Severe acute respiratory syndrome coronavirus 2 RNA contamination of inanimate surfaces and virus viability in a health care emergency unit.

OBJECTIVES: To detect possible severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) RNA contamination of inanimate surfaces in areas at high risk of aerosol formation by patients with coronavirus disease 2019 (COVID-19). METHODS: Sampling was performed in the emergency unit and the sub-intensive care ward. SARS-CoV-2 RNA was extracted from swabbed surfaces and objects and subjected to real-time RT-PCR targeting RNA-dependent RNA polymerase and E genes. Virus isolation from positive samples was attempted in vitro on Vero E6 cells. RESULTS: Twenty-six samples were collected and only two were positive for low-level SARS-CoV-2 RNA, both collected on the external surface of continuous positive airway pressure helmets. All transport media were inoculated onto susceptible cells, but none induced a cytopathic effect on day 7 of culture. CONCLUSIONS: Even though daily contact with inanimate surfaces and patient fomites in contaminated areas may be a medium of infection, our data obtained in real-life conditions suggest that it might be less extensive than hitherto recognized.

Prosthetic Joint Infection from Carbapenemase-Resistant Klebsiella pneumoniae Successfully Treated with Ceftazidime-Avibactam.

Antimicrobial resistance in Gram-negative bacteria, particularly Enterobacteriaceae, has become a leading cause of morbidity and mortality and a serious public health concern. Gram-negative bacteria carrying extended-spectrum beta-lactamase (ESBL) enzymes now represent a significant proportion of all bacteria isolated from different countries worldwide. Furthermore, the increasing number of isolates carrying carbapenemases in recent years includes multidrug-resistant (MDR), extensively drug-resistant (XDR), and pandrug-resistant (PDR) bacteria. Here, we describe what, to our knowledge, is the first case of a patient with a prosthetic joint infection from carbapenemase-resistant Klebsiella pneumoniae (CRKP) successfully treated with ceftazidime-avibactam in Italy.

A prospective multicentre study of the epidemiology and outcomes of bloodstream infection in cirrhotic patients.

OBJECTIVES: To describe the current epidemiology of bloodstream infection (BSI) in patients with cirrhosis; and to analyse predictors of 30-day mortality and risk factors for antibiotic resistance. METHODS: Cirrhotic patients developing a BSI episode were prospectively included at 19 centres in five countries from September 2014 to December 2015. The discrimination of mortality risk scores for 30-day mortality were compared by area under the receiver operator risk and Cox regression models. Risk factors for multidrug-resistant organisms (MDRO) were assessed with a logistic regression model. RESULTS: We enrolled 312 patients. Gram-negative bacteria, Gram-positive bacteria and Candida spp. were the cause of BSI episodes in 53%, 47% and 7% of cases, respectively. The 30-day mortality rate was 25% and was best predicted by the Sequential Organ Failure Assessment (SOFA) and Chronic Liver Failure-SOFA (CLIF-SOFA) score. In a Cox regression model, delayed (>24 hours) antibiotic treatment (hazard ratio (HR) 7.58; 95% confidence interval (CI) 3.29-18.67; p < 0.001), inadequate empirical therapy (HR 3.14; 95% CI 1.93-5.12; p < 0.001) and CLIF-SOFA score (HR 1.35; 95% CI 1.28-1.43; p < 0.001) were independently associated with 30-day mortality. Independent risk factors for MDRO (31% of BSIs) were previous antimicrobial exposure (odds ratio (OR) 2.91; 95% CI 1.73-4.88; p < 0.001) and previous invasive procedures (OR 2.51; 95% CI 1.48-4.24; p 0.001), whereas spontaneous bacterial peritonitis as BSI source was associated with a lower odds of MDRO (OR 0.30; 95% CI 0.12-0.73; p 0.008). CONCLUSIONS: MDRO account for nearly one-third of BSI in cirrhotic patients, often resulting in delayed or inadequate empirical antimicrobial therapy and increased mortality rates. Our data suggest that improved prevention and treatment strategies for MDRO are urgently needed in the liver cirrhosis patients.

Evaluation of a model to improve collection of blood cultures in patients with sepsis in the emergency room.

Sepsis begins outside of the hospital for nearly 80% of patients and the emergency room (ER) represents the first contact with the health care system. This study evaluates a project to improve collection of blood cultures (BCs) in patients with sepsis in the ER consisting of staff education and completion of the appropriate BC pre-analytical phase. A retrospective observational study performed to analyse the data on BC collection in the ER before and after a three-phase project. The first phase (1 January to 30 June 2015) before the intervention consisted of evaluation of data on BCs routinely collected in the ER. The second phase (1 July to 31 December 2015) was the intervention phase in which educational courses on sepsis recognition and on pre-analytical phase procedures (including direct incubation) were provided to ER staff. The third phase (1 January to 30 June 2016; after the intervention) again consisted of evaluation. Before the intervention, out of 24,738 admissions to the ER, 103 patients (0.4%) were identified as septic and had BCs drawn (359 BC bottles); 19 out of 103 patients (18.4%) had positive BCs. After the intervention, out of 24,702 admissions, 313 patients (1.3%) had BCs drawn (1,242 bottles); of these, 96 (30.7%) had positive BCs. Comparing the first and third periods, an increase in the percentage of patients with BCs collected (from 0.4% to 1.3% respectively, p < 0.0001) and an increase in the percentages of patients with true-positive BCs (from 0.08% to 0.39% of all patients evaluated respectively, p < 0.0001) were observed. The isolation of bacteria by BCs increased 3.25-fold after project implementation. These results can be principally ascribed to an improved awareness of sepsis in the staff associated with improved pre-analytical phase procedures in BC collection.

Infective endocarditis in patients with hepatic diseases.

Few data have been published regarding the epidemiology and outcome of infective endocarditis (IE) in patients with chronic hepatic disease (CHD). A retrospective analysis of the Studio Endocarditi Italiano (SEI) database was performed to evaluate the epidemiology and outcome of CHD+ patients compared with CHD- patients. The diagnosis of IE was defined in accordance with the modified Duke criteria. Echocardiography, diagnosis, and treatment procedures were in accordance with current clinical practice. Among the 1722 observed episodes of IE, 300 (17.4 %) occurred in CHD+ patients. The cause of CHD mainly consisted of chronic viral infection. Staphylococcus aureus was the most common bacterial species in CHD+ patients; the frequency of other bacterial species (S. epidermidis, streptococci, and enterococci) were comparable among the two groups. The percentage of patients undergoing surgery for IE was 38.9 in CHD+ patients versus 43.7 in CHD- patients (p = 0.06). Complications were more common among CHD+ patients (77 % versus 65.3 %, p < 0.001); embolization (43.3 % versus 26.1 %, p < 0.001) and congestive heart failure (42 % versus 34.1 %, p = 0.01) were more frequent among CHD+ patients. Mortality was comparable (12.5 % in CHD- and 15 % in CHD+ patients). At multivariable analysis, factors associated with hospital-associated mortality were having an infection sustained by S. aureus, a prosthetic valve, diabetes and a neoplasia, and CHD. Being an intravenous drug user (IVDU) was a protective factor and was associated with a reduced death risk. CHD is a factor worsening the prognosis in patients with IE, in particular in patients for whom cardiac surgery was required.

Differences in implementation of HIV/AIDS clinical research in developed versus developing world: an evidence-based review on protease inhibitor use among women and minorities.

The aim of this revision is to evaluate ethnicity and gender rate of enrolment in registrative clinical trials of the protease inhibitors (Pls) from 1996 to 2009. Company-sponsored, phase II or III registrative clinical trials of PIs were evaluated. Forty-nine clinical trials were included. Clinical trials were conducted in centres in North America (n = 39), Central-South America (n = 22), Europe (n = 22), Africa (n = 8), Asia (n = 5), Australia (n = 10). Overall mean age was 39.6 years; median proportion of women was 16.3%. The most represented ethnic group was Caucasian. A test for trend over time (1996-2009) shows a significant increase in the proportion of women included (P = 0.012), and a decrease in the proportion of Caucasians included, reaching borderline significance (P = 0.061). An inverse correlation was observed between the proportion of Caucasians and that of women enrolled in each study (r = -0.65, P < 0.0001). Women were less likely to be included in double-blind studies (11.2% versus 17%, P = 0.019). Clinical trials for treatment-naive subjects were more likely to enrol ethnicities other than Caucasian compared with Caucasian (44.7% versus 27.1%, respectively, P = 0.04). Rates of enrolment of minorities in registrative clinical trials for Pls show a positive trend since 1996, mirroring the growing number of people of different ethnic groups accessing ART.

Etravirine for the treatment of HIV infection.

Etravirine (TMC125) is a next-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) that is being developed for the treatment of HIV-1 infections. The drug was recently approved by the US FDA to be used in combination with other anti-HIV medications. Etravirine is a highly flexible diarylpyrimidine compound, with favorable binding interactions toward mutant HIV strains as well as wild-type virus. This conformation confers an increased genetic barrier to resistance compared with other NNRTIs: multiple mutations are required before there is a decrease in susceptibility to etravirine; whereas, only one mutation (K103N) is typically needed to confer high-level resistance to the first-generation NNRTIs. In vitro, etravirine is predominantly metabolized by cytochrome P450 (CYP)3A4 and CYP2C (2C9, 2C18 and 2C19). In vivo, the most important metabolic pathway for etravirine is methyl hydroxylation, with subsequent glucuronidation of the metabolites. Etravirine is an inducer of CYP3A4 and a weak inhibitor of CYP2C9, CYP2C19 and P-glycoprotein. In Phase II and III trials in treatment-experienced patients, treatment with etravirine led to better virological suppression than placebo. In the DUET I and II trials (Phase III), approximately 60% of the etravirine group achieved a confirmed viral load of less than 50 copies/ml at week 24, compared with approximately 40% in the placebo arm. The mean change in viral load at week 24 was -2.34 (standard deviation: 1.31) and -1.68 (1.40) log(10) copies/ml in the etravirine and placebo groups, respectively. The presence of three or more NNRTI-associated mutations at baseline negatively influenced the outcome. There were no safety concerns and no major differences in frequency or severity of side effects between etravirine and placebo groups, with the exception of rash. Furthermore, the overall rate of discontinuation due to any adverse event was similar between the etravirine and placebo groups. The most common adverse events reported were rash and nausea.

Osteoprotegerin and bone turnover markers in heavily pretreated HIV-infected patients.

OBJECTIVES: To characterize osteoprotegerin (OPG) levels, bone remodelling and bone mineral density (BMD) in heavily pretreated HIV-infected patients on antiretroviral therapy, and to evaluate the clinical factors associated with bone density decline. METHODS: Heavily pretreated (> 5 years) HIV-positive patients were enrolled in this cross-sectional, observational study, which was based on a total body bone densitometry examination and a comprehensive evaluation of bone and mineral parameters. RESULTS: Sixty-eight patients (55 male and 13 female) with a median age of 41 years (range 25-60 years) were included in the study. Their antiretroviral treatment lasted for 82 months. On the basis of the World Health Organization criteria, nine patients (13.2%) were osteoporotic [T-score < -2.5 standard deviation (SD)] and 19 patients (27.9%) were osteopenic (T-score between -1 and -2.5). The principal outcomes associated with the presence of a low BMD were high OPG and lysylpyridinoline/creatinine ratio (Dpd) values. Most of the patients (39 of 48; 81.25%) showed vitamin D insufficiency [Vitamin D (25(OH)D) < 18 ng/mL] with secondary hyperparathyroidism (13 of 50 patients: 26%), which proved to be correlated to osteocalcin (BGP) levels [parathyroid hormone (PTH) vs. BGP: r = 0.34; P < 0.01]. There was an inverse correlation between T-scores and serum osteocalcin and alkaline phosphatase (AP) levels, on one hand, and Dpd, on the other. High AP and Dpd values were associated with relative risks of 4.1 [95% confidence interval (CI) = 1.01-17.6] and 7.2 (95% CI = 1.67-31.03), respectively, of a pathological T-score. Multivariate analysis revealed that the factors associated with the presence of osteopenia or osteoporosis were older age and lower body mass index. CONCLUSIONS: About 40% of our heavily pretreated subjects with advanced HIV infection had a low BMD, and 56% (24 of 44 patients) showed a high bone turnover rate with marked osteoclast activation. High OPG levels may protect against bone resorption.

Pharmacokinetics of amprenavir given once or twice a day when combined with atazanavir in heavily pre-treated HIV-positive patients.

We studied the pharmacokinetics of amprenavir at doses of 600 mg twice a day or 1200 mg once a day, when co-administered to HIV-positive patients with 400 mg a day of atazanavir without a ritonavir booster. Our preliminary results suggest that amprenavir and atazanavir could be coadministered and that amprenavir could be boosted by atazanavir without the need for ritonavir pharmaco-enhancement.

Role of hydroxyurea during structured treatment interruptions.

Highly active antiretroviral therapies (HAART) represent a major advance in the treatment of HIV infection. Although with HAART a substantial suppression of viral replication can be obtained, eradication of the virus from the body cannot be achieved. Therefore, HIV-infected subjects have to be treated for the rest of their lives. Long term treatment will increase the frequency of: i) drug-related side effects; ii) onset of drug-resistant viral strains; iii) non-adherence of the patients to the treatment. Structured treatment interruptions (STI)-HAART might represent a feasible alternative and preliminary studies have shown that STI-HAART might induce immune control in patients treated in the early stage of infection. This regimen does not produce similar effects in patients treated during the chronic phase of the infection. However, there are some clinical data suggesting a possible role of hydroxyurea (HU) in inducing control of HIV replication in patients with established infection. In this manuscript in vitro and in vivo data indicating that HU might play a major role in the setting of STI-HAART will be presented.

Assessment of atherosclerosis using carotid ultrasonography in a cohort of HIV-positive patients treated with protease inhibitors.

OBJECTIVE: Lipid disorders associated with the use of protease inhibitors (PI) may be a risk factor for premature atherosclerosis development. The aim of this study is to evaluate the extent of carotid intima media thickness (IMT) among HIV-positive patients treated with PI containing regimens compared to PI-naïve and HIV-negative subjects. METHODS: We analysed plasma lipid levels and carotid IMT in 28 HIV-positive patients treated with protease inhibitors (PIs) for a mean of 28.7 months (range 18-43) and in two control groups constituted, respectively, by 15 HIV-positive naïve patients and 16 HIV-negative subjects, that were matched for age, risk factors for HIV infection, cigarette smoke use and CD4+ cell count. RESULTS: PI-treated patients had higher triglyceride, HDL and apo B levels than controls. Carotid IMT was significantly increased in PI-treated patients compared to naïve or HIV-negative subjects. A correlation between cholesterol HDL, triglyceride and ApoB levels and IMT was observed among the entire cohort. CONCLUSIONS: Plasma lipid alterations were associated with an increased IMT and intima media thickening was more pronounced in PI-treated patients than in the two control groups. Periodical evaluation of blood lipid profile and, if required, the use of lipid-lowering agents is advisable. Moreover, physicians should address concurrent risk factor for atherosclerosis that can be modified, including smoking, hypertension, obesity and sedentary life-style.

[Evaluation of the efficacy of a program to control nosocomial spread of methicillin-resistant Staphylococcus aureus]. / Valutazione dell'efficacia di un sistema di controllo della diffusione intraospedaliera di Staphylococcus aureus meticillino-resistente.

OBJECTIVE: To evaluate the efficacy of a program to control nosocomial spread of methicillin-resistant Staphylococcus aureus (MRSA). METHODS: Analysis of the incidence of infection and contamination due to MRSA in patients admitted to the hospital of Cremona 6 months before and 3 years after the introduction of the guidelines (July 1997). RESULTS: During the 42 months of the study period, on 80705 admissions, 511 cases of MRSA contamination/infection were identified, the incidence being 0.57 cases per 100 admissions. The infection rate dropped from 0.34 (IC95%: 0.25-0.45) in the first 6 months of the study, before the introduction of guidelines, to 0.17 (IC95%: 0.14-0.20) in the following 3 years (p=0.01). Severe infection decreased from 0.18 to 0.1 per 100 admissions, with a 44% decrease (p=0.058), while mild infections diminished from 0.16 to 0.07 per 100 admissions (p=0.045). Methicillin resistance among nosocomial isolates of Staphylococcus aureus was reduced from 53 % to 35 % (p<0.0001). CONCLUSIONS: The introduction of a program to control the nosocomial spread of MRSA proved effective in reducing both the incidence of infection and the methicillin-resistance of Staphylococcus aureus isolates. The cost effectiveness of the program seems very favourable.

Nelfinavir suspension obtained from nelfinavir tablets has equivalent pharmacokinetic profile.

The pharmacokinetics of nelfinavir tablets (A) and an oral simplified nelfinavir suspension (B) were studied. Twelve healthy volunteers randomly received either five 250-mg nelfinavir tablets or a simplified oral suspension obtained from tablets dissolved in water (nelfinavir 1250 mg in 100 mL of water) in a single dose before being crossed over to the second treatment after a one-week washout period. Blood samples were drawn up to 24 h after drug administration. Nelfinavir concentrations in plasma were analyzed by a specific and validated reverse-phase high-performance liquid chromatography assay (HPLC) with UV detection, and pharmacokinetic values were determined. For the AUC(0-infinity) with means+/-SD of 31.71+/-7.85, 30.88+/-10.28 (microg/L) respectively for treatments B and A, the ratio (F(B/A)) was of 1.1 with a C.I. of 0.90-1.24. For Cmax with means+/-SD of 3.1+/-0.6 (treatment B) and 3.2+/-0.8 mg/mL (treatment A), the ratio was 1.0. with C.I. of 0.92-1.08. The two treatments evidenced no significant differences in AUC(0-inifnity) and Cmax values and the two-one sided t-test showed that the two preparations are bioequivalent. There was no significant difference in Tmax between the liquid and tablets. Nelfinavir suspension might be a option for treating HIV-infected patients with swallowing disturbances or compliance problems.

Clinical pharmacokinetics of nelfinavir combined with efavirenz and stavudine during rescue treatment of heavily pretreated HIV-infected patients.

Nelfinavir is a novel protease inhibitor that exhibits good inhibitory activity against human immunodeficiency virus type 1 (HIV-1) and is currently used in combination with reverse transcriptase inhibitors for the management of HIV infection. In this study we analysed the pharmacokinetic profile of nelfinavir after multiple oral doses in 18 HIV-infected patients during a combination regimen of nelfinavir plus efavirenz and stavudine. Patients who received the study drug for >/=4 weeks were considered for pharmacokinetic evaluation. Blood samples were obtained at the following times: 0 (before nelfinavir administration), 1, 2, 3, 4, 6 and 8 h after administration. Nelfinavir plasma concentrations were analysed by a specific and validated HPLC assay with ultraviolet detection. Nelfinavir concentration-time data were analysed by compartmental and non-compartmental techniques and the pharmacokinetic parameters of nelfinavir were determined according to a one-compartment model. We found a high variability between individuals in nelfinavir plasma concentrations. The mean average drug plasma concentration was 2.22 +/- 1.25 mg/L and the mean AUC during the dosing interval was 17.7 +/- 10.0 mg*h/L. The mean nelfinavir trough plasma concentration was 1.58 +/- 1.0 mg/L. A good relationship was found between AUC(0-8h) and the plasma concentrations measured at 6 h, and the trough plasma concentrations made total body exposure for nelfinavir less predictable. Alternatively, a 2 h abbreviated AUC provides a good estimate of the full AUC(0-8h). Comparing the pharmacokinetic parameters obtained in our patients with those reported for patients receiving nelfinavir monotherapy or nelfinavir combined with nucleoside analogues, one observes substantial overlap with nelfinavir concentrations achieved without efavirenz.

Different immunologic profiles characterize HIV infection in highly active antiretroviral therapy-treated and antiretroviral-naïve patients with undetectable viraemia. The Master Group.

BACKGROUND: Suppression of human immunodeficiency virus (HIV) replication can be obtained in chronically infected individuals by highly active antiretroviral therapy (HAART) and can also be observed in antiretroviral-naïve patients. The immunological correlates of these two situations were examined. DESIGN AND METHODS: Cross-sectional study involving 32 HIV-infected patients with undetectable HIV plasma viraemia (< 500 copies/ml) and either antiretroviral-naive (n = 14) or undergoing HAART therapy with two nucleoside reverse transcriptase inhibitors (NRTI) plus one (n = 13) or two (n = 5) protease inhibitors (PI). CD4 counts, disease duration, and CDC clinical stage were comparable between the two groups of individuals. Immune parameters (antigen- and mitogen-stimulated proliferation and cytokine production; cytokine mRNA; beta chemokine production; HIV coreceptors mRNA) were analysed in all patients. RESULTS: Results showed immune profiles to be profoundly different in antiretroviral-naive in comparison with HAART-treated patients. Thus: (1) T-cell proliferation to HIV-specific and HIV-unrelated antigens is potent in antiretroviral-naive but suppressed in HAART-treated individuals; (2) interleukin-(IL)2, IL-12 and interferon gamma (IFNgamma) production is robust in naive patients; and (3) a high CCR5/low CXCR4 pattern of HIV coreceptors-specific mRNA is observed in naive but not in HAART-treated patients. In contrast with these observations, no clear differences were detected when beta chemokine production by either peripheral blood mononuclear cells or purified CD8+ T-cells was analysed. Results from HAART-treated patients undergoing therapy with one PI and two NRTI or two PI and two NRTI were in very close agreement. CONCLUSIONS: These data suggest that control over HIV replication can be independently achieved by pharmacological or immunologic means. HAART is associated with weaker HIV-specific and -non-specific immune responses.

Structured treatment interruptions to control HIV-1 infection.

Structured treatment interruptions progressively lowered the rate of viral rebound in some HIV-1 infected patients. This approach should be explored as an alternative to continuous antiretroviral therapies.

Pharmacokinetics of efavirenz (EFV) alone and in combination therapy with nelfinavir (NFV) in HIV-1 infected patients.

AIMS: To define the pharmacokinetic profile of efavirenz (EFV) in HIV-1 infected patients, when administered alone or with nelfinavir (NFV). METHODS: Eleven HIV-positive patients, in steady-state treatment with EFV and 11 patients in steady-state treatment with EFV+NFV, were evaluated. Blood samples for pharmacokinetic analysis were obtained during a dosage interval. Plasma concentrations of EFV were determined by h.p.l.c. RESULTS: No significant difference was found between the principal pharmacokinetic parameters of EFV when administered alone or in combination with NFV (mean AUC: 57.1-7727.3 vs 60.9+/-12.3 microg ml-1 h; mean CL/F: 0.18+/-0.072 vs 0.16+/-0.04 l h-1 kg-1; mean Cmax: 4.0+/-1.7 vs 4.3+/-1.2 microg ml-1, and mean tmax: 4.1+/-1.7 vs 3.5+/-0.5 h) Mean trough plasma concentrations (C0) of EFV were 1.64+/-0.93 microg ml-1, with and without NFV. A good correlation was found between C0 and AUC(0,24h) (r=0.96; P<0. 01). CONCLUSIONS: Despite the common metabolic pathway, there was no significant influence of NFV on the pharmacokinetics of EFV. EFV exhibits a relatively low interindividual variability and a dosing regimen of 600 mg day-1 assures plasma concentrations that are adequate for inhibition of viral replication.

Hydroxyurea and didanosine long-term treatment prevents HIV breakthrough and normalizes immune parameters.

Hydroxyurea and didanosine treatment suppressed HIV replication for more than 2 years, in the absence of viral breakthrough, in chronically infected patients. The profile of viral load reduction was unusual for a two-drug combination, since a continuous gradual decrease in viremia persisted despite residual viral replication. The increase in CD4+ T cell counts was not robust. However, unlike those of patients treated by other therapies, CD4+ T lymphocytes were functionally competent against HIV, mediating a vigorous HIV-specific helper T cell response in half of these patients. In addition, the percentages of naive CD4+ and CD8+ T lymphocytes were not different from those in uninfected individuals. These results demonstrate that prolonged antiretroviral therapy with a simple, well-tolerated combination of two affordable drugs can lead to sustained control of HIV, normalization of immune parameters, and specific anti-HIV immune response.

Hydroxyurea toxicity combined with didanosine (ddl) in HIV-1-seropositive asymptomatic individuals.

OBJECTIVE: Hydroxyurea, a carbamate compound widely used for the treatment of myeloproliferative disorders, has been investigated in several clinical trials conducted in the setting of HIV infection, where it is given in combination regimens almost always containing didanosine (ddI). Hydroxyurea mainly acts as a ribonucleotide reductase inhibitor and can positively modulate the activity of several pyrimidine and purine analogues. Due to its inhibition of DNA synthesis, the main side-effect of hydroxyurea is represented by myelosuppression. DESIGN: The toxicity profile of hydroxyurea plus didanosine (ddI) has been investigated in 40 asymptomatic HIV-positive patients with a baseline CD4+ absolute count between 250 and 500 cells/microl. Bone marrow function tests and adverse events occurring during the trial were analyzed. RESULTS: No major toxic event according to WHO classification was registered. At the dosage of 500 mg twice a day, hydroxyurea could be safely administered for at least 40 weeks of therapy. Minimal reversible bone marrow depression was noted in 2 patients. Even though reductions observed in white blood cell count, lymphocyte count and hemoglobin were statistically significant, they did not have any clinical relevance. CONCLUSIONS: Hydroxyurea seems to be well-tolerated and devoid of severe toxicity effects when used in asymptomatic HIV-positive subjects.