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.

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.

[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.

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.

[Primary chemoprevention of tuberculosis in HIV-infected patients in non-industrialized countries]. / Chimioprophylaxie primaire de la tuberculose chez les personnes infectées par le VIH dans les pays non industrialisés.

In randomized placebo-controlled trials in Haïti, Zambia and Uganda, prophylactic use of isoniazid (INH) for 6 to 12 months reduced the annual incidence of tuberculosis in HIV-infected patients by more than 50 per cent. For several years, WHO, IUTATLD and CDC have recommended that HIV-positive patients testing positive in a PPD test should be treated with INH as a form of anti-tuberculosis chemoprophylaxis (ATC). Whilst these recommendations are easy to follow in industrialized countries, widespread use of ATC in developing countries remains problematic because: (i) It is unknown what proportion of patients are likely to be re-infected at the end of ATC in countries where TB is endemic; (ii) It is possible that resistant bacilli may be selected due to the incomplete exclusion from the ATC program of patients with active TB at enrollment; (iii) It is difficult to identify asymptomatic carriers of M. tuberculosis at enrollment; (iv) It is doubtful that all patients will comply with a treatment regime which lasts several months; (v) The cost of a widespread ATC program, whose full benefit remains to be evaluated, may be difficult to justify. This paper attempts to review these issues and demonstrates the need for more population-based clinical trials in the field.

Life expectancy in hospitalized patients with AIDS: prognostic factors on admission.

In the course of the inevitable hospitalizations of AIDS patients, many difficult questions concerning curative and palliative approaches to care have to be answered. In order to guide these strategies, we conducted a prospective study to identify those variables which can be easily quantified on admission which might be predictive of patient outcomes. Between 1 June 1990 and 25 April 1991, 140 consecutive hospitalizations of 83 AIDS patients were recorded. Demographic, clinical, and biological data were collected within 48 hours of admission. Probable (p <0.10) or definite (p <0.05) factors contributing to a higher mortality included type of opportunistic infections, serum albumin level, total lymphocyte count, weight, CD4 cell count, and neurological manifestations. In the multivariate proportional hazards model, two factors were significantly and independently predictive of lower survival: body weight less than 90% of ideal body weight and neurologic manifestations. The probability of survival was significantly affected by the number of predictive factors present on admission, and patients were significantly more likely to die when these latter two factors were present concomitantly. These factors might be useful to define the optimal mode of care for hospitalized AIDS patients, considering both patients' wishes and an objective assessment of the prognosis.

Activities of roxithromycin against Mycobacterium avium infections in human macrophages and C57BL/6 mice.

The activity of roxithromycin against three clinical isolates of Mycobacterium avium was compared with that of clarithromycin both in a model of infection of human monocyte-derived macrophages and in a model of established infection of C57BL/6 mice. In the cell culture model, roxithromycin and clarithromycin were bactericidal for strains MO-1 and N-92159 and bacteriostatic for strain N-93043. For the three strains, the differences between the intracellular activities of roxithromycin and clarithromycin were not singificant after 7 days of treatment. Mice were infected with the MO-1 strain. Drugs were given by gavage at a dosage of 200 mg/kg of body weight 6 days per week for 16 weeks starting 5 weeks after infection. At the end of treatment, clarithromycin was more effective than roxithromycin in lungs; roxithromycin was as effective as clarithromycin in spleens. Thus, the activity of roxithromycin was comparable to that of clarithromycin both in vitro and in vivo.

Mefloquine-associated hypoglycaemia in a cachectic AIDS patient.

Quinine and its isomer quinidine are well-known causes of iatrogenic hypoglycaemia, due to excessive insulin secretion. The situation is less clear regarding other anti-malarial quinine analogues. In particular, this adverse effect has never been described with mefloquine (Lariam). We report a case of hypoglycaemia after mefloquine therapy (1,500 mg over two days) for severe gastrointestinal cryptosporidiasis in a cachectic AIDS patient with protracted diarrhoea. Blood glucose levels, which were normal before treatment, dropped to 2.3 mmol/l within a few hours and were corrected by i.v. glucose infusion. Hypoglycaemia did not recur despite continued treatment. Rat islets of Langerhans exposed to mefloquine in vitro (10(-8) mol/l to 10(-3) mol/l) secreted significantly more insulin than control islets (up to 980 +/- 180 microU/ml/5 islets incubated with mefloquine 10(-3) mol/l, vs 20 +/- 4 microU/ml/5 untreated islets). Mechanisms and triggering factors of hypoglycaemia induced by mefloquine and some other anti-malarial quinine analogues are discussed. Clinicians who manage cachectic patients, particularly those with protracted diarrhoea and/or receiving anti-malarial drugs including mefloquine, should be aware of the risk of severe hypoglycaemia.

Fever of unknown origin in HIV-infected patients: a critical analysis of a retrospective series of 57 cases.

OBJECTIVES: The aim of the study was to assess the incidence and aetiology of fever of unknown origin in human immunodeficiency virus (HIV)-infected patients, and to evaluate the usefulness of the main diagnostic procedures. DESIGN: A retrospective study. SETTING AND SUBJECTS: We reviewed the records of 270 HIV-infected patients who were hospitalized for the first time in a department of infectious and tropical diseases during the 27 month study period. MAIN OUTCOME MEASURES: Fifty-seven patients (21%) had a history of fever of unknown origin. RESULTS: The aetiology was found in 49 cases (86%). The major cause of the fever was mycobacteriosis: atypical mycobacteria in 10 cases, Mycobacterium tuberculosis in 10, mycobacteria of unspecified type in two, and BCG strain in one. A liver biopsy and a thoracic CT scan greatly contributed to the diagnosis of mycobacterial infection. Seventeen patients were given empiric antimycobacterial therapy as a therapeutic test, of whom seven had a favourable response. The other main causes of fever were cytomegalovirus infection in five patients, leishmaniasis in four, and lymphoma in four. CONCLUSIONS: Fever of unknown origin is a frequent occurrence in the course of HIV infection, and mycobacterial infection should be considered as a first-line diagnosis in such cases. The place of empiric antimycobacterial therapy in the diagnostic strategy requires further evaluation, but appears to be an alternative to multiple investigative procedures.

Pyogenic and tuberculous spondylodiskitis (vertebral osteomyelitis) in 80 adult patients.

Bacterial spondylodiskitis--i.e., adjacent vertebral osteomyelitis and diskitis--was studied in 80 adult patients. The infection was due to Mycobacterium tuberculosis in 31 cases (39%) and to pyogenic bacteria in 49 cases (61%). The latter pathogens included gram-negative bacilli in 16 cases (20%), Staphylococcus species in 15 (19%), Streptococcus species in 9 (11%), and Corynebacterium species in 1 (1%); the pathogens in the 8 remaining cases (10%) were not identified. Of the patients with tuberculous spondylodiskitis, 55% came from countries where tuberculosis is endemic (P < .001). Cases due to staphylococci and those due to M. tuberculosis were associated with a high frequency of previous active infection with those respective organisms at any site (47% and 42%, respectively; P < .001) and with a high rate of neurological complications (33% and 32%, respectively; P < .001). Nine patients with pyogenic spondylodiskitis (18%) but only one patient with tuberculous spondylodiskitis (3%) had diabetes mellitus (P < .05). Blood cultures were positive in 23 (56%) of the 41 cases of pyogenic spondylodiskitis due to an identified bacterium. Discovertebral needle biopsy contributed to the bacteriologic diagnosis in 29 (74%) of 39 cases.

[Multicenter French cohort of adults with HIV infection. Description and course after 4 years of follow-up. SEROCO]. / Cohorte francaise multicentrique d'adultes infectés par le VIH. Description et évolution après 4 ans de suivi. SEROCO.

OBJECTIVES: A prospective multicentric epidemiological study (SEROCO) of subjects with a diagnosis of human immunodeficiency virus (HIV) infection was started on January 1, 1988 in order to better understand the natural history of HIV infection and factors related to outcome. Observations after 4 years of follow-up are reported here. METHODS: After authorization by the French national ethics committee and the national commission for personal freedom, 18 French centres included non-haemophiliac volunteers who were asymptomatic, had had non anti-HIV treatment and whose HIV positivity had been known less than 1 year at inclusion. These last three criteria were not required for patients whose precise date of contamination was known within a range of +/- 3 months. RESULTS: On July 15, 1992, there were 1453 infected subjects in the cohort (1063 males, 417 females; age range at inclusion 18-75 years; mean age 31.3 +/- 9.4). Globally, 2.7% of the subjects were symptomatic at inclusion. Mean CD4 lymphocyte count at inclusion was 508/mm3. Clinically, 51.5% of the patients had a history of sexually transmitted disease at inclusion. After 4 years (on July 15, 1992) mean follow-up was 28 +/- 12.9 months for a total of 3428 patient-years. Disease progression to stage IV was observed in 439 patients including 202 who developed the acquired immuno-deficiency syndrome (AIDS). Among these 202 patients, 113 had died at the end-point of this report. The first manifestation of AIDS was Kaposi sarcoma in 44, pulmonary pneumocystosis in 38 and cerebral toxoplasmosis in 27. The probability of developing AIDS was calculated at 13.9% at 5 years, 27.7% at 7 years and 33.7% at 10 years. The probability of a CD4 count below 200/mm3 was 32.7, 55.6 and 67% at 5, 7 and 10 years respectively. For patients with a CD4 count below 200, the probability of developing AIDS was 18% at 1 year, 39% at 2 years and 51% at 3 years. CONCLUSIONS: SEROCO has been a most useful prospective epidemiological tool due to the diversity of the subjects included. The observed natural history of HIV infection will lead to specific research projects aimed at better understanding the disease process.

Chloroquine does not enhance the activity of clarithromycin against multiplication of Mycobacterium avium within human macrophages.

SETTING: Chloroquine, an alkalinizing lysosomotropic agent, enhances the intracellular activity of antibiotics against Mycobacterium tuberculosis or Coxiella burnetii. OBJECTIVE: To determine if chloroquine modifies the activity of clarithromycin, less effective at acidic pH, against intracellular Mycobacterium avium. DESIGN: The activity of clarithromycin (4 micrograms/ml) against the MO-1 strain of M. avium was evaluated within human macrophages in presence of chloroquine (5 micrograms/ml). The minimal inhibitory concentration of clarithromycin for the strain was 2 micrograms/ml. RESULTS: While clarithromycin alone did decrease the intracellular infection at day 7 of culture (P < 0.01), chloroquine alone did not impede the intracellular growth of M. avium, and did not enhance the activity of clarithromycin. CONCLUSION: Chloroquine should not improve clarithromycin treatment against M. avium infection.

Cytomegalovirus colitis in HIV-1-infected patients: a prospective research in 55 patients.

OBJECTIVE: To determine criteria for the diagnosis of cytomegalovirus (CMV) colitis and to analyse stages of the course and prognosis of CMV colonic involvement in HIV-1-infected patients. DESIGN: Prospective search for CMV colonic involvement with systematic biopsies to search for CMV intranuclear inclusion bodies and for CMV culture. The evolution of CMV colonic involvement was estimated using further coloscopies and autopsy. SETTING: Infectious diseases department in a tertiary referral teaching hospital in Paris, France. PARTICIPANTS: Fifty-five consecutive patients with HIV-1 infection, who had not previously received anti-CMV drugs, and who had at least one coloscopy performed. RESULTS: According to initial coloscopy, colitis, either ulcerative or inflammatory, was found in nine (16%) out of the 55 patients, CMV intranuclear inclusions were present in the colon of four (7%) patients, and colonic cultures were positive for CMV in 15 (27%) patients. The results of the initial coloscopy showed a positive correlation between endoscopic colitis (either ulcerative or inflammatory), CMV inclusions and positive CMV culture from colonic biopsies. The absence of endoscopic ulcerative lesions had a 98% (49 out of 50) negative predictive value for recording CMV inclusions in the colon (95% confidence interval, 89-100). CMV inclusions were recorded in three out of five ulcerative colitis. Male homosexuality, HIV-1 infection stages IVB, C1, D or E, according to the Centers for Disease Control and Prevention classification, CD4 lymphocyte count < 200 x 10(6)/l and CMV viraemia also correlated positively with CMV colonic involvement. During the observation period (mean, 7.3 months), the estimated incidence of CMV colitis according to coloscopic studies was 13%. Deterioration in condition was the most frequent spontaneous evolution of CMV colonic infection, whereas anti-CMV treatment resulted in an improvement. Ulcerative lesions occurred earlier in patients with colonic CMV inclusions or positive colonic CMV culture than in patients without CMV colonic involvement at the initial coloscopy. CMV colitis occurred late in the course of HIV-1 infection, on average 4 months before death. The presence of CMV inclusions was an indicator of poor prognosis with earlier occurrence of CMV viraemia and retinitis and no survival after 9 months. CONCLUSIONS: These results confirm that the colon is a target organ for CMV in HIV-1-infected patients. Coloscopy should be used to diagnose CMV colitis, because of the close correlation between endoscopic and histological data (i.e., intranuclear inclusions). This combination allows us to propose an evolutive staging of CMV colonic involvement and provide stratification criteria to assess the efficacy of anti-CMV drugs.