Simeprevir plus sofosbuvir for eight or 12 weeks in treatment-naïve and treatment-experienced hepatitis C virus genotype 4 patients with or without cirrhosis.

The OSIRIS study investigated efficacy and safety of simeprevir plus sofosbuvir for eight or 12 weeks in hepatitis C virus (HCV) genotype 4-infected patients with METAVIR F0-F4 fibrosis. Sixty-three patients (33 treatment-naïve and 30 peg-interferon/ribavirin (Peg-IFN/RBV)-experienced) enrolled in a partly randomized, open-label, multicentre, phase IIa study. Patients with F0-F3 fibrosis were randomized (1:1) into two groups (A1 and A2), stratified according to treatment experience and METAVIR score, to receive either eight weeks (Group A1, n=20) or 12 weeks (Group A2, n=20) of treatment. Patients with compensated cirrhosis (METAVIR F4) received 12 weeks of treatment (Group B, n=23). Treatment comprised simeprevir 150 mg and sofosbuvir 400 mg daily. The primary efficacy endpoint was sustained virologic response 12 weeks after planned end of treatment (SVR12). Safety and tolerability were assessed throughout. Overall, 92% (95% CI: 82-97) of patients achieved SVR12; 75% (15/20) in Group A1 and 100% in groups A2 and B. Patients who did not achieve SVR12 (n=5) experienced viral relapse during the first 32 days following treatment and were all prior Peg-IFN/RBV null responders. The most commonly reported treatment-emergent adverse events (TEAEs) were asymptomatic lipase increase (14%), pruritus (14%), headache (13%) and hyperbilirubinaemia (11%). No patients discontinued due to TEAEs. In conclusion, simeprevir plus sofosbuvir for 12 weeks achieved a 100% SVR rate in HCV genotype 4-infected patients with or without compensated cirrhosis (ClinicalTrials.gov: NCT02278419). The AE and laboratory profile were favourable and consistent with previous data for simeprevir plus sofosbuvir in eight- and 12-week regimens.

Safety and on-treatment efficacy of telaprevir: the early access programme for patients with advanced hepatitis C.

BACKGROUND AND AIM: Severe adverse events (AEs) compromise the outcome of direct antiviral agent-based treatment in patients with advanced liver fibrosis due to HCV infection. HEP3002 is an ongoing multinational programme to evaluate safety and efficacy of telaprevir (TVR) plus pegylated-interferon-α (PEG-IFNα) and ribavirin (RBV) in patients with advanced liver fibrosis caused by HCV genotype 1 (HCV-1). METHODS: 1782 patients with HCV-1 and bridging fibrosis or compensated cirrhosis were prospectively recruited from 16 countries worldwide, and treated with 12 weeks of TVR plus PEG-IFN/RBV, followed by 12 or 36 weeks of PEG-IFN and RBV (PR) alone dependent on virological response to treatment and previous response type. RESULTS: 1587 patients completed 12 weeks of triple therapy and 4 weeks of PR tail (53% cirrhosis, 22% HCV-1a). By week 12, HCV RNA was undetectable in 85% of naives, 88% of relapsers, 80% of partial responders and 72% of null responders. Overall, 931 patients (59%) developed grade 1-4 anaemia (grade 3/4 in 31%), 630 (40%) dose reduced RBV, 332 (21%) received erythropoietin and 157 (10%) were transfused. Age and female gender were the strongest predictors of anaemia. 64 patients (4%) developed a grade 3/4 rash. Discontinuation of TVR due to AEs was necessary in 193 patients (12%). Seven patients died (0.4%, six had cirrhosis). CONCLUSIONS: In compensated patients with advanced fibrosis due to HCV-1, triple therapy with TVR led to satisfactory rates of safety, tolerability and on-treatment virological response with adequate managements of AEs.

Pharmacokinetic interaction between etravirine or darunavir/ritonavir and artemether/lumefantrine in healthy volunteers: a two-panel, two-way, two-period, randomized trial.

OBJECTIVES: Etravirine is a substrate and inducer of cytochrome P450 (CYP) 3A and a substrate and inhibitor of CYP2C9 and CYPC2C19. Darunavir/ritonavir is a substrate and inhibitor of CYP3A. Artemether and lumefantrine are primarily metabolized by CYP3A; artemether is also metabolized to a lesser extent by CYP2B6, CYP2C9 and CYP2C19. Artemether has an active metabolite, dihydroartemisinin. The objective was to investigate pharmacokinetic interactions between darunavir/ritonavir or etravirine and arthemether/lumefrantrine. METHODS: This single-centre, randomized, two-way, two-period cross-over study included 33 healthy volunteers. In panel 1, 17 healthy volunteers received two treatments (A and B) in random order, with a washout period of 4 weeks between treatments: treatment A: artemether/lumefantrine 80/480 mg alone, in a 3-day course; treatment B: etravirine 200 mg twice a day (bid) for 21 days with artemether/lumefantrine 80/480 mg from day 8 (a 3-day treatment course). In panel 2, another 16 healthy volunteers received two treatments, similar to those in panel 1 but instead of etravirine, darunavir/ritonavir 600/100 mg bid was given. RESULTS: Overall, 28 of the 33 volunteers completed the study. Co-administration of etravirine reduced the area under the plasma concentration-time curve (AUC) of artemether [by 38%; 90% confidence interval (CI) 0.48-0.80], dihydroartemisinin (by 15%; 90% CI 0.75-0.97) and lumefantrine (by 13%; 90% CI 0.77-0.98) at steady state. Co-administration of darunavir/ritonavir reduced the AUC of artemether (by 16%; 90% CI 0.69-1.02) and dihydroartemisinin (by 18%; 90% CI 0.74-0.91) but increased lumefantrine (2.75-fold; 90% CI 2.46-3.08) at steady state. Co-administration of artemether/lumefantrine had no effect on etravirine, darunavir or ritonavir AUC. No drug-related serious adverse events were reported during the study. CONCLUSIONS: Co-administration of etravirine with artemether/lumefantrine may lower the antimalarial activity of artemether and should therefore be used with caution. Darunavir/ritonavir can be co-administered with artemether/lumefantrine without dose adjustment but should be used with caution.

Evolution of genotypic and phenotypic resistance during chronic treatment with the fusion inhibitor T-1249.

T-1249 is a peptide HIV fusion inhibitor (FI) previously under development for use in FI-naive and experienced patients. Here we present prospectively planned longitudinal analyses of FI resistance during 48 weeks of T-1249 dosing in patients with extensive prior FI exposure. T1249-105 was a single-arm rollover study in patients with prior resistance to enfuvirtide (ENF) and 10 days of T-1249 functional monotherapy exposure. The phenotype and genotype of plasma virus envelopes were analyzed at baseline and at study weeks 8, 16, and 48. At study entry, viruses had a geometric mean decrease in susceptibility to ENF of 51.8-fold but to T-1249 of 1.8-fold; extensive genotypic resistance to ENF was observed. A median viral load response of - 1.5 log(10) copies/ml was observed at week 2 that was partially sustained (- 0.5 log(10) copies/ml) through 48 weeks. Resistance to T-1249 gradually increased to a geometric mean 92.7-fold decrease from FI-naive baseline; this occurred concomitant with further evolution of gp41 amino acids 36-45, most commonly the G36D (n = 6, 16%) or N43K (n = 9, 24%) substitutions. A novel substitution, A50V (n = 12, 32%), was also common, as were the N126K and S138A substitutions in heptad-repeat 2 (HR-2). These data point toward a primary role for the gp41 36-45 locus in modulating FI binding and suggest that residues in HR-2 may contribute in a more limited manner to development of peptide FI resistance. These data also point toward a substantial genetic barrier and fitness cost to development of resistance to next-generation fusion inhibitors.

Characterization of envelope glycoprotein gp41 genotype and phenotypic susceptibility to enfuvirtide at baseline and on treatment in the phase III clinical trials TORO-1 and TORO-2.

Enfuvirtide (T-20) is the first entry inhibitor approved for treatment of HIV infection and acts by inhibiting conformational changes in the viral envelope protein gp41 that are necessary for fusion of the virus and host cell membranes. Here we present genotypic and phenotypic data on viral envelopes obtained at baseline (n = 627) and after 48 weeks of enfuvirtide treatment (n = 302) from patients in the TORO (T-20 versus Optimized Regimen Only)-1 and -2 phase III pivotal studies. The amino acid sequence at residues 36-45 of gp41 was highly conserved at baseline except for polymorphism of approximately 16% at position 42. Substitutions within gp41 residues 36-45 on treatment were observed in virus from 92.7% of patients who met protocol defined virological failure criteria and occurred in nearly all cases (98.8%) when decreases in susceptibility to enfuvirtide from baseline of greater than 4-fold were observed. Consistent with previous observations, a wide range of baseline susceptibilities (spanning 3 logs) was observed; however, lower in vitro baseline susceptibility was not significantly associated with a decreased virological response in vivo. Virological response was also independent of baseline coreceptor tropism and viral subtype.

Genotypic changes in human immunodeficiency virus type 1 envelope glycoproteins on treatment with the fusion inhibitor enfuvirtide and their influence on changes in drug susceptibility in vitro.

BACKGROUND: Previous studies have established the importance of substitutions at amino acids 36-45 of HIV-1 gp41 in the development of viral resistance to the peptide fusion inhibitor enfuvirtide. However, the influence of other loci in the HIV-1 envelope is not well established. OBJECTIVE: To identify positions showing genotypic changes that are associated with particularly high levels of changes in enfuvirtide susceptibility. STUDY DESIGN: We examined full-length baseline and on treatment sequences of gp120 and gp41 for isolates from 369 patients in Phase III studies of enfuvirtide, including 281 patients receiving ENF+OB and 88 patients receiving OB alone. Individual changes in gp41 and gp120 were evaluated for correlations with on treatment phenotype changes by analysis of variance (ANOVA). This modeling was done with (two-way) and without (one-way) ANOVA adjusting for the effects of any changes in gp41 amino acids 36-45 modeled as a single variable (ANY(36-45)). Positions displaying significance levels of p<0.05 by either one- or two-way ANOVA were then studied by multi-way ANOVA (stepwise regression). RESULTS: In addition to changes at gp41 amino acids 36-45, changes at three positions in the HR2 domain (126, 129 and 133) occurred significantly more often in patients undergoing virologic failure on enfuvirtide. However, ANY(36-45) alone accounted for slightly more than 90% of the variation in phenotype explained by the ANOVA models. Relative to ANY(36-45) alone, significant increases in the geometric mean of the fold-change in inhibitory concentration (19.6-236.3-fold higher) were observed for amino acid changes at positions gp41: 18, 42,126, 247, 256 and 312; gp120: 330, 389 and 424 and significant reductions (18.8-29.7-fold lower) for gp41: 3, 46, 165, 232 and 324. CONCLUSIONS: This study represents a statistical approach to highlight positions in HIV envelope that undergo mutations in the presence of enfuvirtide. Several of the identified positions have been implicated in the viral fusion process by other studies. The specific impact of positions 330. Three hundred and eighty-nine and 424 on viral fusion kinetics remains to be studied further by site-directed mutagenesis experiments.

The effects of lamivudine treatment on HIV-1 disease progression are highly correlated with plasma HIV-1 RNA and CD4 cell count.

OBJECTIVE: To determine the value of plasma HIV-1 RNA and CD4 cell count as predictors of the clinical benefit of antiretroviral treatment. DESIGN AND SETTING: The CAESAR (Canada, Australia, Europe, South Africa) trial randomized 1840 patients [inclusion CD4 cell count, 25-250 x 10(6)/l] to add either placebo, lamivudine (3TC) or 3TC plus loviride in a double-blinded fashion to baseline treatments (zidovudine, zidovudine-didanosine or zidovudine-zalcitabine) for 1 year. PATIENTS: This analysis included 487 patients with data on CD4 cell count and HIV-1 RNA after 12-20 weeks of treatment and subsequent follow-up for clinical progression. MAIN OUTCOME MEASURES: The correlation between 12-20-week change in CD4 cell count, HIV-1 RNA and progression to AIDS or death in the placebo group was used to predict the clinical benefit of the 3TC-containing arms of the trial, given their effects on CD4 cell count and HIV-1 RNA. RESULTS: After 12-20 weeks of treatment, HIV-1 RNA fell by 0.37 log10 copies/ml in the 3TC arms versus a rise of 0.05 log10 copies/ml in the placebo arm. The 12-20-week CD4 cell count rose by 35 x 10(6)/l in the 3TC arm versus a fall of 8 x 10(6)/l in the placebo arm. After 12-20 weeks of treatment, a reduction in HIV-1 RNA of 1 log10 at 12-20 weeks predicted a 49% reduction in progression [hazard ratio (HR), 0.51; 95% confidence interval (CI), 0.30-0.87] and a rise in CD4 cell count of 50 x 10(6)/l predicted a 51% reduction in progression (HR, 0.49; 95% CI, 0.33-0.73). Using the model from the placebo arm, the rises in CD4 cell count and reductions in HIV-1 RNA during 3TC treatment predicted a 59% reduction in progression to AIDS or death. The observed clinical benefit was a 57% reduction in progression for the 3TC arms versus placebo (HR, 0.43; 95% CI, 0.26-0.71). CONCLUSIONS: Rises in CD4 cell count and reductions in HIV-1 RNA were reliable in predicting the clinical benefit of 3TC in the CAESAR trial.

HIV-1 RNA, CD4 cell count and the risk of progression to AIDS and death during treatment with HIV-1 reverse transcriptase inhibitors.

CONTEXT: There is little information available on the correlation between HIV-1 RNA level, CD4 cell count and the risk of progression to AIDS or death during treatment with reverse transcriptase inhibitors. OBJECTIVES: To define the correlation between HIV-1 RNA level, CD4 cell count and the 1 year risk of progression to AIDS or death. DESIGN: Pooled analysis of six randomized clinical trials of zidovudine/lamivudine versus control treatments. SETTING: Investigational sites in Europe, North America, Australia and South Africa. PATIENTS: The trials recruited 1488 adult HIV-1-infected male and female patients aged > or = 18 years, with inclusion CD4 cell count between 25 and 500 x 10(6) cells/l. Patients were either nucleoside analogue-naive or pre-treated, and at all stages of HIV-1 disease. MAIN OUTCOME MEASURES: : Progression (defined as all new and recurrent AIDS-defining events or death) was correlated with the HIV-1 RNA level and CD4 cell count during the first 8 to 52 weeks of treatment. RESULTS: During a median 1 year follow up, progression was largely restricted to patients with both low CD4 cell count (< or = 200 x 10(6) cells/l) and high HIV-1 RNA level (> 5000 copies/ml). There was an increase in the incidence of progression events with rises in HIV-1 RNA level > 5000 copies/ml and reductions in CD4 cell count under 200 x 10(6) cells/l. The events occurring with HIV-1 RNA < 5000 copies/ml were generally atypical. CONCLUSIONS: Progression to AIDS or death is rare for patients with HIV-1 RNA < or = 5000 copies/ml, particularly when CD4 cell count is more than 200 x 10(6) cells/l.

Overview of the effectiveness of triple combination therapy in antiretroviral-naive HIV-1 infected adults.

AIM: To estimate the effectiveness of triple combination therapy in antiretroviral-naive adults. METHODS: A systematic overview of results from clinical trials involving triple combination therapy with dual nucleoside reverse transcriptase inhibitors (NRTI) and: a protease inhibitor (PI triple); a non-nucleoside reverse transcriptase inhibitor (NNRTI triple); or a third NRTI (triple NUC). Data from 23 clinical trials involving 31 independent treatment groups, 19 unique antiretroviral regimens, and 3257 enrolled patients were included in this study. RESULTS: Median log(10) baseline plasma HIV RNA and CD4 cell count over all trials averaged 4.69 (49,329 copies/ml) and 375 x 10(6) cells/l, respectively. The overall estimated percentage of patients with plasma HIV RNA < or = 400 copies/ml at 24 weeks was 64% [95% confidence interval (CI), 60 to 67%]. The percentages of patients with plasma HIV RNA < or = 50 copies/ml at 48 weeks by drug class were: PI triple, 46% (95% CI, 41 to 52%); NNRTI triple, 51% (95% CI, 43 to 59%); triple NUC, 45% (95% CI, 36 to 54%). The CD4 cell count increase over all trials at 24 and 48 weeks averaged +123 x 10(6) cells/l (95% CI, 111 x 10(6) to 135 x 10(6) cells/l) and +160 x 10(6) cells/l (95% CI, 146 x 10(6) to 175 x 10(6) cells/l), respectively and did not differ between drug classes. In multivariable regression analysis, neither baseline plasma HIV RNA level and CD4 cell count nor treatment regimen predicted plasma HIV RNA < or = 50 copies/ml at week 48. However, pill count was significantly negatively associated with plasma HIV RNA < or = 50 copies/ml at week 48 (P = 0.0085). CONCLUSIONS: The results suggest that three drug regimens containing two NRTI with a PI, a NNRTI, or a third NRTI may provide comparable activity, and practical issues such as daily pill burden should be considered when choosing a treatment regimen.

Viral genetic heterogeneity in HIV-1-infected individuals is associated with increasing use of HAART and higher viremia.

OBJECTIVE: To assess the correlation between the outgrowth of mutant viruses (viral genetic heterogeneity), highly active antiretroviral therapy (HAART), and plasma HIV-1 RNA in a population-based observational cohort study. DESIGN: The study population consisted of 42 HIV-1-infected individuals receiving at least two nucleotide reverse transcriptase (RT) inhibitors and one or more protease inhibitors at study entry. There were no restrictions on antiretroviral therapy after enrollment. METHODS: Plasma samples were obtained from subjects at baseline, at therapy changes, and at quarterly intervals for quantitation of HIV-1 RNA levels and for sequence determination of the entire protease coding region and the first 235 codons of the reverse transcriptase coding region. Data were analyzed using the generalized estimating equation method for longitudinal data and using linear regression analysis. RESULTS: With increased time on HAART there were significant increases in the number of total HIV-1 mutations in the regions sequenced (P = 0.010). There were significant correlations between the increases in the plasma HIV-1 RNA levels and the numbers of total mutations and reverse transcriptase mutations (P = 0.007 and 0.021, respectively). CONCLUSIONS: The number of HIV-1 mutations increased over time. Failure of HAART in this study population was correlated with outgrowth of virus with numerous mutations in the reverse transcriptase and protease coding regions. Phenotypic results correlated with genotypic results, showing decreased susceptibility to antiretrovirals over time in the majority of this population during HAART. Both synonymous and non-synonymous mutations were observed, with a higher incidence of non-synonymous mutations occurring at codons associated with drug resistance.

Meta-analysis of antiretroviral effects on HIV-1 RNA, CD4 cell count and progression to AIDS or death.

There is uncertainty as to how the effects of antiretroviral treatments on human immunodeficiency virus type 1 (HIV-1) RNA levels and CD4 cell counts can predict reductions in clinical progression to AIDS or death. A meta-analysis was conducted for 27 pairwise comparisons of antiretroviral treatments in 15 randomized trials of antiretroviral treatments. For each trial, three measures of treatment effect were used: (i) 16 week change from baseline in HIV-1 RNA; (ii) 16 week change from baseline in CD4 cell count; and (iii) rate of clinical progression. Treatments which caused greater increases in CD4 cell count and greater reductions in HIV-1 RNA were more effective at reducing the rate of clinical progression (P < 0.05 for each comparison). However, there was variability in the consistency of this correlation between different trials and treatments. The results support the use of both CD4 count and HIV-1 RNA levels as the primary markers of the efficacy of antiretroviral treatment.

Prediction of HIV-1 RNA suppression and its durability during treatment with zidovudine/lamivudine.

To predict the probability of long-term viral suppression during treatment with zidovudine and lamivudine, human immunodeficiency virus type 1 (HIV-1) RNA values were retrospectively pooled for 1083 patients from six randomized, double-blind clinical trials. All analyses of HIV-1 RNA were obtained using the Roche Amplicor assay or its earlier prototype. Time to loss of response was evaluated by Kaplan-Meier analysis; Cox proportional hazards models were used to assess the influence of baseline variables. Among 523 patients with < or = 6 months of prior zidovudine treatment, the probability of HIV-1 RNA suppression below 400 copies/ml at 48 weeks was 71% in those with baseline HIV-1 RNA < 5000 copies/ml, but only 14% in those with HIV-1 RNA between 50,000 and 200,000 copies/ml. Among 560 patients with > 6 months of prior zidovudine treatment, the rates of sustained viral suppression were lower, but also significantly associated with the baseline HIV-1 RNA. Multivariate analyses showed no independent effect of CD4 cell count, age, sex, race, or CDC disease stage on the probability of sustained HIV-1 RNA suppression. When patients with < or = 6 months of prior therapy were stratified based on the magnitude of HIV-1 RNA nadir achieved during treatment, those who reached a nadir of < 400 copies/ml retained this response for significantly longer time periods than the ones who only achieved partial viral suppression. In conclusion, baseline HIV-1 RNA levels and the duration of prior zidovudine therapy strongly predict the antiretroviral efficacy of zidovudine/lamivudine. The baseline parameters should influence the choice of the antiretroviral regimen.

Prolongation of xenograft survival after combination therapy with 15-deoxyspergualin and total-lymphoid irradiation in the hamster-to-rat cardiac xenograft model.

Adequate immunosuppression remains a major obstacle to successful xenotransplantation, with early xenograft rejection appearing to be mediated by humoral factors. Total-lymphoid irradiation (TLI) and 15-deoxyspergualin (DOSP) have been shown to be effective immunosuppressive agents in allografs. In this study, TLI alone and in combination with DOSP and cyclosporine were evaluated in the hamster-to-rat heterotopic cardiac xenograft model. The animals were divided into four groups: group 1--control (n = 9); group 2--TLI alone, administered pretransplant at 125 cGy/day, four days per week, for three weeks (n = 12); group 3--TLI plus CsA at 10 mg/kg/day (n = 17); and group 4--TLI plus DOSP at 2.5 mg/kg/day (n = 10). Tissue sections were taken from rejected xenografts in all treatment groups for histological examination. Complement-dependent cytotoxicity assays were performed on the control group and also the TLI-DOSP group. The control animals were found to have a mean graft survival of 3.2 +/- 0.4 days. TLI alone (5.8 +/- 0.7 days) did not significantly improve graft survival in comparison with the control group. Combination of TLI with DOSP (26.3 +/- 5.9 days) results in significantly improved survival (P less than 0.05) in comparison with the control, TLI alone, and combination of TLI and CsA (13.6 +/- 8.6 days). Complement-dependent cytotoxicity assays revealed that control groups have low rat antihamster lymphocytotoxic antibody titer (1/1-1/10) prior to xenografting, and that these antibody titers show a precipitous rise to a level of 1/640-1/1280 by day 3, the time at which rejection occurred. This correlates with the histological findings of the rejected hearts showing a severe humoral type of rejection and no evidence of cellular rejection. In contrast, animals in the TLI-DOSP group had markedly lowered rat antihamster lymphocytotoxic antibody titers (1/20-1/40) on day 3, and these titers only increased to 1/160 at time of rejection. This correlates with the histological findings of a lesser degree of humoral rejection in the TLI-DOSP group. Combination therapy with TLI and DOSP results in a marked increase of survival in xenografts in this model not seen with any other drug combination studied in over 500 xenografts in our laboratory. This study indicates that TLI combined with DOSP results in prolonged suppression of the antixenograft antibody response. This combination of agents appears to have the potential to prevent early xenograft rejection.

Reperfusion injury after temporary coronary occlusion.

In 24 anesthetized open-chest dogs, we examined the time course of changes in contractile function, diastolic muscle stiffness (sonomicrometry), tissue water content, and ultrastructure after 1 hour of occlusion of the left anterior descending coronary artery and after 2 hours of unmodified reperfusion. One hour of occlusion of the left anterior descending artery replaced active shortening with passive bulging (21.4% +/- 2.9% versus -5.9% +/- 0.9%, p less than 0.05) in the involved segment. There was no increase in either subendocardial water content (78.6% +/- 0.1% versus 79.7% +/- 0.7%) or operative muscle stiffness (2.80 +/- 0.72 versus 2.36 +/- 0.42 mm Hg/mm) after the occlusion period. There were only mild to moderate ultrastructural alterations suggestive of reversible injury. In sharp contrast, reperfusion was associated with a 2.48% increase in subendocardial water content (p less than 0.05), a 42% increase in diastolic muscle stiffness (3.34 +/- 0.42 mm Hg/mm, p less than 0.05), and greater ultrastructural damage. We conclude that myocardial injury is significantly extended with unmodified blood reperfusion after temporary coronary occlusion.

Update on the use of distal radial bone density measurements in prediction of hip and Colles' fracture risk.

A controversy has developed around the question as to whether bone density values from the distal radius can be used to accurately predict risk of future fractures. To address this question, two separate studies were undertaken: (a) Bone density was measured in 460 healthy ambulatory women living in retirement centers in the state of North Carolina; 83% of these women were followed for up to 60 months for occurrence of minimal trauma hip and wrist fractures. Thirty-one minimal trauma fractures were reported in our study population, representing 8% of those followed. The fracture incidence density rate showed a close inverse relationship with incremental changes in bone density at the distal site. Twenty-eight of the 31 fractures were reported in women with bone density values below the 325-mg/cm2 "at risk" value. (b) Bone density values of the distal radius and the lumbar spine from 360 women (aged 18-85 years) from the Chapel Hill area were used to analyze the error in predicting individual spinal density from the distal radial density. Although the overall correlation was high (r = 0.67) and the confidence intervals were narrow, the prediction intervals were quite wide. Thus, prediction of an individual value of spine density from the distal radius density would result in a value with a range too wide to be clinically useful. We conclude that single-photon absorptiometry appears to be a useful tool for screening normal populations of asymptomatic women for prediction of hip or Colles' fracture risk even though it has limited usefulness in prediction of spinal fracture risk or individual values for spinal density.

A comparison of surgery for neurogenic thoracic outlet syndrome between laborers and nonlaborers.

OBJECTIVE: To determine factors of outcome following surgical intervention for neurologic thoracic outlet syndrome (NTOS). METHODS: In a retrospective study of patients surgically treated for NTOS, outcome was evaluated by postoperative symptoms and the ability of patients to return to work. RESULTS: Good, fair, and poor results were obtained in 26 (48%), 21 (39%), and 7 (13%) patients, respectively. The best predictor of a good outcome was occupation. Nonlaborers were more likely to have good outcome (21 of 32, 66%) when compared with laborers (5 of 22, 23%; P = 0.0025). Only 6 of 20 (30%) laborers were able to return to their original occupation compared with 17 of 26 (65%) nonlaborers (P = 0.036). CONCLUSIONS: Laborers with NTOS are less likely to have a good result from surgical intervention, are unlikely to return to their original occupation, and may require retraining for a non-labor-intensive occupation if they cannot return to their original work.

The current status of prosthetic-vein composite grafts for lower extremity revascularization.

When infrageniculate lower extremity vascular reconstructions are required in the face of inadequate or insufficient autogenous vein, prosthetic-vein composite grafts remain a viable alternative. Graft patency and limb salvage for composite grafts are intermediate between those of completely autogenous and prosthetic bypasses alone. The sequential technique may offer superior patency in patients with the appropriate anatomy. The addition of adjunctive techniques such as a distal arteriovenous fistula and/or anticoagulation may further improve results. An algorithm illustrating the proper role of composite grafts for distal lower extremity reconstructions is shown in Figure 6. Any significant interval of patency is important in this group of patients in whom limb salvage can often be achieved by healing ischemic lesions and in whom overall life expectancy is limited.

Case report: penicillin-resistant pneumococcal meningitis: navigating a therapeutic minefield.

Pneumococcal meningitis is a common infection in adults for which penicillin has long been the drug of choice. Optimal treatment has recently become controversial, however, owing to an alarming increase in the number of penicillin-resistant isolates. The authors report a representative case of meningitis caused by such an organism, and provide a discussion of the history, mechanisms of resistance, laboratory evaluation, and treatment of these infections. Guidelines for prevention are also reviewed, including a renewed call for utilization of the 23-valent pneumococcal vaccine.

Heparin-induced thrombocytopenia.

Heparin-induced thrombocytopenia (HIT) is a rare complication of heparin with significant morbidity and mortality. In this study, a retrospective review of all patients referred to the platelet study lab at East Carolina University who tested positive for heparin-induced platelet aggregation was performed. From May 1988 through March 1991, 40 patients with clinically suspected HIT were referred for platelet aggregation studies. Ten patients tested positive for in-vitro platelet aggregation in the presence of heparin. The clinical characteristics of these patients are reviewed. Results show a preponderance of surgical patients with 8/10 patients having undergone a primary major surgical procedure. Six of the eight surgical patients underwent a major vascular or cardiac procedure. The mortality rate for patients with heparin-induced in-vitro platelet aggregation was 30 per cent. Major thromboembolic morbidity was substantial (80%) with 5/10 patients requiring an extremity amputation. The estimated incidence of HIT in surgical patients in this series was 0.3 per cent. HIT is an unusual complication of heparin therapy with devastating morbidity and mortality. Patients undergoing a major vascular or cardiac procedure appear to be at increased risk. Increased awareness of the syndrome and careful monitoring of platelet counts in patients at high risk may reduce the morbidity and mortality.

Coexistent abdominal aortic aneurysm and renal carcinoma: management options.

Renal carcinoma (RCA) presenting in association with abdominal aortic aneurysm (AAA) is extremely rare, with only sporadic case reports previously described. The management of six cases of AAA and concomitant RCA presenting to a single institution from March, 1991 through December, 1993 was reviewed and management options considered. AAAs ranged in size from 4.5-7.0 cm (mean, 5.6 cm). Three left renal carcinomas were resected via a retroperitoneal approach simultaneous to repair of the AAA. One right renal carcinoma was resected in combination with repair of an AAA through a transperitoneal approach. The fifth case was managed by left nephrectomy, followed by interval aneurysmectomy, and the sixth case was managed by nonsurgical methods because of the presence of widely metastatic disease. Renal malignancies included five renal cell carcinomas and one transitional cell carcinoma. Three patients remain free of disease 8-11 months postoperatively, and one patient had metastatic disease detected 19 months postoperatively. Two deaths have occurred; one due to a massive CVA 1 month following a combined aneurysmectomy and left nephrectomy, and a second due to unknown etiology in the patient managed non-surgically. No peripheral vascular or aortic graft related complications have occurred. The treatment of AAA and RCA should be governed by the size of the AAA, the location of the cancer, and the extent of malignant disease. Simultaneous resection is safe and effective in patients with coexistent AAA and renal cancer. Left sided tumors should be resected via a retroperitoneal approach that also provides excellent exposure for simultaneous AAA resection.(ABSTRACT TRUNCATED AT 250 WORDS)