Virologic and immunologic benefits of initial combination therapy with zidovudine and zalcitabine or didanosine compared with zidovudine monotherapy. Wellcome Resistance Study Collaborative Group

A randomized controlled study was done to determine whether initial combination therapy with zidovudine and zalcitabine or zidovudine and didanosine would delay the emergence of zidovudine-resistant virus. Human immunodeficiency virus (HIV)-1-infected patients with <300 CD4 cells/mm3 and <4 weeks of prior zidovudine therapy were randomized to zidovudine, zidovudine plus zalcitabine, or zidovudine plus didanosine. Combination therapy did not delay the emergence of zidovudine-resistant virus isolates. However, combination therapy resulted in a significant increase in CD4 cells through 72 weeks compared with zidovudine monotherapy and a greater and more sustained decline in serum HIV-1 RNA. Although this trial was not designed as a clinical end-point study, patients assigned to zidovudine plus didanosine combination therapy experienced a significant delay in time to first AIDS-defining event or death compared with those assigned to zidovudine monotherapy.     

A randomized study of combined zidovudine-lamivudine versus didanosine monotherapy in children with symptomatic therapy-naive HIV-1 infection. The Pediatric AIDS Clinical Trials Group Protocol 300 Study Team

Platelet-derived adherence-inhibiting factor (AIF) has been demonstrated to regulate the neutrophil binding to type IV collagen. In this study, we have examined the effect of AIF on neutrophil adherence to confluently cultured human umbilical vein endothelial cells (EC). AIF inhibited neutrophil adherence to thrombin- or tumor necrosis factor alpha (TNF-alpha)-stimulated EC by 75 or 43%, respectively, but hardly affected neutrophil adherence to resting EC. It is interesting to note that the inhibitory activity of AIF was reduced by N-formyl-methionyl-leucyl-phenylalanine (fMLP) stimulation of neutrophils. Pretreatment of neutrophils or EC with AIF inhibited neutrophil adherence to thrombin- or TNF-alpha-stimulated EC, suggesting that neutrophils and EC have AIF-binding proteins. Using AIF-Sepharose affinity chromatography, AIF-binding proteins containing L-selectin were isolated from 125I-labeled resting neutrophils. However, L-selectin was markedly decreased in the AIF-binding fraction from fMLP-stimulated neutrophils. With the use of AIF-affinity chromatography, P- and E-selectins were obtained in the AIF-binding fractions from resting, thrombin-, and TNF-alpha-stimulated EC. It is important to note that P- and E-selectin were greatly increased in the AIF-binding fractions from thrombin- and TNF-alpha-stimulated EC, respectively. Furthermore, AIF was able to bind to L-selectin-IgG chimeric protein and inhibit the binding of chimeric protein to thrombin or TNF-alpha-stimulated EC. In addition, AIF inhibited the binding of anti-P- or anti-E-selectin monoclonal antibody to the lysates of thrombin- or TNF-alpha-stimulated EC. Together these observations indicate that AIF could recognize L-, P-, and E-selectins, and modulate neutrophil adherence to EC through interactions with selectin molecules.     

A placebo-controlled trial of didanosine plus stavudine, with and without hydroxyurea, for HIV infection. The Swiss HIV Cohort Study

OBJECTIVE: To explore the short-term effects on surrogate markers for HIV progression of didanosine (ddl) plus stavudine (d4T), with or without hydroxyurea. DESIGN: Randomized, double-blinded, prospective study. SETTING: Swiss HIV Cohort Study. PATIENTS: A total of 144 patients (75% antiretroviral-naive) were studied (mean baseline HIV-1 RNA, 4.53 log10 copies/ml; mean CD4 cell count, 370 x 10(6)/l). INTERVENTION: Patients received ddl (200 mg twice daily) plus d4T (40 mg twice daily), with additional hydroxyurea (500 mg twice daily) or placebo. MAIN OUTCOME MEASURES: The primary endpoint was a reduction of viraemia below 200 copies/ml after 12 weeks. At that time, patients who did not reach the primary endpoint were withdrawn in the hydroxyurea arm, whereas patients in the placebo group had the option of adding hydroxyurea to ddl and d4T. All patients were followed until week 24. RESULTS: After 12 weeks, 54% of the patients randomized to hydroxyurea had viraemia below 200 copies/ml, compared with 28% on placebo (P < 0.001). Using an ultrasensitive assay with a limit of detection of 20 copies/ml, 19% of patients receiving hydroxyurea had viraemia levels below 20 copies/ml, compared with 8% on placebo (P = 0.05). Mean decrease in HIV-1 RNA was 2.3 and 1.7 log10 copies/ml for hydroxyurea and placebo groups, respectively (P = 0.001). Hydroxyurea was found to induce lymphopenia (-124 x 10(6)/l). Increase in CD4 cell counts was +28 x 10(6)/l during hydroxyurea treatment compared with +107 x 10(6)/l on placebo (P = 0.001). CONCLUSIONS: Hydroxyurea improved the antiviral activity of d4T and ddl over a 12-week period, but was associated with a smaller increase in CD4 cell counts due to hydroxyurea-induced lymphopenia.     

Incidence and consequences of pregnancy in women with known duration of HIV infection. Italian Seroconversion Study Group

BACKGROUND: The increasing incidence of human immunodeficiency virus (HIV) infection in women of childbearing age led us to evaluate whether pregnancy affects the natural history of this disease. OBJECTIVES: To conduct a prospective study of women with known dates of HIV seroconversion to describe the incidence and outcome of pregnancy and to assess differences according to age and exposure group. To compare the rate of disease progression between pregnant and nonpregnant women. PATIENTS: All participants, recruited from 14 clinical centers in Italy, had documented HIV-seronegative test results followed by confirmed positive test results within 2 years. RESULTS: A total of 331 women, who had seroconversion between 1981 and 1994, were followed up for a median of 5.5 years from seroconversion; 94 developed HIV-related diseases, 47 developed acquired immunodeficiency syndrome, and 53 had at least 1 CD4 cell count lower than 0.10 x 10(9)/L (< 100 cells/mm3). Thirty-eight women (11.5%) were pregnant at the time of HIV seroconversion and 31 (9.4%) became pregnant after HIV seroconversion (cumulative incidence of pregnancy within 8 years of seroconversion, 28.9%; 95% confidence interval, 21.6%-36.2%). Forty-five (65.2%) of the 69 pregnancies were carried to term. There were no discernible differences in these findings by age or exposure group. Pregnant women did not experience a more rapid rate of progression of disease, even when adjusting for age, exposure group, CD4 cell count, or use of treatment (adjusted relative hazards: HIV-related diseases, 0.72; acquired immunodeficiency syndrome, 0.69; CD4 cell count <0.10 x 10(9)/L, 1.24). CONCLUSION: Women infected with HIV continue to become pregnant after seroconversion, yet pregnancy does not appear to influence the rate of progression of HIV disease.     

Oligonucleotide ligation assay for detecting mutations in the human immunodeficiency virus type 1 pol gene that are associated with resistance to zidovudine, didanosine, and lamivudine

Nonpregnant adults with group B streptococcus bacteremia were identified by active surveillance in three hospitals. Serum samples collected within 2 days of the time of blood culture were assayed for IgG antibodies to the capsular polysaccharide of the infecting strain: serotype Ia (3 isolates), III (5 isolates), or V (4 isolates). In 7 of 12 bacteremia episodes, the serum level of IgG to the infecting isolate was > or = 3.5 microg/mL, higher than the 1-2 microg/mL level thought to be protective in neonates. Among selected acute-phase sera, 4 of 5 that contained > or = 3.5 microg/mL specific IgG mediated efficient opsonophagocytic killing of the corresponding group B streptococcus isolate in vitro. High levels of specific antibodies during the acute phase of invasive group B streptococcus infection in nonpregnant adults may reflect a rapid antibody response to infection or, in some cases, may indicate that susceptibility is due to defects in other immune effectors.     

Evaluation of human immunodeficiency virus (HIV) type 1 RNA levels in cerebrospinal fluid and viral resistance to zidovudine in children with HIV encephalopathy

The amount of human immunodeficiency virus (HIV) type 1 RNA and the presence of a codon 215 mutation indicative of zidovudine resistance were evaluated in cerebrospinal fluid (CSF) and plasma obtained from HIV-1-infected children. The level of HIV-1 RNA in CSF was highest in children with severe encephalopathy (n = 25; median, 430 copies/mL; range, 0-2.2 x 10(5) copies/mL) followed by the moderately encephalopathic (n = 7; median, 330; range, 0-1130) and nonencephalopathic groups (n = 9; median, 0; range, 0-566) (P = .007). There was no correlation between CSF and plasma HIV-1 RNA levels. Five of 7 children with the codon 215 mutation in CSF had a progression of encephalopathy, while all 8 children with wild type codon 215 had improved or stable disease during zidovudine treatment (P = .007). These findings suggest that increased viral replication and emergence of drug-resistant HIV-1 variants within the central nervous system may play a role in progression of HIV encephalopathy.     

HIV type 1 resistance in Kenyan sex workers is not associated with altered cellular susceptibility to HIV type 1 infection or enhanced beta-chemokine production

A small group of women (n = 80) within the Nairobi-based Pumwani Sex Workers Cohort demonstrates epidemiologic resistance to HIV-1 infection. Chemokine receptor polymorphisms and beta-chemokine overproduction have been among the mechanisms suggested to be responsible for resistance to HIV-1 infection. This study attempts to determine if any of those mechanisms are protecting the HIV-1-resistant women. Genetic analysis of CCR5 and CCR3 from the resistant women demonstrated no polymorphisms associated with resistance. Expression levels of CCR5 among the resistant women were shown to be equivalent to that found in low-risk seronegative (negative) controls, while CXCR4 expression was greater among some of the resistant women. In vitro infection experiments showed that phytohemagglutinin (PHA)-stimulated peripheral blood mononuclear cells (PBMCs) from resistant women were as susceptible to infection to T cell- and macrophage-tropic North American and Kenyan HIV-1 isolates as were the PBMCs from negative controls. No significant difference in circulating plasma levels of MIP-1alpha and MIP-1beta were found between the resistant women and negative or HIV-1-infected controls. In vitro cultures of media and PHA-stimulated PBMCs indicated that the resistant women produced significantly less MIP-1alpha and MIP-1beta than did negative controls and no significant difference in RANTES levels were observed. In contrast to studies in Caucasian cohorts, these data indicate that CCR5 polymorphisms, altered CCR5 and CXCR4 expression levels, cellular resistance to in vitro HIV-1 infection, and increased levels of beta-chemokine production do not account for the resistance to HIV-1 infection observed among the women of the Pumwani Sex Workers Cohort.     

Effectiveness of potent antiretroviral therapy on time to AIDS and death in men with known HIV infection duration. Multicenter AIDS Cohort Study Investigators

CONTEXT: Time to development of acquired immunodeficiency syndrome (AIDS) and time to death have been extended with the increased use of combination therapy and protease inhibitors. Cohort studies following up persons with human immunodeficiency virus (HIV) infection in periods characterized by different therapies offer the opportunity to estimate therapy effectiveness at the population level. OBJECTIVE: To assess the effectiveness of self-reported, long-term potent antiretroviral therapy in a cohort of 536 men whose duration of HIV infection was known (seroconverters). DESIGN: Cohort study. The cohort was compared for time to development of AIDS and time to death in 1984 to 1990, 1990 to 1993, 1993 to July 1995, and July 1995 to July 1997 when the major treatments were no therapy, monotherapy, combined therapy, and potent antiretroviral therapy, respectively. Survival analysis methods with time zero set as the date of seroconversion and incorporating staggered entries into each period were used. Mean CD4 cell change, stratified by infection duration, was determined for each period using a random effects model. SETTING: The Multicenter AIDS Cohort Study (MACS) in 4 urban areas (Baltimore, Md; Chicago, III; Los Angeles, Calif; and Pittsburgh, Pa). PARTICIPANTS: A total of 5622 men who were 18 years or older were enrolled into MACS. Of the 5622, there were 2191 HIV-positive individuals at enrollment. Of the 3431 men who were HIV-negative, 536 were observed to seroconvert and were followed up for up to 13 years. The group of 536 who seroconverted constituted the study population. MAIN OUTCOME MEASURES: Time from seroconversion to development of AIDS and to death and change in CD4 cell count. RESULTS: A total of 231 seroconverters developed AIDS, and 200 men died. Using 1990 to 1993 as the reference period, the relative hazard of AIDS was 1.04 (95% confidence interval [CI], 0.73-1.48) during 1993 to July 1995 and 0.35 (95% CI, 0.20-0.61) during July 1995 to July 1997. Relative hazards of death were 0.87 (95% CI, 0.58-1.31) and 0.62 (95% CI, 0.38-1.01 ) for the same periods. The relative time (the factor by which times are contracted or expanded) to development of AIDS was 0.97 (95% CI, 0.86-1.09) for 1993 to July 1995 and 1.63 (95% CI, 1.40-1.89) for July 1995 to July 1997. Relative survival time for 1993 to July 1995 was 1.01 (95% CI, 0.91-1.12) and for July 1995 to July 1997 was 1.21 (95% CI, 1.07-1.36) relative to 1990 to 1993. The rate of CD4 cell count decline in July 1995 to July 1997 was significantly lower (P<.05) compared with the previous 2 periods. CONCLUSIONS: In the calendar period when potent antiretroviral therapy was introduced, the time to development of AIDS and time to death were extended, and rate of CD4 cell count decline was arrested.     

Antiretroviral treatment of men infected with human immunodeficiency virus type 1 reduces the incidence of heterosexual transmission. Italian Study Group on HIV Heterosexual Transmission

OBJECTIVE: To determine the incidence of heterosexual human immunodeficiency virus type 1 disease transmission and the effect of zidovudine therapy on this risk of transmission. DESIGN: A cohort of 436 monogamous seronegative female sexual partners of human immunodeficiency virus type 1-infected males was followed up for 740 person-years with regular structured interviews and laboratory tests. PATIENTS: At enrollment of the women, 50% of their infected partners had one or more signs of disease progression (symptoms of acquired immunodeficiency syndrome, p24 antigen positivity, or CD4+ cell counts lower than 0.4 x 10(9)/L) and 15% were treated with zidovudine. MAIN OUTCOME MEASURE: Incidence rates of seroconversion were calculated and relative risks were estimated as incidence rate ratios. RESULTS: Twenty-seven women seroconverted during follow-up, and the incidence of seroconversion was 3.7 per 100 person-years. Seroconversion was about six times more frequent (relative risk, 5.8; 95% confidence interval, 2.2 to 15.3) in couples not using condoms. Men with signs of disease progression transmitted infection to their partners more frequently and were more frequently treated with zidovudine. When the risk of transmission was estimated accounting for disease progression, the rate of transmission in zidovudine-treated men was lower than in untreated men (relative risk, 0.5; 95% confidence interval, 0.1 to 0.9). CONCLUSION: Treatment of human immunodeficiency virus type-1 infected men with zidovudine reduces, but does not eliminate, heterosexual transmission of infection. Behavioral counseling that encourages sexual practices with a lower risk of transmission remains the most important method of prevention.     

Maternal viral genotypic zidovudine resistance and infrequent failure of zidovudine therapy to prevent perinatal transmission of human immunodeficiency virus type 1 in pediatric AIDS Clinical Trials Group Protocol 076

Maternal samples were assessed from 96 women enrolled in Pediatric AIDS Clinical Trials Group protocol 076 to determine the prevalence of human immunodeficiency virus type 1 (HIV-1) genotypic zidovudine resistance at entry, if zidovudine resistance developed on study, and the role of zidovudine resistance in vertical transmission of HIV-1 despite zidovudine therapy. Low and high levels of genotypic resistance were assessed by differential hybridization, oligoligation, or direct sequencing of plasma HIV-1 RNA for codons K70R and T215Y/F. None of the women had high-level genotypic resistance to zidovudine at study entry or delivery. For low-level zidovudine resistance, the 95% confidence intervals were 0.3%-6.8% for baseline prevalence and 0.3%-14% for delivery incidence. Low-level zidovudine resistance, adjusted for plasma viral RNA level at delivery, was not strongly associated with an increase in vertical transmission risk (odds ratio, 4.8; 95% confidence interval, 0.2-131; P = .35).     

Effect of aspirin on mortality in women with symptomatic or silent myocardial ischemia. Israeli BIP Study Group

The benefit of aspirin therapy among women with coronary artery disease (CAD) is not well established. Previous studies have shown conflicting results among women. Data from 2,418 women with CAD screened for participation in the ongoing Bezafibrate Infarction Prevention (BIP) study were analyzed: 45% reported aspirin therapy. Baseline characteristics were similar in both groups. Cardiovascular mortality at 3.1 +/- 0.9 years of follow-up was 2.7% in the aspirin treated group versus 5.1% in the non-aspirin-treated women (p = 0.002). All cause mortality was 5.1% and 9.1%, respectively (p = 0.0001). Treatment with aspirin emerged as an independent predictor of reduced cardiovascular (RR = 0.61, 95% confidence interval [CI] 0.38 to 0.97) and all cause (RR = 0.66, 95% CI 0.47 to 0.93) mortality after multiple adjustment for possible confounders such as age, history of myocardial infarction, systemic hypertension, diabetes mellitus, peripheral vascular disease, current smoking, New York Heart Association classification, and concomitant treatment with digitalis. Women who benefited the most from aspirin therapy were older, diabetic, symptomatic, or had a previous myocardial infarction. Thus, treatment with aspirin was associated with reduced mortality among women with CAD. This study suggests that women with CAD should be treated with aspirin, unless specific contraindications exist.     

Doxorubicin and cisplatin therapy in children with neuroblastoma resistant to conventional therapy: a Southwest Oncology Group Study

Fifteen children with metastatic neuroblastoma resistant to vincristine and cyclophosphamide were treated with two drugs which were known to be effective as single drugs against neuroblastoma. The drugs were given in courses every 3 weeks. Doxorubicin (50 mg/m2 iv) was given on Day 1 and cisplatin (50 mg/m2) was administered on Day 2 as an 8-hour infusion, using a forced diuretic-hydration program. Three of the 15 children achieved partial or complete remission. Three children showed improvement. The other children either did not respond to the therapy or had progressive disease. The combination of doxorubicin and cisplatin given in the sequence outlined is no more effective than either drug given singly. The side effects of the drug combination were tolerable and were in keeping with previously described toxicity.     

A multicentre study of fluconazole versus oral polyenes in the prevention of fungal infection in children with hematological or oncological malignancies. Multicentre Study Group

A randomized, comparative study was conducted in 502 patients in 23 centres world-wide to assess the efficacy and safety of fluconazole versus nystatin and amphotericin B for prevention of fungal infection in a severely immunocompromised pediatric population. Patients scheduled within 48 hours to undergo chemotherapy or radiotherapy for hematological or oncological malignancies were randomly allocated to receive 3 mg/kg oral fluconazole once daily, 50,000 U/kg oral nystatin four times daily or 25 mg/kg oral amphotericin B four times daily. Prophylaxis began with the initiation of chemotherapy or radiotherapy and continued throughout a patient's hospital stay or period of neutropenia as necessary. The mean duration of fluconazole prophylaxis was 27.8 days and of the oral polyenes 29.2 days. The outcome of prophylaxis with fluconazole was significantly superior to that with the polyenes (p = 0.01). Mycologically verified infections occurred in 5 patients (2.1%) given fluconazole and in 21 (8.4%) given polyenes (p = 0.002). Clinical evaluation at the end of prophylaxis showed that the clinical outcome was definitely or possibly successful in 87% in the fluconazole group and 82% in the polyenes group with no significant differences between the treatment groups. Mycological evaluation demonstrated reduction or control of colonization in 84% in the fluconazole group and 85% in the polyenes group, again with no significant between-group differences. Possibly drug-related side effects, mainly mild to moderate gastrointestinal disturbances, were reported in 38 patients given fluconazole, with eight subsequent withdrawals, and in 21 patients given oral polyenes, with three subsequent withdrawals. Laboratory test abnormalities occurred in 28 patients given fluconazole and 24 given polyenes.(ABSTRACT TRUNCATED AT 250 WORDS)     

Serum beta-carotene and antioxidant micronutrients in children with cancer. The 'Cancer in Children and Antioxidant Micronutrients' French Study Group

Serum antioxidant vitamins A (retinol) and E (alpha-tocopherol), beta-carotene, zinc and selenium for 418 children with newly diagnosed malignancy were compared with those of 632 cancer-free controls. Incident cancer cases and controls were 1-16 years old and recruited in 1986-1989. Age- and sex-adjusted serum concentrations of retinol, beta-carotene and alpha-tocopherol were significantly inversely associated with cancer. In similar models, the odds ratio (OR) comparing the highest with the lowest quintile was 2.06 (95% confidence interval [CI] 1.40-3.02) for retinol, 3.87 (95% CI: 2.54-5.90) for beta-carotene, 2.15 (95% CI: 1.48-3.10) for alpha-tocopherol, 1.29 (95% CI: 0.75-2.23) for selenium, and 1.94 (95% CI: 1.17-2.23) for zinc. The cancer sites that were associated with serum beta-carotene were, in general, leukaemia, lymphoma, central nervous system, bone and renal tumours. Moreover, leukaemia was associated with low mean serum levels of retinol, selenium and zinc. Subjects with lymphoma, bone and renal tumours also had lower mean retinol and alpha-tocopherol levels than controls. Brain tumour patients had low vitamin E levels. Low serum values of antioxidant vitamins were associated with childhood neoplasm occurrence. Some site-specific effect was reported. Low peripheral nutrient levels are not considered as cancer promoters but rather as an impairment of the body's defence mechanism occurring during the cancer-related metabolic and nutritional disturbances and inflammation processes.     

Effect of quinapril on the albumin excretion rate in patients with mild to moderate essential hypertension. Multicenter Study Group

The rising number of emergency admissions and the increasing specialisation of medicine sometimes cause problems in the organisation of care for patients admitted as emergencies to medical beds. A multidisciplinary working group from general practice and the hospital sector identified five main areas in which problems occurred-communication, appropriateness of referral, finding beds, waiting by patients, and the organisation of clinical care. Guidelines and standards were suggested. We then carried out an audit of acute care in 42 hospitals with 400 or more acute beds. The most significant problems that emerged were the suboptimal involvement of consultants in acute care, the frequent lack of appropriateness of the admitting specialty to the patient's condition, and confusion about policies for admitting elderly patients.     

Randomized, open-label trial of azithromycin plus ethambutol vs. clarithromycin plus ethambutol as therapy for Mycobacterium avium complex bacteremia in patients with human immunodeficiency virus infection. Veterans Affairs HIV Research Consortium

Disseminated Mycobacterium avium complex (MAC) infection continues to be a common opportunistic infection in patients infected with human immunodeficiency virus (HIV). The optimal therapy for disseminated MAC infection is unclear. We compared azithromycin plus ethambutol with clarithromycin plus ethambutol in the treatment of disseminated MAC infection in HIV type 1-infected patients, examining the frequency of bacteremia clearance, time to clearance, and study drug tolerance after 16 weeks of therapy. Fifty-nine patients for whom blood cultures were positive for MAC were enrolled in the study from 10 university-affiliated Veterans Affairs Medical Centers. Thirty-seven patients were evaluable for determination of quantitative bacteremia and clinical outcomes. Clearance of bacteremia was seen at the final visit in 37.5% of azithromycin-treated patients and in 85.7% of clarithromycin-treated patients (P = .007). The estimated median time to clearance of bacteremia was also significantly different between the two treatment arms: 4.38 weeks for clarithromycin recipients vs. > 16 weeks for azithromycin recipients (P = .0018). Only one isolate developed macrolide resistance during therapy. Abatement of symptoms, other laboratory-evident abnormalities, and adverse effects were similar in the two groups. At the doses used in this study, clarithromycin/ethambutol produced a more rapid resolution of bacteremia than did azithromycin/ethambutol, and clarithromycin/ethambutol was more effective at sterilization of blood cultures after 16 weeks of therapy.