 RNA levels. Normalization of activation marker expression on CD4+ and CD8+ T cell subsets was demonstrated.

Serious renal impairment occurs rarely with use of tenofovir DF.

PURPOSE: The purpose of this study was to evaluate the short-term effects (up to 6 months) of tenofovir disoproxil fumarate (DF) use on renal function in patients being treated for HIV-1 infection. METHOD: The charts of 447 HIV-1-infected patients who received at least three months of tenofovir DF treatment were reviewed. Data collected included demographics, concurrent antiretrovirals, other concurrent medications, CD4 counts and HIV-1 viral loads, and serum creatinine values while on tenofovir DF. Data collection was truncated at 6 months. RESULTS: Baseline serum creatinine (SCr) was 1.0 mg/dL, with a calculated creatinine clearance (CLCr) of 95.2 mL/min (using the Cockroft-Gault equation). There was no significant change in SCr or CLCr at 12 weeks (1.1 mg/dL and 92.7 mL/min, respectively) or 24 weeks (1.1 mg/dL and 92.9 mL/min, respectively). All three patients with grade 2 increases in SCr had other medical reasons for an increased SCr (one patient each had indinavir-associated nephrolithiasis, lactic acidosis, and pancreatitis). No patients experienced any complications from these increases in SCr. CONCLUSION: Increases in SCr and CLCr within the first 6 months of tenofovir DF therapy were rare. Although no clinical nephrotoxicity was observed, continued observation of renal function is warranted in patients predisposed to renal impairment.

A controlled Phase II trial assessing three doses of enfuvirtide (T-20) in combination with abacavir, amprenavir, ritonavir and efavirenz in non-nucleoside reverse transcriptase inhibitor-naive HIV-infected adults.

Enfuvirtide is a novel antiretroviral that blocks HIV-1 cell fusion and viral entry. This Phase II, controlled, open-label, randomized, multicentre dose-ranging trial explored the safety, antiviral activity and pharmacokinetics of enfuvirtide, administered by subcutaneous (s.c.) injection, in 71 HIV-1-infected, protease inhibitor-experienced, non-nucleoside reverse transcriptase inhibitor (NNRTI)-naive adults for 48 weeks. Study participants were randomized to receive enfuvirtide at a deliverable dose of 45, 67.5 or 90 mg twice daily; the 45 mg twice daily dose required 2 injections/day, while the higher doses required 4 injections/day. A background oral antiretroviral (ARV) regimen of abacavir (300 mg twice daily), amprenavir (1200 mg twice daily), ritonavir (200 mg twice daily) and efavirenz (600 mg once daily) was provided with enfuvirtide. A control group received the background ARV regimen alone. All potential participants underwent an HIV genotype at screen to ensure a homogenous population and to exclude patients with evidence of genotypic resistance to NNRTIs. Overall, the tolerability of the combination of abacavir, amprenavir, ritonavir, efavirenz and enfuvirtide was generally comparable to control through 48 weeks. No enfuvirtide dose-dependent adverse events (AEs) were observed across treatment groups. Injection site reactions (ISRs) occurred at least once in 68.5% of the enfuvirtide-treated population, and most ISRs were mild to moderate in severity, with no apparent dose relationship. Excluding ISRs, the most common treatment-emergent AEs were nausea, diarrhoea, dizziness and fatigue; with no clinically significant differences in the incidence of AEs observed between the control and enfuvirtide groups. Each treatment group benefited from ARV therapy, with a trend of increasing antiviral and immunological activity associated with increasing enfuvirtide dose. At 48 weeks, the median HIV-1 RNA change from baseline for the ITT population was -2.24 log10 copies/ml for the combined enfuvirtide groups compared with -1.87 log10 copies/ml for the control group. In addition, 54.9% of patients in the enfuvirtide group achieved HIV-1 RNA < or = 400 copies/ml versus 36.8% of patients in the control group. These results indicate that enfuvirtide has a favourable safety profile and is a promising new antiviral agent for HIV-infected patients who have been on previously failing ARV regimens.