Juan Ambrosioni

Treatment-Naive Individuals Are the Major Source of Transmitted HIV-1 Drug Resistance in Men Who Have Sex With Men in the Swiss HIV Cohort Study

BACKGROUND Human immunodeficiency virus type 1 (HIV-1) transmitted drug resistance (TDR) can compromise antiretroviral therapy (ART) and thus represents an important public health concern. Typically, sources of TDR remain unknown, but they can be characterized with molecular epidemiologic approaches. We used the highly representative Swiss HIV Cohort Study (SHCS) and linked drug resistance database (SHCS-DRDB) to analyze sources of TDR. METHODS ART-naive men who have sex with men with infection date estimates between 1996 and 2009 were chosen for surveillance of TDR in HIV-1 subtype B (N = 1674), as the SHCS-DRDB contains pre-ART genotypic resistance tests for >69% of this surveillance population. A phylogeny was inferred using pol sequences from surveillance patients and all subtype B sequences from the SHCS-DRDB (6934 additional patients). Potential sources of TDR were identified based on phylogenetic clustering, shared resistance mutations, genetic distance, and estimated infection dates. RESULTS One hundred forty of 1674 (8.4%) surveillance patients carried virus with TDR; 86 of 140 (61.4%) were assigned to clusters. Potential sources of TDR were found for 50 of 86 (58.1%) of these patients. ART-naive patients constitute 56 of 66 (84.8%) potential sources and were significantly overrepresented among sources (odds ratio, 6.43 [95% confidence interval, 3.22-12.82]; P < .001). Particularly large transmission clusters were observed for the L90M mutation, and the spread of L90M continued even after the near cessation of antiretroviral use selecting for that mutation. Three clusters showed evidence of reversion of K103N or T215Y/F. CONCLUSIONS Many individuals harboring viral TDR belonged to transmission clusters with other Swiss patients, indicating substantial domestic transmission of TDR in Switzerland. Most TDR in clusters could be linked to sources, indicating good surveillance of TDR in the SHCS-DRDB. Most TDR sources were ART naive. This, and the presence of long TDR transmission chains, suggests that resistance mutations are frequently transmitted among untreated individuals, highlighting the importance of early diagnosis and treatment.

Impact of highly active antiretroviral therapy on the molecular epidemiology of newly diagnosed HIV infections

Objective:To evaluate HIV-1 transmission trends and the impact of highly active antiretroviral therapy (HAART) on newly diagnosed HIV infections in Geneva, Switzerland. Design:Retrospective molecular epidemiology analysis of all newly HIV-diagnosed individuals between 2008 and 2010. Methods:Phylogenetic analyses were performed using pol sequences of 780 newly HIV-1 diagnosed individuals between 2000 and 2010 (mandatory reporting) and 1058 individuals diagnosed before 2000. All clusters (bootstrap value >98%) including individuals diagnosed in 2008–2010 were analyzed. Recent HIV infections (<1 year) were determined by documented seroconversion and/or fraction of ambiguous nucleotides. Median viral load and HAART coverage during the study period were obtained from patients included in the Swiss HIV Cohort Study (SHCS). Results:Among 142 newly diagnosed individuals during 2008–2010, 49% had a recent infection and 42% were included in transmission clusters. Among the latter, two-thirds were included in new clusters and one-third expanded previously known clusters. MSM carrying resistant strains were more frequently included in clusters. Only 1.8% of individuals diagnosed before 2000 and 10.8% diagnosed during 2000–2008 were included in clusters involving individuals diagnosed between 2008 and 2010. During 2008–2010, the median population viral load of SHCS-enrolled individuals was significantly lower for individuals diagnosed before 2000 than for those diagnosed during 2000–2008 and 2008–2010 and HAART coverage significantly higher. Conclusions:MSM with recent HIV infection are a significant source of onward transmission. Individuals diagnosed before 2000 were only exceptionally related to newly diagnosed infections between 2008 and 2010. Prevention campaigns need to be focused on improving diagnosis for recently infected individuals.

Responses of solid organ transplant recipients to the AS03-adjuvanted pandemic influenza vaccine.

BACKGROUND Solid organ transplant (SOT) recipients are a priority group for influenza vaccination and strategies enhancing immunogenicity are needed. METHODS We determined adverse reactions, changes in biomarkers of graft function and immune responses to two doses of the AS03-adjuvanted influenza A/09/H1N1 vaccine in 216 SOT recipients and in 138 controls after one dose. Antibody responses were measured by haemagglutination inhibition and confirmed by microneutralization. We calculated geometric mean titres (GMT) and seroprotection rates (GMT≥40). RESULTS Adverse reactions were fewer than in controls and graft function remained unaffected. Seroprotection was achieved by only 70.3% of SOT recipients, with significant differences between groups (lung 43.6%, heart 72.0%, kidney 83.3%, liver 83.3% and pancreas 85%), compared to 87% of controls (P<0.001). The weakest responses (seroprotection 43.5%) were elicited in lung transplant recipients. GMT remained threefold lower (115 versus 340) in SOT recipients than controls. Multivariate analyses identified increasing age, type of transplant and increasing blood levels of mycophenolate as independently associated to weaker responses. In contrast, even high blood levels of calcineurin inhibitors remained without significant influence on vaccine responses. CONCLUSIONS The squalene-based adjuvanted A/09/H1N1 vaccine was safe in SOT recipients. However, even two doses of this adjuvanted influenza vaccine did not provide adequate protection for lung transplant recipients and those with high mycophenolate blood levels. Additional prophylactic measures should, therefore, be considered for these high-risk groups.

Tuberculous meningitis in HIV-infected patients: drug susceptibility and clinical outcome.

The objective of this study was to identify prognostic factors of death in patients with tuberculous meningitis (TM) and show the impact of infection by multidrug-resistant strains on the outcome of this disease. We retrospectively analysed clinical charts of HIV-infected patients with culture-confirmed TM attending our institution during 1996–2004. The following variables were associated with death during hospitalization: neurological signs at admission, a CD4 T-cell count less than 50 cells/μl and infection by multidrug-resistant strains.

High hepatic and extrahepatic mortality and low treatment uptake in HCV-coinfected persons in the Swiss HIV cohort study between 2001 and 2013

BACKGROUND & AIMS The landscape of HCV treatments is changing dramatically. At the beginning of this new era, we highlight the challenges for HCV therapy by assessing the long-term epidemiological trends in treatment uptake, efficacy and mortality among HIV/HCV-coinfected people since the availability of HCV therapy. METHODS We included all SHCS participants with detectable HCV RNA between 2001 and 2013. To identify predictors for treatment uptake uni- and multivariable Poisson regression models were applied. We further used survival analyses with Kaplan-Meier curves and Cox regression with drop-out as competing risk. RESULTS Of 12,401 participants 2107 (17%) were HCV RNA positive. Of those, 636 (30%) started treatment with an incidence of 5.8/100 person years (PY) (95% CI 5.3-6.2). Sustained virological response (SVR) with pegylated interferon/ribavirin was achieved in 50% of treated patients, representing 15% of all participants with replicating HCV-infection. 344 of 2107 (16%) HCV RNA positive persons died, 59% from extrahepatic causes. Mortality/100 PY was 2.9 (95% CI 2.6-3.2) in untreated patients, 1.3 (1.0-1.8) in those treated with failure, and 0.6 (0.4-1.0) in patients with SVR. In 2013, 869/2107 (41%) participants remained HCV RNA positive. CONCLUSIONS Over the last 13 years HCV treatment uptake was low and by the end of 2013, a large number of persons remain to be treated. Mortality was high, particularly in untreated patients, and mainly due to non-liver-related causes. Accordingly, in HIV/HCV-coinfected patients, integrative care including the diagnosis and therapy of somatic and psychiatric disorders is important to achieve mortality rates similar to HIV-monoinfected patients.

Epidemiology of viral respiratory infections in a tertiary care centre in the era of molecular diagnosis, Geneva, Switzerland, 2011–2012

Abstract Few studies have examined the epidemiology of respiratory viral infections in large tertiary centres over more than one season in the era of molecular diagnosis. Respiratory clinical specimens received between 1 January 2011 and 31 December 2012 were analysed. Respiratory virus testing was performed using a large panel of real-time PCR or RT-PCR. Results were analysed according to sample type (upper versus lower respiratory tract) and age group. In all, 2996 (2469 (82.4%) upper; 527 (17.6%) lower) specimens were analysed. Overall positivity rate was 47.4% and 23.7% for upper and lower respiratory samples, respectively. The highest positivity rate was observed in patients under 18 years old (p <0.001); picornaviruses were the most frequent viruses detected over the year. Influenza virus, respiratory syncytial virus, human metapneumovirus and coronaviruses showed a seasonal peak during the winter season, while picornaviruses and adenoviruses were less frequently detected in these periods. Multiple viral infections were identified in 12% of positive cases and were significantly more frequent in children (p <0.001). In conclusion, we observed significant differences in viral infection rates and virus types among age groups, clinical sample types and seasons. Follow-up of viral detection over several seasons allows a better understanding of respiratory viral epidemiology.

Report of a successful treatment of pulmonary Cunninghamella bertholletiae infection with liposomal amphotericin and posaconazole in a child with GvHD and review of the literature.

Zygomycosis is an emerging, opportunistic fungal infection particularly affecting immunocomprised patients. We report the case of a 10-year-old girl who developed pulmonary zygomycosis because of Cunninghamella bertholletiae 1 year after undergoing bone marrow transplantation complicated with severe cutaneous and digestive graft-versus-host disease. Treatment with surgery and liposomal amphotericin B followed by posaconazole successfully treated the infection.

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

In this large cohort of HIV-infected patients with an incident HCV infection, treatment uptake and outcomes improved in recent years. As a consequence, the proportion of patients with a detectable HCV viral load decreased significantly with time.

Invasive microsporidiosis in allogeneic haematopoietic SCT recipients

Microsporidia are opportunistic pathogens causing localized and disseminated disease in immunocompromised and especially in AIDS patients. Although classically considered as parasites, taxonomy is under revision and genome molecular analyses have shown that microsporidia may be closely related to fungi. Two main genera are recognized: Enterocytozoon spp., responsible for approximately 80-90% of the clinically symptomatic infections, which are mainly localized, and Encephalytoyzoon spp., responsible of approximately 10% of infections with a higher tendency to disseminate. Localized infections affect the digestive tract more frequently (chronic diarrhoea or biliary tract involvement). Disseminated infection can involve the lungs and the central nervous system (CNS). In the era preceding highly active antiretroviral therapy, microsporidia were an important cause of diarrhoea in AIDS patients; nowadays its incidence has decreased. Infection in solid organ transplant recipients is rare, with some case reports and small series published. Only two cases of pulmonary infection have been reported in allogeneic haematopoietic SCT (allo-HSCT) recipients, both with fatal outcomes. Here we report the first case of an allo-HSCT recipient who survived disseminated microsporidiosis infection with gut, pulmonary and CNS involvement.

Changes in biomarkers of liver disease during successful combination antiretroviral therapy in HIV-HCV-coinfected individuals.

BACKGROUND We investigated changes in biomarkers of liver disease in HIV-HCV-coinfected individuals during successful combination antiretroviral therapy (cART) compared to changes in biomarker levels during untreated HIV infection and to HIV-monoinfected individuals. METHODS Non-invasive biomarkers of liver disease (hyaluronic acid [HYA], aspartate aminotransferase-to-platelet ratio index [APRI], Fibrosis-4 [FIB-4] index and cytokeratin-18 [CK-18]) were correlated with liver histology in 49 HIV-HCV-coinfected patients. Changes in biomarkers over time were then assessed longitudinally in HIV-HCV-coinfected patients during successful cART (n=58), during untreated HIV-infection (n=59), and in HIV-monoinfected individuals (n=17). The median follow-up time was 3.4 years on cART. All analyses were conducted before starting HCV treatment. RESULTS Non-invasive biomarkers of liver disease correlated significantly with the histological METAVIR stage (P<0.002 for all comparisons). The mean ±sd area under the receiver operating characteristic (AUROC) curve values for advanced fibrosis (≥F3 METAVIR) for HYA, APRI, FIB-4 and CK-18 were 0.86 ±0.05, 0.84 ±0.08, 0.80 ±0.09 and 0.81 ±0.07, respectively. HYA, APRI and CK-18 levels were higher in HIV-HCV-coinfected compared to HIV-monoinfected patients (P<0.01). In the first year on cART, APRI and FIB-4 scores decreased (-35% and -33%, respectively; P=0.1), mainly due to the reversion of HIV-induced thrombocytopaenia, whereas HYA and CK-18 levels remained unchanged. During long-term cART, there were only small changes (<5%) in median biomarker levels. Median biomarker levels changed <3% during untreated HIV-infection. Overall, 3 patients died from end-stage liver disease, and 10 from other causes. CONCLUSIONS Biomarkers of liver disease highly correlated with fibrosis in HIV-HCV-coinfected individuals and did not change significantly during successful cART. These findings suggest a slower than expected liver disease progression in many HIV-HCV-coinfected individuals, at least during successful cART.