[Management of 90 patients presenting with suspected severe acute respiratory syndrome. Experience of a collaboration between epidemiologists and clinicians facing an emerging infectious disease health alert]. / Prise en charge de 90 patients suspects de syndrome respiratoire aigu sévère. Expérience d'une collaboration épidémioclinique en situation d'alerte sanitaire liée à une infection émergente.

OBJECTIVE: The characteristics of patients with a suspected SARS hospitalized in a Paris hospital were studied to analyze the hypothetic differences between epidemiologic and clinical teams in the management of an epidemic emerging disease, and to gather experience for the management of the next outbreak. STUDY DESIGN: All 90 patients hospitalized between March 16 and April 30, 2003, were included. Epidemiological and clinical data were shared with the French National Institute for Health. Cases were classified according to both the official definition ("possible", "probable", "excluded") and a local one, adapted from the official definition but including an additional level of suspicion ("equivocal"), intermediate between "possible" and "excluded". RESULTS: The initial assessment was different in 39% of the cases (n=35), according to epidemiological (n=24) or clinical (n=11) elements. The final assessment diverged in 54% of the cases (n=47). All patients were officially considered as "excluded" for epidemiologists, while 47 remained as "possible" or "equivocal" cases of SARS according to the clinicians. CONCLUSION: The risk assessment was different in almost 40% of the cases, with no impact on epidemic diffusion or hospital-borne exposure as no probable case of SARS was diagnosed among these patients or their households. The confrontation of these different but complementary points of view will thus enrich the interdisciplinary management of eventual future outbreaks.

Docetaxel in anthracycline-pretreated AIDS-related Kaposi's sarcoma: a retrospective study.

BACKGROUND: Kaposi's sarcoma (KS) is a potentially life-threatening multifocal neoplasm. Despite the significant decline in the incidence of acquired immune deficiency syndrome (AIDS)-related KS with the use of highly active antiretroviral therapy (HAART), some patients, even those with a good immune restoration, still have aggressive disease. Liposomal anthracyclines or combination chemotherapy are widely used but adverse effects limit their utilization. OBJECTIVES: We studied the efficacy and tolerance of docetaxel in the treatment of AIDS-related KS after pretreatment with anthracycline. PATIENTS/METHODS AND MAIN OUTCOME MEASURE: A retrospective cohort study was done. Nine human immunodeficiency virus (HIV)-infected patients were treated from 1997 to 2002 with docetaxel. Tumour response was evaluated using the AIDS Clinical Trial Group (ACTG) staging criteria. Clinical and biological toxicity was evaluated. AIDS status with HIV viral load and CD4 T-cell count were measured at the beginning and at the end of the treatment. RESULTS: A major (complete or partial) response and a stabilization of the disease were demonstrated in seven and two patients, respectively. Grade 4 neutropenia and thrombocytopenia were observed in four of nine and one of nine patients, respectively. One patient died after sepsis. CONCLUSIONS: Docetaxel has a good and rapid efficacy in anthracycline-pretreated patients with severe AIDS-related KS. Phase II/III trials should be done to compare docetaxel with liposomal anthracyclines as a first-line treatment.

Maintenance therapy with cotrimoxazole for toxoplasmic encephalitis in the era of highly active antiretroviral therapy.

To reduce the number of daily pills for improving adherence to antiretrovirals, 17 protease inhibitor-treated patients receiving toxoplasmic encephalitis (TE) standard maintenance therapy were instead given cotrimoxazole 960 mg twice daily. After a median follow-up of 31 months, one relapsed after three months, TE relapse incidence = 2.1 cases per 100 patient-years (95% confidence interval, 0.05-11.3). This strategy could be useful for patients awaiting immune reconstitution which allows the interruption of TE maintenance therapy.

Determination of indinavir and nelfinavir trough plasma concentration efficacy thresholds according to virological response in HIV-infected patients.

BACKGROUND: There is evidence to suggest a pharmacokinetic-pharmacodynamic relationship in HIV-infected patients receiving protease inhibitor (PI)-containing highly active antiretroviral therapy (HAART); however, the effective trough PI plasma concentrations achieved have not been precisely determined. METHODS: The relationship between HIV viral load and concomitant PI trough plasma concentration (C(trough)) was evaluated in 101 patients receiving at least 4 months of thrice daily indinavir (IDV)-containing (n=68) or nelfinavir (NFV)-containing (n=33) HAART. The more discriminating C(trough) efficacy thresholds were determined statistically for each PI by using the raw C(trough) and the time-corrected C(trough), using the precise delay since the last PI intake and the half-life of each PI. RESULTS: For IDV (P=0.002) and NFV (P=0.019) median C(trough) levels were higher in patients with undetectable viral load [0.23 mg/L (n=30) and 2.3 mg/L (n=16) respectively] than in patients with detectable viral load [0.11 mg/L (n=38) and 0.6 mg/L (n=17) respectively]. C(trough) levels of IDV (r=-0.45; P<0.0001) and NFV (r=-0.43; P=0.011) were correlated with the concomitant viral load. The more discriminating C(trough) efficacy thresholds were estimated statistically as 0.12 mg/L for IDV and 0.5 mg/L for NFV. When C(trough) values were time-corrected, the C(trough) efficacy thresholds, 8 h after the last intake, were 0.15 mg/L for IDV and 0.65 mg/L for NFV. CONCLUSIONS: These results support the importance of achieving minimal effective C(trough) to improve the virological efficacy of PI-containing HAART, and specify the target concentrations for IDV and NFV.

Failure of valacyclovir for herpes zoster in a moderately immunocompromised HIV-infected patient.

Whereas valacyclovir is widely used and is recommended by some authors in moderately immunocompromised HIV-infected patients, its use has not been validated by clinical studies. We report a case of herpes zoster in an HIV-infected patient for whom neurologic complication was not avoided despite valacyclovir therapy. Clinical outcome was favorable after intravenous acyclovir. This case suggests careful monitoring of valacyclovir in HIV-infected patients is necessary.

Decreases in plasma TNF-alpha level and IFN-gamma mRNA level in peripheral blood mononuclear cells (PBMC) and an increase in IL-2 mRNA level in PBMC are associated with effective highly active antiretroviral therapy in HIV-infected patients.

In this study, we investigated the cytokine profiles of 14 treatment-naive HIV-infected patients on the initiation of highly active antiretroviral therapy (HAART). At baseline, plasma levels of TNF-alpha and its mRNA in peripheral blood mononuclear cells (PBMC) were highest in the most severely immunocompromised patients (<200 CD4+ cells/mm3). After 12 months of HAART, the virus was undetectable in the plasma of all patients (<200 copies/ml), and median CD4 T cell counts had increased (+164 cells/mm3). We also observed a gradual decrease in the number of proviral DNA copies in PBMC and in immune activation, with lower levels of IFN-gamma mRNA in PBMC associated with weaker activation of CD8+ T cells and lower levels of plasma TNF-alpha. IL-2 mRNA levels in PBMC were found to increase in parallel. The decrease in TNF-alpha and IFN-gamma levels and the increase in IL-2 production appear to be correlated with the efficacy of HAART in naive immunocompromised HIV-infected individuals.

Salivary cytomegalovirus (CMV) shedding, glycoprotein B genotype distribution, and CMV disease in human immunodeficiency virus-seropositive patients.

To assess the frequency of shedding of cytomegalovirus (CMV) in saliva, the distribution of CMV glycoprotein B (gB) genotypes, and the occurrence of CMV diseases, we screened 98 human immunodeficiency virus (HIV)-seropositive patients without CMV disease. CMV was detected by culture more frequently in saliva (45 [46%] of 98 patients) than in blood (7 [7.5%] of 93) and was associated with CD4 cell counts <100 cells/mm3 (P=.013). CMV in the saliva of 37 patients was successfully genotyped. Three patients (8%) were infected by a gB1 strain, 26 (70%) by a gB2 strain, 2 (5.5%) by a gB3 strain, 1 (3%) by a gB4 strain, and 5 (13.5%) by mixed gB strains. Thirteen patients developed CMV disease after a mean period of 143+/-112 days; at inclusion, 9 (69%) had salivary CMV shedding and 2 had CMV viremia. CMV salivary shedding (P=.043), low CD4+ cell count (P=.041), and CMV viremia (P=.011) were associated with occurrence of CMV disease.

Definite streptococcus bovis endocarditis: characteristics in 20 patients.

OBJECTIVE: To determine the specific characteristics of Streptococcus bovis infective endocarditis (IE) by reviewing our own experience of S. bovis IE. METHODS: Twenty episodes of definite S. bovis IE were reviewed in 20 patients hospitalized from 1980 to 1996. RESULTS: The mean age was 62 +/- 14 years, and 14 (70%) patients had no known predisposing cardiac condition. The principal antimicrobials used were penicillin G (N = 10) and amoxycillin (N = 8). Surgery was required in four (20%) patients. Neurologic complications occurred in eight (40%) patients, after initiation of therapy in six (75%) (mean time: 14 days). An unfavorable outcome was observed in four of 20 patients and tended to be more frequent in patients who had had neurologic complications (P = 0.10). Colonic tumors were present in 11 of 16 (69%) patients. CONCLUSIONS: Advanced age, occurrence of IE on presumably normal valves, high rate of neurologic complications, associated gastrointestinal diseases and low mortality rate during initial follow-up are characteristic features of S. bovis IE observed in this study.

[Long-term immunologic response in HIV-infected patients with CD4 cell counts

From March to July 1996, 61 patients with CD4<50/mm(3)began a therapy with protease inhibitors. Increase and maintenance of CD4>100/mm(3) was observed in 39/61 patients with a protective effect for occurrence of AIDS or death. This immunological response was correlated with the duration of the virological response. However, 38% of patients with long-term immunological response never had a undetectable viral load.

[Skin manifestations of immune restoration syndrome in treated tuberculosis]. / Manifestations cutanées d'un syndrome de restauration immune au cours d'une tuberculose traitée.

INTRODUCTION: Immune restoration syndrome was first described in 1998 and involved mycobacterium avium complex. We report the case of a patient with acquired immunodeficiency syndrome who had disseminated cutaneous lesions due to Mycobacterium tuberculosis, following initiation of highly active antiretroviral therapy. CASE REPORT: A 42 year-old HIV-infected man, was admitted for fever, cough, nocturnal sweat and impaired of general condition. He had a viral load of 127,200 copies/ml and 199/ml CD4 T-cells. He was treated with triple tuberculosis combination therapy according to tuberculous contagium, positivity of the tuberculin intradermoreaction (15 mm) and right upper lung nodule on thoracic scan. M. tuberculosis was not found. Fever improved at day 3. Highly active antiretroviral therapy with zidovudine, lamivudine, indinavir, was started at day 11 and 33 days after, fever and dermohypodermal nodules with necrotising evolution appeared. Skin biopsy specimen showed tuberculoid granuloma. The levels of viral load and CD4 T-cells were less than 200 copies/ml and 497/ml respectively. Fever and cutaneous lesions spontaneously resolved without changing therapy. DISCUSSION: Immune restoration syndrome appears after initiation of antiretroviral therapy, in patients with advanced HIV infection and without prophylactic treatment versus MAC. This case report probably involves mycobacterium tuberculosis. Bacterial lysis and immune restoration take part in cutaneous pathogenesis. Subclinical mycobacterial infection should be monitored during initiation of antiretroviral therapy in patients with advanced HIV infection.

[Paradoxical aggravation of tuberculosis after antiretroviral therapy in HIV-infected patients]. / Aggravation paradoxale de la tuberculose après traitement antirétroviral chez des patients infectés par le VIH.

BACKGROUND: Restoration of immunocompetence in HIV-infected patients after antiretroviral treatment can have unexpected effects. CASE REPORTS: An unusual course of treated tuberculosis was observed in four HIV-infected patients soon after initiation of antiretroviral therapy. These patients developed fever and enlarged necrotic adenopathies despite an efficacious antituberculous therapy. They were in the initial stage of their antituberculous therapy that had been initiated a mean 12 days prior to initiation of antiretroviral therapy. The antiretroviral therapy led to an undetectable HIV load within 2 months. DISCUSSION: These unusual features, which also occurred with an increase in CD4 cell counts, could be related to the immunological restoration and to the reappearance of delayed type hypersensitivity. The onset of antiretroviral therapy could thus be delayed by several weeks in HIV-infected patients treated for active tuberculosis and who have never received antiretroviral therapy.

Possible mechanism of toxicity of zidovudine by induction of apoptosis of CD4+ and CD8+ T-cells in vivo.

Some HIV-infected patients have a discordant response to highly active antiretroviral therapy with a low virus load and an incomplete restoration of CD4+ T-cell counts. Zidovudine may limit CD4+ restoration by a hematotoxic mechanism. Apoptosis and T-cell counts were assessed in two patients before and after they switched from zidovudine to stavudine. Whereas CD4+ T-cell apoptosis fell from 52% and 66% before the zidovudine switch to 7% and 12%, respectively, after the switch, the patients' CD4+ counts rose gradually to +183 and +150 cells, respectively. It was therefore hypothesized that zidovudine directly induced apoptosis. Zidovudine withdrawal could be tested before immunological interventions such as interleukin-2 therapy are considered.

High levels of IL-10 and determination of other cytokines and chemokines in HIV-associated haemophagocytic syndrome.

Haemophagocytic syndrome (HPS) and HIV infection are both associated with cytokine network dysregulation. We therefore analysed plasma levels and mRNA synthesis in peripheral blood mononuclear cells (PBMC) of cytokines, chemokines and chemokine receptors in one HIV-infected patient with HPS. We compared the results with those for eight HIV-infected patients with similar CD4+ T cell counts (207/mm3 versus controls: median 214/mm3) and plasma virus load (4.1 log copies/ml, versus controls: median 4.2 log copies/ml). The HPS patient had a lower viral DNA load in PBMC and higher plasma levels of interferon-gamma, IL-10, and macrophage inflammatory protein (MIP)-1beta. No difference in plasma tumour necrosis factor-alpha (TNF-alpha), IL-6 and MIP-1alpha concentration was observed between the HPS patient and control patients. No difference was observed in TNF-alpha, IL-1beta, IL-10, IL-4, MIP-1alpha, MIP-1beta, RANTES, CXCR-4, and CCR-5 mRNA levels in PBMC, but IL-6 levels were higher in the HPS patient. Our results emphasize the role of IL-10 in the control of immune hyperactivation that is observed in HPS.

Modalities of palliative care in hospitalized patients with advanced AIDS.

This prospective multidisciplinary survey started in October 1994. The survey assessed the modalities of care of hospitalized patients with advanced AIDS in an Infectious and Tropical Diseases Unit with regards to the practices of palliative care in a Palliative Care Unit. Seventy-eight (78) AIDS patients with CD4 < or = 30/mm3 who had 102 consecutive hospitalizations were recruited. Types (symptomatic or curative) and number of drugs administered to the patients, as well as biological and radiological investigations performed were recorded. Symptoms were concomitantly assessed on a weekly basis by self-evaluation of the patients themselves and by physicians. The results showed that the practices of care were different in the two units according to the specific goals and norms of each unit. A higher density of care was delivered at the Infectious and Tropical Diseases Unit. Symptoms assessed by both patients and physicians were underestimated by physicians in frequency and in intensity. In conclusion, an integrated approach including objective and subjective criteria should enable a better adjustment of the palliative and curative therapeutic strategies in advanced AIDS. These would concomitantly take into account the wishes of the patient and the goals regarding care in the unit where the patient is hospitalized.

Natural history of serum HIV-1 RNA levels in 330 patients with a known date of infection. The SEROCO Study Group.

OBJECTIVE: To describe the spontaneous course, before the introduction of highly active antiretroviral therapy (HAART), of HIV-1 RNA during the AIDS-free period of the disease. To assess the predictive value of changes in HIV-1 RNA levels. DESIGN: A total of 330 patients with a known date of infection followed in the SEROCO cohort. METHODS: HIV-1 RNA levels (threshold, 200 copies/ml) were evaluated from 2243 frozen sera obtained from enrolment until the onset of AIDS or until February 1996. Lowess curves were used to describe the variations of viraemia during follow-up. A Cox regression model was used to assess the predictive value of early and updated CD4 cell count and viral load. RESULTS: In addition to a lower early viral load, patients who remained AIDS-free had, on average, a longer period of viral load decrease after infection (36 versus 18 months), followed by a slower viral load increase compared with those who progressed to AIDS. A true plateau-phase after the seroconversion period, lasting approximately 4 years, was identified only in patients who remained AIDS-free for at least 90 months. In multivariate analysis, both early viral load and later changes were significant predictors of progression to AIDS. A decrease in the CD4 cell count to less than 200 cells/microl and the onset of a group B condition remained significant predictors of progression. CONCLUSION: Our study extends to the early post-seroconversion phase the prognostic value of extracellular HIV-1 RNA levels. Moreover, our data suggest that, in most HIV-infected individuals, a progressive loss of control of viral replication arises during the early years of HIV-1 infection.