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.

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.

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.

A case of Capnocytophaga canimorsus sacral abscess in an immunocompetent patient.

We report a unique case of sacral Capnocytophaga canimorsus abscess successfully treated with surgery and antibiotics. Close contact to a dog was assumed to be the most likely source of infection. Established risk factors for invasive C. canimorsus infection such as splenectomy, alcoholism or overt immunosuppression could not be identified. The role of cigarette smoking, portal of entry and the possible relevance of altered skin microbiota as well as the diagnostic value of polymerase chain reaction are discussed in the light of the scarce literature of spinal C. canimorsus infections.

[First case of nephropathia epidemica acquired in Switzerland]. / Premier cas de néphropathie epidémique endémique en Suisse.

A 43 year healthy old man complains of fever with abdominal pain, vomiting, diarrhoea, followed by the development of thrombocytopenia and acute renal failure. The laboratory tests show the presence of Hantavirus specific IgM and IgG which is confirmed by a specific test revealing Puumala serotype as responsible. The patient received a symptomatic treatment with a favourable evolution allowing discharge about ten days after the beginning of symptoms. Hantavirus are transmitted by rodents, and this patient has certainly been infected in Switzerland in the absence of travel abroad during the incubation period. This means that when confronted in Switzerland with an acute nephritis of unknown origin, a diagnosis of nephropathia epidemica must be taken into account.

Membrane-associated respiratory syncytial virus F protein expressed from a human rhinovirus type 14 vector is immunogenic.

Human rhinovirus (HRV) replicons have the potential to serve as respiratory vaccine vectors for mucosal immunization in humans. However, since many vaccine immunogens of interest are glycosylated, an important concern is whether HRV replicons are capable of expressing glycosylated proteins. The human respiratory syncytial virus (RSV) fusion (F) protein was chosen as a model glycoprotein and the HRV replicon DeltaP1FVP3 was generated by inserting the F protein-coding sequence in frame and in lieu of the 5' proximal 1489 nucleotides of the capsid-coding segment in the HRV-14 genome. When transfected into H1-HeLa cells, DeltaP1FVP3 replicated and led to the expression of the F protein. Inhibition with guanidine demonstrated that F-protein expression was dependent on DeltaP1FVP3 replication and did not result from translation of input RNA. Although most of the F protein remained as an immature, glycosylated precursor (F0), a readily detectable fraction of the protein was processed into the mature glycosylated subunit F1, an event known to occur within the Golgi apparatus. Packaged DeltaP1FVP3 replicons were generated in transfected HeLa cells by coexpression of homologous HRV capsid proteins using the vaccinia virus/T7 RNA polymerase hybrid system. Packaged replicon RNAs were capable of infecting fresh cells, leading to accumulation of the F protein as in RNA-transfected cells. Mice immunized with HeLa cell lysates containing F protein expressed from DeltaP1FVP3 produced neutralizing antibodies against RSV. These results indicate that an HRV-14 replicon can express a foreign glycosylated protein, providing further support for the potential of HRV replicons as a vaccine delivery system.

Update on antiviral DNA vaccine research (1998-2000).

DNA vaccines can induce protective cellular and humoral immune responses and have therefore been used during the last decade to develop vaccines against a variety of different pathogens. Because current antiviral vaccines predominantly generate humoral immunity, DNA immunization may be especially useful to provide long-term protection against viral diseases that also require cellular immunity (e.g. HIV). A significant number of articles published in the field of DNA vaccines are dealing with viral diseases, reflecting the need for better and alternative vaccination strategies against viruses. The success of DNA immunization depends on a variety of parameters (e.g. type of antigen, method of application and usage of adjuvants). Therefore, different strategies have been explored to modulate the induced immune response with respect to the requirements necessary to protect against a specific pathogen (e.g. induction of mucosal or cell-mediated immunity). The following article provides an update on different aspects of antiviral DNA vaccine research that have previously been reviewed by others.

Identification of active-site residues in protease 3C of hepatitis A virus by site-directed mutagenesis.

Picornavirus 3C proteases (3Cpro) are cysteine proteases related by amino acid sequence to trypsin-like serine proteases. Comparisons of 3Cpro of hepatitis A virus (HAV) to those of other picornaviruses have resulted in prediction of active-site residues: histidine at position 44 (H44), aspartic acid (D98), and cysteine (C172). To test whether these residues are key members of a putative catalytic triad, oligonucleotide-directed mutagenesis was targeted to 3Cpro in the context of natural polypeptide precursor P3. Autocatalytic processing of the polyprotein containing wild-type or variant 3Cpro was tested by in vivo expression of vaccinia virus-HAV chimeras in an animal cell-T7 hybrid system and by in vitro translation of corresponding RNAs. Comparison with proteins present in HAV-infected cells showed that both expression systems mimicked authentic polyprotein processing. Individual substitutions of H44 by tyrosine and of C172 by glycine or serine resulted in complete loss of the virus-specific proteolytic cascade. In contrast, a P3 polyprotein in which D98 was substituted by asparagine underwent only slightly delayed processing, while an additional substitution of valine (V47) by glycine within putative protein 3A caused a more pronounced loss of processing. Therefore, apparently H44 and C172 are active-site constituents whereas D98 is not. The results, furthermore, suggest that substitution of amino acid residues distant from polyprotein cleavage sites may reduce proteolytic activity, presumably by altering substrate conformation.