Role of Gag mutations in PI resistance in the Swiss HIV cohort study: bystanders or contributors?

Background: HIV Gag mutations have been reported to confer PI drug resistance. However, clinical implications are still controversial and most current genotyping algorithms consider solely the protease gene for assessing PI resistance. Objectives: Our goal was to describe for HIV infections in Switzerland the potential role of the C-terminus of Gag (NC-p6) in PI resistance. We aimed to characterize resistance-relevant mutational patterns in Gag and protease and their possible interactions. Methods: Resistance information on plasma samples from 2004-12 was collected for patients treated by two diagnostic centres of the Swiss HIV Cohort Study. Sequence information on protease and the C-terminal Gag region was paired with the corresponding patient treatment history. The prevalence of Gag and protease mutations was analysed for PI treatment-experienced patients versus PI treatment-naive patients. In addition, we modelled multiple paths of an assumed ordered accumulation of genetic changes using random tree mixture models. Results: More than half of all PI treatment-experienced patients in our sample set carried HIV variants with at least one of the known Gag mutations, and 17.9% (66/369) carried at least one Gag mutation for which a phenotypic proof of PI resistance by in vitro mutagenesis has been reported. We were able to identify several novel Gag mutations that are associated with PI exposure and therapy failure. Conclusions: Our analysis confirmed the association of Gag mutations, well known and new, with PI exposure. This could have clinical implications, since the level of potential PI drug resistance might be underestimated.

Mining for pairs: shared clinic visit dates identify steady HIV-positive partnerships.

OBJECTIVES: Here we examined the hypothesis that some stable HIV-infected partnerships can be found in cohort studies, as the patients frequently attend the clinic visits together. METHODS: Using mathematical approximations and shuffling to derive the probabilities of sharing a given number of visits by chance, we identified and validated couples that may represent either transmission pairs or serosorting couples in a stable relationship. RESULTS: We analysed 434 432 visits for 16 139 Swiss HIV Cohort Study patients from 1990 to 2014. For 89 pairs, the number of shared visits exceeded the number expected. Of these, 33 transmission pairs were confirmed on the basis of three criteria: an extensive phylogenetic tree, a self-reported steady HIV-positive partnership, and risk group affiliation. Notably, 12 of the validated transmission pairs (36%; 12 of 33) were of a mixed ethnicity with a large median age gap [17.5 years; interquartile range (IQR) 11.8-22 years] and these patients harboured HIV-1 of predominantly non-B subtypes, suggesting imported infections. CONCLUSIONS: In the context of the surge in research interest in HIV transmission pairs, this simple method widens the horizons of research on within-pair quasi-species exchange, transmitted drug resistance and viral recombination at the biological level and targeted prevention at the public health level.

Emergence of Acquired HIV-1 Drug Resistance Almost Stopped in Switzerland: A 15-Year Prospective Cohort Analysis.

BACKGROUND: Drug resistance is a major barrier to successful antiretroviral treatment (ART). Therefore, it is important to monitor time trends at a population level. METHODS: We included 11 084 ART-experienced patients from the Swiss HIV Cohort Study (SHCS) between 1999 and 2013. The SHCS is highly representative and includes 72% of patients receiving ART in Switzerland. Drug resistance was defined as the presence of ≥1 major mutation in a genotypic resistance test. To estimate the prevalence of drug resistance, data for patients with no resistance test was imputed based on the patient's risk of harboring drug-resistant viruses. RESULTS: The emergence of new drug resistance mutations declined dramatically from 401 to 23 patients between 1999 and 2013. The upper estimated prevalence limit of drug resistance among ART-experienced patients decreased from 57.0% in 1999 to 37.1% in 2013. The prevalence of 3-class resistance decreased from 9.0% to 4.4% and was always <0.4% for patients who initiated ART after 2006. Most patients actively participating in the SHCS in 2013 with drug-resistant viruses initiated ART before 1999 (59.8%). Nevertheless, in 2013, 94.5% of patients who initiated ART before 1999 had good remaining treatment options based on Stanford algorithm. CONCLUSIONS: Human immunodeficiency virus type 1 drug resistance among ART-experienced patients in Switzerland is a well-controlled relic from the era before combination ART. Emergence of drug resistance can be virtually stopped with new potent therapies and close monitoring.

HIV-1 Transmission During Recent Infection and During Treatment Interruptions as Major Drivers of New Infections in the Swiss HIV Cohort Study.

BACKGROUND: Reducing the fraction of transmissions during recent human immunodeficiency virus (HIV) infection is essential for the population-level success of "treatment as prevention". METHODS: A phylogenetic tree was constructed with 19 604 Swiss sequences and 90 994 non-Swiss background sequences. Swiss transmission pairs were identified using 104 combinations of genetic distance (1%-2.5%) and bootstrap (50%-100%) thresholds, to examine the effect of those criteria. Monophyletic pairs were classified as recent or chronic transmission based on the time interval between estimated seroconversion dates. Logistic regression with adjustment for clinical and demographic characteristics was used to identify risk factors associated with transmission during recent or chronic infection. FINDINGS: Seroconversion dates were estimated for 4079 patients on the phylogeny, and comprised between 71 (distance, 1%; bootstrap, 100%) to 378 transmission pairs (distance, 2.5%; bootstrap, 50%). We found that 43.7% (range, 41%-56%) of the transmissions occurred during the first year of infection. Stricter phylogenetic definition of transmission pairs was associated with higher recent-phase transmission fraction. Chronic-phase viral load area under the curve (adjusted odds ratio, 3; 95% confidence interval, 1.64-5.48) and time to antiretroviral therapy (ART) start (adjusted odds ratio 1.4/y; 1.11-1.77) were associated with chronic-phase transmission as opposed to recent transmission. Importantly, at least 14% of the chronic-phase transmission events occurred after the transmitter had interrupted ART. CONCLUSIONS: We demonstrate a high fraction of transmission during recent HIV infection but also chronic transmissions after interruption of ART in Switzerland. Both represent key issues for treatment as prevention and underline the importance of early diagnosis and of early and continuous treatment.

[Biomarkers in clinical immunology]. / Biomarqueurs en immunologie générale.

In a current perspective of individualized medicine, biomarkers appear as a simple and readily available aid to assist clinicians in the identification and monitoring of diseases whose diagnosis is difficult. Basically, we know the limited performance of medical history and of clinical examination; therefore, the use of laboratory tests is often seen as the panacea to solve the clinical enigma. The purpose of this article is to analyze a few biomarkers commonly processed in the immunology laboratory (AAN, ANCA, anti-tTG, rheumatoid factor and anti-CCP) and to review the principle, the usefulness and the performance of these tests in specific clinical situations. We will see that, far from supplanting history and physical examination, these immunological biomarkers take their full value as a supplement to clinical information!

[An update on celiac disease]. / Maladie coeliaque: état des lieux.

Celiac disease is a well-known entity in pediatrics and pediatric gastroenterology that is now also frequently encountered in the adult population. Apart from typical symptoms, celiac disease can present with a wide range of manifestations that are sometimes atypical, scarce or purely extraintestinal. Serologic and genetic testing are useful tools in case of low clinical probability in the early diagnostic algorithm. Upper gastrointestinal endoscopy remains the mainstay to confirm the diagnosis especially in atypical clinical presentations. Complications are rare but can be severe. Although gluten-free diet often leads to complete recovery, compliance is not universal and alternative treatment strategies are under investigation.

Effect of Lactobacillus paracasei ST11 on a nasal provocation test with grass pollen in allergic rhinitis.

BACKGROUND: Probiotics have been associated with prevention and improvement of symptoms in atopic diseases such as atopic dermatitis. However, few studies exist that document their efficacy for upper airways allergies such as allergic rhinitis. OBJECTIVE: To investigate the effect of short-term oral administration of Lactobacillus paracasei ST11 on a nasal provocation test (NPT) with grass pollen. METHODS: Thirty-one adult volunteers with allergic rhinitis were enrolled in a randomized, double-blind, placebo-controlled study, based on two 4-week cross-over periods of product consumption (ST11-fermented milk vs. placebo), separated by a wash-out period of 6-8 weeks. Objective and subjective clinical parameters of NPT as well as systemic and nasal immunological parameters were compared between the two treatment periods (registration number: NCT 011 50 253). RESULTS: Subjects that received ST11-fermented milk had lower nasal congestion than subjects under placebo (visual analogical scale; P<0.05). Nasal pruritus followed the same trend. However, no significant change in combined nasal reaction threshold was observed between the two periods. IL-5 secretion by peripheral blood mononuclear cells and serum allergen-specific IgG4 were significantly lower in ST11-fermented milk group compared to placebo group. IL-8 and IL-10 secretion followed the same trend. CONCLUSION AND CLINICAL RELEVANCE: Short-term treatment with ST11-fermented milk before NPT significantly improved a clinical marker of NPT (subjective nasal congestion) and down-regulated systemic immune markers (IL-5 from peripheral blood mononuclear cells and serum IgG4). These data strongly suggest that probiotics may down modulate key parameters of allergic rhinitis and warrant future evaluation in seasonal trials.

Identification of a novel HLA-B*18 allele, B*18:119, using sequence-based typing in a caucasoid individual.

HLA-B*18:119 differs from HLA-B*18:01:01 at nucleotide 28 C>T in exon 4 changing histidine to tyrosine.

Increases in Condomless Sex in the Swiss HIV Cohort Study.

Condomless sex is a key driver of sexually transmitted diseases. In this study, we assess the long-term changes (2000-2013) of the occurrence of condomless sex among human immunodeficiency virus (HIV)-infected individuals enrolled in the Swiss HIV Cohort study. The frequencies with which HIV-infected individuals reported condomless sex were either stable or only weakly increasing for 2000-2008. For 2008-2013, these rates increased significantly for stable relationships among heterosexuals and men who have sex with men (MSM) and for occasional relationships among MSM. Our results highlight the increasing public health challenge posed by condomless sex and show that condomless sex has been increasing even in the most recent years.

Strong Impact of Smoking on Multimorbidity and Cardiovascular Risk Among Human Immunodeficiency Virus-Infected Individuals in Comparison With the General Population.

Background. Although acquired immune deficiency syndrome-associated morbidity has diminished due to excellent viral control, multimorbidity may be increasing among human immunodeficiency virus (HIV)-infected persons compared with the general population. Methods. We assessed the prevalence of comorbidities and multimorbidity in participants of the Swiss HIV Cohort Study (SHCS) compared with the population-based CoLaus study and the primary care-based FIRE (Family Medicine ICPC-Research using Electronic Medical Records) records. The incidence of the respective endpoints were assessed among SHCS and CoLaus participants. Poisson regression models were adjusted for age, sex, body mass index, and smoking. Results. Overall, 74 291 participants contributed data to prevalence analyses (3230 HIV-infected; 71 061 controls). In CoLaus, FIRE, and SHCS, multimorbidity was present among 26%, 13%, and 27% of participants. Compared with nonsmoking individuals from CoLaus, the incidence of cardiovascular disease was elevated among smoking individuals but independent of HIV status (HIV-negative smoking: incidence rate ratio [IRR] = 1.7, 95% confidence interval [CI] = 1.2-2.5; HIV-positive smoking: IRR = 1.7, 95% CI = 1.1-2.6; HIV-positive nonsmoking: IRR = 0.79, 95% CI = 0.44-1.4). Compared with nonsmoking HIV-negative persons, multivariable Poisson regression identified associations of HIV infection with hypertension (nonsmoking: IRR = 1.9, 95% CI = 1.5-2.4; smoking: IRR = 2.0, 95% CI = 1.6-2.4), kidney (nonsmoking: IRR = 2.7, 95% CI = 1.9-3.8; smoking: IRR = 2.6, 95% CI = 1.9-3.6), and liver disease (nonsmoking: IRR = 1.8, 95% CI = 1.4-2.4; smoking: IRR = 1.7, 95% CI = 1.4-2.2). No evidence was found for an association of HIV-infection or smoking with diabetes mellitus. Conclusions. Multimorbidity is more prevalent and incident in HIV-positive compared with HIV-negative individuals. Smoking, but not HIV status, has a strong impact on cardiovascular risk and multimorbidity.

Incident Hepatitis C Virus Infections in the Swiss HIV Cohort Study: Changes in Treatment Uptake and Outcomes Between 1991 and 2013.

Background. The hepatitis C virus (HCV) epidemic is evolving rapidly in patients infected with human immunodeficiency virus (HIV). We aimed to describe changes in treatment uptake and outcomes of incident HCV infections before and after 2006, the time-point at which major changes in HCV epidemic became apparent. Methods. We included all adults with an incident HCV infection before June 2012 in the Swiss HIV Cohort Study, a prospective nationwide representative cohort of individuals infected with HIV. We assessed the following outcomes by time period: the proportion of patients starting an HCV therapy, the proportion of treated patients achieving a sustained virological response (SVR), and the proportion of patients with persistent HCV infection during follow-up. Results. Of 193 patients with an HCV seroconversion, 106 were diagnosed before and 87 after January 2006. The proportion of men who have sex with men increased from 24% before to 85% after 2006 (P < .001). Hepatitis C virus treatment uptake increased from 33% before 2006 to 77% after 2006 (P < .001). Treatment was started during early infection in 22% of patients before and 91% after 2006 (P < .001). An SVR was achieved in 78% and 29% (P = .01) of patients treated during early and chronic HCV infection. The probability of having a detectable viral load 5 years after diagnosis was 0.67 (95% confidence interval [CI], 0.58-0.77) in the group diagnosed before 2006 and 0.24 (95% CI, 0.16-0.35) in the other group (P < .001). Conclusions. In recent years, increased uptake and earlier initiation of HCV therapy among patients with incident infections significantly reduced the proportion of patients with replicating HCV.

Evaluation of an intrathecal immune response in amyotrophic lateral sclerosis patients implanted with encapsulated genetically engineered xenogeneic cells.

A phase I/II clinical trial has been performed in 12 amyotrophic lateral sclerosis (ALS) patients to evaluate the safety and tolerability of intrathecal implants of encapsulated genetically engineered baby hamster kidney (BHK) cells releasing human ciliary neurotrophic factor (CNTF). These patients have been assessed for a possible intrathecal or systemic immune response against the implanted xenogeneic cells. Hundreds of pg CNTF/ml could be detected for several weeks in the cerebrospinal fluid (CSF) of 9 out of 12 patients, in 2 patients up to 20 weeks after capsule implantation. Slightly elevated leukocyte counts were observed in 6 patients. Clear evidence for a delayed humoral immune response was found in the CSF of only 3 patients out of 12 (patients #4, #6, and #10). Characterization of the antigen(s) recognized by the antibodies present in these CSF samples allowed to identify bovine fetuin as the main antigenic component. The defined medium used for maintaining the capsules in vitro before implantation contains bovine fetuin. Fetuin may therefore still be adsorbed to the surface of the cells and/or the polymer membrane, or be present in the medium surrounding the encapsulated cells at the time of implantation. Because of the insufficient availability of CSF samples, as well as the relatively poor sensitivity of the assays used, a weak humoral immune response against components of the implanted cells themselves cannot be excluded. However, the present study demonstrates that encapsulated xenogeneic cells implanted intrathecally can survive for up to 20 weeks in the absence of immunosuppression and that neither CNTF nor the presence of antibodies against bovine fetuin elicit any adverse side effects in the implanted patients.

Anaphylactoid purpura like vasculitis following fibrinolytic therapy: role of the immune response to streptokinase.

We report the case of a patient who presented with a clinical picture of serum sickness with some characteristics of anaphylactoid purpura (Henoch-Schönlein purpura) five days after receiving streptokinase as a treatment for myocardial infarction. The appearance of Henoch-Schönlein like vasculitis after streptokinase treatment was particularly intriguing in view of the common association of streptococcus infection with this type of vasculitis. The production of streptokinase specific IgG and IgA antibodies was studied in the patient and compared with six controls treated with identical doses of streptokinase without adverse effects. A more rapid increase of streptokinase specific IgA was detected in the patient, with a significant higher amount of streptokinase specific IgA and IgG after six days of treatment. These results suggest that different kinetics could induce a precipitation of the immune complexes responsible for vasculitis. However, we cannot exclude that the IgA found in the vessel walls was only an "innocent bystander" deposited as a secondary event.

Evaluation of a new semiquantitative immunodot assay for the screening of specific IgE.

The Immunodot CMG is a new, simple assay for the semiquantitative screening of specific IgE. It does not necessitate any particular equipment. It consists of two nitrocellulose strips on which either five indoor or five outdoor allergens are bound. In the present evaluation, 82 serum samples from allergic patients were tested with the first strip and 101 with the second. The results were compared with those obtained with the CAP System (Kabi Pharmacia). A version using undiluted serum and a short incubation time (short version) appeared to be more sensitive than a long version using serum diluted 1:5. In most cases, the results agreed with those of the CAP System. Discordant results were found in 2-9% of the cases according to the allergen, and were most often negative with Immunodot CMG and positive with the CAP System, indicating a slightly lower sensitivity for the new test. When compared to the CAP System, the Immunodot CMG showed a sensitivity of 84.5% and a specificity of 94%. Readings were found to be reproducible and easy to perform with the naked eye. Our results showed that the Immunodot CMG test is comparable to the CAP System, which is slightly more sensitive but requires much more elaborate and expensive equipment.

Bronchial provocation with cat allergen: long-term outcome of the late allergic reaction and the individual IgE CRIE pattern.

In bronchial provocation tests with allergen, about 50% of the patients experienced a late allergic reaction (LAR), which has been associated with a specific IgE pattern as determined by crossed radioimmunoelectrophoresis (CRIE). Long-term outcome of this LAR is still unknown. Six patients allergic to cat, with documented LAR and specific IgE CRIE patterns were rechallenged in the same conditions after a mean interval of 2.5 years. Forced expiratory volume in one second (FEV1) and resistance results of the bronchial provocation tests (BPT) were compared, as well as specific IgE level and IgE CRIE patterns. All six patients were still suffering from asthma when exposed to a cat, although they were not being treated for asthma. Three patients (50%) had lost their LAR without specific treatment. They were older, with a longer history of asthma, but presented a very similar early allergic reaction to similar allergen doses. The other 3 were more reactive to the allergen but presented similar LAR after a slightly worse early allergic reaction (EAR). Specific IgE levels had decreased and the IgE CRIE pattern showed a diminished intensity of staining in the three patients who had lost their LAR, as opposed to the other three. These data suggest that asthmatic patients can lose their LAR over time without treatment. The occurrence of a LAR seems to be associated with a specific IgE CRIE pattern and IgE level. Further analysis of the individual antigen fractions might help to understand the mechanism of allergic reactions.

[Physiological role of PTHrP]. / Rôle physiologique de la PTHrP.

Parathyroid hormone related protein (PTHrP) is the aetiological factor for the syndrome of humoral hypercalcemia of malignancy. The PTHrP gene encodes three isoforms of respectively 139, 141 and 173 amino acids with N-terminal homology to parathormone (PTH). PTHrP, which has a wide tissue distribution, appears to be a polyhormone with different physiologic functions that depend on the particular fragment secreted. PTHrP may act in an autocrine, a paracrine or an endocrine fashion. There is evidence for a role in the growth and development of both embryonic and mature tissues, in cellular differentiation, in smooth muscle relaxation, lactation and calcium and magnesium transport. The best known PTHrP functions are those mediated by the N-terminal domain fixation on the classical PTH/PTHrP receptor. Nevertheless, several other functions are mediated by different fragments of PTHrP such as midregion fragments or carboxy-terminal forms. Each of these functional forms of PTHrP has one or several physiological function(s) which is (are) mediated by his own specific receptors and signal transduction pathways, some of which may be tissue specific.

[Total laparoscopic hysterectomy. Operative technique, results and indications]. / Hystérectomie totale per-coelioscopique. Technique opératoire, résultats et indications.

Total hysterectomy was performed via laparoscopy alone in 50 patients. In all cases, the operation was carried out using conventional, re-usable instruments (grasping forceps, laparoscopic scissors, bipolar coagulation). The mean duration of the operation was 163 min (range: 110-270 min). The mean drop in haemoglobin was 1.97 g/100 ml (range: 0-4 g/100 ml) and the average length of hospital stay was 3.9 days (range: 2-13 days). In one case (2%), we converted to laparotomy because a lateral myoma made it impossible to achieve haemostasis of the uterine pedicule under suitably safe conditions. No serious peri or post-operative complications were encountered. No second surgery was necessary and no transfusion was required. These results confirm that total laparoscopic hysterectomy via laparoscopy is a safe, feasable and reproductible technique. Future work will establish the exact place and methods for laparoscopic surgery for hysterectomy. Laparoscopic surgery is only indicated when vaginal hysterectomy is contraindicated or impossible. Laparoscopic hysterectomy constitutes an alternative to laparotomy rather than the vaginal hysterectomy. The combination of an immobile uterus and poor vaginal accessibility is the prime indication for total hysterectomy via laparotomy.

[Heart and thyroid]. / Coeur et thyroïde.

Thyroid hormones may exert cardiovascular actions by direct effects on the myocardium, by interacting with the sympathetic nervous system and through alterations of the peripheral circulation. Then, thyroid hormones increase myocardial contractility and relaxation, sensitise the myocardium to sympathetic nervous system and decrease arterial resistance. Hyperthyroidism results in an enhanced myocardial contractility, an increased cardiac output and a fall in systemic vascular resistance. Nevertheless "high output" cardiac decompensation may occur. Thyrotoxicosis may trigger arrythmia and disease seems to be associated with an increase in the frequency of mitral valve prolapse. Even in mild or subclinical hyperthyroidism complication may occur. Sympathetic blocking agents are the treatment of choice in addition to aetiologic treatment. Hypothyroidism is associated with bradycardia, a decreased cardiac output, increased vascular resistance and perhaps a decreased sensitivity of the sympathoadrenal system. An increase in cholesterolemia leads to an additional risk for the development of atherosclerosis. Main cardiovascular complications of hypothyroidism are angina pectoris, diastolic hypertension, atrio-ventricular blocks or pericarditis. Mild hypothyroidism might also be correlated with an increase in adverse effects.

[Thyroid metastases from cancer of the kidney. Two cases]. / Métastases thyroïdiennes des cancers du rein. Deux observations.

Non-thyroid cancers rarely metastases to the thyroid gland. Metastases can be divided into those with clinical expression and those identified at necropsy. Symptom producing thyroid metastases are usually due to a primary renal cell cancer. We report two cases of thyroid metastasis of a clear cell renal carcinoma. In the first case, an 82-year-old woman presented with an enlarged thyroid gland. This inaugural element led to the diagnosis of thyroid metastasis and identification of recurrent renal cell carcinoma which had been treated by radiotherapy 24 years earlier. After radiotherapy for a concomitant pulmonary metastasis, the patient is in good general health with no signs of recurrence. In the second case, increased thyroid volume led to signs of compression in a 71-year-old man. The pathology report after left lobular thyroidectomy suggested trabecular adenoma or metastasis of a clear-cell primary tumour. Abdominal CT-scan revealed a 3.5 cm tumour found to be a clear-cell renal carcinoma at nephrectomy. Another osteolytic metastasis to the femur was also observed three months after surgery. The patient is in good health 15 months after the initial diagnosis. The significance of thyroid metastasis of renal cell carcinoma would vary according to the different cases reported in the literature with survival ranging from 32 months to 3-7 years after surgical exeresis. Prognosis would thus not appear to be as poor as for thyroid metastasis from other primary tumours.

[Classification and epidemiology of thyroid tumors]. / Classification et epidémiologie des tumeurs thyroïdiennes.

Thyroid diseases are the most prevalent endocrine diseases. Faced with a thyroid enlargement or nodule, it is a challenge for the physician to determine with the best sensibility and specificity and the least cost which one are benign tumours and which are malignant neoplasms that need to be removed. The prevalence of solitary nodules is 1 to 5%. Only 2 to 12% of these nodules are cancers. Papillary and follicular carcinomas, two carcinomas derived from follicular cells, are the most common types and occur more frequently in women. Both have a good prognosis. Medullary carcinoma derives from C-cells. Familial forms have to be searched. Anaplastic carcinoma and other malignant tumours are less frequent but have poor prognosis.