Safety, efficacy and pharmacokinetics of vedolizumab in patients with simultaneous exposure to an anti-tumour necrosis factor.

BACKGROUND: Data on combination-biologic treatment in (IBD) are still scant. AIM: To explore outcomes of patients co-exposed to anti-TNF and vedolizumab. METHODS: Patients starting vedolizumab having measurable anti-TNF levels after recently stopping adalimumab/infliximab ('VDZ-aTNF' group), were compared with control vedolizumab patients in a retrospective 1:2 matched case-control study. RESULTS: Seventy-five patients were included (25 VDZ-aTNF, 50 VDZ). Adverse events were experienced by 9/25 VDZ-aTNF compared to 13/50 VDZ patients (P = 0.4, follow-up 14 weeks in all). Week 14 clinical remission was attained in 10/25 (40%) of VDZ-aTNF patients versus 23/50 (46%) of VDZ patients (OR = 0.8, 95% CI 0.3-2.1, P = 0.6) and clinical response in 19/25 (76%) versus 39/50 (78%) respectively (OR = 0.9, 95% CI 0.3-2.7, P = 0.8). Corticosteroid-free remission and corticosteroid-free response were experienced by 30% and 54%, respectively, of the entire cohort, and were similar between the two groups. Vedolizumab drug concentrations at week 2, 6 and 14 were similar among VDZ-aTNF and VDZ patients (P > 0.5). Multi-variable analysis showed independent association of some vedolizumab drug-levels time-points with baseline albumin and weight, but not with anti-TNF co-exposure. In a prospective study of a separate cohort of patients starting infliximab (n = 12), the percentage of α4ß7+ memory T cells, slightly but nonsignificantly increased throughout weeks 0, 2 to 14 (26 ± 2.3%, 27.8 ± 2.9%, 29.5 ± 2.6% respectively, P = 0.06). CONCLUSIONS: Vedolizumab/anti-TNF co-exposure did not generate new safety signals during 14-weeks induction, nor did it reduce efficacy or alter vedolizumab pharmacokinetics. These observations may aid the design of future co-biologics trials and also suggest that a deliberate waiting-interval between anti-TNF cessation and subsequent vedolizumab initiation may not be warranted.

Early drug and anti-infliximab antibody levels for prediction of primary nonresponse to infliximab therapy.

BACKGROUND: Primary nonresponse, defined as lack of clinical benefit during the induction phase, occurs in up to 30% of IBD patients treated with infliximab. The mechanisms underlying primary nonresponse have not yet been clearly defined. AIM: To evaluate the association of early (week 2 and week 6) induction infliximab and anti-infliximab antibody levels with primary nonresponse. METHODS: A retrospective observational case-control study of inflammatory bowel disease patients treated with infliximab and followed at Sheba Medical Center between 2009 and 2016 was performed. Pre-infusion infliximab and antibodies to infliximab (ATI) levels were measured by our previously described drug-tolerant ELISA assay. RESULTS: Thirty-five primary nonresponders have been identified and matched with 105 primary responders (1:3 ratios). Both week 2 and week 6 infliximab levels were significantly lower among primary nonresponders compared to responders (week 2, 6: median level 7.2, 2.2 µg/mL vs 13.5, 9.5 µg/mL, P = .0019, P < .0001 respectively). Antibodies to infliximab appeared more frequently (either week 2 or 6, 68% vs 28% prevalence, P = .0004) and at higher levels in nonresponders compared to responders (week 2, 6: median ATI 7.3, 10.8 µg/mL-eq vs 3.8, 4.4 µg/mL-eq, P = .005, P = .008 respectively). Moreover, week 2 infliximab levels <6.8 µg/mL (AUC = 0.68, P = .002, sensitivity 50%, specificity 86%) and antibodies to infliximab levels >4.3 µg/mL-eq (AUC = 0.78, P = .0004, sensitivity 77%, specificity 71%) were predictive of primary nonresponse. Among the other clinical and demographic variables, higher baseline ulcerative colitis clinical score, infliximab monotherapy, prior adalimumab therapy and previous Crohn's disease-related surgeries were also associated with an increased risk of primary nonresponse. CONCLUSIONS: Infliximab levels below 6.8 µg/mL and antibodies to infliximab levels above 4.3 µg/mL-eq before the second infusion are associated with primary nonresponse, especially among Crohn's disease patients.

Addition of an immunomodulator can reverse antibody formation and loss of response in patients treated with adalimumab.

BACKGROUND: Anti-adalimumab antibodies (AAA) are associated with loss of clinical response (LOR). Addition of an immunomodulator has been shown to reverse immunogenicity and regain response with infliximab monotherapy. Similar data on adalimumab are lacking. AIM: To study the impact of immunomodulator addition on the emergence of AAA and LOR among adalimumab therapy patients. METHODS: The databases of three tertiary medical centres were reviewed to identify patients who developed AAA during adalimumab monotherapy with resultant LOR, and received an immunomodulator as a salvage combination therapy. All sera were prospectively analysed using previously described ELISA assays. Clinical response was determined using appropriate clinical scores. Elimination of AAA, designated as 'sero-reversal', elevation of drug levels and regained clinical response were the sought outcomes. RESULTS: Twenty-three patients (21 Crohn's disease, and 2 ulcerative colitis) developed AAA with subsequent LOR and were thereafter prescribed an immunomodulator as salvage therapy (thiopurine n = 14, methotrexate n = 9). Eleven patients (48%) underwent sero-reversal with gradual elimination of AAA, increase in drug trough levels and restoration of clinical response (median time to sero-reversal 5 months). In 12 patients (52%), immunogenicity and loss of response could not be reversed. There was no difference between responders and nonresponders in the type of immunomodulators used or baseline clinical characteristics. CONCLUSIONS: In almost half of inflammatory bowel disease patients developing anti-adalimumab antibodies and loss of response, established immunogenicity of adalimumab can be gradually reversed by the addition of immunomodulator therapy with restoration of a clinico-biological response. However, these observations need to be confirmed with larger studies.

Induction infliximab levels among patients with acute severe ulcerative colitis compared with patients with moderately severe ulcerative colitis.

BACKGROUND: Infliximab is effective as salvage therapy for patients with steroid refractory acute severe ulcerative colitis (UC). Although current data suggest that the pharmacokinetics of infliximab are influenced by inflammatory burden in patients with acute severe UC, data comparing infliximab trough levels in patients with acute severe UC vs. moderately severe UC are scarce. AIM: To compare infliximab trough and anti-infliximab antibody levels at a standard fixed time-point during induction between patients with acute severe and moderately severe UC. METHODS: A multi-centre retrospective study comparing infliximab drug and antibody levels 14 days after the first infusion in hospitalised acute severe UC versus out-patients with moderately severe UC was performed. RESULTS: Sixteen acute severe UC patients, hospitalised between 2010-2015 and refractory to intravenous corticosteroids, were treated with infliximab 5 mg/kg salvage therapy. They were compared to 16 moderately severe UC out-patient controls. Mean infliximab trough levels at day 14 were significantly lower in patients with acute severe UC compared to moderately severe UC (7.15 ± 5.3 vs. 14.4 ± 11.2 µg/mL, P = 0.007). Seven patients (three acute severe and four moderate severe UC) were primary nonresponders to infliximab induction therapy. Infliximab level at day 14 did not differ between responders and nonresponders (9.8 ± 9 vs. 12.1 ± 10.6 µg/mL, respectively, P = N.S.). However, week 2 median antibody-to-infliximab levels were numerically higher among primary nonresponders (3.4 ± 5.7 vs. 1.2 ± 4 µg/mL-eq, respectively, P = 0.06). CONCLUSIONS: Infliximab trough levels at day 14 were lower in patients with acute severe UC compared to moderately severe UC, possibly due to a higher inflammatory burden and/or increased drug clearance. However, drug levels at day 14 were not lower among nonresponders compared with responders. Controlled trials are warranted to examine whether an a-priori-intensified infliximab induction protocol will lead to an improved outcome in acute severe UC.

The decline of anti-drug antibody titres after discontinuation of anti-TNFs: implications for predicting re-induction outcome in IBD.

BACKGROUND: Anti-drug antibodies can be elicited by infliximab and adalimumab, but the rate of their decay after therapy is stopped is unknown. AIM: To investigate the decline of anti-drug antibody titre after anti-TNF cessation, and to evaluate the clinical utility of anti-drug antibody measurement before anti-TNF re-induction. METHODS: Inflammatory bowel disease (IBD) patients who stopped anti-TNF therapy and had measurable anti-drug antibodies were prospectively followed up by serial blood measurements of antibodies levels. The clinical outcome of a second cohort of patients who received re-induction by infliximab or adalimumab after a drug holiday >4 months was determined vis-à-vis their anti-drug antibodies status before re-induction. RESULTS: The first cohort included 22 patients with anti-drug antibodies who were prospectively followed up after cessation of anti-TNF. Sixteen had antibodies-to-infliximab (ATI) and six had antibodies-to-adalimumab (ATA). ATI titres declined within 12 months to below detection levels in 13/16 infliximab-treated patients, whereas ATA titres became undetectable in only 2/6 adalimumab-treated patients (P = 0.04). The second cohort comprised 27 patients who resumed anti-TNFs (24 infliximab, 3 adalimumab). Of these, 3/5 patients with measurable anti-drug antibodies before re-induction experienced severe hypersensitivity reaction and/or nonresponse mandating drug-discontinuation, compared to 11/22 patients who were re-induced without measurable anti-drug antibodies (OR = 1.5, 95% CI 0.2-11, P = 0.7). CONCLUSIONS: Antibodies to infliximab titres decline to undetectable levels within one year of cessation of infliximab in the majority of patients, whereas antibodies to adalimumab seem to persist longer after adalimumab discontinuation. Measuring antibodies to infliximab prior to infliximab re-induction is probably of little clinical utility, especially if more than a 12-month drug-holiday has elapsed.

Early preservation of effector functions followed by eventual T cell memory depletion: a model for the delayed onset of the effect of thiopurines.

OBJECTIVE: The onset of the effect of thiopurines is delayed for several months. The aim of this study was to investigate immune mechanisms for this delay. METHODS: The effects of thiopurines on human peripheral blood T cells and on lamina propria lymphocytes were investigated for apoptosis induction by Annexin V/propidium iodide (PI) and for cytokine secretion by intracellular staining and ELISA assays. To investigate the mechanism of the effect of thiopurines in vivo, Balb/C mice were co-immunised with HEL/OVA (hen egg lysozyme/ovalbumin) antigens, and then repeatedly challenged by HEL only, while being treated by mercaptopurine or vehicle alone for either 4 or 20 weeks. The memory response of CD4+ splenocytes towards HEL/OVA was then determined by CFSE (carboxyfluorescein succinimidyl ester) dilution. RESULTS: Thiopurines arrested the proliferation of stimulated T cells but did not enhance the apoptosis of either resting T cells or activated T cells until day 5 poststimulation. Despite the proliferation arrest, stimulated T cells successfully differentiated into effector cells, as evidenced by their capacity for proinflammatory cytokine secretion, potent adhesion and cytotoxicity. Prolonged mercaptopurine treatment of mice for 20 weeks selectively reduced the CD4+ memory response to a repeatedly encountered HEL antigen, but did not affect the T cell memory pool to the previously presented OVA antigen. A shorter, 4 weeks, treatment with mercaptopurine did not inhibit the memory response to either antigen. CONCLUSIONS: T cells arrested from cycling by thiopurines can still differentiate into potent effector cells capable of propagating the inflammatory process. Thiopurine treatment results in depletion of antigen-specific memory T cells, but this effect is dependent upon repeated encounters with the antigen over a prolonged time course.

Lidocaine down-regulates nuclear factor-kappaB signalling and inhibits cytokine production and T cell proliferation.

Lidocaine is a commonly used local anaesthetic agent which has also been found to possess anti-inflammatory activity in several disorders. However, the mechanism of this effect has been little explored. The aim of this study was to investigate the effect of lidocaine on stimulated human T cells. The effect of lidocaine on Jurkat T cells was examined by enzyme-linked immunosorbent assay (ELISA) to determine secretion of interleukin (IL)-2, and by the [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] viability assay. Tumour necrosis factor (TNF)-alpha and IL-2 mRNA expression was determined by reverse transcription-polymerase chain reaction. In addition, the effect of lidocaine on the proliferation of freshly isolated peripheral blood (PB) CD3(+) T cells was examined by carboxyfluorescein succinimidyl ester dilution. Apoptosis induction and cytokine production and secretion were determined by annexin V/PI assay, intracellular immunostaining and ELISA respectively. The results showed that lidocaine exerts a dose-dependent inhibition of IL-2 and TNF-alpha secretion by Jurkat T cells at the protein and mRNA levels. Moreover, lidocaine reduced nuclear factor-kappaB (NF-kappaB) signalling in clinically relevant concentrations. Similarly, proliferation of anti-CD3 stimulated PB T cells was abrogated significantly by lidocaine, and the percentage of interferon-gamma- and TNF-alpha-producing T cells was diminished after culture with this agent. In both experimental systems, lidocaine's effect was not mediated by cytotoxic mechanism, as no significant apoptosis or necrosis was demonstrated following co-culture of T cells with this drug. In conclusion, lidocaine's anti-inflammatory effect may be mediated by a drug-induced abrogation of T cell proliferation and cytokine secretion independent of cell death. These effects are mediated at least partly by inhibition of NF-kappaB signalling.

[Health related quality of life and lipodystrophy syndrome among HIV-infected patients]. / Qualité de vie et syndrome lipodystrophique chez les patients infectés par le VIH.

AIM OF THE STUDY: The aim of this work is to show to what extent a psychosocial evaluation can lead bring to comprehension of the subjectivity of Quality of Life (QoL) among HIV-infected patients. Evaluation of QoL makes it possible to understand the link between the therapeutic effectiveness and the subjective evaluation of the treatment, but also to estimate more precisely how people live and take their treatment in the context of HIV infection. METHOD: This work confronts the variation of QoL with the variation of several social and psychosocial parameters identified as of the components of the system, which is the subjective evaluation, and more precisely to a specific side effect of Highly Active AntiRetroviral Therapies (HAART): lipodystrophy syndrome that consists in body fat redistribution. This side effect could consist in an accumulation of body fat, or a loss of body fat or a combination of both symptoms. The analysis was made on the data from APROCO-COPILOTE cohort composed of HIV-infected patients initiating HAART. RESULTS: Among a sample of 706 patients follow-up for three years and with available QoL data, we identified the variations of QoL according to the variation of this specific side effect and according to gender. Results show that lipodystrophy syndrome has a determinant impact on QoL different among male and female patients. Adjusted on clinical and socio-demographic characteristics, impaired women's QoL is associated with accumulation of body fat and impaired men's QoL is associated with loss of body fat. CONCLUSION: These results underline the role of body image on subjective evaluation of QoL. The analysis of empirical data made it possible to highlight the social implication of the evaluation of QoL from the role of the social support, patient-provider relationship and the social context.

Impact of early-untreated HIV infection on chronic hepatitis C in intravenous drug users: a case-control study.

OBJECTIVE: The impact of early-untreated HIV infection on chronic hepatitis C was determined in a case-control study, aimed at limiting factors associated with the progression of immunodeficiency. METHODS: HIV-infected patients attending for a medical examination during 1995-1996 were systematically screened for: previous intravenous drug use without other HIV or Hepatitis C virus (HCV) risk factor, CD4 cell count > 200/microl, no AIDS, no antiretroviral treatment, positive anti-HCV antibody, negative hepatitis B surface antigen, abnormal aminotransferase activity. Thirty-eight consecutive eligible HIV-infected patients (cases) were included. Thirty-eight HCV-infected patients without HIV infection whose unique risk factor was intravenous drug use (controls) were paired to cases according to age, sex, and duration of HCV infection. RESULTS: Cases and controls had similar ages, sex ratios, duration of HCV infection, and alcohol intake. They were infected predominantly by genotypes 1 and 3. Viraemia was higher in cases than in controls. METAVIR histological scores of activity and fibrosis in cases versus controls were 2.2 +/- 0.8 versus 1.6 +/- 0.7 (P = 0.0008) and 1.8 +/- 1 versus 1.5 +/- 0.8 (P = 0.06), respectively. The percentage of cirrhosis was higher in cases, without reaching statistical difference. The progression rate of fibrosis was higher in cases. Age at contamination and METAVIR activity score were significantly associated with the progression of fibrosis in cases. CONCLUSION: Early-untreated HIV infection is associated with higher HCV viraemia and more severe liver injury in intravenous drug users with chronic hepatitis C.

Differential pattern in circulating nitrogen derivatives, lactoferrin, and anti-lactoferrin antibodies in HIV type 1 and HIV type 2 infections.

HIV-1 infection is associated with a dramatic reduction in antioxidative molecules both at the cellular level and in the circulation. This is particularly so for lactoferrin, an iron-binding protein involved in natural defenses (antimicrobial and antiviral activities, etc.) and found in whole secretions, including milk and mucus. In addition to its ability to chelate iron ions, lactoferrin inhibits hydroxy radical formation and interacts with nitric oxide (NO). Levels of plasma lactoferrin decreased in HIV-1-infected patients in correlation with progression of the disease, and highly specific anti-lactoferrin autoantibodies increased. This profile was specific to HIV-1 infection; it was not found in HIV-2-infected patients. In parallel with the drop in lactoferrin, a marked increase in circulating nitrogen derivatives was observed in HIV-1-infected patients, whereas low levels were found in normal donors and in HIV-2-infected patients. These data suggested hyperstimulation of the NO pathway throughout HIV-1 but not HIV-2 infection. This overproduction of NO could play an important role in the development of AIDS symptoms and signs.

Mutation analysis of the MEN1 gene in Israeli patients with MEN1 and familial isolated hyperprolactinemia.

Multiple endocrine neoplasia type 1 (MEN-1) is characterized by hyperfunction and tumor formation of the parathyroids, anterior pituitary and endocrine pancreas. We carried out exon-specific, PCR-based DNA sequencing of the coding exons of the MEN1 gene in 8 Israeli MEN1 patients: 4 familial and 4 sporadic. We similarly analyzed Israeli families with a unique phenotype of isolated hyperprolactinemia (HPRL). Four mutations were detected in 4 MEN1 patients: C to T alteration at nucleotide 2608 resulting in R108X, and three intronic insertions/deletions (a 13 basepair (bp) deletion and a 1 bp insertion both in intron 1, and a 2 bp insertion in intron 3) leading to exonic frame shifts as they encompass the splice junctions. An additional patient exhibited a compound mutation: a G to T change at position 7614 resulting in E463X, and insertion/deletion of 9 bp at position 7622-7630 resulting in EAE466-468X. Haplotype analysis showed no segregation of phenotype with 11q13 markers in 4 familial HPRL, and no men 1 germline mutations were detected in three representative individuals, from 3 families. Our results confirm that men 1 gene germline mutations occur in the majority of patients with clinically diagnosed MEN1, and that familial HPRL is a genetically distinct disorder.

Neurological complications of varicella-zoster virus infection in adults with human immunodeficiency virus infection.

This multicentre retrospective study describes the clinical features and prognostic significance of Varicella-zoster virus (VZV)-associated neurological complications. The study was performed in patients with human immunodeficiency virus (HIV) infection, hospitalized for VZV neurological complications, confirmed in every case by positive VZV polymerase chain reaction (PCR) in cerebrospinal fluid (CSF). Between 1990 and 1995, 34 HIV-infected patients were included in the study. At diagnosis, 59% had AIDS, with a median CD4 count of 11 x 10(9)/l. A past history of zoster was noted in 35% of cases. A concomitant herpes zoster rash and/or acute retinal necrosis were noted in 71% and 12% of patients, respectively. The predominant neurological manifestations were encephalitis (13), myelitis (8), radiculitis (7) and meningitis (6). The mean CSF white blood cell count was 126/mm3 and the mean CSF protein concentration was 2.3 g/l. Interferon-alpha level was increased in 36% of patients. VZV was isolated from CSF cultures in 2/6 cases. Magnetic resonance imaging was abnormal, demonstrating encephalitis lesions. After intravenous antiviral therapy, complete recovery was obtained in 18 cases (53%), serious sequelae were observed in 10 cases (29%) and 6 patients died (18%). Severe symptoms and a low CD4 cell count appeared to be associated with death or sequelae. In conclusion, VZV should be considered as a possible cause of encephalitis, myelitis, radiculitis or meningitis in HIV-infected patients, especially in patients with a history of or concomitant herpes zoster or acute retinal necrosis. VZV-PCR in the CSF may allow rapid diagnosis and early specific antiviral treatment.

[A paraneoplastic acrosyndrome]. / Un acrosyndrome paranéoplasique.

BACKGROUND: Paraneoplastic digital ischemia is an uncommon complication of metastatic adenocarcinomas. CASE REPORT: Two years after remission of an uterine adenocarcinoma, the patient developed an acrosyndrome involving all four limbs with digital ischemia. Recurrent carcinoma was evidenced by a very high antinuclear antibody titer. Chemotherapy improved the acrosyndrome. DISCUSSION: Vasomotor disorders which developed in older subjects with no other signs of autoimmune disorders should suggest a neoplastic origin. Icshemia of the fingers would be caused by vasculitis. An elevated antinuclear antibody titer may be a supplementary argument suggesting a neoplastic etiology.

Polyarthralgia-arthritis syndrome induced by low doses of rifabutin.

We describe 2 cases of polyarthralgia-arthritis syndrome induced by rifabutin, an effective treatment for infections of Mycobacterium avium intracellulare complex. This syndrome has been reported with doses higher than 1 g per day when rifabutin is given in monotherapy. But our cases were treated with low doses, 300-450 mg per day, in combination with clarithromycin. The plasma concentration of rifabutin has been shown to be increased by clarithromycin, suggesting that co-prescription of clarithromycin could lead to development of rifabutin induced polyarthralgia-arthritis syndrome.

[Mixed corticomedullary tumor]. / Tumeur mixte corticomédullaire.

BACKGROUND: Pheochromocytoma and primary hyperaldosteronism rarely occur simultaneously. Few cases have been reported in the literature. CASE REPORT: A patient explored for hypertension was found to have hypokalemia related to primary hyperaldosteronism. Pathology examination of the ablated adrenal showed a co-existing pheochromocytoma suspected at history taking although urine catecholamines were normal. DISCUSSION: Different pathogenic hypothesis have been proposed. Such dual tumors could be a simple coincidence, occur in a particular genetic setting, be related to direct contact between cortical and medullary tissue leading to reactional cortical hyperplasia, pheochromocytoma produced factors stimulating aldosterone synthesis, or factor X, a substance produced by cortical adenomas and favoring growth of the pheochromocytoma.

HHV8 status in Kaposi's sarcoma associated with multiple myeloma.

Kaposi's sarcoma in its sporadic or HIV-related form is due to a gamma herpesvirus, the human herpes virus 8 (HHV8). No data have been published on the potential role of the HHV8 in Kaposi's sarcoma occurring in multiple myeloma patients. A case is reported of a patient in whom four serum samples taken between the diagnosis of multiple myeloma and the occurrence of a Kaposi's sarcoma one year later tested positive for antibody to the HHV8. Similar findings have been reported in patients with other types of Kaposi's sarcoma. PCR studies for HHV8 DNA were positive on a Kaposi's sarcoma biopsy but negative on a bone biopsy, militating against a role for the HHV8 in the genesis of multiple myeloma.

AIDS-related Kaposi's sarcoma patients with visceral manifestations. Response to human chorionic gonadotropin preparations.

OBJECTIVE: In vitro cell culture studies and a murine model for human Kaposi's sarcoma (KS) have shown that human chorionic gonadotropin (hCG)-associated factor (HAF) isolated from commercial hCG preparations has antiproliferative and cell killing effects on neoplastic KS cells, without toxic effects on normal endothelial cells and lymphocytes. These findings prompted preliminary study of hCG preparations for patients with early-stage KS with skin lesions only and no known visceral involvement. Complete or partial regression of the skin lesions occurred after intralesional injections of hCG (hCG-Pregnyl, hCG-APL). The current study sought to extend these early observations to evaluation of the safety of hCG in acquired immunodeficiency syndrome (AIDS) KS patients with aggressive disease and visceral involvement. These patients present in a more advanced stage of the disease that is coupled with serious immunodeficiency. They commonly respond poorly to conventional chemotherapy and have a reduced median life expectancy of only 4 to 9 months. STUDY DESIGN/METHODS: After approval by the local institutional review boards, 13 patients with advanced AIDS-KS gave informed consent and were treated with hCG preparations. These hCG preparations are known to have antiproliferative activity in laboratory tests. Patients were monitored for tumor size by clinical evaluation, ultrasonography, radiography, respiratory functions, and endoscopic examination. Histologic examinations of biopsied tissues were used for studies of apoptosis using in situ hybridization techniques. The patients were also monitored for CD4+ T-cell numbers and human immunodeficiency virus type 1 (HIV-1) plasma viral load according to common clinical practice. RESULTS: Thirteen patients with advanced AIDS-KS and visceral KS were treated with hCG. Five of 13 (38%) patients had dramatic responses to therapy, and overall tolerance to the drug was excellent for all patients. Some hCG preparations also showed beneficial effects against HIV-associated markers. An accompanying decrease in viral load (plasma HIV-1 RNA) was observed in one patient, a dramatic increase in CD4+ cells occurred in another, and significant weight gain was seen in seven patients. CONCLUSIONS: These clinical observations suggest that patients with aggressive visceral forms of KS, usually indicative of an extremely poor prognosis and poor response to combined chemotherapy, can benefit from this new therapeutic approach. In some patients, these preparations also induce several other beneficial effects, such as weight gain, reduction in HIV-1 RNA load, or increase in the CD4+ T-cell count. Additional controlled clinical trials comparing this new therapeutic option with standard cytotoxic chemotherapy are needed. These trials should be extended to patients with KS not related to HIV-1 infection. Because we showed elsewhere that pure hCG had no effect on KS, identification and subsequent clinical use of the active molecules in hCG preparations is urgently needed.

Cerebral infarction associated with vasculitis due to varicella zoster virus in patients infected with the human immunodeficiency virus.

Cases of herpes zoster ophtalmicus (HZO) with delayed contralateral hemiparesis caused by hemispheric stroke secondary to granulomatous angiitis have been reported and are a well-recognized complication of herpes zoster. Similar cases have been reported more recently during infection with human immunodeficiency virus (HIV). We describe two HIV+ patients without any clinical history of zoster dermatitis who developed a sudden hemiparesis followed 2 weeks later for one by an acute retinal necrosis. Computerized tomography (CT) scan, magnetic resonance imaging (MRI), magnetic resonance angiography (MRA), and digital subtraction angiography (DSA) were performed and showed a hemispheric stroke with evidence of a segmental arteritis of the carotid syphon. Varicella zoster virus (VZV) was found in the cerebro spinal fluid (CSF) in the two patients and after puncture of the vitreous fluid of the patient with the acute retinal necrosis. These two cases exemplify the difficulty of diagnosis of stroke in HIV+ patients, which seems to be more frequent than in similarly aged non-infected patients and demonstrates that VZV needs to be taken in consideration and identified even without any past history of zoster dermatitis.