Rapid decline of anti-hepatitis C virus (HCV) antibodies following early treatment of incident HCV infections in HIV-infected men who have sex with men.

OBJECTIVES: Following clearance of incident hepatitis C virus (HCV) infections, HCV antibody levels may decline, resulting in seroreversion. It is unclear to what extent HCV antibody level trajectories differ between patients with treatment-induced sustained virological response (SVR), those with spontaneous clearance and those with untreated replicating HCV infection. We investigated HCV antibody level dynamics in HIV-infected MSM with different clinical outcomes. METHODS: We investigated anti-HCV antibody level dynamics following an incident HCV infection in 67 HIV-infected men who have sex with men (MSM) with different clinical outcomes: SVR (n = 33), spontaneous clearance (n = 12), and untreated replicating infection (n = 22). Antibody levels were measured at the time of HCV diagnosis, and at yearly intervals for 3 years thereafter. RESULTS: At baseline, median HCV antibody levels were similar in the three groups: 13.4, 13.8 and 13.5 sample to cut-off (S/CO) for SVR, spontaneous clearance and untreated infection, respectively. Over 3 years of follow-up, SVR was associated with a more pronounced decrease in anti-HCV levels compared with spontaneous clearance and untreated infection [median decline 71% [interquartile range (IQR: 43-87%), 38% (IQR: 29-60%) and 12% (IQR: 9-22%), respectively; P < 0.001]. Seroreversions occurred in five of 33 (15%) patients with SVR and in one of 12 (8%) with spontaneous clearance. A shorter delay between time of infection and treatment start correlated with higher rates of decline in antibody levels. Seven patients experienced a reinfection. CONCLUSIONS: Treatment-induced HCV clearance was associated with a more pronounced decline in anti-HCV antibody levels and with higher rates of seroreversion compared with spontaneous clearance or untreated replicating HCV infection among HIV-infected MSM with incident HCV infections. Rapid clearance of HCV RNA following early HCV treatment might impair the development of persistent antibody titres.

Who is more likely to respond to dual treatment with pegylated-interferon and ribavirin for chronic hepatitis C? A gender-oriented analysis.

We assessed, in real-life practice, viral, demographic, genetic and metabolic factors influencing the sustained virologic response (SVR), with a gender-oriented analysis, in patients with chronic hepatitis C virus (HCV) treated with pegylated interferon and ribavirin. Six hundred and seventy naïve patients were treated with dual therapy and evaluated by gender and HCV genotype. Associations between baseline variables and SVR were assessed by multivariate logistic regression analysis. Among 362 genotype 1 patients, SVR was achieved in 158 patients (44%), and SVR was independently associated with age less than 50 years (OR 2.12; 95% CI 1.09-4.30; P=0.039) and C/C genotype rs12979860 SNP (OR 2.83; 1.19-6.74; P=0.002) in 163 females, while absence of visceral obesity (OR 2.491; 1.131-5.487; P=0.023), HCV-RNA lower than 400,000 IU/mL (OR 2.66; 1.273-5.558; P=0.009) and C/C genotype rs12979860 SNP (OR 4.969; 2.401-10.283; P<0.001) were independently associated with SVR in 199 males. Combining favourable baseline variables, the probability of obtaining SVR ranged from 27.6% to 84.2% in females, and from 14.3% to 85.7% in males. The rate of SVR was 81.1% in 175 genotype 2 patients, and 69% in 100 genotype 3 patients. Rapid virologic response was the only valid predictor of SVR regardless of other features. In conclusions, in the setting of HCV genotype 1, chronic hepatitis, combining rapid virologic response and predictive factors, which are different for females and males, allows clinicians to single out a group of patients whose likelihood of SVR exceeds 80%. For these patients, triple therapy with first-generation protease inhibitors may be unwarranted.

Changing Italian nosocomial-community trends and heteroresistance in Staphylococcus aureus from bacteremia and endocarditis.

Bloodstream infections due to Staphylococcus aureus (BSI) are serious infections both in hospitals and in the community, possibly leading to infective endocarditis (IE). The use of glycopeptides has been recently challenged by various forms of low-level resistance. This study evaluated the distribution of MSSA and MRSA isolates from BSI and IE in 4 Italian hospitals, their antibiotic susceptibility--focusing on the emergence of hVISA--and genotypic relationships. Our results demonstrate that the epidemiology of MRSA is changing versus different STs possessing features between community-acquired (CA)- and hospital-acquired (HA)-MRSA groups; furthermore, different MSSA isolated from BSI and IE were found, with the same backgrounds of the Italian CA-MRSA. The hVISA phenotype was very frequent (19.5%) and occurred more frequently in isolates from IE and in both the MSSA and MRSA strains. As expected, hVISA were detected in MRSA with vancomycin minimum inhibitory concentrations (MICs) of 1-2 mg/l, frequently associated with the major SCCmec I and II nosocomial clones; this phenotype was also detected in some MSSA strains. The few cases of MR-hVISA infections evaluated in our study demonstrated that 5 out of 9 patients (55%) receiving a glycopeptide, died. Future studies are required to validate these findings in terms of clinical impact.

Epidemiology, characteristics, and outcome of infective endocarditis in Italy: the Italian Study on Endocarditis.

BACKGROUND: The characteristics of patients with infective endocarditis (IE) vary significantly by region of the world. The aim of this study was to evaluate the contemporary epidemiology, characteristics, and outcome of IE in a large, nationwide cohort of Italian patients. METHODS: We conducted a prospective, observational study at 24 medical centers in Italy, including all the consecutive patients with a definite or possible diagnosis of IE (modified Duke criteria) admitted from January 2004 through December 2009. A number of clinical variables were collected through an electronic case report form and analyzed to comprehensively delineate the features of IE. We report the data on patients with definite IE. RESULTS: A total of 1,082 patients with definite IE were included. Of these, 753 (69.6%) patients had infection on a native valve, 277 (25.6%) on a prosthetic valve, and 52 (4.8%) on an implantable electronic device. Overall, community-acquired (69.2%) was more common than nosocomial (6.2%) or non-nosocomial (24.6%) health care-associated IE. Staphylococcus aureus was the most common pathogen (22.0%). In-hospital mortality was 15.1%. From the multivariate analysis, congestive heart failure (CHF), stroke, prosthetic valve infection, S. aureus, and health care-associated acquisition were independently associated with increased in-hospital mortality, while surgery was associated with decreased mortality. CONCLUSIONS: The current mortality of IE remains high, and is mainly due to its complications, such as CHF and stroke.

Causes of death and risk factors among HIV-infected persons in the HAART era: analysis of a large urban cohort.

OBJECTIVE: We aimed to examine the clinical outcome in HIV-1-infected patients after more than 10 years of highly active antiretroviral therapy (HAART). METHODS: We analyzed data from 1,236 treatment-naïve adults who had started HAART. The primary endpoint was the yearly prevalence of death for AIDS-related causes (ARC) or for non-AIDS related causes (non-ARC). The data from our cohort were compared with that of the general population (GP) of our region. RESULTS: We observed that 116 patients died, and 58.6% of deaths were non-ARC. The death incidence decreased from 18.8% in 1998-1999 to 1.2% in 2008-2009. The leading causes of death were malignancies (35.3%), infections (21.6%), end-stage liver diseases (18.1%), and cardiovascular diseases (CVD) (6.9%). Yearly death rates were similar in the HIV-infected cohort and in the crude GP (odds ratio [OR] 1.1, 95% confidence interval [CI] 0.5-2.5), but when adjusted for age, HIV-infected patients showed a greater risk (OR 7.4, 95% CI 4.1-13.4). The difference was still highly significant when the analysis was restricted to non-ARCs (OR 4.3, 95% CI 2.07-9.2). Overall, malignancies (OR 5.7, 95% CI 2.6-12.8) and end-stage liver diseases (OR 35.0, 95% CI 15.5-78.8) were significantly more frequent than in the age-adjusted GP. CONCLUSIONS: Despite HAART, HIV-infected patients are at greater risk of death compared to a reference uninfected population.

In vitro activity effects of twelve antibiotics alone and in association against twenty-seven Enterococcus faecalis strains isolated from Italian patients with infective endocarditis: high in vitro synergistic effect of the association ceftriaxone-fosfomycin.

BACKGROUND: In 2004-2008, the epidemiological and clinical Infective Endocarditis Study Group (SEI) evaluated 852 cases of infective endocarditis. Staphylococcus aureus was the main involved pathogen (24.5%) and Enterococcus faecalis etiology was described in 11% of the cases. The aim of this study was to evaluate the in vitro activity of 12 antibiotics alone and in association against 27 strains of E. faecalis isolated from blood cultures of patients with infective endocarditis. RESULTS: The results showed high in vitro activity of tigecycline, daptomycin and linezolid. A high synergistic effect was obtained with the association ceftriaxone-fosfomycin [fractional inhibitory concentration (FIC)(50) = 0.34, FIC(90) = 0.78]. Furthermore, ceftriaxone plus ampicillin presented additive results (FIC(50) = 0.66, FIC(90) = 1.00), and ceftriaxone plus fosfomycin and ceftriaxone plus ampicillin were significantly more active in vitro than each drug alone. The efficacy of ceftriaxone plus fosfomycin was confirmed by the association testing using the broth dilution technique. CONCLUSION: Fosfomycin seems particularly significant and its association with ceftriaxone could be considered as a useful therapeutic option in medical treatment of E. faecalis infective endocarditis.

Scedosporium apiospermum soft-tissue infection: a case report and review of kidney transplant literature.

Scedosporium apiospermum is an environmental mould. Human infections caused by this organism have been observed; however, only a few case reports show its role as a telluric contaminant to kidney recipients. We have reported here a case of a dramatic soft tissue infection by S. apiospermum in a kidney-transplanted man. Surgical drainage together with voriconazole systemic therapy was successful.

Molecular structure of the bilin binding protein (BBP) from Pieris brassicae after refinement at 2.0 A resolution.

The bilin binding protein (BBP) from the insect Pieris brassicae has been analysed for amino acid sequence, spectral properties and three-dimensional structure. The crystal structure that had been determined by isomorphous replacement has been refined at 2.0 A (1 A = 0.1 nm) resolution to an R-value of 0.20. The asymmetric unit contains four independent subunits of BBP. The co-ordinate differences are 0.25 A, in accord with the estimated error in co-ordinates. The polypeptide chain fold is characterized by an eight-stranded barrel. The connecting loops splay out at the upper end of the barrel and open it, whilst the lower end is closed. The overall shape resembles a calyx. The biliverdin IX gamma chromophore is located in a central cleft at the upper end of the barrel. The bilatriene moiety is in cyclic helical geometry with configuration Z,Z,Z and conformation syn,syn,syn. The geometry is in accord with the spectral properties and permits a correlation between sign of the circular dichroism bands and sense of the bilatriene helices. The fold of BBP is related to retinol binding protein (RBP), as had been recognized in the preliminary analysis, although the amino acid sequences of RBP and BBP show only 10% homology. There are large differences in the loops at the upper end of the barrel, whilst the segments of the centre and the lower end of the barrel superimpose closely. The ligands of BBP and RBP, biliverdin and retinol, respectively, are also similarly located.

Zidovudine prophylaxis after accidental exposure to HIV: the Italian experience. The Italian Study Group on Occupational Risk of HIV Infection.

OBJECTIVES: To evaluate the use of zidovudine prophylaxis in HIV-exposed health-care workers (HCW) in Italy and to determine its short-term toxicity. DESIGN: Longitudinal, open study with retrospective and prospective collection of data. SETTING: All Italian clinical centres that care for HIV-infected patients and are licensed by the Ministry of Health to dispense zidovudine and 30 hospitals participating in the Italian Multicentre Study on Occupational Risk of HIV Infection. STUDY POPULATION: HCW and other individuals who accepted zidovudine prophylaxis after accidental exposure to HIV. RESULTS: Data were collected for 224 HIV-exposed individuals until 30 June 1991. An increase in zidovudine prophylaxis was observed. All but 10 subjects received 1000-1250 mg zidovudine per day. Anaemia (five cases), neutropenia (one case) and an increase in serum alanine aminotransferase levels (two cases) were the only haematochemical side-effects observed; none of the subjects ceased prophylaxis because of side-effects. More than 50% of subjects had constitutional reactions; as a result, prophylaxis was stopped by 29 patients. These adverse effects began within 10 days of prophylaxis; all resolved after prophylaxis was stopped. No HIV-antibody seroconversions were observed after a mean follow-up of 8 months. CONCLUSIONS: Zidovudine prophylaxis has become a feature of the management of occupational exposures to HIV in health-care settings; short-term toxicity is mild, dose-related and reversible. Further studies are needed to assess the risk of long-term sequelae.

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.

Molecular analysis of a Phanerochaete chrysosporium lignin peroxidase gene.

The basidiomycete fungus Phanerochaete chrysosporium produces a number of extracellular peroxidases which appear to be important for lignin degradation. We present here the isolation and complete nucleotide (nt) sequence of a gene (lpo) coding for lignin peroxidase (LPO), the coding region of which is identical to a lpo cDNA sequence which had previously been described [M. Tien and C.-P.D. Tu, Nature 326 (1987) 520-523]. The deduced amino acid (aa) sequence corresponds to 372 aa residues and the coding region is interrupted by eight short introns that range in size from 50 to 62 nt. Southern blot experiments using the cloned lpo gene as hybridization probe revealed a complex restriction fragment pattern, indicating that there are a number of lpo-related nucleotide sequences present in P. chrysosporium DNA which cross-hybridize. We also present data on the in vivo expression of the lpo genes and show that they are regulated at the RNA level and that the structure of the transcripts as judged from S1 experiments is complex. These data are consistent with the idea that there are a number of related lpo genes in P. chrysosporium which constitute a gene family.

Complete amino acid sequence of the B875 light-harvesting protein of Rhodopseudomonas sphaeroides strain 2.4.1. Comparison with R26.1 carotenoidless-mutant strain.

The complete amino acid sequence was determined for the alpha- and beta-chains of the B875 light-harvesting protein purified from photosynthetic membranes of Rhodopseudomonas sphaeroides 2.4.1. The sequence of the B875-alpha-polypeptide was identical to that reported for the R26.1 carotenoidless mutant [(1985) Biochim. Biophys. Acta 806, 185-186] and contained 58 amino acid residues with a blocked methionine and a glutamic acid at the N- and C-termini, respectively. The B875-beta-polypeptide contained 48 amino acid residues with alanine and phenylalanine as respective N- and C-termini; although otherwise identical, the leucine at position 29 in the wild-type strain was replaced by proline in the mutant. This radical amino acid substitution occurred within the central hydrophobic domain of the beta-polypeptide chain and is thought to result in a weakening of the structure of the alpha/beta heterodimer since it was not possible to isolate the intact pigment-protein complex from the R26.1 mutant strain.

Virological and immunological responses to a once-a-day antiretroviral regimen with didanosine, lamivudine and efavirenz.

Current antiretroviral drugs cannot eradicate HIV infections, and persons living with HIV are often faced with very demanding daily therapeutic schedules that can induce poor adherence. More conveniently dosed and patient-friendly regimens are needed. We investigated, in this 48-week pilot study, a once-a-day highly active antiretroviral therapy regimen of didanosine, lamivudine and efavirenz. Seventy-five consecutive antiretroviral-naive subjects were enrolled. Over the 48-week period, plasma HIV-RNA levels declined sharply, with a median decrease at the end of the observation time >3.4 log copies/ml. The proportion of patients achieving a plasma HIV-RNA level below the limit of detection (50 copies/ml) was 77% (intention to treat analysis) at the end of the study period. The mean CD4 cell count increased steadily over time from 251 to 459 cells/microl. Antiviral efficacy was similar in patients with a baseline HIV-RNA level above or below 100,000 copies/ml. However, patients with a baseline CD4 cell count <200 cells/microl showed a significantly worse virological response than that observed in patients with higher baseline CD4 counts. Overall 15 patients interrupted therapy. In four cases treatment interruption was due to lack of treatment response; three additional patients were lost to follow-up or withdrew informed consent. Eight patients stopped therapy because of adverse events. The once-daily combination of didanosine, lamivudine and efavirenz resulted in sustained viral suppression and was well-accepted by patients. This regimen may offer advantages in selected difficult-to-treat populations, allows directly observed therapy and can be a safe and effective alternative in antiretroviral-naive patients. These encouraging pilot results need to be confirmed in a comparative clinical trial.

A randomized trial comparing the introduction of ritonavir or indinavir in 1251 nucleoside-experienced patients with advanced HIV infection.

ISS-IP1, a multicenter, randomized, 48-week open trial, was designed to compare the introduction of ritonavir or indinavir in patients with previous nucleoside experience and CD4+ cell counts below 50/mm3. Concomitant antiretroviral treatment with nucleoside analogs was allowed. Primary efficacy measures were survival and time to a new AIDS-defining event or death, analyzed through the whole period of observation by the intention-to-treat approach. Primary toxicity measures were time to treatment discontinuation and adverse events, grade at least 3/serious, analyzed by an on-treatment approach. Evaluation-of efficacy also included CD4+ cell and RNA response. The trial enrolled 1251 patients in 5 months. At baseline, mean CD4+ cell count was about 20 cells/mm3 and mean HIV RNA copy number was 4.9 log10/ml in both groups. Overall, 402 patients in the ritonavir group and 250 patients in the indinavir group permanently discontinued the assigned treatment (relative risk, 1.96; 95% CI, 1.68-2.30; p = 0.0001), with most of this difference dependent on a higher number of discontinuation for adverse events in the ritonavir group. After a mean follow-up of 307 days (ritonavir, 304; indinavir, 309), 124 deaths (ritonavir, 61; indinavir, 63; relative risk, 0.96; 95% CI, 0.67-1.36; p = 0.80) and 330 new AIDS-defining events (ritonavir, 170; indinavir, 160; relative risk, 1.05; 95% CI, 0.85-1.31; p = 0.60) were observed. CD4+ cell counts increased in both groups in patients still receiving treatment, with about 100 cells gained by week 24 and 150 cells gained by week 48. Body weight also increased over time in both groups. Analysis of RNA response showed a decrease of 1.5 log10 or higher in both treatment groups. Overall, 400 patients in the ritonavir group and 338 patients in the indinavir group developed at least one grade 3/serious new adverse event during follow-up (relative risk, 1.48; 95% CI, 1.28-1.72; p = 0.0001). Favorable CD4+ cell and RNA responses at 24 and 48 weeks were observed in both groups of patients remaining on treatment. Indinavir showed slightly better effects in sustaining RNA, CD4+ cell, and body weight responses. Ritonavir and indinavir results were comparable in terms of clinical outcome (survival and AIDS-defining events).

Quantification of the impact of HIV-1 reverse transcriptase and protease mutations on the efficacy of rescue HAART.

The reduction in the efficacy of rescue treatment (administered on a clinical basis) due to drug resistance was retrospectively quantified in 55 human immunodeficiency virus type 1 (HIV-1)-infected patients failing highly active antiretroviral therapy (HAART) by using a novel score calculation system based upon HIV-1 reverse transcriptase (RT) and protease (PR) mutations. Patients were all naive for nelfinavir (NFV) and efavirenz (EFV) and were assigned to one of the following rescue therapy schedules: (i) 17 patients received NFV + EFV + stavudine (d4T) (group A); (ii) 14 patients received NFV + saquinavir (SQV) + lamivudine (3TC) + d4T/zidovudine (AZT) (group B); (iii) 19 patients received NFV + d4T + didanosine (ddI)/3TC/zalcitabine (ddC) (group C); (iv) five patients received miscellaneous treatments including NFV (group D). Responders were considered patients showing a drop in HIV-1 RNA level > 0.5 log10 after 3 months of therapy. Forty-eight (28 responders and 20 non-responders) out of 55 patients completed the first 3 months of rescue therapy and reduction in HIV-1 viral load was found to be significantly higher in group A compared to groups B and C (81.2% responders vs. 38.5 and 40.0%, respectively). At baseline, no patient carried EFV- or d4T-resistant HIV-1 strains, despite prolonged administration of d4T, while 41/48 (87.2%) patients had mutations conferring resistance to NFV in the absence of previous treatment with this drug. A significant inverse correlation between reduction in viral load and reduction in therapy efficacy due to drug resistance, as determined by the score calculation system, was found (r = 0.62). A cut-off value of 36% reduction in therapy efficacy showed a positive predictive value (capacity to detect failure of rescue treatment) of 81.2% and a negative predictive value (ability to detect successful treatment) of 75.8%. In addition, 45 out of 48 patients completed also the 9-12 month period of rescue therapy and 10/28 responders had a rebound in HIV-1 viral load level detected after the first 3 months of rescue therapy. Of these, 5/7 (71.4%) showed a further reduction in rescue therapy efficacy due to the emergence of new mutations.

Antiviral potency of HAART regimens and clinical success are not strictly coupled in real life conditions: evidence from the MASTER-1 study.

PURPOSE: To compare in a real clinical setting the largely unknown midterm clinical effectiveness of two protease inhibitor (PI)-based highly active antiretroviral therapy (HAART) regimens with different potency and tolerability profiles in naïve patients. METHOD: This study was a multicenter, open-label, randomized trial in naïve patients with less than 400 CD4+ cell count/microL, regardless of viral load. Treatment arms were hard gel capsule saquinavir (HGC-SQV)-based HAART (Arm A), with an expected more favorable tolerability profile, and indinavir (IDV)-based HAART (Arm B), with more potent virologic activity. While viro-immunological surrogate markers and World Health Organization (WHO) grade III toxicity (secondary endpoints) were regularly monitored, primary endpoints of the study were clinical and defined as any AIDS-defining event, AIDS-related death, WHO grade IV toxicity, drop outs, and protocol violations. RESULTS: 262 consecutive patients were enrolled in the study from March 1, 1997 to December 31, 1997, in 24 different Italian clinical centers (132, Arm A; 130, Arm B). After 24 months of follow-up, patients who were enrolled in Arm B showed a significantly higher rate of virological success (75% had viremia below 500 copies/mL, CI = 12.9%, in the on-treatment analysis) and immunological gain (mean CD4+ cell count increase of 274 CD4+ cells/microL, SD = 234) when compared to patients enrolled in arm A (57%, CI = 15.5% and 223 CD4+ cells/microL, SD = 192; p =.0353 and.026, respectively). Despite the significant difference observed in surrogate markers, the number of total primary endpoints did not differ in the two groups (55 out of 132 in Arm A vs. 58 out of 130 person-years in Arm B; p =.86). CONCLUSION: Our results suggest that, after 24 months of follow-up in a real clinical setting, a PI-based HAART induces significant clinical benefits in naïve patients even in the absence of a complete suppression of viral replication. However, the long-term clinical impact of the possible accumulation of viral mutations in the presence of low-grade viral replication remains to be elucidated.

Long-term clinical benefit after highly active antiretroviral therapy in advanced HIV-1 infection, even in patients without immune reconstitution.

Our objective was to assess, in the clinical setting, the predictors of immune reconstitution (IR) and its relation with long-term clinical benefit, in HIV patients with advanced disease after highly active antiretroviral therapy (HAART) through an observational study. A retrospective cohort study in a clinical setting of 383 consecutive adult patients with advanced HIV infection (CD4+ cells <200/mm(3) at baseline), starting their first protease inhibitor (PI)-containing regimen was observed. Immune reconstitution was defined as CD4 count >200 cells/mm(3) and an increase > or =100 cells from baseline, anytime since starting HAART. Clinical benefit was defined as decreased mortality and reduction in AIDS-defining events, AIDS-related complex (ARC) events, major infections and hospitalization (days spent in hospital). During a mean follow-up of 808 days, 261 patients (68.1%) achieved IR. About 50% of these patients reached this result within one year after starting HAART. In multivariate analysis, predictors of immune recovery were sex (female) and baseline CD4 count higher than 50 cells/mm(3). The group of patients with IR had greater clinical benefit with lower mortality, fewer AIDS-defining events, shorter lengths of stay in hospital, fewer ARC events and fewer major infections during all the follow-up (P < 0.0001, tests for trends). However, although they did less remarkably than the first group of patients, even those patients who did not achieve IR experienced a significant decrease in the incidence of all the above events, as compared with the first and sometimes the second trimester after starting their HIV therapy. About 70% of HIV patients with advanced disease achieved IR after starting HAART. Such a benefit is a time-dependent effect and may even take more than 2 years to occur. Predictors of IR were sex (female) and higher baseline CD4 count (>50 cells/mm(3)). The patients who achieved immune recovery performed clinically better than patients who did not. Also the patients who failed to gain such a strong immunological recovery experienced a long-term clinical benefit. This suggests that PI-containing regimens, in advanced HIV disease, may produce a significant clinical benefit, at least temporary, even for patients who do not achieve a substantial immune response.

Severe lactic acidosis and thiamine administration in an HIV-infected patient on HAART.

Severe lactic acidosis has been increasingly reported as a potentially fatal complication of HIV treatment. We report on an asymptomatic HIV-infected woman treated with stavudine, lamivudine and indinavir for one year. She was hospitalized because of progressive dispnoea, oedema, cyanosis and severe lactic acidosis. Arterial blood pH was 6.98, bicarbonate 4.4 mmol/l (normal value 22-26), blood lactate: 29.7 mmol/l (normal value <2.2). Hepatic function was normal. She had an impressively rapid response (within a few hours) to empirical treatment with thiamine (100 mg i.v.). No evidence of sepsis or malabsorption were identified and vitamin B1 level was not tested before thiamine infusion. Three months later she was re-started successfully on nelfinavir plus nevirapine. The rapid response to thiamine infusion deserves a careful attention and such an approach should be considered in similar cases as a support treatment of this potentially life-threatening complication of HIV therapy.

Effects of subinhibitory concentrations of moxifloxacin in an in-vitro dynamic model.

The postantibiotic effect (PAE), sub-MIC effect (SME) and postantibiotic sub-MIC effect (PASME) of moxifloxacin were investigated in an in-vitro dynamic model reproducing in-vivo elimination kinetics of the antibiotic. The PAE was induced by exposing strains of Staphylococcus aureus, Streptococcus pneumoniae, Escherichia coli and Klebsiella pneumoniae to 5 x MIC of the antibiotic for 1.5 hours. After induction, cultures were washed to eliminate the antibiotic and resuspended into the dynamic model either in the presence or absence of a subinhibitory concentration of the antibacterial agent of 0.5 x MIC. Unexposed controls were treated similarly. PASMEs were constantly longer than corresponding SMEs, but differences between them were not statistically significant. Both PASMEs (mean 11:17 hours, range from 8:17 to 14:57) and SMEs (mean 9:23 hours, range from 6:03 to 12:34) had an initial bactericidal effect and were significantly longer than PAEs (mean 1:31 hours, range from 0:21 to 2:14). The primary effect of moxifloxacin sub-MICs appears to be prevalent in PAE. The possibility of once-daily dosing of the drug is strengthened.