Dolutegravir/Lamivudine Is Noninferior to Continuing Dolutegravir- and Non-Dolutegravir-Based Triple-Drug Antiretroviral Therapy in Virologically Suppressed People With Human Immunodeficiency Virus: DUALING Prospective Nationwide Matched Cohort Study.

Background: Confirming the efficacy of dolutegravir/lamivudine in clinical practice solidifies recommendations on its use. Methods: Prospective cohort study (DUALING) in 24 human immunodeficiency virus (HIV) treatment centers in the Netherlands. HIV RNA-suppressed cases were on triple-drug antiretroviral regimens without prior virological failure or resistance and started dolutegravir/lamivudine. Cases were 1:2 matched to controls on triple-drug antiretroviral regimens by the use of dolutegravir-based regimens, age, sex, transmission route, CD4+ T-cell nadir, and HIV RNA zenith. The primary endpoint was the treatment failure rate in cases versus controls at 1 year by intention-to-treat and on-treatment analyses with 5% noninferiority margin. Results: The 2040 participants were 680 cases and 1380 controls. Treatment failure in the 390 dolutegravir-based cases versus controls occurred in 8.72% and 12.50% (difference: -3.78% [95% confidence interval {CI}, -7.49% to .08%]) by intention-to-treat and 1.39% and 0.80% (difference: 0.59% [95% CI, -.80% to 1.98%]) by on-treatment analyses. The treatment failure risk in 290 non-dolutegravir-based cases was also noninferior to controls. Antiretroviral regimen modifications unrelated to virological failure explained the higher treatment failure rate by intention-to-treat. A shorter time on triple-drug antiretroviral therapy and being of non-Western origin was associated with treatment failure. Treatment failure, defined as 2 consecutive HIV RNA >50 copies/mL, occurred in 4 cases and 5 controls but without genotypic resistance detected. Viral blips occured comparable in cases and controls but cases gained more weight, especially when tenofovir-based regimens were discontinued. Conclusions: In routine care, dolutegravir/lamivudine was noninferior to continuing triple-drug antiretroviral regimens after 1 year, supporting the use of dolutegravir/lamivudine in clinical practice. Clinical Trials Registration: NCT04707326.

Switching to Doravirine in cART-Experienced Patients: An Effective and Highly Tolerated Option With Substantial Cost Savings.

BACKGROUND: Doravirine is a non-nucleoside reverse transcriptase inhibitor with demonstrated efficacy as a third agent in treatment-naive and treatment-experienced people living with HIV (PLWH) in registration studies. However, limited real-world data are available. METHODS: By searching electronic health care records, PLWH using doravirine-based regimens were selected with at least 1 year of follow-up after their first prescription. All stable PLWH who were switched to a doravirine-based regimen were included in the analysis. The primary outcome was the durability of a doravirine-based regimen 1 year after prescription. Reasons for stopping were also collected. Secondary outcomes for PLWH continuing a doravirine-based regimen after 1 year were routine laboratory assessment, body mass index, and differences in medication costs compared with their previous cART. RESULTS: A total of 687 patients (92% men) were included from September 2019 to August 2022: 97.7% switched to doravirine/tenofovir/lamivudine (DOR/TDF/3TC). After 1 year, 94/687 (13.6%) PLWH stopped this therapy. The main reason for discontinuation was patient-reported adverse events in 70/687 (10.2%). Medical reasons for discontinuation included increased alanine tranaminase levels in 6/687 (0.9%), decreased estimated glomerular filtration rate in 3/687 (0.4%), and precautions after diagnosis of osteoporosis in 2/687 (0.3%) patients. Virologic failure occurred in 4/687 cases (0.6%), and 1 case demonstrated resistance mutations. The secondary outcomes demonstrated a statistically significant increase in alanine tranaminase levels and decrease in LDL-c levels. The switch to a doravirine-based regimen in the Netherlands reduced medication costs by 27%. CONCLUSIONS: This study demonstrated that switching to a doravirine-based regimen, mostly DOR/TDF/3TC, was highly effective and generally well tolerated, with substantial cost savings.

[Peritoneal tuberculosis in a postmenopausal woman with progressive ascites]. / Peritoneale tuberculose.

BACKGROUND: The non-specific symptomatology in peritoneal tuberculosis often results in a delay in the diagnosis. Due to clinical overlap symptoms may be confused with metastatic ovarian carcinoma. This can lead to delayed treatment, unnecessary surgical interventions and a deteriorated prognosis. CASE DESCRIPTION: A 75-year-old female of Moroccan descent was referred to the gastroenterology department with increasing ascites and weight loss. Based on the clinical picture metastatic ovarian cancer was suspected. However, repeatedly no malignant cells were found in both ascitic fluid and tissue biopsies. Peritoneal tuberculosis was considered and ovarian malignancy could not be excluded. A diagnostic laparoscopyand biopsy was considered necessary. The laparoscopic view was pathognomic for tuberculosis after which antituberculosis treatment was started with good result. CONCLUSION: Peritoneal tuberculosis should be included in the differential diagnosis in women from endemic areas with symptoms of abdominal pain, ascites, weight loss and/or increased CA-125. Laparoscopy should be considered if less invasive tests are inconclusive about the diagnosis.

Role of Self-Stigma in Pathways from HIV-Related Stigma to Quality of Life Among People Living with HIV.

This study examined the relationships between perceived public stigma, experienced stigma, and quality of life in people living with HIV (PLHIV), and whether self-stigma mediates these relationships. Cross-sectional data were analyzed from 1704 PLHIV in care at OLVG hospital in the Netherlands. We measured different types of stigma (perceived public stigma, experienced stigma, and self-stigma), and various quality-of-life outcomes (disclosure concerns, depression, anxiety, sexual problems, sleeping difficulties, self-esteem, general health, and social support). Structural equation modeling was used to test the paths from different types of stigma to quality-of-life outcomes. All direct effects of self-stigma on quality-of-life outcomes were significant. The final mediation model showed that the effects of both perceived public and experienced stigma on quality-of-life outcomes were mediated by self-stigma. These findings highlight the importance of addressing self-stigma in PLHIV, and call for (psychosocial) interventions that reduce the harmful effects of HIV-related stigma.

Evaluation of the Hepatitis C Testing Strategy for Human Immunodeficiency Virus-Positive Men Who Have Sex With Men at the Sexually Transmitted Infections Outpatient Clinic of Amsterdam, the Netherlands.

INTRODUCTION: As the incidence of hepatitis C virus (HCV) infections remains high among human immunodeficiency virus (HIV)-positive men who have sex with men (MSM) an HCV testing strategy was introduced at the sexually transmitted infections (STI) clinic in Amsterdam in 2017. We aimed to evaluate this HCV testing strategy. METHODS: The HIV-positive MSM and transgender women (TGW) were eligible for HCV testing (anti-HCV and HCV ribonucleic acid) at the STI clinic if they did not visit their HIV clinician in the 3 months before the consultation and had not been tested for HCV at the STI clinic in the previous 6 months. All eligible individuals were administered the 6 questions on risk behavior of the HCV-MSM observational study of acute infection with hepatitis C (MOSAIC) risk score; a risk score of 2 or greater made a person eligible for testing. RESULTS: From February 2017 through June 2018, 1015 HIV-positive MSM and TGW were eligible for HCV testing in 1295 consultations. Eleven active HCV infections (HCV ribonucleic acid positive) were newly diagnosed (positivity rate, 0.9%; 95% confidence interval [CI], 0.4-1.5%). Sensitivity and specificity of the HCV-MOSAIC score for newly diagnosed active HCV infections were 80.0% (95% CI, 49.0-94.3%) and 53.7% (95% CI, 50.8-56.5%), respectively. If an HCV-MOSAIC score of 2 or greater were used to determine whom to test, 46.6% of individuals currently tested for HCV would be eligible for testing. CONCLUSIONS: Using the new HCV testing strategy, HCV testing was done in 1295 consultations with HIV-positive MSM and TGW in 17 months. We newly diagnosed 11 active HCV infections. The HCV-MOSAIC risk score could reduce the number of tests needed, but some active HCV infections will be missed.

Host Cell Deoxyribonucleic Acid Methylation Markers for the Detection of High-grade Anal Intraepithelial Neoplasia and Anal Cancer.

BACKGROUND: High-grade anal intraepithelial neoplasia (AIN2/3; HGAIN) is highly prevalent in human immunodeficiency virus positive (HIV+) men who have sex with men (MSM), but only a minority will eventually progress to cancer. Currently, the cancer risk cannot be established, and therefore all HGAIN is treated, resulting in overtreatment. We assessed host cell deoxyribonucleic acid (DNA) methylation markers for detecting HGAIN and anal cancer. METHODS: Tissue samples of HIV+ men with anal cancer (n = 26), AIN3 (n = 24), AIN2 (n = 42), AIN1 (n = 22) and HIV+ male controls (n = 34) were analyzed for methylation of 9 genes using quantitative methylation-specific polymerase chain reaction. Univariable and least absolute shrinkage and selection operator logistic regression, followed by leave-one-out cross-validation, were used to determine the performance for AIN3 and cancer detection. RESULTS: Methylation of all genes increased significantly with increasing severity of disease (P < 2 × 10-6). HGAIN samples revealed heterogeneous methylation patterns, with a subset resembling cancer. Four genes (ASCL1, SST, ZIC1,ZNF582) showed remarkable performance for AIN3 and anal cancer detection (area under the curve [AUC] > 0.85). ZNF582 (AUC = 0.89), detected all cancers and 54% of AIN3 at 93% specificity. Slightly better performance (AUC = 0.90) was obtained using a 5-marker panel. CONCLUSIONS: DNA methylation is associated with anal carcinogenesis. A marker panel that includes ZNF582 identifies anal cancer and HGAIN with a cancer-like methylation pattern, warrantingvalidation studies to verify its potential for screening and management of HIV+ MSM at risk for anal cancer.

The effect of switching protease inhibitors to raltegravir on endothelial function, in HIV-infected patients.

Objective Lipid management is one of the cornerstones of cardiovascular risk reduction. Treatment of HIV infection with protease inhibitors (PIs) may cause dyslipidaemia, whilst the integrase inhibitor raltegravir (RAL) has a relatively favorable effect on plasma lipids. We examined the effect of switching from PIs to RAL on endothelial function, and its effect on immunological and inflammatory parameters. Methods We performed a 16-week open-label prospective crossover study: 8 weeks intervention (switch PIs to RAL) and 8 weeks control (unchanged cART regimen). Flow-mediated dilatation (FMD), inflammatory plasma, and cellular markers of immune activation were measured at weeks 0, 8, and 16. Results Study participants (n = 22) with a median age of 50 years (IQR 42-60) and known HIV infection of 6.5 years (IQR 5.0-17.3) were on stable cART with undetectable HIV viral loads. After 8 weeks of RAL therapy, a reduction in FMD of -0.81% was seen, compared to +0.54% control (pairwise, p = 0.051), while fasting total cholesterol (-17% versus +10%; p < 0.001), LDL cholesterol (-21% versus -3%; p = 0.026), and triglycerides (-41% versus +18%; p = 0.001) significantly decreased during RAL therapy compared to the control. Furthermore, a relation between the change in percentage of B-1 cells and the change in FMD was found (ß 0.40, 95%CI 0.16; 0.64, p = 0.005) during treatment with RAL. Finally, during RAL therapy, 27% of the patients experienced an increased ALT rise. Conclusions We present an overall negative study, where switching from PIs to RAL slightly reduced the endothelial function while decreasing plasma lipids, thus possibly decreasing the CVD risk in the long term. A transient elevation of ALT was seen upon switch to RAL.

Intolerance of dolutegravir-containing combination antiretroviral therapy regimens in real-life clinical practice.

OBJECTIVE: Dolutegravir (DGV) is one of the preferred antiretroviral agents in first-line combination antiretroviral therapy (cART). Though considered to be a well tolerated drug, we aimed to determine the actual rate, timing and detailed motivation of stopping DGV in a real-life clinical setting. DESIGN: A cohort study including all patients who started DGV in two HIV treatment centers in The Netherlands. METHODS: All cART-naïve and cART-experienced patients who had started DGV were identified from the institutional HIV databases. Clinical data, including motivation and timing of discontinuation of DGV, were extracted from the patient files. Factors that potentially influenced discontinuation of DGV were compared between patients who stopped or continued DGV by multivariate and Kaplan-Meier analyses. RESULTS: In total, 556 patients were included, of whom 102 (18.4%) were cART-naïve at initiation of DGV. Median follow-up time was 225 days. Overall, in 85 patients (15.3%), DGV was stopped. In 76 patients (13.7%), this was due to intolerability. Insomnia and sleep disturbance (5.6%), gastrointestinal complaints (4.3%) and neuropsychiatric symptoms such as anxiety, psychosis and depression (4.3%) were the predominant reasons for switching DGV. In regimens that included abacavir, DGV was switched more frequently (adjusted relative risk 1.92, 95% confidence interval 1.09-3.38, P log-rank 0.01). No virologic failures were observed. CONCLUSION: A relatively high rate of preliminary discontinuation of DGV due to intolerability was detected in our patient population. In particular, DGV was stopped more frequently if the regimen included abacavir. Multiple factors may explain these unexpected postmarketing observations, which warrant further investigation.

The Effect of Rosuvastatin on Markers of Immune Activation in Treatment-Naive Human Immunodeficiency Virus-Patients.

Background. Immune activation has been implicated in the excess mortality in human immunodeficiency virus (HIV)-infected patients, due to cardiovascular diseases and malignancies. Statins may modulate this immune activation. We assessed the capacity of rosuvastatin to mitigate immune activation in treatment-naive HIV-infected patients. Methods. In a randomized double-blind placebo-controlled crossover study, we explored the effects of 8 weeks of rosuvastatin 20 mg in treatment-naive male HIV-infected patients (n = 28) on immune activation markers: neopterin, soluble Toll-like receptor (TLR)2, sTLR4, interleukin (IL)-6, IL-1Ra, IL-18, d-dimer, highly sensitive C-reactive protein, and CD38 and/or human leukocyte antigen-DR expression on T cells. Baseline data were compared with healthy male controls (n = 10). Furthermore, the effects of rosuvastatin on HIV-1 RNA, CD4/CD8 T-cell count, and low-density lipoprotein cholesterol were examined and side effects were registered. Results. T-cell activation levels were higher in patients than in controls. Patients had higher levels of circulating IL-18, sTLR2, and neopterin (all P < .01). Twenty patients completed the study. Rosuvastatin increased the CD4/CD8 T-cell ratio (P = .02). No effect on other markers was found. Conclusions. Patients infected with HIV had higher levels of circulating neopterin, IL-18, sTLR2, and T-cell activation markers. Rosuvastatin had a small but significant positive effect on CD4/CD8 T-cell ratio, but no influence on other markers of T-cell activation and innate immunity was identified (The Netherlands National Trial Register [NTR] NTR 2349, http://www.trialregister.nl/trialreg/index.asp).

Boceprevir, peginterferon and ribavirin for acute hepatitis C in HIV infected patients.

BACKGROUND & AIMS: Acute hepatitis C virus infections (AHCV) are prevalent among HIV positive men having sex with men and generally treated with pegylated interferon-alpha (PegIFN) and ribavirin (RBV) during 24weeks. The addition of a protease inhibitor could shorten therapy without loss of efficacy. METHODS: We performed an open-label, single arm study to investigate the efficacy and safety of a 12-week course of boceprevir, PegIFN and RBV for AHCV genotype 1 infections in 10 Dutch HIV treatment centers. The primary endpoint of the study was achievement of sustained virological response rate at week 12 (SVR12) in patients reaching a rapid viral response at week 4 (RVR4) and SVR12 in the intent to treat (ITT) entire study population was the most relevant secondary endpoint. RESULTS: One hundred twenty-seven AHCV patients were screened in 16 months, of which 65 AHCV genotype 1 patients were included. After spontaneous clearance in six patients and withdrawal before treatment initiation in two, 57 started therapy within 26 weeks after infection. RVR4 rate was 72%. SVR12 rate was 100% in the RVR4 group. SVR12 rate in the ITT group was 86% and comparable to the SVR12 rate of 84% in 73 historical controls treated for 24 weeks with PegIFN and RBV in the same study centers. CONCLUSION: With the addition of boceprevir to PegIFN and RBV, treatment duration of AHCV genotype 1 can be reduced to 12 weeks without loss of efficacy. Given the high drug costs and limited availability of interferon-free regimens, boceprevir PegIFN and RBV can be a considered a valid treatment option for AHCV. ClinicalTrials.gov, number NCT01912495.

Protective effect of hepatitis B virus-active antiretroviral therapy against primary hepatitis B virus infection.

OBJECTIVE: Current guidelines advise to vaccinate every hepatitis B virus (HBV)-susceptible HIV patient against HBV until sufficient antibody titers have been reached. However, in this era of combination antiretroviral therapy (cART), acute HBV infection rarely occurs in patients who lack this immune protection. We analyzed whether HBV-active cART (lamivudine, emtricitabine, tenofovir) might work as a preexposure prophylaxis (PrEP) to explain this effect. METHODS: From our HIV cohort at the Onze Lieve Vrouwe Gasthuis hospital (N=2942), patients were selected retrospectively for negative HBV serology (HBsAg, anti-HBs and anti-HBc-negative) at cohort entry. Men who have sex with men (MSM) with a second HBV serology available were included for analysis. The incidence of anti-HBc conversion was determined and correlated with the use of HBV-active drugs. Kaplan-Meier curves and log-rank tests were used to compare HBV-free survival for MSM. RESULTS: In total, 33 HBV infections occurred in 381 eligible MSM over a median follow-up of 2470 days (interquartile range 1146-3871.5). The incident rate per 100 patient-years of follow-up was 1.10 overall, but differed strongly dependent on the use of HBV-active drugs: 2.85/100 patient-years of follow-up in the absence of HBV-active drugs, 1.36 when only lamivudine was used, and 0.14 in the presence of tenofovir. Furthermore, HBV-free survival rate was significantly higher when HBV-active cART was used, in particular when this HBV-active cART contained tenofovir (log-rank P<0.001). CONCLUSION: Our findings demonstrate that HBV-active cART protects against the occurrence of de-novo HBV infection, most strongly when tenofovir is used.

Hookworm with hypereosinophilia: atypical presentation of a typical disease.

We describe a 55-year-old man returning from the Philippines infected with a hookworm, the novel bacterium Laribacter hongkongensis, and a Blastocystis hominis and presenting with both gastrointestinal and neurological symptoms. The high eosinophilia caused by the hookworm infection resulted in both gastrointestinal and neurological symptoms, resembling a hypereosinophilic syndrome.

Interaction between antiretroviral drugs and acenocoumarol.

The authors report a case of an HIV type-1-infected patient concomitantly using highly active antiretroviral therapy and acenocoumarol anticoagulant for secondary prevention of recurrent venous thromboembolism. This is the first report of a possible drug interaction between efavirenz and atazanavir/ritonavir with acenocoumarol and also of the uncomplicated concurrent use of raltegravir with acenocoumarol.

A fatal pseudo-tumour: disseminated basidiobolomycosis.

BACKGROUND: Basidiobolomycosis is a rare disease caused by the fungus Basidiobolus ranarum, member of the class Zygomycetes, order Entomophthorales, found worldwide. Usually basidiobolomycosis is a subcutaneous infection but rarely gastrointestinal manifestations have been described; 13 adults and 10 children and a few retroperitoneal or pulmonary cases. In gastrointestinal basidiobolomycosis the colon is most frequently involved, usually presenting with subacute mild abdominal pain. In contrast to children only very few described adult patients had hepatic masses. Definitive diagnosis requires culture, serological testing can be helpful. The fungal morphology and the Splendore-Hoeppli phenomenon are characteristic histological features. There are no prominent risk factors. Usually surgery and prolonged antifungal therapy are required. CASE PRESENTATION: A 61 year old man presented with progressive left abdominal pain and constipation since a few months. Colonoscopy showed an obstructing tumour in the descending colon, and a hemicolectomy was performed. Histology showed inflammation, possibly caused by a fungal or parasitic infection, without definite identification of an organism. A few weeks postoperatively a CT scan made because of abdominal discomfort, revealed a livermass (6 cm). Treatment with metronidazole, directed against an amoebic liver abscess, was unsuccessful. He developed a marked eosinophilia (27.7%). A liver biopsy was performed and the patient was referred to a university hospital.A repeated CT scan showed a livermass of 9 cm diameter. Review of colon and liver biopsy samples showed extensive necrosis and histiocytes, multinucleated giant cells and numerous eosinophils. Grocott stained sections contained unusually large hyphae surrounded by strongly eosinophilic material in haematoxylin and eosin stained sections (Splendore-Hoeppli phenomenon). A presumptive diagnosis of Basidiobolus spp. infection was made and treated with amphotericin B (Itraconazol contra-indicated because of renal insufficiency). A few days later the patient died of a septic shock. After autopsy Basidiobolus ranarum was cultured from liver, gallbladder and colon. CONCLUSION: Our patient died of gastrointestinal basidiobolomycosis with an obstructing colon tumour and a large hepatic mass. This was a rare presentation of basidiobolomycosis and the second fatal case described worldwide.

Effectiveness of discontinuing antibiotic treatment after three days versus eight days in mild to moderate-severe community acquired pneumonia: randomised, double blind study.

OBJECTIVE: To compare the effectiveness of discontinuing treatment with amoxicillin after three days or eight days in adults admitted to hospital with mild to moderate-severe community acquired pneumonia who substantially improved after an initial three days' treatment. DESIGN: Randomised, double blind, placebo controlled non-inferiority trial. SETTING: Nine secondary and tertiary care hospitals in the Netherlands. PARTICIPANTS: Adults with mild to moderate-severe community acquired pneumonia (pneumonia severity index score < or = 110). INTERVENTIONS: Patients who had substantially improved after three days' treatment with intravenous amoxicillin were randomly assigned to oral amoxicillin (n = 63) or placebo (n = 56) three times daily for five days. MAIN OUTCOME MEASURES: The primary outcome measure was the clinical success rate at day 10. Secondary outcome measures were the clinical success rate at day 28, symptom resolution, radiological success rates at days 10 and 28, and adverse events. RESULTS: Baseline characteristics were comparable, with the exception of symptom severity, which was worse in the three day treatment group. In the three day and eight day treatment groups the clinical success rate at day 10 was 93% for both (difference 0.1%, 95% confidence interval--9% to 10%) and at day 28 was 90% compared with 88% (difference 2.0%,--9% to 15%). Both groups had similar resolution of symptoms. Radiological success rates were 86% compared with 83% at day 10 (difference 3%,--10% to 16%) and 86% compared with 79% at day 28 (difference 6%,--7% to 20%). Six patients (11%) in the placebo group and 13 patients (21%) in the active treatment group reported adverse events (P = 0.1). CONCLUSIONS: Discontinuing amoxicillin treatment after three days is not inferior to discontinuing it after eight days in adults admitted to hospital with mild to moderate-severe community acquired pneumonia who substantially improved after an initial three days' treatment.