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Background Long-acting (LA) intramuscular cabotegravir and rilpivirine are prone to drug-drug interactions (DDI). However, given the long dosing interval, the conduct of clinical DDIs studies with LA antiretrovirals is challenging. We performed virtual clinical DDI studies using physiologically based pharmacokinetic (PBPK) modeling to provide recommendations for the management of DDIs with strong or moderate inducers such as rifampicin or rifabutin. Methods Each DDI scenario included a cohort of virtual individuals (50% female) between 20 and 50 years of age with a body mass index of 18–30 kg/m2. Cabotegravir and rilpivirine were given alone and in combination with rifampicin or rifabutin. The predictive performance of the PBPK model to simulate cabotegravir and rilpivirine pharmacokinetics after oral and intramuscular administration and to reproduce DDIs with rifampicin and rifabutin was first verified against available observed clinical data. The verified model was subsequently used to simulate unstudied DDI scenarios. Results At steady state, the strong inducer rifampicin was predicted to decrease the area under the curve (AUC) of LA cabotegravir by 61% and rilpivirine by 38%. An increase in the dosing frequency did not overcome the DDI with rifampicin. The moderate inducer rifabutin was predicted to reduce the AUC of LA cabotegravir by 16% and rilpivirine by 18%. The DDI with rifabutin can be overcome by administering LA cabotegravir/rilpivirine monthly together with a daily oral rilpivirine dose of 25 mg. Conclusions LA cabotegravir/rilpivirine should be avoided with strong inducers but coadministration with moderate inducers is possible by adding oral rilpivirine daily dosing to the monthly injection.

Background Identifying local outbreaks and their drivers is a key step toward curbing human immunodeficiency virus (HIV) transmission and potentially achieving HIV elimination. Such outbreaks can be identified as transmission clusters extracted from phylogenetic trees constructed of densely sampled viral sequences. In this study, we combined phylogenetic transmission clusters with extensive data on virological suppression and behavioral risk of cluster members to quantify the drivers of ongoing transmission over 10 years. Methods Using the comprehensive Swiss HIV Cohort Study and its drug-resistance database, we reconstructed phylogenetic trees for each year between 2007 and 2017. We identified HIV transmission clusters dominated by men who have sex with men (MSM) and determined their annual growth. We used Poisson regression to assess if cluster growth was associated with a per-cluster infectivity and behavioral risk score. Results Both infectivity and behavioral risk scores were significantly higher in growing MSM transmission clusters compared to nongrowing clusters (P ≤ .01). The fraction of transmission clusters without infectious members acquiring new infections increased significantly over the study period. The infectivity score was significantly associated with per-capita incidence of MSM transmission clusters in 8 years, while the behavioral risk score was significantly associated with per-capita incidence of MSM transmission clusters in 3 years. Conclusions We present a phylogenetic method to identify hotspots of ongoing transmission among MSM. Our results demonstrate the effectiveness of treatment as prevention at the population level. However, the significantly increasing number of new infections among transmission clusters without infectious members highlights a relative shift from diagnosed to undiagnosed individuals as drivers of HIV transmission in Swiss MSM.

BackgroundSince the advent of universal test-and-treat , more people living with human immunodeficiency virus (PLHIV) initiating antiretroviral therapy (ART) are asymptomatic with a preserved immune system. We explored the impact of asymptomatic status on adherence and clinical outcomes.MethodsPLHIV registered in the Swiss HIV Cohort Study (SHCS) between 2003 and 2018 were included. We defined asymptomatic as Centers for Disease Control and Prevention stage A within 30 days of starting ART, non-adherence as any self-reported missed doses and viral failure as two consecutive viral load>50 copies/mL after >24 weeks on ART. Using logistic regression models, we measured variables associated with asymptomatic status and adherence and Cox proportional hazard models to assess association between symptom status and viral failure.ResultsOf 7131 PLHIV, 76% started ART when asymptomatic and 1478 (22%) experienced viral failure after a median of 1.9 years (interquartile range, 1.1–4.2). In multivariable models, asymptomatic PLHIV were more likely to be younger, men who have sex with men, better educated, have unprotected sex, have a HIV-positive partner, have a lower viral load, and have started ART more recently. Asymptomatic status was not associated with nonadherence (odds ratio, 1.03 [95% confidence interval {CI}, .93–1.15]). Asymptomatic PLHIV were at a decreased risk of viral failure (adjusted hazard ratio, 0.87 [95% CI, .76–1.00]) and less likely to develop resistance (14% vs 27%, P ConclusionsDespite concerns regarding lack of readiness, our study found no evidence of adherence issues or worse clinical outcomes in asymptomatic PLHIV starting ART.

Background Preliminary studies that analyzed surrogate markers have suggested that operating room (OR) door openings may be a risk factor for surgical site infection (SSI). We therefore aimed to estimate the effect of OR door openings on SSI risk in patients undergoing cardiac surgery. Methods This prospective, observational study involved consecutive patients undergoing cardiac surgery in 2 prespecified ORs equipped with automatic door-counting devices from June 2016 to October 2017. Occurrence of an SSI within 30 days after cardiac surgery was our primary outcome measure. Respective outcome data were obtained from a national SSI surveillance cohort. We analyzed the relationship between mean OR door opening frequencies and SSI risk by use of uni- and multivariable Cox regression models. Results A total of 301 594 OR door openings were recorded during the study period, with 87 676 eligible door openings being logged between incision and skin closure. There were 688 patients included in the study, of whom 24 (3.5%) developed an SSI within 30 days after surgery. In uni- and multivariable analysis, an increased mean door opening frequency during cardiac surgery was associated with higher risk for consecutive SSI (adjusted hazard ratio per 5-unit increment, 1.49; 95% confidence interval, 1.11–2.00; P = .008). The observed effect was driven by internal OR door openings toward the clean instrument preparation room. Conclusions Frequent door openings during cardiac surgery were independently associated with an increased risk for SSI. This finding warrants further study to establish a potentially causal relationship between OR door openings and the occurrence of SSI.

We analyzed changes in hepatitis B virus and hepatitis delta virus (HDV) viral loads (VL) during tenofovir-containing antiretroviral therapy among patients with a replicating HDV infection in the Swiss HIV Cohort Study. Only 28.6% experienced a ≥2.0 log reduction in HDV RNA, and 14.3% had undetectable HDV VL within 5 years.

Background Data on infections associated with cerebrospinal fluid (CSF) shunts among adults are limited. Therefore, we performed a retrospective study of shunt-associated infections in adults. Methods Patients aged > or = 12 years with infections associated with CSF shunts and admitted to our institution(University Hospital Basel, Basel, Switzerland) from January 1996 through December 2006 were included retrospectively. Hospital charts were reviewed, and follow-up was performed by assessment of later hospitalizations and telephone contact with patients, their families, and general practitioners. Results Seventy-eight episodes of infection associated with ventriculoperitoneal shunt (65 episodes), ventriculoatrial shunt (7), lumboperitoneal shunt (5), and central nervous system reservoir (1) were included. Median patient age was 50 years (range, 12-80 years); 49 (63%) of the patients were men. Most infections (48 [62%])manifested within 1 month after shunt surgery. Fever was present in 61 episodes (78%), neck stiffness was present in 35 (45%), and local signs of infection were present in 38 (49%). In CSF, leukocyte count was >5 x 10(6) cells/L in 80% of episodes, and lactate level was 11.9 mmol/L in 81% of episodes. Leukocyte counts were significantly higher in CSF obtained by use of lumbar puncture (median leukocyte count, 573 x 10(6) cells/L; P = .001) and valve puncture (median leukocyte count, 484 x 10(6) cells/L; P = .016) than in ventricular CSF (median leukocyte count, 8.5 x 10(6) cells/L). Overall, results of CSF cultures were positive in 66% of episodes (48 of 73 episodes for which CSF was collected), and microorganisms were isolated more often from valve puncture CSF specimens(91% of specimens) and ventricular CSF specimens (70%) than from lumbar CSF specimens (45%). The most prevalent organisms were coagulase-negative staphylococci (found in 37% of specimens), Staphylococcus aureus(18%), and Propionibacterium acnes (9%). A surgical procedure was performed to treat infection in 63 (81% of the episodes) (shunt removal in 37 episodes and shunt replacement in 26). The shunt was retained without surgery for 15 episodes (19% of episodes). Median duration of patient follow-up was 4.6 years (range, 0.1-11.1 years),with favorable treatment outcome in 75 (96%) of 78 cases. One of the 63 patients who underwent surgical treatment of shunt-associated infection experienced infection relapse; of the 15 patients who received treatment with antibiotics alone, 1 experienced infection relapse and 1 died. The 2 relapses involved rifampin-resistant coagulase-negative staphylococci. Conclusions Shunt-associated infections among adults often present with nonspecific clinical signs, and affected patients can have normal CSF leukocyte counts and lactate levels; therefore, a high index of suspicion and improved methods are required for diagnosing shunt-associated infection.

The prognosis of patients infected with human immunodeficiency virus (HIV) type 1 has dramatically improved since the advent of potent antiretroviral therapies (ARTs), which have enabled sustained suppression of HIV replication and recovery of CD4 T cell counts. Knowledge of the function of CD4 T cells in immune reconstitution was derived from large clinical studies demonstrating that primary and secondary prophylaxis against infectious agents, such as Pneumocystis jirovecii (Pneumocystis carinii), Mycobacterium avium complex, cytomegalovirus, and other pathogens, can be discontinued safely once CD4 T cell counts have increased beyond pathogen-specific threshold levels (usually >200 CD4 T cells/mm3) for 3-6 months. The downside of immune reconstitution is an inflammatory syndrome occurring days to months after the start of ART, with outcomes ranging from minimal morbidity to fatal progression. This syndrome can be elicited by infectious and noninfectious antigens. Microbiologically, the possible pathogenic pathways involve recognition of antigens associated with ongoing infection or recognition of persisting antigens associated with past (nonreplicating) infection. Specific antimicrobial therapy, nonsteroidal anti-inflammatory drugs, and/or steroids for managing immune reconstitution syndrome should be considered.

portant mode of HIV transmission worldwide. IDUs may transmit HIV not only by needle-sharing but also by unprotected sexual intercourse. Likewise, they may expose themselves to HIV through high-risk sexual behavior. In this context, IDUs may exchange sex for drugs or money to support their drug use. An important concern is the reports of increased sexual risk-taking among HIVinfected individuals, in particular among IDUs receiving HAART. Nonetheless, only a few prospective studies have investigated risk behavior for HIV transmission among IDUs. Active IDUs may not have the same access to antiretroviral therapy as do HIVinfected individuals from other risk groups, may seek less medical advice, and

A retrospective analysis of hospitalizations due to infection in 175 injection drug users was performed for the 3 years before and the period during their participation in an injection opiate maintenance program (mean duration during program, 2.6 years). Skin infections were the main reason for hospitalization. The injection opiate maintenance program did not reduce the incidence of infection leading to hospitalization among the injection drug users studied.