Presence of HIV-1 Nef specific CD4 T cell response is associated with non-progression in HIV-1 infection.

The ex vivo response to three HLA-DR-restricted Nef peptides (Nef 66-97, Nef 133-159, Nef 180-202) and one HLA-DQ-restricted Nef peptide (Nef 56-68) was evaluated in 28 HIV-seropositive patients and 6 Long-term Non-Progressors (LTNPs). Analyzing specific proliferative response and IFN-gamma secretion, patients were identified as high responders, medium responders and non-responders to peptides. As high responder patients, LTNP patients showed strong proliferative response to all the Nef-peptides as strong IFN-gamma secretion. Twenty-four months later, all high responder patients were always without antiretroviral treatment whereas 50% of medium responders and at least 66% of low responder patients followed bi-therapy. CDC classification confirmed also unfavourable evolution for these two last groups. All high responder patients conserved stable CD4 counts, proliferative response to Nef peptides as strong IFN-gamma secretion during this 24-month period. So, early good T CD4 response to peptides of the Nef protein could thus be regarded as a factor of good prognosis in HIV infection and a tool of importance in the decision to put or not a patient under treatment.

Effectiveness and tolerability of prolonged linezolid treatment for chronic osteomyelitis: a retrospective study.

BACKGROUND: Linezolid is an oxazolidinone agent which is apparently well designed for treating chronic osteomyelitis, but data on effectiveness and tolerability as prolonged therapy is currently lacking. OBJECTIVE: The purpose of this study was to assess the effectiveness and tolerability of linezolid in the treatment of chronic osteomyelitis. METHODS: The charts of hospitalized patients who had been treated with linezolid for >4 weeks because of chronic osteomyelitis and were followed up for > or =12 months after the end of treatment were retrospectively reviewed for clinical outcome and tolerability. Cure was defined as the absence of clinical, biological, or radiological evidence of infection throughout the posttreatment follow-up. Linezolid tolerability was assessed on the basis of hematologic properties during treatment. RESULTS: Of the 66 patients included, all were white (mean [SD] age, 67.7 [18.1] years; 41 men and 25 women; mean [SD] weight, 80.7 [18.6] kg). Thirty-seven (56.1%) patients had infection due to implants including 27 prosthetic joints. Pathogens were predominantly methicillin-resistant staphylococci (49/72 strains, 68.1 %). Every patient was administered N linezolid (600 mg BID) treatment for 6 to 8 days as inpatients, and then, as outpatients, they were switched to PO treatment. Fifty (75.8%) patients received a combination of linezolid and other antimicrobial agents, including rifampin (32 [48.5%]). Surgery was performed in 52 (78.8%) patients. The median hospital stay was 14 days (mean [SD], 19 [11.4] days [range, 7-70 days] ). The median duration of treatment was 13 weeks (mean [SD], 14.3 [8.2] weeks [range, 5-36 weeks]). At the end of treatment, 56 (84.8%) patients were cured, and during the post-treatment follow-up (median duration, 15 months [range, 12-36 months]), 4 relapses occurred, resulting in an overall successful cure for 52 (78.8%) patients. Reversible anemia was reported in 21 patients (31.8%), of whom 16 (24.2%) required blood transfusions. Median time from treatment initiation to anemia onset was 7.3 weeks (range, 4-12 weeks). Peripheral neuropathy was reported in 6 (9.1%) patients, of whom 4 remained symptomatic for up to 24 months after linezolid discontinuation. Other reported adverse events included nausea (6 [9.1%]), diarrhea (1 [1.5%]), and headache (2 [3.0%]), although none of these patients discontinued treatment. CONCLUSIONS: In this retrospective chart review, treatment with linezolid as monotherapy or in combination with antimicrobials and/or surgery was associated with cure of chronic osteomyelitis in 84.8% of subjects at 12 weeks after the end of treatment and 78.8% at follow-up. Adverse events were reported in 51.5% of subjects, and 34.8% of subjects discontinued the study because of adverse events. The potential for severe complications justifies close monitoring of these patients.

Improved aero-anaerobe recovery from infected prosthetic joint samples taken from 72 patients and collected intraoperatively in Rosenow's broth.

INTRODUCTION: Recovery of the bacteria responsible for prosthetic joint infections is a major problem, which is due in part to the alteration of their ability to grow by storage during transportation to the laboratory. METHODS: In this prospective study, we assessed the benefit of inoculating an enriched liquid medium (Rosenow's broth) with intraoperative samples from 72 patients with prosthetic joint revision due to infection. We compared the results of culture of specimens collected in a standard receptacle with the results for specimens collected in Rosenow's broth. RESULTS AND INTERPRETATION: 144 samples were taken by each of the 2 collection methods for subsequent culture. Concordance between standard and Rosenow samples was observed for 52 of the 58 strains cultured on agar and for 42 of the 97 strains (p < 0.001) which grew only in liquid medium. Infection would not have been diagnosed in 26 patients (almost one-third of all patients) without combining sample collection in Rosenow's broth with standard collection. The bacteria that were not recovered from standard samples but which were recovered from those collected in Rosenow's broth included not only strict anaerobes, in particular Propionibacterium acnes, but also coagulase-negative staphylococci and streptococci.

Culture of percutaneous bone biopsy specimens for diagnosis of diabetic foot osteomyelitis: concordance with ulcer swab cultures.

BACKGROUND: We assessed the diagnostic value of swab cultures by comparing them with corresponding cultures of percutaneous bone biopsy specimens for patients with diabetic foot osteomyelitis. METHODS: The medical charts of patients with foot osteomyelitis who underwent a surgical percutaneous bone biopsy between January 1996 and June 2004 in a single diabetic foot clinic were reviewed. Seventy-six patients with 81 episodes of foot osteomyelitis who had positive results of culture of bone biopsy specimens and who had received no antibiotic therapy for at least 4 weeks before biopsy constituted the study population. RESULTS: Pathogens isolated from bone samples were predominantly staphylococci (52%) and gram-negative bacilli (18.4%). The distributions of microorganisms in bone and swab cultures were similar, except for coagulase-negative staphylococci, which were more prevalent in bone samples (P < .001). The results for cultures of concomitant foot ulcer swabs were available for 69 of 76 patients. The results of bone and swab cultures were identical for 12 (17.4%) of 69 patients, and bone bacteria were isolated from the corresponding swab culture in 21 (30.4%) of 69 patients. The concordance between the results of cultures of swab and of bone biopsy specimens was 42.8% for Staphylococcus aureus, 28.5% for gram-negative bacilli, and 25.8% for streptococci. The overall concordance for all isolates was 22.5%. No adverse events--such as worsening peripheral vascular disease, fracture, or biopsy-induced bone infection--were observed, but 1 patient experienced an episode of acute Charcot osteoarthropathy 4 weeks after bone biopsy was performed. CONCLUSIONS: These results suggest that superficial swab cultures do not reliably identify bone bacteria. Percutaneous bone biopsy seems to be safe for patients with diabetic foot osteomyelitis.

Impact of human immunodeficiency virus type 1 subtype on first-line antiretroviral therapy effectiveness.

OBJECTIVE: The effectiveness of antiretroviral treatment (ART) was compared in 416 naive patients from a French clinical cohort infected with B and non-B HIV-1 subtypes. METHODS: Time to HIV viral load (VL) undetectability was calculated for each subtype group. Three other parameters were estimated 3, 6 and 12 months after enrolment: clinical progression (that is, AIDS-defining events or death), changes in CD4 cell counts from baseline and proportion of patients achieving an undetectable VL (<400 HIV-RNA copies/ml). RESULTS: In this cohort, 317 patients (76%) were infected with a B subtype and 99 (24%) with a non-B subtype. Median time to VL undetectability was similar in the B subtype group [147 days, 95% confidence interval (CI) 119-165] and non-B subtype group (168 days, 95% CI: 105-234; P=0.16). After adjusting for AIDS-defining events at enrolment, baseline CD4 cell counts and VL, and for the treatment on which patients were initiated, no association was found between HIV subtypes and time to VL undetectability (B subtype vs non-B subtype: hazard ratio=0.80, 95% CI: 0.62-1.02, P=0.07). In the 3, 6 and 12 months after enrolment, subtype had no impact on clinical progression, CD4 cell count or VL responses to ART. This suggests that B and non-B subtypes do not affect first-line therapy efficacy, which is encouraging in view of the worldwide spread of non-B HIV-1 subtypes and the increasing availability of ART in developing countries. However, in this study we did not take into account individual non-B subtype species, therefore further studies should be designed to evaluate the efficacy of these regimens in patients with particular non-B subtypes.

Risk factors for anaemia in patients on prolonged linezolid therapy for chronic osteomyelitis: a case-control study.

OBJECTIVES: The intrinsic properties of the new antibiotic linezolid make it an attractive candidate for the treatment of chronic osteomyelitis. However, data regarding the tolerance of long-term linezolid administration are still lacking. METHODS: The medical charts of patients given linezolid for >4 weeks were retrospectively analysed, especially their haematology. In a case-control study, we compared the respective characteristics of patients who developed anaemia during linezolid therapy and those who did not. RESULTS: Forty-five adults with chronic osteomyelitis received 600 mg linezolid intravenously twice daily for 7 days, and then orally, for a mean total duration of 15.9 weeks (range, 6-36). Anaemia episodes requiring blood transfusion occurred in 13/45 patients (28.9%). Median time from treatment initiation to anaemia onset was 7.4 weeks (range, 4-16). Anaemia was significantly associated with premature linezolid therapy cessation (P = 0.0012). No linezolid-related thrombocytopenia was observed. By univariate analysis, four variables were associated with the occurrence of anaemia: age >58 years, alcohol abuse, diabetes mellitus and low haemoglobin before linezolid treatment. Logistic regression analysis revealed two independent risk factors for anaemia: age >58 years (OR = 20.5, 95% CI 0.69-599; P = 0.0001) and pre-treatment haemoglobin <10.5 g/dL (OR = 16.49, 95% CI 1.06-255; P = 0.04). CONCLUSIONS: Profound anaemia may occur in adult patients with chronic osteomyelitis on prolonged linezolid therapy, and often necessitates linezolid cessation. These patients are likely to be aged >58 years and to have low pre-treatment haemoglobin. The results for the present series might help physicians to identify patients who should not be given long-term linezolid treatment for chronic osteomyelitis.

Clinical efficacy of antiretroviral combination therapy based on protease inhibitors or non-nucleoside analogue reverse transcriptase inhibitors: indirect comparison of controlled trials.

OBJECTIVE: To compare the clinical efficacy of triple antiretroviral regimens based on protease inhibitors and non-nucleoside analogue reverse transcriptase inhibitors (NNRTIs) in adults positive for antibodies to HIV-1. DESIGN: Systematic review and meta-analysis using indirect comparisons of clinical trials comparing three drug regimens based on two nucleoside reverse transcriptase inhibitors (NRTIs) and either a protease inhibitor or an NNRTI with two drug regimens (two NRTIs). Participants had no previous exposure to protease inhibitors or NNRTIs. DATA SOURCES: Medline, the Cochrane controlled trials register, Aidstrials, Aidsdrugs, conference proceedings, and trial registers. MAIN OUTCOME MEASURE: Progression to AIDS or death. RESULTS: 14 trials, totalling 6785 patients, were identified. Most patients had been exposed to an NRTI and had advanced immunodeficiency at baseline; 1096 progressed to AIDS or died. Seven trials assessed protease inhibitors based triple regimens and seven assessed NNRTI based triple regimens (nevirapine or delavirdine). Triple therapy was more effective than dual therapy. The effect was pronounced for protease inhibitor based regimens (odds ratio 0.49, 95% confidence interval 0.41 to 0.58) but non-significant for NNRTI based regimens (0.90, 0.71 to 1.15). Indirect comparison of the two regimens gave an odds ratio of 0.54 (0.49 to 0.73) in favour of protease inhibitor based treatments. Increases in CD4 cell counts were smaller and suppression of viral replication less with NNRTI based regimens. CONCLUSIONS: Indirect evidence shows that protease inhibitor based triple regimens are superior to regimens based on the NNRTIs nevirapine and delavirdine in patients with advanced immunodeficiency who have been exposed to NRTIs. Large trials with clinical end points are required.

Thymidine analogue mutations in antiretroviral-naive HIV-1 patients on triple therapy including either zidovudine or stavudine.

AIMS: The aims of this study were to: (i) determine the incidence of thymidine-associated mutations (TAMs) in an observational clinical cohort of naive HIV-1 patients who stopped first-line therapy including either zidovudine or stavudine; and (ii) assess the immunological and virological responses to subsequent second-line therapy in patients who switched from zidovudine to stavudine or conversely. PATIENTS AND METHODS: Plasma samples from 165 patients who stopped first-line antiretroviral therapy containing either zidovudine or stavudine were examined for the presence of drug-resistant genotypes. Subsequent second-line immunological and virological follow-up was performed in 136 patients who switched from zidovudine to stavudine and conversely. RESULTS: Among the 93 patients who stopped first-line therapy including zidovudine and the 72 who stopped first-line therapy including stavudine, genotypic resistance testing was available for 67 (72%) and 54 (75%), respectively. The presence of TAMs was significantly more frequent in the zidovudine than the stavudine group (23.8% versus 5.5; P = 0.006). The short- and long-term immunological and virological responses to second-line therapy were comparable in the zidovudine and stavudine groups, despite different baseline profiles of viral resistance (median increase in CD4 cells/mm3 at 1 year of therapy, 118 versus 119; viral load <400 copies/mL, 47% versus 47%). CONCLUSIONS: These results suggest that TAMs occur in more patients on antiretroviral regimens including zidovudine than on regimens including stavudine. Although the results from observational studies should be interpreted cautiously, these findings may be useful in determining the optimal sequencing of zidovudine and stavudine for the treatment of naive HIV-1-infected patients.

Hyperlactataemia during antiretroviral therapy: incidences, clinical data and treatment.

Lactic acidosis is a serious complication of antiretroviral therapy. Symptomatic hyperlactataemia is a milder form of this syndrome, but its incidence is unclear. In this prospective ongoing observational study of a large cohort of HIV-infected adults, hyperlactataemia was diagnosed in 64 patients. Incidences were 18.3/1000 person-years with antiretroviral therapy, and 35.8/1000 person-years for stavudine (d4T) regimens. Ten of the 64 patients developed lactic acidosis during the first 13 months of treatment (incidence 2.9/1000 treated person-years). In four of ten patients, symptoms were absent or mild. More patients on d4T first-line therapy developed lactic acidosis than patients previously treated with other drugs (p = 0.008). Despite the occurrence of one death, the subsequent outcome for the remaining patients was favourable after antiretroviral therapy was stopped and supportive treatment with vitamins and antioxidants initiated. The early diagnosis of cases was the result of great vigilance and, combined with routine measurements of the anion gap, might be the most crucial factor explaining the low mortality rate observed here.

A phase I study of a six-week cycle of immunotherapy with Murabutide in HIV-1 patients naive to antiretrovirals.

BACKGROUND: Limitations in the use of antiretroviral therapy suggest the need for additional approaches to enhance immune restoration and the control of HIV-1 replication. Therefore, we evaluated the clinical tolerance and biological effects of immunotherapy with the synthetic immunomodulator Murabutide in 9 treatment-naive HIV-1 patients presenting with CD4+ lymphocyte counts >500 cells/mm3 and plasma viral loads <30.000 copies/ml. MATERIAL/METHODS: Murabutide was administered at a daily dose of 7 mg on 5 consecutive days per week, for a period of 6 weeks. The study duration extended over 22 weeks, and clinical, virological, and immunological evaluations were carried out on 2 occasions before, during, and after immunotherapy. RESULTS: With acceptable clinical tolerance and only 2 reversible grade III adverse events, clinical and virological parameters remained highly stable throughout the study period. However, maintained or improved lymphoproliferative responses to several recall and HIV-1 antigens, as well as modest but significant increases in the percentages of naive cells were noted during or/and after immunotherapy. These changes could not be demonstrated in an observation group of 9 additional patients who were identically followed for a 22-week period. CONCLUSIONS: Our results suggest that non-specific immunotherapy targeting dysfunctions in innate immunity could bring about restoration of immune responses in HIV disease.

Clinical and immunological effects of a 6 week immunotherapy cycle with murabutide in HIV-1 patients with unsuccessful long-term antiretroviral treatment.

In an effort to evaluate the potential of non-specific immunotherapy in restoring global immunity, we have examined the clinical tolerance and biological effects of a 6 week administration of the immunomodulator, murabutide, in chronically infected HIV-1 patients. Forty-two subjects, presenting weak immune reconstitution and ineffective virus suppression following long-term highly active antiretroviral therapy (HAART), were randomized to receive, or not, murabutide 7 mg/day on five consecutive days/week. Clinical and immunological parameters were monitored before and after the immunotherapy period. Administration of murabutide was generally well tolerated, although some grade III adverse events, reversible on treatment cessation, were observed. Interestingly, in comparison with pre-inclusion levels, at 1 week after the immunotherapy cycle, only murabutide recipients presented a significant increase in CD4 cells, platelet counts, and in the percentage of patients with undetectable viral loads (<50 copies/mL). Statistical significance between the two groups was only evident with the latter parameter. Some of these clinical changes were maintained even up to 12 weeks after murabutide administration, and were accompanied by an increased ability to mount cellular responses to active immunization with a recall antigen, and by a significant increase in the percentage of patients presenting positive lymphoproliferative responses to the viral antigen gp160. These results warrant further evaluation of extended periods or cycles of murabutide immunotherapy as adjunct to HAART.

Clinical tolerance and immunologic effects after single or repeated administrations of the synthetic immunomodulator murabutide in HIV-1-infected patients.

Correction of the virus-induced deficits in innate immunity of HIV-infected subjects could well contribute to enhanced immune recovery and efficacious control of viral replication. The safe synthetic immunomodulator Murabutide (ISTAC Biotechnology, Lille, France) has been found to regulate the function of antigen-presenting cells and to selectively activate CD4 lymphocytes leading to dramatic suppression of HIV replication, in vitro. Therefore, as a first step toward the evaluation of the immunotherapeutic potential of Murabutide in HIV disease, we have conducted two phase 1/2 clinical trials to address the safety and the immunologic effects of Murabutide administration into HIV-infected subjects receiving antiretroviral therapy. The first study revealed that single administration of 5, 7, or 9 mg of Murabutide, to 6 patients per dose, was well tolerated. This was accompanied by a selective induction of cytokines and chemokines detectable in the serum, and the levels appeared to plateau at the 7-mg dose. The second study then evaluated the safety and biological effects of repeated administrations of 7 mg Murabutide, on 5 consecutive days, in 12 HIV-1-infected patients. A good clinical tolerance was noted throughout the study. Moreover, changes in several immune parameters, including downregulation of coreceptor expression on lymphocytes and improved lymphoproliferative responses, were detected during or/and up to 3 weeks after Murabutide administration. These encouraging results warrant further evaluation of longer periods or cycles of immunotherapy with Murabutide in HIV-infected subjects.

Lifetime cost of HIV care in France during the era of highly active antiretroviral therapy.

OBJECTIVE: To estimate the treatment and health care costs of HIV infection or AIDS in France during the era of highly active antiretroviral therapy (HAART). DESIGN: We used a clinical database of HIV-infected patients to calculate the resource use and cost of care for different stages of HIV infection. Costs were incorporated into a computer-based, probabilistic simulation model of the natural history and treatment of HIV infection to estimate the lifetime cost of treating patients with HIV disease. SETTING: A northern France HIV clinical cohort. PARTICIPANTS: 1232 HIV-infected patients followed from January 1994 through July 1998. RESULTS: In the absence of an AIDS-defining event, the average total cost of care ranged from 670 euros (1 euro=US $1.19) per person-month in the highest CD4 stratum (>500/microl) to 1060 euros per person-month in the lowest CD4 stratum (< or = 50/microl). The mean cost of care was estimated at 3370 euros per person-month during the initial months around the occurrence of an AIDS-defining event; at 1750 euros per person-month during the period spanning from 2 months after the diagnosis of specific AIDS-defining event to 1 month prior to death; and at 13010 euros per person-month in the final month prior to death. If clinical management of HIV infection began at a CD4 cell count of 378/microl, as in this cohort, the discounted lifetime cost of treating an HIV-infected French patient was estimated at 214000 euros. The undiscounted costs were 309000 euros over a projected life expectancy of 16.4 years. CONCLUSION: The cost of HIV disease varies widely depending upon the stage of illness. These estimates of stage-specific and lifetime costs of HIV care will assist health policy planners in assessing the burden of disease in the era of HAART and projecting future resource requirements.

Imported malaria: presentation and outcome of 111 cases.

OBJECTIVE: To evaluate the presentation and outcome of imported malaria. PATIENTS AND METHODS: Retrospective charts review of hospitalized patients with smear-proven malaria from January 1989 to October 1994. RESULTS: Of a total of 111 cases, 95 were caused by Plasmodium falciparum. Chemoprophylaxis was used in 57% of patients but only 41% were compliant. Parasitemia ranged from 0.1% to 22%. Clinical and biological signs at admission were unspecific. In all cases where both platelets and C-reactive protein were measured, at least one abnormality was noted. More than two WHO gravity criteria were present in 14 cases. Outcome was marked by two deaths and 18 adverse drug reactions. Plasmodium falciparum was associated to only one independent factor in multivariate analysis: symptom onset less than 30 days after return. Chemoprophylaxis use did not modify clinical presentation, mean parasitemia or outcome. CONCLUSIONS: P. falciparum is the most usual cause of imported malaria in France. Normal platelet count and C-reactive protein value probably exclude the diagnosis of malaria in febrile travelers.