Anita Rachlis

Efavirenz plus Zidovudine and Lamivudine, Efavirenz plus Indinavir, and Indinavir plus Zidovudine and Lamivudine in the Treatment of HIV-1 Infection in Adults

BACKGROUND Efavirenz is a nonnucleoside reverse-transcriptase inhibitor of human immunodeficiency virus type 1 (HIV-1). We compared two regimens containing efavirenz, one with a protease inhibitor and the other with two nucleoside reverse-transcriptase inhibitors, with a standard three-drug regimen. METHODS The study subjects were 450 patients who had not previously been treated with lamivudine or any nonnucleoside reverse-transcriptase inhibitor or protease inhibitor. In this open-label study, patients were randomly assigned to one of three regimens: efavirenz (600 mg daily) plus zidovudine (300 mg twice daily) and lamivudine (150 mg twice daily); the protease inhibitor indinavir (800 mg every eight hours) plus zidovudine and lamivudine; or efavirenz plus indinavir (1000 mg every eight hours). RESULTS Suppression of plasma HIV-1 RNA to undetectable levels was achieved in more patients in the group given efavirenz plus nucleoside reverse-transcriptase inhibitors than in the group given indinavir plus nucleoside reverse-transcriptase inhibitors (70 percent vs. 48 percent, P<0.001). The efficacy of the regimen of efavirenz plus indinavir was similar (53 percent) to that of the regimen of indinavir, zidovudine, and lamivudine. CD4 cell counts increased significantly with all combinations (range of increases, 180 to 201 cells per cubic millimeter). More patients discontinued treatment because of adverse events in the group given indinavir and two nucleoside reverse-transcriptase inhibitors than in the group given efavirenz and two nucleoside reverse-transcriptase inhibitors (43 percent vs. 27 percent, P=0.005). CONCLUSIONS As antiretroviral therapy in HIV-1-infected adults, the combination of efavirenz, zidovudine, and lamivudine has greater antiviral activity and is better tolerated than the combination of indinavir, zidovudine, and lamivudine.

Effect of Early versus Deferred Antiretroviral Therapy for HIV on Survival

BACKGROUND The optimal time for the initiation of antiretroviral therapy for asymptomatic patients with human immunodeficiency virus (HIV) infection is uncertain. METHODS We conducted two parallel analyses involving a total of 17,517 asymptomatic patients with HIV infection in the United States and Canada who received medical care during the period from 1996 through 2005. None of the patients had undergone previous antiretroviral therapy. In each group, we stratified the patients according to the CD4+ count (351 to 500 cells per cubic millimeter or >500 cells per cubic millimeter) at the initiation of antiretroviral therapy. In each group, we compared the relative risk of death for patients who initiated therapy when the CD4+ count was above each of the two thresholds of interest (early-therapy group) with that of patients who deferred therapy until the CD4+ count fell below these thresholds (deferred-therapy group). RESULTS In the first analysis, which involved 8362 patients, 2084 (25%) initiated therapy at a CD4+ count of 351 to 500 cells per cubic millimeter, and 6278 (75%) deferred therapy. After adjustment for calendar year, cohort of patients, and demographic and clinical characteristics, among patients in the deferred-therapy group there was an increase in the risk of death of 69%, as compared with that in the early-therapy group (relative risk in the deferred-therapy group, 1.69; 95% confidence interval [CI], 1.26 to 2.26; P<0.001). In the second analysis involving 9155 patients, 2220 (24%) initiated therapy at a CD4+ count of more than 500 cells per cubic millimeter and 6935 (76%) deferred therapy. Among patients in the deferred-therapy group, there was an increase in the risk of death of 94% (relative risk, 1.94; 95% CI, 1.37 to 2.79; P<0.001). CONCLUSIONS The early initiation of antiretroviral therapy before the CD4+ count fell below two prespecified thresholds significantly improved survival, as compared with deferred therapy.

Once-daily dolutegravir versus raltegravir in antiretroviral-naive adults with HIV-1 infection: 48 week results from the randomised, double-blind, non-inferiority SPRING-2 study

BACKGROUND Dolutegravir (S/GSK1349572) is a once-daily HIV integrase inhibitor with potent antiviral activity and a favourable safety profile. We compared dolutegravir with HIV integrase inhibitor raltegravir, as initial treatment for adults with HIV-1. METHODS SPRING-2 is a 96 week, phase 3, randomised, double-blind, active-controlled, non-inferiority study that began on Oct 19, 2010, at 100 sites in Canada, USA, Australia, and Europe. Treatment-naive adults (aged ≥ 18 years) with HIV-1 infection and HIV-1 RNA concentrations of 1000 copies per mL or greater were randomly assigned (1:1) via a computer-generated randomisation sequence to receive either dolutegravir (50 mg once daily) or raltegravir (400 mg twice daily). Study drugs were given with coformulated tenofovir/emtricitabine or abacavir/lamivudine. Randomisation was stratified by screening HIV-1 RNA (≤ 100,000 copies per mL or >100,000 copies per mL) and nucleoside reverse transcriptase inhibitor backbone. Investigators were not masked to HIV-1 RNA results before randomisation. The primary endpoint was the proportion of participants with HIV-1 RNA less than 50 copies per mL at 48 weeks, with a 10% non-inferiority margin. Main secondary endpoints were changes from baseline in CD4 cell counts, incidence and severity of adverse events, changes in laboratory parameters, and genotypic or phenotypic evidence of resistance. Our primary analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01227824. FINDINGS 411 patients were randomly allocated to receive dolutegravir and 411 to receive raltegravir and received at least one dose of study drug. At 48 weeks, 361 (88%) patients in the dolutegravir group achieved an HIV-1 RNA value of less than 50 copies per mL compared with 351 (85%) in the raltegravir group (adjusted difference 2·5%; 95% CI -2·2 to 7·1). Adverse events were similar between treatment groups. The most common events were nausea (59 [14%] patients in the dolutegravir group vs 53 [13%] in the raltegravir group), headache (51 [12%] vs 48 [12%]), nasopharyngitis (46 [11%] vs 48 [12%]), and diarrhoea (47 [11%] in each group). Few patients had drug-related serious adverse events (three [<1%] vs five [1%]), and few had adverse events leading to discontinuation (ten [2%] vs seven [2%] in each group). CD4 cell counts increased from baseline to week 48 in both treatment groups by a median of 230 cells per μL. Rates of graded laboratory toxic effects were similar. We noted no evidence of treatment-emergent resistance in patients with virological failure on dolutegravir, whereas of the patients with virologic failure who received raltegravir, one (6%) had integrase treatment-emergent resistance and four (21%) had nucleoside reverse transcriptase inhibitors treatment-emergent resistance. INTERPRETATION The non-inferior efficacy and similar safety profile of dolutegravir compared with raltegravir means that if approved, combination treatment with once-daily dolutegravir and fixed-dose nucleoside reverse transcriptase inhibitors would be an effective new option for treatment of HIV-1 in treatment-naive patients. FUNDING ViiV Healthcare.

A Comparison of Two Regimens for the Treatment of Mycobacterium avium Complex Bacteremia in AIDS: Rifabutin, Ethambutol, and Clarithromycin versus Rifampin, Ethambutol, Clofazimine, and Ciprofloxacin

BACKGROUND Bacteremia with the Mycobacterium avium complex is common in patients with the acquired immunodeficiency syndrome (AIDS), but the most effective treatment for this infection remains unclear. METHODS We randomly assigned 229 patients with AIDS and M. avium complex bacteremia to receive either rifampin (600 mg daily), ethambutol (approximately 15 mg per kilogram of body weight daily), clofazimine (100 mg daily), and ciprofloxacin (750 mg twice daily) (the four-drug group) or rifabutin (600 mg daily), ethambutol (as above), and clarithromycin (1000 mg twice daily) (the three-drug group). In the three-drug group the dose of rifabutin was reduced by half after 125 patients were randomized, because 24 of 63 patients had uveitis. RESULTS Among 187 patients who could be evaluated, blood cultures became negative more often in the three-drug group than in the four-drug group (69 percent vs. 29 percent, P<0.001). Among patients treated for at least four weeks, the bacteremia resolved more frequently in the three-drug group (78 percent vs. 40 percent, P<0.001). In the three-drug group, bacteremia resolved more often with the 600-mg dose of rifabutin than with the 300-mg dose (P=0.025), but the latter regimen was more effective than the four-drug regimen (P<0.05). The median survival was 8.6 months in the three-drug group and 5.2 months in the four-drug group (P = 0.001). The median Karnofsky performance score was higher in the three-drug group than in the four-drug group from week 2 to week 16 (P<0.05). Mild uveitis developed in 3 of the 53 patients receiving the 300-mg dose of rifabutin, an incidence about one quarter that observed with the 600-mg dose (P<0.001). CONCLUSIONS In patients with AIDS and M. avium complex bacteremia, treatment with the three-drug regimen of rifabutin, ethambutol, and clarithromycin leads to resolution of the bacteremia more frequently and more rapidly than treatment with rifampin, ethambutol, clofazimine, and ciprofloxacin, and survival rates are better.

Late Presentation for Human Immunodeficiency Virus Care in the United States and Canada

BACKGROUND. Initiatives to improve early detection and access to human immunodeficiency virus (HIV) services have increased over time. We assessed the immune status of patients at initial presentation for HIV care from 1997 to 2007 in 13 US and Canadian clinical cohorts. METHODS. We analyzed data from 44,491 HIV-infected patients enrolled in the North American-AIDS Cohort Collaboration on Research and Design. We identified first presentation for HIV care as the time of first CD4(+) T lymphocyte (CD4) count and excluded patients who prior to this date had HIV RNA measurements, evidence of antiretroviral exposure, or a history of AIDS-defining illness. Trends in mean CD4 count (measured as cells/mm(3)) and 95% confidence intervals were determined using linear regression adjusted for age, sex, race/ethnicity, HIV transmission risk, and cohort. RESULTS. Median age at first presentation for HIV care increased over time (range, 40-43 years; P < .01), whereas the percentage of patients with injection drug use HIV transmission risk decreased (from 26% to 14%; P < .01) and heterosexual transmission risk increased (from 16% to 23%; P < .01). Median CD4 count at presentation increased from 256 cells/mm(3) (interquartile range, 96-455 cells/mm(3)) to 317 cells/mm(3) (interquartile range, 135-517 cells/mm(3)) from 1997 to 2007 (P < .01). The percentage of patients with a CD4 count > or = 350 cells/mm(3) at first presentation also increased from 1997 to 2007 (from 38% to 46%; P < .01). The estimated adjusted mean CD4 count increased at a rate of 6 cells/mm(3) per year (95% confidence interval, 5-7 cells/mm(3) per year). CONCLUSION. CD4 count at first presentation for HIV care has increased annually over the past 11 years but has remained <350 cells/mm(3), which suggests the urgent need for earlier HIV diagnosis and treatment.

Infection in hospitalized trauma patients: incidence, risk factors, and complications.

BACKGROUND Several factors place victims of multiple trauma at increased risk for infection. The purpose of this study was to delineate the frequency of, types of, and risk factors for infection in hospitalized trauma patients. METHODS Prospective surveillance for nosocomial infection was conducted for all trauma patients who were admitted for more than 24 hours to a tertiary-care regional trauma center between January 1 and December 31, 1996. RESULTS A total of 563 patients (414 males) with a mean age of 40 years (range, 15-97 years) were followed. Most (86%) sustained blunt traumatic injuries. A total of 367 infections occurred in 209 (37%) patients for an incidence of 32.1/1,000 patient-days. The hospital stay of 37% of patients was complicated by at least one infection, involving the following sites: lower respiratory tract (28%), urinary tract (24%), surgical wound (18%), skin/soft tissue (13%), intra-abdominal (5%), primary bloodstream (5%), and other sites (8%). Infection was complicated by septic shock in 36 (10%) cases, acute respiratory distress syndrome in 32 (9%) cases, and multiorgan failure in 13 (4%) cases. Death was attributed to infection in four patients. In a multivariate analysis, infected patients were more likely to have been ventilated (odds ratio [OR] = 2.6; p<0.001), to have had multiple surgical procedures (OR = 2.8; p = 0.02), to have received multiple blood transfusions (OR = 2.3; p = 0.04), and to have had a spinal cord injury (OR = 5.0; p = 0.002). First surgical procedure within 24 hours of admission was protective (OR = 0.4, p = 0.001). CONCLUSION Trauma patients are at high risk for developing infection. Identifying patients who are at increased risk for infection may allow for early intervention and subsequent decrease in infectious morbidity.

Fertility desires and intentions of HIV-positive women of reproductive age in Ontario, Canada: a cross-sectional study.

Background Improvements in life expectancy and quality of life for HIV-positive women coupled with reduced vertical transmission will likely lead numerous HIV-positive women to consider becoming pregnant. In order to clarify the demand, and aid with appropriate health services planning for this population, our study aims to assess the fertility desires and intentions of HIV-positive women of reproductive age living in Ontario, Canada. Methodology/Principal Findings A cross-sectional study with recruitment stratified to match the geographic distribution of HIV-positive women of reproductive age (18–52) living in Ontario was carried out. Women were recruited from 38 sites between October 2007 and April 2009 and invited to complete a 189-item self-administered survey entitled “The HIV Pregnancy Planning Questionnaire” designed to assess fertility desires, intentions and actions. Logistic regression models were fit to calculate unadjusted and adjusted odds ratios of significant predictors of fertility intentions. The median age of the 490 participating HIV-positive women was 38 (IQR, 32–43) and 61%, 52%, 47% and 74% were born outside of Canada, living in Toronto, of African ethnicity and currently on antiretroviral therapy, respectively. Of total respondents, 69% (95% CI, 64%–73%) desired to give birth and 57% (95% CI, 53%–62%) intended to give birth in the future. In the multivariable model, the significant predictors of fertility intentions were: younger age (age<40) (p<0.0001), African ethnicity (p<0.0001), living in Toronto (p = 0.002), and a lower number of lifetime births (p = 0.02). Conclusions/Significance The proportions of HIV-positive women of reproductive age living in Ontario desiring and intending pregnancy were higher than reported in earlier North American studies. Proportions were more similar to those reported from African populations. Healthcare providers and policy makers need to consider increasing services and support for pregnancy planning for HIV-positive women. This may be particularly significant in jurisdictions with high levels of African immigration.

Audit and Feedback to Reduce Broad-Spectrum Antibiotic Use among Intensive Care Unit Patients A Controlled Interrupted Time Series Analysis

OBJECTIVE We aimed to rigorously evaluate the impact of prospective audit and feedback on broad-spectrum antimicrobial use among critical care patients. DESIGN Prospective, controlled interrupted time series. SETTING Single tertiary care center with 3 intensive care units. PATIENTS AND INTERVENTIONS A formal review of all critical care patients on their third or tenth day of broad-spectrum antibiotic therapy was conducted, and suggestions for antimicrobial optimization were communicated to the critical care team. OUTCOMES The primary outcome was broad-spectrum antibiotic use (days of therapy per 1000 patient-days; secondary outcomes included overall antibiotic use, gram-negative bacterial susceptibility, nosocomial Clostridium difficile infections, length of stay, and mortality. RESULTS The mean monthly broad-spectrum antibiotic use decreased from 644 days of therapy per 1,000 patient-days in the preintervention period to 503 days of therapy per 1,000 patient-days in the postintervention period (P < .0001); time series modeling confirmed an immediate decrease (± standard error) of 119 ± 37.9 days of therapy per 1,000 patient-days (P = .0054). In contrast, no changes were identified in the use of broad-spectrum antibiotics in the control group (nonintervention medical and surgical wards) or in the use of control medications in critical care (stress ulcer prophylaxis). The incidence of nosocomial C. difficile infections decreased from 11 to 6 cases in the study intensive care units, whereas the incidence increased from 87 to 116 cases in the control wards (P = .04). Overall gram-negative susceptibility to meropenem increased in the critical care units. Intensive care unit length of stay and mortality did not change. CONCLUSIONS Institution of a formal prospective audit and feedback program appears to be a safe and effective means to improve broad-spectrum antimicrobial use in critical care.

Filgrastim prevents severe neutropenia and reduces infective morbidity in patients with advanced HIV infection : results of a randomized, multicenter, controlled trial

Objective:To assess the effect of filgrastim treatment on the incidence of severe neutropenia in patients with advanced HIV infection, and the effect of initial filgrastim treatment on prevention of infectious morbidity. Design:Randomized, controlled, open-label, multicenter study. Setting:Outpatient centers and physician offices. Patients:Men and women aged > 13 years, who were HIV antibody-positive, and had a CD4 cell count < 200 × 106/l, absolute neutrophil count (ANC) 0.7−1.0 × 109/l, and platelet count ≥ 50 × 109/l within 7 days of randomization were eligible. Two hundred and fifty-eight patients entered and 201 completed the study. Intervention:Daily filgrastim (starting at 1 µg/kg daily, adjusted up to 10 µg/kg daily) or intermittent filgrastim (starting at 300 µg daily one to three times per week to a maximum of 600 µg daily 7 days weekly) was administered to maintain an ANC between 2 and 10 × 109/l. Patients in the control group received filgrastim if severe neutropenia developed. Main outcome measures:Incidence of severe neutropenia (ANC < 0.5 × 109/l) or death, incidence of bacterial and fungal infections, duration of hospitalization and intravenous antibacterial use, and safety. Results:The primary endpoint of severe neutropenia or death was less frequent in patients who received daily (12.8%) or intermittent (8.2%) filgrastim compared with control patients (34.1%; P < 0.002 and P < 0.0001 for comparison with daily and intermittent groups, respectively). Filgrastim-treated patients developed 31% fewer bacterial infections and 54% fewer severe bacterial infections than control patients, required 26% less hospital days including 45% fewer hospital days for bacterial infections, and needed 28% fewer days of intravenous antibacterials. Filgrastim was not associated with an increase in HIV-1 plasma RNA level in a subset of patients in whom this was measured or any new or unexpected adverse events. Conclusion:Filgrastim was safe and effective in preventing severe neutropenia in patients with advanced HIV infection, and may reduce the incidence and duration of bacterial infections, incidence of severe bacterial infections, duration of hospital days for infections, and days of intravenous antibacterial agents.

Predictive accuracy of the veterans aging cohort study index for mortality with HIV infection: A north american cross cohort analysis

Background:By supplementing an index composed of HIV biomarkers and age (restricted index) with measures of organ injury, the Veterans Aging Cohort Study (VACS) index more completely reflects risk of mortality. We compare the accuracy of the VACS and restricted indices (1) among subjects outside the Veterans Affairs Healthcare System, (2) more than 1–5 years of prior exposure to antiretroviral therapy (ART), and (3) within important patient subgroups. Methods:We used data from 13 cohorts in the North American AIDS Cohort Collaboration (n = 10, 835) limiting analyses to HIV-infected subjects with at least 12 months exposure to ART. Variables included demographic, laboratory (CD4 count, HIV-1 RNA, hemoglobin, platelets, aspartate and alanine transaminase, creatinine, and hepatitis C status), and survival. We used C-statistics and net reclassification improvement (NRI) to test discrimination varying prior ART exposure from 1 to 5 years. We then combined Veterans Affairs Healthcare System (n = 5066) and North American AIDS Cohort Collaboration data, fit a parametric survival model, and compared predicted to observed mortality by cohort, gender, age, race, and HIV-1 RNA level. Results:Mean follow-up was 3.3 years (655 deaths). Compared with the restricted index, the VACS index showed greater discrimination (C-statistics: 0.77 vs. 0.74; NRI: 12%; P < 0.0001). NRI was highest among those with HIV-1 RNA <500 copies per milliliter (25%) and age ≥50 years (20%). Predictions were similar to observed mortality among all subgroups. Conclusions:VACS index scores discriminate risk and translate into accurate mortality estimates over 1–5 years of exposure to ART and for diverse patient subgroups from North American.