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BACKGROUND Interleukin (IL)-2 therapy impacts T-cell homeostasis. Whether IL-2 expanded CD4(+) T cells may persist following viral rebound has not been fully investigated. METHODS Patients with CD4(+) T cells 500/μl or more and HIV RNA less than 50 copies/ml were randomized to continue antiretroviral therapy (ART) either alone (n = 67) or combined with three IL-2 cycles (n = 81; 6 million units) twice daily for 5 days at weeks 0, 8, and 16 before stopping ART (week 24). Patients were followed up to 168 weeks. RESULTS At week 24, median CD4(+) T-cell counts were 1198 and 703 cells/μl in the IL-2 and control groups, respectively (P

Tegobuvir (GS-9190), a non-nucleoside nonstructural protein (NS)5B polymerase inhibitor, and GS-9256, an NS3 serine protease inhibitor, individually have activity against hepatitis C virus (HCV) genotype 1. The antiviral activity of tegobuvir and GS-9256 as oral combination therapy, or together with ribavirin (RBV) or pegylated interferon (Peg-IFN) alpha-2a and RBV, was assessed in a phase II, randomized, open-label trial. Treatment-naïve patients with genotype 1 HCV were assigned 28 days of tegobuvir 40 mg twice-daily (BID) and GS-9256 75 mg BID (n = 16), tegobuvir and GS-9256 plus RBV 1,000-1,200 mg daily (n = 15), or tegobuvir and GS-9256 plus Peg-IFN alpha-2a (180 μg once-weekly)/RBV (n = 15). The primary efficacy endpoint was rapid virologic response (RVR), with HCV RNA25 IU/mL at day 28. After 28 days, all patients received Peg-IFN/RBV. All patients with viral rebound or nonresponse, defined as0.5-log(10) increase in HCV RNA from nadir or2-log decrease at day 5, initiated Peg-IFN/RBV immediately. Median maximal reductions in HCV RNA were -4.1 log(10) IU/mL for tegobuvir/GS-9256, -5.1 log(10) IU/mL for tegobuvir/GS-9256/RBV, and -5.7 log(10) IU/mL for tegobuvir/9256/Peg-IFN/RBV. RVR was observed in 7% (1 of 15) of patients receiving tegobuvir/GS-9256, 38% (5 of 13) receiving tegobuvir/GS-9256/RBV, and 100% (14 of 14) receiving tegobuvir/9256/PEG-IFN/RBV. The addition of Peg-IFN/RBV at day 28 or earlier resulted in HCV RNA25 IU/mL at week 24 in 67% (10 of 15), 100% (13 of 13), and 94% (13 of 14) of patients in the three treatment groups. Transient elevations in serum bilirubin occurred in all treatment groups.In genotype 1 HCV, adding RBV or RBV with Peg-IFN provides additive antiviral activity to combination therapy with tegobuvir and GS-9256.

BACKGROUND once-daily combinations of efavirenz and two nucleoside analogues are recommended for the treatment of HIV infection. Long-term efficacy and safety data are scarce for the combination of efavirenz, emtricitabine and didanosine. METHODS the ALIZE ANRS 099 trial enrolled 355 adults with plasma HIV RNA levels of

Tuberculosis (TB)-associated immune restoration syndrome (IRS) is a frequent event (10 to 30%) in HIV-1-infected patients receiving antiretroviral treatment and is associated with an increased number of IFN-gamma-producing tuberculin-specific cells. To further understand the immune mechanisms of TB-IRS and to identify predictive factors, we prospectively analyzed the Th1 and TCRgammadelta T cells known to be involved in mycobacterial defenses and dendritic cells at baseline and after antiretroviral and TB treatment in 24 HIV-1(+) patients, 11 with and 13 without IRS. At baseline, these two groups differed by significantly lower proportions of TCRgammadelta and Vdelta2(+) T cells displaying the inhibitory receptors CD94/NKG2 and CD158ah,b in IRS patients. The two groups did not differ in the baseline characteristics of CD8 or CD4 T cells or TLR-2 expression on monocytes or myeloid/plasmacytoid dendritic cells. During IRS, the increase in tuberculin-specific IFN-gamma-producing cells involved only highly activated effector memory multifunctional (IFN-gamma(+)TNF-alpha(+)IL-2(-)) CD4 T cells, whereas activated HLA-DR(+) CD4(+) T cells also increased during IRS. In contrast, dendritic cells decreased significantly during IRS and there were no changes in TLR-2 expression. Finally, the Vdelta2(+) T cells, mostly killer Ig-related receptor (KIR) (CD94/NKG2(-) and CD158(-)), significantly peaked during IRS but not in non-IRS patients. In conclusion, IRS is associated with an increase in the number of activated tuberculin-specific effector memory CD4 T cells and of KIR(-)Vdelta2(+) TCRgammadelta(+) T cells. Higher proportions of Vdelta2(+)TCRgammadelta(+) T cells lacking KIR expression are present as baseline and distinguish patients who will develop IRS from those who will not.

Pulmonary arterial hypertension (PAH) is an infrequent but nevertheless serious life-threatening severe complication of HIV infection. As a result of its non-specific presentation, PAH tends to be recognized at a late stage of the disease, and patients have generally been in New York Heart Association functional class III or IV by the time of diagnosis. The widespread use of HAART has improved overall survival in HIV-infected individuals, but its effect on the incidence and severity of PAH in particular has been controversial. Data on the long-term impact of HAART on the course of PAH and patient survival in this context have been lacking. This article presents key data from two recent major European studies (the Swiss HIV Cohort Study and a prospective French national study) investigating the prevalence of PAH in the HIV-infected population and the effect of HAART on the long-term course of the disease. Data from these large studies do not suggest that HAART has a major effect on the course of PAH or on survival in these patients. Although there is evidence that new cases of PAH are declining, the overall prevalence is currently similar to the pre-HAART era, and there is still a significant number of HIV-infected individuals who have or are at risk of PAH. Given recent improvements in the treatment of PAH, the early recognition of these individuals is essential.

There has been substantial progress in our understanding of the pathogenesis and clinical consequences of infection with H IV since the virus was first identified more than 20 years ago. The details of the viral replication cycle are increasingly better understood as are the identification of host elements that both regulate viral replication and are necessary for it. Greater understanding of these events has resulted in the development of therapies for HIV infection and as a consequence there has been a dramatic improvement in overall survival in the era of HAART. With this improvement in survival has come an increasing recognition of the importance of many long-term sequelae of subclinical immune deficiency and the attendant immune activation that characterize HIV infection. One complication of chronic HIV infection for which the pathogenesis is obscure is pulmonary arterial hypertension (PAH). Cases of HIV-related PAH (PAH-HIV) have been recognized with increasing frequency in recent years. Although it is likely that PAH-HIV has an underlying etiology specifically related to HIV infection, it shares several key clinical and pathological similarities with other forms of PAH. This article outlines the features, classification and treatment of PAH, and recent theories about the underlying etiology of the disease. We will also discuss the occurrence of PAH in HIV infection and propose some hypotheses regarding pathogenesis that will be covered in more detail in the accompanying articles in this supplement.

A prospective and multi-centre study has allowed us to analyse antibody responses and Mycobacterium tuberculosis clinical isolate genotypes on 24 consecutive HIV-TB co-infected patients treated with Highly Active Antiretroviral Therapy (HAART) who either went on to develop a TB Immune Restoration Syndrome (TB-IRS), or not. Circulating free and immune-complexed antibodies against ManLAM, ESAT-6/CFP10 and PGL-Tb1 in HIV-TB co-infected patients were measured by ELISA at the initiation of anti-TB treatment, at the date of HAART initiation and thereafter. Presence of circulating B cells was also monitored by in vitro antibody production (IVAP) against ESAT-6/CFP10 and PGL-Tb1. Finally, 16 out of 24M. tuberculosis clinical isolates from patients with TB-IRS were genotyped using spoligotyping and MIRUs-VNTR typing. Eleven patients (45.8%) experienced TB-IRS (TB-IRS+). Significantly, lower anti-PGL-Tb1 antibody levels were identified in TB-IRS+ compared to TB-IRS-negative patients prior to TB-IRS development. These very low levels were neither related to CD4 counts nor with complexed antibodies. No difference in antibody levels was observed with the other tested antigens. In addition, no specific strain genotype was associated with TB-IRS. The presence of specific anti-PGL-Tb1 antibodies only in TB-IRS-negative patients represents for the first time an indicator of a potential protective response or a diagnostic biomarker for the detection of non-progression to TB-IRS in HIV-TB co-infected patients starting HAART.

The prevalence of HIV-associated pulmonary arterial hypertension (PAH) has not been evaluated since introduction of combined, highly active antiretroviral treatments.To establish the current prevalence of PAH in a large HIV-positive population.Prospective study conducted in 7,648 consecutive HIV-positive adults in 14 HIV clinics in France. PAH was identified through screening with a predefined algorithm. Patients with dyspnea unexplained by other causes underwent transthoracic Doppler echocardiography. PAH was suspected if peak velocity of tricuspid regurgitation was greater than 2.5 m/second and was confirmed by right heart catheterization.PAH was diagnosed if mean pulmonary arterial pressure at rest was 25 mm Hg or greater (with pulmonary capillary wedge pressureor = 15 mm Hg) or 30 mm Hg or greater on exercise. A total of 739 patients had dyspnea, of which 312 met exclusion criteria and 150 refused to participate. Among the remaining 277, 30 had known PAH and 247 had unexplained dyspnea and underwent echocardiography; PAH was suspected in 18 and confirmed in 5, to give a total of 35 cases. The prevalence was thus 0.46% (95% confidence interval, 0.32-0.64%). All new cases had relatively milder PAH.The prevalence of HIV-associated PAH is about the same as it was in the early 1990s. Given the current good long-term prognosis of patients with HIV, the severity of PAH in HIV-infected patients, and the absence of predictive factors, careful screening for PAH is warranted for patients with unexplained dyspnea.

In an attempt to enhance the quality of internal medicine practice and to reform the education of internists across Europe, the European Board of Internal Medicine (formed by the European Federation of Internal Medicine and the European Union of Medical Specialists Section of Internal Medicine) has launched a project aimed at defining core competencies that are common to all internists. The compilation of six core competencies presented in this paper consists of patient care; medical knowledge; communication skills; professionalism, ethical, and legal issues; organizational planning and service management skills; and academic activities. These core competencies are the foundation required for the provision of high-quality medical care everywhere, regardless of the professional traditions and organization of health care in different countries. The authors hope this paper will stimulate constructive discussion and thoughtful debate, and that it will be followed by a collaborative effort to develop and endorse a European consensus.

Resume Propos. – Evaluer l’utilisation du Medical Outcome Study Short Form 36 (SF-36), score evaluant la qualite de vie, dans la sclerodermie systemique et apprecier l’impact de cette maladie sur la qualite de vie. Methodes. – Etude transversale de 86 patients atteints de sclerodermie systemique (66 femmes et 20 hommes, 64 formes diffuses, 22 formes limitees). La qualite de vie a ete evaluee par le score SF-36. La severite de la maladie a ete evaluee par l’examen clinique, des tests paracliniques et le score de retentissement fonctionnel S–HAQ (HAQ modifie pour la sclerodermie). Resultats. – Les scores du SF-36 sont plus bas (moins bonne qualite de vie) dans les formes diffuses que dans les formes limitees de sclerodermie systemique. La composante physique du score de la qualite de vie est plus alteree en presence qu’en l’absence des atteintes cliniques, et ce d’autant plus que le nombre d’atteintes augmente. La qualite de vie des patients atteints de sclerodermie systemique est correlee au retentissement fonctionnel de la maladie. Conclusion. – La qualite de vie des patients atteints de sclerodermie systemique est correlee a la severite de l’atteinte clinique de la maladie. Le SF-36 est un outil utile pour l’evaluation clinique des patients atteints de sclerodermie systemique.

Resume L’aggravation paradoxale d’une tuberculose lors de la restauration immunitaire sous traitement antiviral chez les patients co-infectes par le VIH est connue sous le nom d’IRIS. Nous decrivons ici un cas d’aggravation paradoxale d’une tuberculose lors de l’arret des anti-TNFα contemporaine de la restauration d’une immunite specifique anti-infectieuse. Cette observation permet d’attirer l’attention sur la possible aggravation des complications, ici tuberculose, apres l’arret des anti-TNFα et pouvant necessiter paradoxalement parfois la reprise de l’immunosuppression.

After the age of 65 years, iron deficiency anemia (IDA) requires the elimination of digestive neoplasia and is explored with upper and lower gastrointestinal (GI) endoscopy. However, such explorations are negative in 14% to 37% of patients. To further evaluate this issue, we evaluated the outcomes of patients aged over 65 years with endoscopy-negative IDA.We retrospectively analyzed the outcomes of in-patients over the age of 65 years with IDA (hemoglobin

We report the first case of acute drug-induced aseptic meningitis (DIAM) due to rifampin in a young female with systemic lupus erythematosus (SLE). DIAM is uncommon and its diagnosis is often difficult. This type of drug hypersensitivity is more frequently observed in patients with a history of auto-immune disease, particularly SLE. The major categories of causative agents are: nonsteroidal anti-inflammatory drugs, antimicrobials, intravenous immunoglobulins and biotherapies.

Retroperitoneal fibrosis may reveal many diseases, including neoplasias. An 83-year-old man presented with an acute renal failure due to compressive retroperitoneal fibrosis. Clinically the only abnormal feature was a cutaneous subclavicular infiltrated lesion and laboratory features included hypereosinophilia, anemia and elevated acute phase reactants. A thoracic CT-scan showed pleuritis and para-esophageal lymph node and the 18FDG-PET-scan an hypermetabolism lesion of the oesophagus. Gastroscopy and colonoscopy found a gastric linitis, already multi-metastatic at diagnosis. The gastric linitis can present with many decepting clinical forms, increasing the risk of delayed diagnosis.

Trecovirsen, a 25-mer antisense phosphorothioate oligonucleotide targeted at the gag site of the HIV gene, was administered to HIV-positive volunteers as an i.v. infusion. Single doses ranged from 0.1 to 2.5 mg/kg in an ascending escalation in cohorts of 6 to 12 subjects. Plasma trecovirsen concentrations and pharmacokinetic parameters could be assessed at doses > or = 0.3 mg/kg. Peak plasma concentrations and AUC values increased disproportionately with increasing dose while elimination half-life increased and plasma clearance decreased, indicating a saturable process over this dose range. The only significant adverse event observed was an isolated, transitory increase in activated partial thromboplastin time at doses > or = 2.0 mg/kg that was related to plasma trecovirsen concentrations and is attributed to the polyanionic character of the molecule. Thus, trecovirsen administration was well tolerated in single i.v. doses up to 2.5 mg/kg.

The impact of highly active antiretroviral treatment (HAART) on anti-human immunodeficiency virus (HIV) cytotoxic T lymphocytes (CTL) was studied in 17 patients with recent symptomatic HIV-1 primary infection receiving triple combination therapy. Anti-HIV CTL were initially detected in 15 patients. In 6, CTL disappeared rapidly and persistently after initiation of therapy. Most of them had a rapid and sustained decrease in plasma HIV RNA to undetectable levels. Conversely, in 6 other patients, CTL remained detectable, which was associated with a less efficient control of viral replication. In 3 others, CTL disappeared only transiently, without clear correlation with the virologic profile. Altogether, despite individual variations, there was a positive correlation between viral replication and anti-HIV-1 cytotoxicity in most subjects, suggesting that the persistence of viral antigens is the main determinant for the maintenance of CTL activity. This raises the question of the potential benefit of anti-HIV CTL induction by immunotherapy in acute seroconverters treated by HAART.

A multicenter case-control study (588 cases and 1807 controls) was performed to assess the risk of syncope in the elderly according to drug consumption within the three days before syncope, controlling the underlying cardiovascular diseases. Pair-matched and non-pair-matched analyses using logistic regression were performed, providing consistent results. After adjustment for age, sex, and cardiovascular disease, cases were shown to consume more often than non-cases drugs in classes of non-tricyclic antidepressants, neuroleptic drugs, and antiparkinsonians. A detailed analysis has shown that only four drugs were significantly associated with an excess risk of syncope: fluoxetine (OR = 2.6; 95% CI: [1.8-3.5]), aceprometazine (OR = 2.0; [1.5-2.5]), haloperidol (OR = 2.8; [2.0-3.6]), and L-dopa (OR = 2.8; [2.2-3.7]). This analysis shows that these drugs should be prescribed with special caution in the elderly.

Resume La primo-infection symptomatique (PIS) par le virus de l'immunodeficience humaine (VIH) a ete initialement decrite comme un syndrome mononucleosique associe a une meningite lymphocytaire, survenant au cours de la seroconversion. Cependant, les manifestations cliniques depassent ce cadre originel, conduisant a evoquer le diagnostic devant tout syndrome infectieux d'installation brutale chez un patient presentant des facteurs de risque pour le VIH et, par consequent, a rechercher l'antigenemie p24 et l'apparition des anticorps diriges contre le VIH. L'intensite de l'expression clinique de cette phase precoce pourrait etre un indicateur de l'evolution de l'infection par le VIH. Ainsi, elle est dans de nombreuses etudes un facteur pronostique pejoratif de la maladie. Les mecanismes pathogeniques font intervenir des facteurs inherents a l'hote et au virus. Une intervention therapeutique precoce pourrait modifier le cours evolutif de la maladie.

Herpetic esophagitis (HE) associated with human immunodeficiency virus (HIV) is a rare condi­ tion mainly reported as isolated cases. We thus decided to study this association and analyze the possible predisposing factors, clinical and endoscopic presentations, and clinical response to treat­ ment. Thirty-four HIV-l-infected patients were identified: 27 had histologically or virologically confirmed HE and seven had probable HE, a retrospective diagnosis based on the efficacy of acyclovir given alone. The median CD4 cell count was 15/mm 3 • Recent predisposing factors (such as nasogastric procedures, steroid therapy, and anticancer therapy) were noted with regard to 16 of the 34 patients (47%). Odynophagia and/or chest pain occurred in 30 patients (88%). At the time of diagnosis of HE, extraesophageal herpes was found in only 13 patients (38%). Superficial ulcers of the distal third of the esophagus were present in 17 (50%). Among 20 of the 27 patients with confirmed HE that could be evaluated, therapy with acyclovir led to complete resolution in 16 and partial response in 3; 1 patient died of HE. Five patients (15%) suffered confirmed or possible relapses. The mean interval between the diagnosis of HE and death was 8.8 months. Herpes simplex virus may be responsible for ulcerated esophagitis that occurs in the advanced stages of AIDS and that can be safely treated with acyclovir before a definitive diagnosis is made.

To determine the influence of neurologic manifestations of primary human immunodeficiency virus (HIV) infection on disease progression, 277 nonhemophiliac adults enrolled < 1 year after HIV infection were studied. Patients with neurologic manifestations during symptomatic primary HIV infection (PSI) (group N+; n = 23), with nonneurologic manifestations (group N-; n = 112) during PSI, and without any clinical manifestation during primary infection (group NPI; n = 142) were compared for disease progression. Age at infection, sex, mode of infection and CD4+ cell count at first visit did not differ between groups. In a Cox model, the relative risk (RR) of developing AIDS was 6.11 (95% confidence interval [CI], 1.94-19.28) in group N+ and 2.32 (95% CI, 0.93-5.83) in group N- compared with group NPI. The RR of AIDS onset after adjustment for treatment and age at infection was, respectively, 4.65 (95% CI, 1.43-15.03) and 2.03 (95% CI, 0.80-5.19) in groups N+ and N-. Neurologic manifestations of primary HIV infection are associated with an accelerated progression of disease.

SummaryThrombin clotting time (TCT) and reptilase clotting time (RCT) were found significantly prolonged in a series of 72 HIV-infected patients drawn for routine coagulation testing. Both TCT and RCT were highly significantly correlated with albumin (r = -0.64, and r = -0.73 respectively, p

The atherothrombotic conditions, coronary artery disease, cerebrovascular disease and peripheral arterial disease (PAD), together account for almost one-half of all deaths in Europe each year; however, perception of the specific risks associated with PAD is generally poor compared with its related conditions. PAD is not just a localised disease — it has serious systemic effects, and affected individuals have a higher risk of serious cardiovascular sequelae or death within 1 year of diagnosis compared with those with coronary artery or cerebrovascular disease. PAD, which currently affects approximately 16% of the general population aged over 55 years, is increasing because of the population aging and the continuing rise in cardiovascular risk factors. The management of PAD is a multi-disciplinary approach, and while this can have its advantages, it can also mean that responsibility for patient care is unclear. Globally, almost one-third of all patients with PAD are under internist care. Internists are ideally placed to identify patients at risk of PAD and initiate prompt risk factor management because of their role in the continued care of elderly patients and those with diabetes, hypertension, dyslipidaemia, and chronic renal disease. Multi-disciplinary guidelines for the clinical management of PAD, based on consensus among international specialists in a number of fields, have been developed to create an informed, unified and proactive approach to the treatment of PAD. They stress the continuity of care, the use of office-based ankle–brachial index testing to aid early diagnosis, and prompt and aggressive risk factor management.

OBJECTIVES: To assess the sustainable efficacy and safety of a switch from enfuvirtide to raltegravir in patients with multidrug-resistant HIV infection. METHODS: One hundred and seventy patients with multidrug-resistant HIV infection and suppressed plasma HIV RNA levels < 400 copies/mL under an enfuvirtide-based regimen were randomized to maintain their regimen or to switch to a raltegravir-based regimen (immediate group) in a 48 week prospective, randomized, open-label trial. At week 24, patients in the maintenance arm also switched to raltegravir (deferred group). Baseline genotypic susceptibility scores (GSSs) were calculated using available historical resistance tests. Efficacy was assessed by the cumulative proportion of patients with virological failure, defined as a confirmed plasma HIV RNA ≥ 400 copies/mL up to week 48. The EASIER ANRS 138 trial is registered at ClinicalTrials.gov (NCT00454337). RESULTS: At baseline, 86% of patients had plasma HIV RNA levels

Purpose: To evaluate the long-term efficacy and safety of inhaled pentamidine as primary prophylaxis against Pneumocystis carinii pneumonia (PCP) in patients infected with human immunodeficiency virus (HIV). Patients: Two hundred thirty-two HIV-infected patients with a CD4 cell count below 20% of the total lymphocyte count were given aerosolized pentamidine once every 4 weeks for more than 3 months. Pentamidine aerosols were administered at the hospital under medical supervision. Prevention of bronchospasm was carried out using inhaled salbutamol. Results: Mean duration of prophylaxis was 15.9 months. Eleven patients (4.7%; [95% confidence interval 2% to 7.4%]) developed PCP. Probability to remain free of PCP is 95.6% at 12 months, 94% at 18 months, and 88% at 24 months. Mean delay between the onset of the prophylaxis and the occurrence of PCP for the 11 patients was 12.9 months (range: 4 to 26 months). No major side effect was observed, and minor side effects (cough, acute dyspnea) were infrequent. Conclusion: The efficacy and tolerance of aerosolized pentamidine as shown in our study support its use as primary prophylaxis against P. carinii in HIV-infected patients.

SummaryIn human plasma, heparin cofactor II (HCII) is a thrombin inhibitor, whose deficiency has been reported to be associated with recurrent thrombosis. The finding of two cases of low plasma HCII activity in two patients infected with the human immunodeficiency virus (HIV) led us to investigate this coagulation inhibitor in the plasma of a larger population of HIV-infected patients. The mean plasma HCII activity was significantly lower in 96 HIV-infected patients than in 96 age- and sex-matched healthy individuals (0.75 ± 0.24 vs 0.99 ± 0.17 U/ml, p

Strains of human immunodeficiency virus (HIV) transmitted between individuals use the CCR5 coreceptor, but no preferential depletion of particular Th-lymphocyte subpopulations has been reported during primary HIV infection (PHI). In contrast, gut-associated Th lymphocytes are preferentially depleted in macaques recently infected by simian immunodeficiency virus. The expression of CCR5 and the intestinal homing receptor integrin α4β7 on subpopulations of Th lymphocytes was studied in 12 patients with PHI. There was a profound decrease of circulating α4β7+ Th lymphocytes and CCR5+ memory Th lymphocytes with nonlymphoid homing potential (CD62L−CD45RO+). Unlike other Th lymphocytes, this cell population remained depleted despite early control of viral replication under antiretroviral treatment. Therefore, HIV preferentially targets a specific CCR5+ subpopulation of Th lymphocytes early during infection, inducing its persistent depletion despite treatment. Protective immunity in vivo depends on Th lymphocytes carrying homing capacity to nonlymphoid tissue, and therefore these data may explain the persistent abnormalities of immune functions in patients infected with HIV.

Paradoxical worsening of tuberculosis associated with immune reconstitution during antiretroviral therapy in patients with HIV infection is known as the immune reconstitution inflammatory syndrome (IRIS). Here, we report a case of paradoxical worsening of IFN-alpha induced tuberculosis in a patient experiencing reconstitution of pathogen-specific immune responses after discontinuing TNFα antagonist therapy. This case serves to alert clinicians that complications such as tuberculosis may worsen after TNFα antagonist discontinuation. This situation may paradoxically require readministration of the immunosuppressive drug in some patients.

Internal medicine is a rather young medical specialty in France. Its growth has been a difficult one. There are about 2000 internists in France, the majority of them working in hospitals. The training in internal medicine takes 5 years. It is the longest training of all the medical specialities. Qualified internists may acquire an additional subspecialty in oncology, geriatrics, immunology, vascular medicine, infectious diseases, nutrition and metabolism, or intensive care medicine. In private practice, internists often examine patients referred by other doctors. In hospitals, the spectrum of the internist’s work is wide and depends on local needs. In universities, internists play a major role in the training of medical students. There are two national organizations of internal medicine: a scientific society and a professional syndicate. They work together very closely on matters such as initial and continuing education, congresses, defense, promotion of the specialty, etc. The place of the specialty in the French health system is now generally acknowledged. The Society has succeeded in organizing two national congresses each year; however, efforts are still necessary to improve public awareness of the usefulness of internal medicine and to increase the recruitment of young internists.

The atherothrombotic conditions, coronary artery disease, cerebrovascular disease and peripheral arterial disease (PAD), together account for almost one-half of all deaths in Europe each year; however, perception of the specific risks associated with PAD is generally poor compared with its related conditions. PAD is not just a localised disease--it has serious systemic effects, and affected individuals have a higher risk of serious cardiovascular sequelae or death within 1 year of diagnosis compared with those with coronary artery or cerebrovascular disease. PAD, which currently affects approximately 16% of the general population aged over 55 years, is increasing because of the population aging and the continuing rise in cardiovascular risk factors. The management of PAD is a multi-disciplinary approach, and while this can have its advantages, it can also mean that responsibility for patient care is unclear. Globally, almost one-third of all patients with PAD are under internist care. Internists are ideally placed to identify patients at risk of PAD and initiate prompt risk factor management because of their role in the continued care of elderly patients and those with diabetes, hypertension, dyslipidaemia, and chronic renal disease. Multi-disciplinary guidelines for the clinical management of PAD, based on consensus among international specialists in a number of fields, have been developed to create an informed, unified and proactive approach to the treatment of PAD. They stress the continuity of care, the use of office-based ankle-brachial index testing to aid early diagnosis, and prompt and aggressive risk factor management.

Summary Introduction Features of Kluver-Bucy syndrome (KBS) include hypersexuality, hyperorality, placidity, visual agnosia, amnesia, hypermetamorphosis, and emotional and nutritional behavior changes. It is a clinical presentation of bitemporal disorders with limbic system abnormalities. The most common cause of KBS is herpes encephalitis. Case description An otherwise healthy 61-year-old woman presented with mental status changes (MMSE-0) after 6 days of severe vomiting. Extracellular dehydration, hyponatremia (107 mmol/L), low levels of natriuresis, and mild hypokalemia were noted. The initial computed tomography (CT) of the brain was normal. Over 36 hours of hospitalization in a district hospital she developed unusual neuropsychiatric disorders: hypersexuality, hyperorality, absence, visual agnosia, sensory aphasia, amnesia, and depression typical of KBS. She was then transferred to a neurology department. Clear improvement was visible 3 months later: MMSE-22, moderation of hypersexuality and hyperorality, partial correction of amnesia and aphasia, regression of visual agnosia. But the prosopagnosia (face blindness) persisted, and the patient remained unable to differentiate positive and negative facial expressions. Discussion Intracranial mass, epilepsy, neuromeningeal infection and head trauma were all ruled out. Antiepileptic and antiherpetic agents were tested without success. There was no evidence of adrenal insufficiency or inappropriate vasopressin secretion. Only severe vomiting, corrected by water intake, could explain the hyponatremia. The first MRI showed bitemporal edema; 3 months later it showed large bitemporal lesions, both internal and external, with atrophy of the hippocampus and limbic system. These MRI findings are characteristic of KBS. To our knowledge, this is the only the second case of KBS with bitemporal myelinolysis reported related to excessively rapid correction of hyponatremia (increase of 30 mmol/L over 36 h), which leads more usually to central pontine myelinolysis.

OBJECTIVES To test the hypothesis that an acute exacerbation of mycobacteria-specific Th1 response after HIV infection control by HAART causes immune restoration syndrome (IRS) in HIV-tuberculosis (TB) coinfected patients. DESIGN Prospective, multicenter study of 19 consecutive untreated HIV-TB coinfected patients included when initiating antimycobacterial therapy and sequentially evaluated during HAART and at time of IRS. IRS was defined according to classical clinical diagnostic criteria. Patients were declared IRS- if no IRS occurred within 3 months after HAART initiation. METHODS Mycobacteria-specific [purified protein derivative (PPD), ESAT-6, 85B] Th1 cells producing interferon (IFN)-gamma quantified by ELISpot, in vitro production of 25 cytokines/chemokines in antigen-stimulated peripheral blood mononuclear cell (PBMC) supernatants quantified by chemiluminescence. RESULTS Seven patients (37%) experienced IRS (IRS+). Mycobacteria-specific (PPD) Th1 IFN-gamma-producing cells increased sharply during IRS (median, 2970 spot forming cells/10 PBMC), but not the cytomegalovirus-specific responses tested as control. Only three IRS+ patients had low ESAT-6- but no 85B-specific responses. IRS- patients did not develop acute PPD-specific responses except in one case. In addition, at time of IRS a peak of PPD-specific Th1 cytokines/chemokines [interleukin (IL)-2, IL-12, IFN-gamma, IP10 and monokine-induced by IFN-gamma] without Th2 cytokines, and a peak of non-specific inflammatory cytokines/chemokines (TNF-alpha, IL-6, IL-1beta, IL-10, RANTES and MCP-1) occurred. These findings were independent from CD4 cell count, viral loads or time of HAART initiation. CONCLUSION An acute exacerbation of Th1 responses against mycobacterial antigens appears to cause IRS in patients co-infected with HIV and TB. This key event provides new evidence valuable for the diagnosis and treatment of IRS.

Objectives To assess the antiviral response to optimized therapy following genotypic resistance testing and to identify factors associated with virological response in HIV-1-infected patients failing antiretroviral therapy. Methods A prospective cohort study was conducted in 344 HIV-1-infected patients who underwent genotypic resistance testing because of virological failure. Virological response was defined as a plasma HIV RNA level below 200 HIV-1 RNA copies/mL or a drop of plasma viral load from baseline of more than 1 log10. A multivariate logistic regression analysis was performed to identify factors associated with virological response. Results The median age of the patients was 40 years, with a male to female ratio of 4:1. Fifty-one per cent of patients had received the three major classes of antiretrovirals and the median duration of previous antiretroviral therapy was 4.6 years. At baseline, the median plasma HIV RNA level was 4.4 log10 copies/mL and the median CD4 cell count was 274 cells/μL. At 3 months, 55% of patients (188 of 344) had a virological response, which was sustained at 6 months (53%). Predictors of virological response were exposure to two or fewer protease inhibitors [odds ratio (OR) 1.8; P=0.046], and use in optimized therapy of a new class of antiretrovirals (OR 2.9; P=0.006), of more than two new drugs (OR 3.0; P

Current therapies available for the treatment of chronic hepatitis B are limited in their ability to result in a cure. Clevudine is a new pyrimidine analog with potent anti-hepatitis B virus (HBV) activity in vitro. A multicenter dose-escalation study evaluated clevudine at 10, 50, 100, and 200 mg once daily for 28 days. Eligible patients had HBV DNA levels of 3 x 10(6) copies/mL or more, had not undergone nucleoside treatment, and were without human immunodeficiency or hepatitis C virus coinfection. Thirty-two patients were enrolled (5, 10, 10, and 7 patients in the 10-, 50-, 100-, and 200-mg dose groups, respectively), 81% were male, 81% Asian, and 88% were hepatitis Be antigen (HBeAg) positive at baseline. Median pretreatment serum HBV DNA levels ranged from 7.3 to 8.8 log(10) copies/mL. After 28 days, the median HBV DNA log(10) change from baseline was -2.5, -2.7, -3.0, and -2.6 log(10). Six months after dosing, median changes from baseline were -1.2, -1.4, -2.7 and -1.7 log(10) in the 10-, 50-, 100-, and 200-mg cohorts, respectively. Six of 27 patients lost HBeAg, and 3 of 27 patients seroconverted to HBe antibody. Clevudine was well tolerated, with no dose-limiting toxicities. A transient increase in alanine aminotransferase of up to 7.8 times the upper limit of normal (increase ranged from 20 to 186 IU/L) was observed in six patients in the 100-mg cohort, without signs of liver failure. These increases were associated with improved viral suppression. The pharmacokinetic profile of clevudine was proportional to the dose. In conclusion, these results demonstrate the tolerability and potent activity of clevudine in HBV-infected patients and support further clinical study.

Background. The objective of this work was to assess the role of human immunodeficiency virus (HIV) reservoirs in the risk of disease progression, by studying the relationship between HIV DNA level in peripheral blood mononuclear cells (PBMCs) and progression toward acquired immunodeficiency syndrome (AIDS). Methods. HIV-1 DNA levels in PBMCs were determined by quantitative polymerase chain reaction for 383 patients enrolled in the SEROCO Cohort Study who had experienced seroconversion and had been followed up for >8 years. We compared the predictive values of HIV DNA level, HIV RNA level, and CD4 + cell count. Results. Between 6 and 24 months after seroconversion, HIV DNA level was a major predictor of progression to AIDS independently of HIV RNA level and CD4 + T cell count (adjusted relative risk [RR] for a 1-log 10 increase, 3.20 [95% confidence interval {CI}, 1.70-6.00]). HIV DNA level was also a major predictor of disease progression during the first 6 months after seroconversion (adjusted RR, 4.16 [95% CI, 1.70-10.21]), when HIV RNA level and CD4' T cell count were less predictive. Thus, a combination of these 3 markers provides the best estimate of the risk of disease progression for each patient. Conclusions. Our results suggest that HIV DNA level could be a useful additional marker in clinical practice and could aid in helping to define the best time to initiate treatment for each patient.

Objective This study was conducted to investigate the pharmacokinetics of emtricitabine (FTC), didanosine (ddI), and efavirenz (EFV) when administered in a once-daily combination. Methods Nine antiretroviral-naive HIV-infected adults who received FTC [200 mg once a day (qd)], ddI (400 mg qd if ≥60 kg; 250 mg qd if

We report 3 cases of renal toxicity associated with use of the antiviral agent tenofovir. Renal failure, proximal tubular dysfunction, and nephrogenic diabetes insipidus were observed, and, in 2 cases, renal biopsy revealed severe tubular necrosis with characteristic nuclear changes. Patients receiving tenofovir must be monitored closely for early signs of tubulopathy (glycosuria, acidosis, mild increase in the plasma creatinine level, and proteinuria).

A key resistance mutation on the reverse transcriptase gene was observed in 8.8% of 204 patients enrolled during primary infection between 1996 and 1999 in ANRS 053 and the PRIMO cohort; the prevalence was stable over time. The prevalence of key protease gene mutations increased from 0% in 1996 to 8.3% in 1999. After the initiation of highly active antiretroviral therapy, HIV RNA in patients with one or more resistance to a prescribed drug decreased to under 20-50 copies/ml more slowly than in other patients.