Frank S. Rhame

The Safety and Efficacy of Zidovudine (AZT) in the Treatment of Subjects with Mildly Symptomatic Human Immunodeficiency Virus Type 1 (HIV) Infection: A Double-Blind, Placebo-Controlled Trial

OBJECTIVE To evaluate the efficacy and safety of zidovudine early in the treatment of human immunodeficiency virus type 1 (HIV) infection. DESIGN A double-blind, randomized, placebo-controlled trial with subject stratification by pretreatment CD4 T lymphocyte counts. SETTING Multicenter trial at AIDS Clinical Trial units. SUBJECTS Seven hundred eleven subjects with mildly symptomatic HIV infection. INTERVENTION Three hundred fifty-one subjects were assigned to placebo and 360 to zidovudine, 200 mg orally every 4 hours. The median duration of follow-up was 11 months. MEASUREMENTS AND MAIN RESULTS Fifty-one subjects developed the acquired immunodeficiency syndrome (AIDS), advanced AIDS-related complex, or death as a first critical event. For the stratum of subjects with more than 200 but less than 500 CD4 T lymphocytes/mm3 before treatment, 34 events occurred in placebo recipients and 12 in zidovudine recipients (P = 0.0002; relative risk [RR] estimate, 3.23 [95% CI, 1.67 to 6.24]). For the stratum of subjects with 500 to 799 CD4 T lymphocytes/mm3 before treatment, 2 events occurred in placebo recipients and 3 in zidovudine recipients. Candidiasis at study entry independently increased the risk for having an event (P = 0.005; RR estimate, 2.3 [95% CI, 1.29 to 4.12]); HIV antigenemia at study entry also increased this risk (P = 0.01; RR estimate, 2.1 [95% CI, 1.2 to 3.8]). Significant differences between the treatment groups in CD4 T-lymphocyte counts occurred in subjects with more than 200 but less than 500 CD4 T lymphocytes/mm3 after 4 weeks of therapy (P = 0.002). Differences persisted through week 52. Less prominent changes occurred in subjects with 500 or more CD4 T lymphocytes/mm3. Serum levels of HIV antigen decreased significantly in zidovudine recipients. Serious anemia and neutropenia occurred in 5% and 4% of zidovudine recipients, respectively, and in 0% and 1% of placebo recipients, respectively. CONCLUSION Zidovudine delayed progression of HIV disease and produced little toxicity in subjects with mildly symptomatic HIV disease and less than 500 CD4 T lymphocytes/mm3.

Infection Control in Intravenous Therapy

Abstract The intravenous infusion has become indispensable in modern medical therapy, but infection, especially infusion-associated septicemia, remains a life-threatening hazard. In 1970 to 1971 a ...

Low Vitamin D among HIV-Infected Adults: Prevalence of and Risk Factors for Low Vitamin D Levels in a Cohort of HIV-Infected Adults and Comparison to Prevalence among Adults in the US General Population

BACKGROUND we explored serum 25-hydroxyvitamin D (25[OH]D) levels and associated factors for insufficiency or deficiency in an adult human immunodeficiency virus (HIV) cohort and compared 25(OH)D levels with those in the general US population. METHODS using baseline data from the Study to Understand the Natural History of HIV and AIDS in the Era of Effective Therapy (SUN), a prospective, observational cohort study of HIV-infected adults enrolled at 7 HIV specialty clinics in 4 US cities from March 2004 to June 2006, we estimated the prevalence of vitamin D insufficiency or deficiency (defined as 25(OH)D levels <30 ng/mL), standardized by age, race, and sex. Using multiple logistic regression, we examined risk factors for vitamin D insufficiency or deficiency. RESULTS among 672 SUN participants with baseline serum 25(OH)D determinations who were not receiving vitamin D supplements, 70.3% (95% confidence interval [CI], 68.1%-74.9%) were vitamin D insufficient or deficient, compared with 79.1% (95% CI, 76.7-81.3) of US adults. Factors associated with vitamin D insufficiency or deficiency included black race (adjusted odds ratio [aOR], 4.51; 95% CI, 2.59-7.85), Hispanic ethnicity (aOR, 2.78; 95% CI, 1.31-5.90), higher body mass index (aOR, 1.04; 95% CI, 1.00-1.09), hypertension (aOR, 1.88; 95% CI, 1.10-3.22), lack of exercise (aOR, 3.14; 95% CI, 1.80-5.47), exposure to efavirenz (aOR, 1.98; 95% CI, 1.18-3.34), higher exposure to ultraviolet light (aOR, .78; 95% CI, .71-.86), renal insufficiency (aOR, .55; 95% CI, .36-.83), and exposure to ritonavir (aOR, .56; 95% CI, .35-0.89). CONCLUSIONS similar to findings in US adults generally, vitamin D insufficiency or deficiency is highly prevalent among HIV-infected adults and is associated with known risk factors. Observed associations of vitamin D levels with renal insufficiency and with use of ritonavir- and efavirenz-containing regimens are consistent with both HIV-related and therapy-mediated alterations in vitamin D metabolism. Clinicians should consider screening all patients for vitamin D insufficiency or deficiency.

Nationwide epidemic of septicemia caused by contaminated intravenous products. I. Epidemiologic and clinical features.

Between mid-1970 and April 1, 1971, Enterobacter cloacae or E. agglomerans septicemia developed in 378 patients in 25 American hospitals while they were receiving intravenous products manufactured by one company. Each of the hospitals noted a marked increase in the incidence of such septicemia during this period. Enterobacter agglomerans (formerly designated Erwinia, herbicola-lathyri group) was better known as a plant pathogen and had been a human blood pathogen only rarely in the past. Septicemia caused by E. cloacae had also been uncommon.

Extrinsic risk factors for pneumonia in the patient at high risk of infection

Most nosocomial pathogens cause pneumonia through the following sequence: transit to the patient on the hands of medical personnel or perhaps in food, proliferation in the nasopharynx, and subsequent pulmonary aspiration. There are three exceptional pathogens, each of particular concern as a cause of pneumonia in the immunocompromised patient, which follow atypical routes. Important recent advances in understanding these routes permit more rational preventive measures. This report examines the evidentiary basis for the following pathophysiolgic propositions about these three pathogens: Aspergillus, Pneumocystis carinii, and Legionella. Aspergillus spores are almost ubiquitous. Spore generation, except in very unusual circumstances, takes place outside the hospital. Most spores enter the hospital borne in air by infiltration or because of incomplete filtration. Air filtration systems of moderate efficiency remove Aspergillus spores. Nosocomial pulmonary and disseminated aspergillosis arises from inhalation of airborne spores. A nasopharygeal colonization intermediate step before pulmonary disease has not yet been solidly established. It is now firmly established that airborne Pneumocystic carinii transmission occurs between animals. Airborne acquisition probably occurs early in human life. However, in-hospital, person-to-person transmission has yet to be convincingly demonstrated. Most or all cases of pneumocystosis in adults are due to reactivation of endogenous pulmonary organisms. Intensive diagnostic efforts reveal that Legionella is a common cause of community-acquired and nosocomial pneumonia in hospitals where it had not previously been recognized. However, there are at least a few hospitals where it is an uncommon source of pneumonia. Several hospitals have demonstrated a temporal association between the presence of Legionella in hot water systems and nosocomial cases of Legionella pneumonia. The mechanism or mechanisms of transmission to the patient remain to be delineated. It is also not determined if all hospital hot water systems should be maintained Legionella free.

The Case for Wider Use of Testing for HIV Infection

There has been reluctance by the medical establishment and government to promote extensive human immunodeficiency virus (HIV) testing, even though it can be done economically and accurately. There are good arguments for more testing of 1 of the most serious epidemics of a infectious diseases in history. In 1987 there was estimated to be over 1 million people infected with HIV and most of them are unaware of the infection. The current methods to make people with HIV infection aware of the disease are not effective. Many people do not realize that early detection of HIV is important and that it is treatable. Where increased testing has been done there is evidence that unsafe sexual practices have been reduced by those with HIV. Another benefit of early detection of HIV is the identification of candidates for experimental therapies. There are reports that zidovudine is effective immediately after exposure to HIV, and hospitals should offer this treatment free to personnel exposed to blood or body fluids of an infected person. The effectiveness of hospital precautions should be evaluated and routine screening of patients can then be decided. Testing for HIV in the health care system could drive away those infected or who fear they are. Another argument against wider testing is false positive test results, but use of screening with sequential enzyme immunoassays followed by Western blot should rarely produce false positive results. It is a minimum requirement to test all patients that acknowledge sexual contact with homosexual men, any needle sharing, and any multiple unsafe heterosexual contacts. Also, testing of prenatal patients is strongly recommended, since early detection can allow abortion decision to be made, and also further pregnancies can be prevented.

Week 96 efficacy and safety of rilpivirine in treatment-naive, HIV-1 patients in two Phase III randomized trials.

Background:In the week 48 primary analysis of ECHO and THRIVE, rilpivirine demonstrated noninferior efficacy and more favourable tolerability versus efavirenz in treatment-naive, HIV-1-infected adults. Pooled 96-week results are presented. Methods:Patients (N = 1368) received rilpivirine 25 mg once-daily (q.d.) or efavirenz 600 mg q.d., with two background nucleoside/nucleotide reverse transcriptase inhibitors, in two randomized, double-blind, double-dummy Phase III trials. Results:At week 96, response rate (% confirmed viral load <50 copies/ml; intent-to-treat, time-to-loss-of-virologic response) was 78% in both groups. Responses were similar for both treatments by background regimen, sex, race, and in patients with more than 95% adherence (M-MASRI) or baseline viral load 100 000 copies/ml or less. Responses were lower and virologic failure higher for rilpivirine versus efavirenz in patients with 95% or less adherence or baseline viral load more than 100 000 copies/ml. Beyond week 48, the incidence of virologic failure was comparable (3 versus 2%) between treatment groups, rilpivirine resistance-associated mutations were consistent with those observed in year 1, there were few adverse events in both groups and no new safety concerns. Over 96 weeks, discontinuations due to adverse events (4 versus 9%), treatment-related grade 2–4 adverse events (17 versus 33%), rash (4 versus 15%), dizziness (8 versus 27%) and abnormal dreams/nightmares (8 versus 13%), and grade 2–4 lipid abnormalities were lower with rilpivirine than efavirenz. Only 2 and 4% of patients in the rilpivirine and efavirenz treatment groups, respectively, reported at least possibly treatment-related grade 2–4 adverse events during the second year of treatment. Conclusions:Rilpivirine 25 mg q.d. and efavirenz 600 mg q.d. had comparable responses at week 96. Rilpivirine had more virologic failures but improved tolerability versus efavirenz. The majority of virologic failures occurred in the first 48 weeks.

Guidelines for infection control in intravenous therapy.

Abstract Infusion-associated septicemia is an appreciable hazard to the more than 8 million patients who receive intravenous therapy in U.S. hospitals each year. Rigorous infection control measures...

The use of a transscrotal testosterone delivery system in the treatment of patients with weight loss related to human immunodeficiency virus infection.

PURPOSE Weight loss is a strong predictor of morbidity and mortality in human immunodeficiency virus (HIV)-infected patients. Men with acquired immunodeficiency syndrome (AIDS) lose body cell mass. Hypogonadism is also common. This study tested the efficacy of a testosterone transscrotal patch (6 mg/day) in improving body cell mass and treating hypogonadism in these patients. SUBJECTS AND METHODS This multicenter, randomized, double-blinded, placebo-controlled trial was conducted from August 1995 to October 1996 in 133 men, 18 years of age and older, who had AIDS, 5% to 20% weight loss, and either a low morning serum total testosterone level (<400 ng/dL) or a low free testosterone level (<16 pg/mL). Outcomes included weight, body cell mass as measured using bioelectrical impedance analysis, quality of life, and morning measurements of serum testosterone and dihydrotestosterone levels, lymphocyte subsets, and HIV quantification. RESULTS There were no significant differences in baseline weight, CD4 cell counts, or HIV serum viral quantification between treatment arms. Morning total and free testosterone levels increased in those treated with testosterone, but not with placebo. Following 12 weeks of treatment there were no differences (testosterone-placebo) in mean weight change (-0.3 kg [95% confidence interval (CI): -1.4 to 0.8]) or body cell mass (-0.2 kg [95% CI: -1.0 to 0.6]) in the two groups. There were also no changes in quality of life in either group. CONCLUSION Hypogonadal men with AIDS and weight loss can achieve adequate morning serum sex hormone levels using a transscrotal testosterone patch. However, this system of replacement does not improve weight, body cell mass, or quality of life.

Pharmacological Basis for Concentration-Controlled Therapy with Zidovudine, Lamivudine, and Indinavir

ABSTRACT Conventional antiretroviral therapy involves administration of standard fixed doses to adults and adolescents. This approach ignores interindividual variability in pharmacokinetics and results in substantial differences in systemic concentrations among patients. Thus, variability in systemic concentrations contributes to variability in response to therapy. This study was designed to evaluate the feasibility and safety of a regimen of zidovudine, lamivudine, and indinavir designed to achieve select target concentrations versus standard dose therapy. Twenty-four antiretroviral-naı̈ve subjects completed the 24-week study; 13 received standard therapy, and 11 received concentration-controlled therapy. There were no differences in baseline characteristics. Oral clearance for all three drugs was not different between weeks 2 and 28; average ratios of week 2 oral clearance to week 28 oral clearance were 0.95, 1.09, and 1.06 for zidovudine, lamivudine, and indinavir, respectively, with 95% confidence intervals including 1. The selected target concentrations were average steady-state concentrations of 0.19 mg/liter for zidovudine and 0.44 mg/liter for lamivudine and a trough concentration of 0.15 mg/liter for indinavir; mean concentrations achieved at week 28 in the concentration-controlled arm were 0.20, 0.54, and 0.19 mg/liter, respectively. Concentration-controlled therapy significantly reduced interpatient variability in zidovudine concentrations and significantly increased indinavir concentrations. There was no difference in adverse drug effects or adherence. This investigation has provided a pharmacologic basis for concentration-controlled therapy by demonstrating that it is feasible and has a safety profile no different from that of standard therapy. Additional studies to evaluate the virologic effect of the concentration-controlled approach to antiretroviral therapy are warranted.