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Objective: To assess the efficacy and safety of itraconazole in preventing relapse of histoplasmosis after induction therapy with amphotericin B in patients with the acquired immunodeficiency syndrome (AIDS) and disseminated histoplasmosis.Design: A prospective, multicenter, open-label clinical trial, with follow-up for at least 52 weeks.Setting: Tertiary care hospitals participating in a clinical investigation sponsored by the National Institutes of Allergy and Infectious Diseases (AIDS Clinical Trial Group and Mycoses Study Group).Patients: Forty-two patients with AIDS who had successfully completed induction therapy for disseminated histoplasmosis amphotericin B, at least 15 mg/kg body weight given over 4 to 12 weeks.Interventions: Itraconazole, 200 mg given orally twice daily.Main Outcome Measures: Response to therapy, specifically prevention of histoplasmosis relapse, was the main outcome measure. Secondary end points were survival and the effect of therapy on Histoplasma capsulatum variety capsulatum antigen levels in urine and serum. Plasma itraconazole concentrations were measured to document drug absorption and compliance with therapy.Results: The median follow-up was 109 weeks, and median survival was 98 weeks. Two relapses occurred (5%; 95% CI, 0.5% to 16%), one in a patient withdrawn from the study 18 weeks earlier and one in a patient who did not comply with the study therapy. Patients with elevated antigen levels at study entry showed clearance of antigen from urine and serum; urine specimens became negative in 43% of patients (CI, 26% to 59%), and serum specimens became negative in 75% of patients (CI, 56% to 94%). Only one patient discontinued treatment because of itraconazole toxicity (hypokalemia).Conclusions: Itraconazole, 200 mg twice daily, is safe and effective in preventing relapse of disseminated histoplasmosis in patients with AIDS. Antigen clearance from blood and urine correlates with clinical efficacy. [ABSTRACT FROM AUTHOR]

Background: Resistance to antiretroviral agents remains a leading cause of treatment failure for patients infected with HIV-1.Objective: To describe the efficacy and safety of tenofovir disoproxil fumarate (tenofovir DF) compared with placebo in patients with detectable viral replication despite current antiretroviral therapy.Design: Randomized, double-blind, placebo-controlled study through 24 weeks. After 24 weeks, all patients received open-label tenofovir DF for the remainder of the 48-week study.Setting: 75 North American, European, and Australian HIV clinics.Patients: 552 HIV-1-infected adults who were receiving antiretroviral therapy and had stable HIV-1 RNA levels ranging from 400 to 10,000 copies/mL.Measurements: Change in HIV-1 RNA level (time-weighted average from baseline through week 24); proportion of patients with grade 3 or 4 laboratory abnormalities and adverse events; and genotypic HIV-1 resistance testing in a separate substudy at baseline, week 24, and week 48.Results: A statistically significant decrease in HIV-1 RNA level through week 24 (the primary end point) was observed in the tenofovir DF group versus the placebo group (-0.61 log10 copies/mL vs. -0.03 log10 copies/mL, respectively [P < 0.001]; difference, -0.58 log10 copies/mL [95% CI, -0.68 to -0.49 log10 copies/mL]). In a virologic substudy, 94% of 253 patients had plasma isolates expressing reverse transcriptase mutations associated with nucleoside resistance mutations at baseline. Through week 24, the incidence of clinical adverse events was similar between patients receiving placebo and those receiving tenofovir DF (14% vs. 13%). No evidence of tenofovir DF-related toxicity was seen through week 48.Conclusion: In treatment-experienced patients with suboptimal viral suppression, tenofovir DF significantly reduced HIV-1 RNA level and had a safety profile similar to that of placebo. [ABSTRACT FROM AUTHOR]

Context: Adefovir dipivoxil is a nucleotide analog that has demonstrated effective antiretroviral activity against human immunodeficiency virus (HIV) with once-daily administration.Objective: To determine if adefovir confers antiretroviral or immunologic benefit when added to stable antiretroviral therapy.Design: Multicenter, 24-week, randomized, double-blind, placebo-controlled study. Enrollment was conducted from June 3, 1996, through May 6, 1997.Setting: Thirty-three US HIV treatment centers.Participants: Of 1171 patients screened, 442 patients infected with HIV receiving stable antiretroviral therapy for at least 8 weeks with plasma HIV RNA greater than 2500 copies/mL and CD4+ cell count above 0.20 x 10(9)/L were randomized.Intervention: Patients were randomized to receive either a single 120-mg/d dose of adefovir dipivoxil (n = 219) or an indistinguishable placebo (n = 223). All patients received L-carnitine, 500 mg/d. Open-label adefovir was offered after 24 weeks and was continued until the end of the study.Main Outcome Measures: Changes in HIV RNA from baseline, based on area under the curve and CD4+ cell levels, adverse events, and effect of baseline genotypic resistance on response to adefovir.Results: Patients assigned to adefovir demonstrated a 0.4-log10 decline from baseline in HIV RNA compared with no change in the placebo group (P<.001), which continued through 48 weeks. CD4+ cell counts did not change. During the initial 24 weeks, elevated hepatic enzyme levels (P<.001), gastrointestinal tract complaints (P<.001), and weight loss (P<.001) were associated with use of adefovir. Between 24 weeks and 48 weeks elevations in serum creatinine occurred in 60% of patients, usually returning to baseline after discontinuation of adefovir. Patients with lamivudine or lamivudine and zidovudine resistance mutations demonstrated anti-HIV effects with adefovir (P< or =.01 vs placebo group).Conclusions: This study suggests that once-daily adefovir therapy reduces HIV RNA and is active against isolates resistant to lamivudine or lamivudine and zidovudine. Nephrotoxicity occurred when treatment extended beyond 24 weeks but was reversible. [ABSTRACT FROM AUTHOR]

HIV-1 infection is a serious chronic illness that is caused by a virus. The virus attacks the body's immune system and interferes with its ability to fight infection and certain types of cancer. Antiretroviral agents have greatly improved outcomes for HIV-1-infected patients. These drugs can suppress viral levels below limits of detection and improve the immune function of cells. There are several types of antiretroviral drugs. Most people with HIV-1 infection are treated with combinations of different drugs. One category of antiretroviral drug that is available is tenofovir disoproxil fumarate (tenofovir DF), a nucleotide analogue. The benefits of adding this drug to ongoing therapy with other antiretroviral drugs in people who already have some drug resistance aren't clear.

Background: The COBAS AMPLICOR HIV-1 MONITOR Test, version 1.5 (Amplicor) has been replaced with the COBAS AmpliPrep/COBAS TaqMan HIV-1 Test, version 2.0 (TaqMan 2.0), a real-time polymerase chain reaction human immunodeficiency virus type 1 (HIV-1) assay with higher sensitivity and broader dynamic range. HIV-1 RNA values at the 50 copies/mL cutoff drive major patient management decisions and clinical study outcomes., Methods: A total of 2217 samples were collected from 1922 HIV-1-infected subjects taking antiretroviral therapy for at least 48 weeks and had at least 2 consecutive samples with HIV-1 RNA <50 copies/mL by Amplicor from 7 recent clinical trials. HIV-1 RNA results were obtained from the Amplicor and TaqMan 2.0 assays in parallel by a reference laboratory., Results: The overall concordance between assay results was 96% at the cutoff of 50 copies/mL. However, statistically significant discordance at the 50 copies/mL cutoff was found between the assays for 3.9% of samples (n = 87). By TaqMan 2.0, virologic failure defined as HIV-1 RNA ≥ 50 copies/mL was reported for 2.8% more samples than Amplicor. Of these 87 samples, 68 samples fell within the predicted range of assay variability. Retesting of HIV-1 RNA by TaqMan 2.0 confirmed the discordance in only 28 of the 87 samples., Conclusions: The TaqMan 2.0 assay reports fewer subjects below the clinical endpoint of HIV-1 RNA <50 copies/mL in HIV clinical trials than the Amplicor assay. This difference must be considered when assessing disease progression, designing clinical trials, and comparisons with historical trials that used the Amplicor assay., (© The Author 2015. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.)

Study GS-99-907 was a 48-week, phase 3, double-blind, placebo-controlled intensification trial of tenofovir disoproxil fumarate (tenofovir DF). Antiretroviral-experienced patients added tenofovir DF 300 mg once daily to their existing regimen. The patterns of HIV-1 resistance development and the corresponding virologic responses were evaluated in a virology substudy at week 48. Although 94% of these treatment-experienced patients had nucleoside-associated resistance mutations (NAMs) at baseline, addition of tenofovir DF resulted in a mean reduction in viral load of -0.59 log10 copies/mL after 24 weeks that was durable through 48 weeks. Relative to the placebo-controlled arm, patients in the tenofovir DF arm had a reduced frequency of development of resistance mutations to all classes of HIV-1 inhibitors, with reduction in new protease inhibitor (PI)-associated mutations achieving statistical significance. The K65R mutation, which occurred in 8 patients (3%), was the only emergent mutation directly associated with tenofovir DF therapy. New thymidine analogue-associated mutations (TAMs) emerged in 19% of patients by week 48. Other than K65R, the patterns of mutations that developed were not significantly different between the tenofovir DF and placebo control arms, suggesting that the background therapies caused their development. The K65R mutation emerged only in patients with no detectable TAMs at baseline, whereas new TAMs developed similarly between patients with or without TAMs at baseline. Development of K65R was associated with mostly low-level changes in phenotypic susceptibility to tenofovir DF and other nucleoside reverse transcriptase inhibitors and was not associated with viral load rebound. No novel patterns of genotypic or phenotypic resistance to tenofovir were identified. Therefore, intensification with once-daily tenofovir DF therapy resulted in a sustained reduction in HIV-1 viral load and a low risk for development of the K65R mutation in this treatment-experienced patient population.

Results from 2 placebo-controlled intensification trials of tenofovir disoproxil fumarate (DF) in treatment-experienced human immunodeficiency type 1 (HIV-1)-infected patients (n=332) were integrated to determine the effects of resistance at baseline on HIV-1 RNA response. In these trials, there was a high prevalence of HIV-1 resistance mutations, with 94% of patients having nucleoside-associated mutations and 71% having thymidine analogue-associated mutations (TAMs). Statistically significant HIV-1 RNA reductions associated with tenofovir DF treatment, relative to placebo (P<.001), were observed for patients without TAMs (n=97) or for patients with 1-2 (n=88) or >or=3 TAMs (n=147). Response to tenofovir DF was reduced among patients with HIV-1 with >or=3 TAMs inclusive of either the M41L or L210W mutation (n=86) or patients who had a preexisting K65R mutation (n=6). Slightly increased treatment responses were observed when the M184V mutation was present. Phenotypic cutoffs were established at 1.4-fold and 4-fold, respectively, for the beginning of reduced response to tenofovir DF and for a strongly reduced response. The results from these controlled clinical trials provide guidance for the use of tenofovir DF for treatment-experienced patients.

Seven hundred nucleoside treatment-naive patients were enrolled in two phase 3 trials of adefovir dipivoxil (ADV) for the treatment of chronic hepatitis B. To monitor for the emergence of potential adefovir resistance mutations over the first 48 weeks, all intent-to-treat patients (467 ADV-treated and 228 placebo patients) were included in a prospectively defined, treatment-blinded, virology substudy. The study protocol mandated genotypic analysis for all patients with detectable hepatitis B virus (HBV) DNA by Roche Amplicor polymerase chain reaction (PCR) at baseline and week 48, and in vitro phenotypic analyses for patients with conserved site substitutions in HBV polymerase or 1.0 log(10) or greater increase in HBV DNA from nadir. Paired sequences of the entire HBV reverse transcriptase were obtained for 271 ADV-treated and 227 placebo patients by using a sequencing method that detects down to 30% of minor species present within mixtures. Four substitutions (rtS119A, rtH133L, rtV214A, and rtH234Q) developed once each at conserved sites in HBV polymerase in 4 ADV-treated patients. Seven conserved site substitutions developed in 6 placebo patients. HBV mutants encoding the 4 substitutions that emerged in ADV-treated patients remained fully susceptible to adefovir in vitro. Furthermore, these 4 ADV-treated patients had HBV-DNA reductions of 3.3 to 5.9 log(10) copies/mL by week 48 with no rebound. All other substitutions occurred at very low frequencies (<1.6%) at polymorphic sites and were not associated with HBV-DNA increases in patients or adefovir resistance in vitro. In conclusion, no adefovir resistance mutations were identified in a large group of chronic hepatitis B patients treated with ADV for 48 weeks.

The relationship between a longitudinal covariate and a failure time process can be assessed using the Cox proportional hazards regression model. We consider the problem of estimating the parameters in the Cox model when the longitudinal covariate is measured infrequently and with measurement error. We assume a repeated measures random effects model for the covariate process. Estimates of the parameters are obtained by maximizing the joint likelihood for the covariate process and the failure time process. This approach uses the available information optimally because we use both the covariate and survival data simultaneously. Parameters are estimated using the expectation-maximization algorithm. We argue that such a method is superior to naive methods where one maximizes the partial likelihood of the Cox model using the observed covariate values. It also improves on two-stage methods where, in the first stage, empirical Bayes estimates of the covariate process are computed and then used as time-dependent covariates in a second stage to find the parameters in the Cox model that maximize the partial likelihood.

Vietnam combat veterans with current posttraumatic stress disorder (PTSD), with other Axis-I disorders, or with no Axis-I disorders completed a series of tasks designed to elucidate the psychophysiological parameters of information-processing in PTSD. These tasks included a modified Stroop procedure (MSP), a standard Stroop procedure, a recognition memory task, and a threat rating task. Physiological responses were recorded throughout the study. Our data supported several predictions derived from information-processing models of PTSD. PTSD subjects exhibited greater MSP interference to high threat words than both comparison groups, and a liberal response bias toward recognizing military-related words. PTSD symptoms and threat reactions contributed to MSP interference effects for high-threat words after controlling for medications, depression, and baseline physiological activity.

Objective: To document response to foscarnet salvage therapy in patients with cytomegalovirus (CMV) retinitis who are intolerant of or resistant to ganciclovir., Methods: Patients with AIDS and CMV retinitis who had documented hematologic intolerance or resistance to ganciclovir therapy received an induction course of foscarnet, 60 mg/kg every 8 h for 14 days, and subsequent chronic maintenance foscarnet therapy at a daily dose of 60, 90 or 120 mg/kg/day. The first 87 patients were randomly assigned to receive maintenance foscarnet at a dose of 60 or 90 mg/kg/day; all subsequent patients were assigned a maintenance dose of 120 mg/kg/day., Results: A total of 156 evaluable patients were enrolled. Median time to retinitis progression and survival did not differ significantly among groups assigned to different maintenance foscarnet doses. Among patients with retinitis progression documented ophthalmologically occurring at < or = 2 week intervals, despite optimal doses of ganciclovir, time to progression on foscarnet therapy was a median 8 weeks at all doses studied. By dose assignment, there were no significant differences in serious drug-associated toxicity, although trends toward increased renal and hypocalcemic adverse events were observed at higher maintenance doses., Conclusion: In patients intolerant of ganciclovir, salvage foscarnet therapy resulted in a longer time to retinitis progression than reported previously in historic controls who terminated ganciclovir therapy. In patients who exhibited clinical resistance to ganciclovir, foscarnet appeared to have efficacy in controlling retinitis. No significant differences in either efficacy or toxicity were observed in the range of foscarnet maintenance doses studied.

CD4 lymphocyte and survival data from two completed trials, a double-blind placebo-controlled trial of zidovudine in patients with advanced human immunodeficiency virus type 1 (HIV) disease (BW-02 study) and a randomized trial of two different doses of zidovudine in patients with advanced HIV disease (ACTG-002 study) were used to determine the degree to which CD4 lymphocyte counts reflect zidovudine-associated survival benefit. Proportional hazards models were used, and CD4 lymphocyte counts were smoothed by using empirical Bayes estimates. The geometric mean of the CD4 lymphocyte counts increased by 71 and 46 cells/mm3 for patients in the BW-02 and ACTG-002 studies, respectively, followed by a progressive decline. Higher pretreatment CD4 lymphocyte counts (p = 0.001), greater increases in CD4 lymphocytes at 8 weeks (p = 0.1), and smaller declines in the slope (p = 0.001) were associated with a lower risk of death. The most current CD4 lymphocyte count was most prognostic of death (p = 0.001). The risk of death was greater for patients with lower CD4 lymphocytes and this risk increased sharply when the CD4 lymphocyte counts fell below 50 cells/mm3. The hazard of death was higher for placebo recipients at all levels of CD4 lymphocytes compared with zidovudine recipients. Although higher CD4 lymphocyte counts are associated with improved survival, these increases account for only a small proportion of the survival benefit of zidovudine in these two studies.

Background and Methods: Zidovudine has been shown to be an effective antiretroviral treatment in adults with human immunodeficiency virus (HIV) infection. We examined the safety of zidovudine and the tolerance of and therapeutic response to the drug in 88 children with advanced HIV disease. During a 24-week outpatient trial, zidovudine (180 mg per square meter of body-surface area per dose) was given by mouth every six hours and serial measurements were made of clinical, immunologic, and virologic indexes. Children who completed 24 weeks of treatment were permitted to continue receiving zidovudine., Results: Of the 88 children (mean age, 3.9 years; range, 4 months to 11 years), 61 completed the initial 24-week trial, and 49 continued to receive zidovudine for up to 90 weeks (median follow-up, 56 weeks). The patients generally tolerated zidovudine well. One or more episodes of hematologic toxicity occurred in 54 children (61 percent)--anemia (hemoglobin level, less than 75 g per liter) in 23 children (26 percent) and neutropenia (neutrophil count, less than 0.75 x 10(9) per liter) in 42 (48 percent). Many of these abnormalities resolved spontaneously, but 30 children required transfusions or a modification of the dose of zidovudine. Only three children had to stop receiving the drug because of hematologic toxicity. Kaplan-Meier analysis demonstrated that the probability of survival was 0.89 after 24 weeks and 0.79 after 52 weeks. There was marked improvement in weight gain, cognitive function (mainly in children less than 3 years old), serum and cerebrospinal fluid concentrations of p24 antigen, and the proportion of cerebrospinal fluid cultures negative for HIV. CD4+ lymphocyte counts (mean at base line, 0.263 x 10(9) per liter) improved during the first 12 weeks, although the improvement was not sustained through the 24th week., Conclusions: Zidovudine in a dose of 180 mg per square meter every six hours can be safely administered to children with advanced HIV disease. The resultant clinical, immunologic, and virologic improvements in children are similar to those reported with zidovudine in adults.

Background: The initially tested dose of zidovudine for the treatment of patients with advanced disease caused by the human immunodeficiency virus type 1 (HIV) was 1500 mg. Although this dose is effective, it is associated with substantial toxicity., Methods: To evaluate the efficacy and safety of a reduced dose, we conducted a randomized controlled trial in 524 subjects who had had a first episode of Pneumocystis carinii pneumonia. The subjects were assigned to receive zidovudine in either a dose of 250 mg taken orally every four hours (the standard-treatment group, n = 262) or a dose of 200 mg taken orally every four hours for four weeks and thereafter 100 mg taken every four hours (the low-dose group, n = 262)., Results: The median length of follow-up was 25.6 months. At 18 months the estimated survival rates were 52 percent for the standard-treatment group and 63 percent for the low-dose group (P = 0.012 by the log-rank test). At 24 months the estimated survival rates were 27 percent for the standard-treatment group and 34 percent for the low-dose group (P = 0.033). In both groups, 82 percent of the subjects had another opportunistic infection, and the length of time to that infection was similar in the two groups (P = 0.56 by the log-rank test). CD4 T-lymphocyte counts improved transiently in both groups, and serum levels of HIV antigen decreased in the subjects with antigenemia. The hemoglobin level declined to less than 5 mmol per liter (80 g per liter) in 101 subjects in the standard-treatment group and in 77 in the low-dose group (39 vs. 29 percent, P = 0.0009 by the log-rank test). The neutrophil count declined to less than 0.750 x 10(9) per liter in 134 subjects in the standard-treatment group and in 96 in the low-dose group (51 vs. 37 percent, P = 0.0001)., Conclusions: The reduced daily dose of zidovudine used in this study was at least as effective as the standard dose and was less toxic; however, with the use of a four-week induction period with a high dose followed by low-dose treatment, severe anemia and neutropenia were common complications of treatment with zidovudine.

The rapid increase in the number of vascular surgical procedures done has led to a new class of iatrogenic ureteral injuries. Vena caval ligation, bilateral lumbar sympathectomy, bypass procedures and abdominal aortic aneurysmectomy produce the majority of these injuries. Established principles useful in the repair of iatrogenic injuries following a gynecologic or colonic operation often are inapplicable.

Acute renal failure secondary to rhabdomyolysis is a well-known entity. A case of rhabdomyolysis with renal failure secondary to positioning during urethral surgery is presented.

Accurate staging of prostatic carcinoma requires determination of the status of the regional draining lymph nodes. Pelvic lymphadenectomy is the definitive examination but has certain morbidity and even mortality. Lymphography is safe but may not be sufficiently accurate. A total of 41 patients with clinically localized disease and abnormal or suspicious lymphograms underwent percutaneous lymph node biopsy. Ten of 11 patients (91 per cent) with abnormal lymphograms and 14 of 30 (47 per cent) with suspicious lymphograms had positive cytology studies. Of the suspicious defects an unopacified void in a nodal chain most frequently was positive. Of 22 potentially curable patients with stages A and B1 disease 12 had metastatic disease.

Extended pyelolithotomy is a technique applicable for removal of most staghorn, and large pelvic and caliceal calculi. Nephrotomy incisions can be avoided in many cases. The efficiency of extended pyelolithotomy in difficult cases can be improved by renal artery occlusion combined with regional renal hypothermia. Devascularization of the kidney produces softening of the renal substance, which facilitates stone removal. The operative method is described and 5 cases are presented.