Dynamics of Low-Level Viremia and Immune Activation after Switching to a Darunavir-Based Regimen

There is an ongoing debate regarding whether low-level viremia (LLV), in particular persistent LLV, during HIV treatment with optimal adherence originates from low-level viral replication, viral production, or both. We performed an observational study in 30 individuals with LLV who switched to a boosted darunavir (DRV)-based therapy. In-depth virological analyses were used to characterize the viral population and the (activity) of the viral reservoir. Immune activation was examined using cell-bound and soluble markers. The primary outcome was defined as the effect on HIV-RNA and was categorized by responders (50 cp/mL). At week 24, 53% of the individuals were considered responders, 40% non-responders, and 7% could not be assigned. Sequencing showed no evolution or selection of drug resistance in the non-responders. Production of defective virus with mutations in either the protease (D25N) or RT active site contributed to persistent LLV in two individuals. We show that in about half of the study participants, the switch to a DRV-based regimen resulted in a viral response indicative of ongoing low-level viral replication as the cause of LLV before the switch. Our data confirm that in clinical management, high genetic barrier drugs like DRV are a safe choice, irrespective of the source of LLV

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 &gt;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.</p

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 &gt;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.</p

Chronic Q Fever Diagnosis—Consensus Guideline versus Expert Opinion

Chronic Q fever, caused by Coxiella burnetii, has high mortality and morbidity rates if left untreated. Controversy about the diagnosis of this complex disease has emerged recently. We applied the guideline from the Dutch Q Fever Consensus Group and a set of diagnostic criteria proposed by Didier Raoult to all 284 chronic Q fever patients included in the Dutch National Chronic Q Fever Database during 2006–2012. Of the patients who had proven cases of chronic Q fever by the Dutch guideline, 46 (30.5%) would not have received a diagnosis by the alternative criteria designed by Raoult, and 14 (4.9%) would have been considered to have possible chronic Q fever. Six patients with proven chronic Q fever died of related causes. Until results from future studies are available, by which current guidelines can be modified, we believe that the Dutch literature-based consensus guideline is more sensitive and easier to use in clinical practice

The value of 18F-FDG PET/CT in diagnosis and during follow-up in 273 patients with chronic Q fever

In 1%–5% of all acute Q fever infections, chronic Q fever develops, mostly manifesting as endocarditis, infected aneurysms, or infected vascular prostheses. In this study, we investigated the diagnostic value of 18F-FDG PET/CT in chronic Q fever at diagnosis and during follow-up. Methods: All adult Dutch patients suspected of chronic Q fever who were diagnosed since 2007 were retrospectively included until March 2015, when at least one 18F-FDG PET/CT scan was obtained. Clinical data and results from 18F-FDG PET/CT at diagnosis and during follow-up were collected. 18F-FDG PET/CT scans were prospectively reevaluated by 3 nuclear medicine physicians using a structured scoring system. Results: In total, 273 patients with possible, probable, or proven chronic Q fever were included. Of all 18F-FDG PET/CT scans performed at diagnosis, 13.5% led to a change in diagnosis. Q fever–related mortality rate in patients with and without vascular infection based on 18F-FDG PET/CT was 23.8% and 2.1%, respectively (P 5 0.001). When 18F-FDG PET/CT was added as a major criterion to the modified Duke criteria, 17 patients (1.9-fold increase) had definite endocarditis. At diagnosis, 19.6% of 18F-FDG PET/CT scans led to treatment modification. During follow-up, 57.3% of 18F-FDG PET/CT scans resulted in treatment modification. Conclusion: 18F-FDG PET/CT is a valuable technique in diagnosis of chronic Q fever and during follow-up, often leading to a change in diagnosis or treatment modification and providing important prognostic information on patient survival