The dolutegravir/valproic acid drug-drug interaction is primarily based on protein displacement.

OBJECTIVES: The dolutegravir/valproic acid drug-drug interaction (DDI) is suggested to be caused by protein displacement. Here, we assess the underlying mechanism. METHODS: Participants in a randomized controlled trial investigating valproic acid as an HIV latency reversing agent were recruited in a predefined pharmacokinetic substudy if they were on once-daily 50 mg dolutegravir-containing combination ART (cART) for >12 months with a plasma HIV-RNA <50 copies/mL (trial registration: ClinicalTrials.gov NCT03525730). Participants were randomized to receive 30 mg/kg/day valproic acid orally (divided into two equal doses) for 14 days or not. Total and unbound dolutegravir concentrations were measured on day 0 (before intake of valproic acid and 6 h after intake of valproic acid) and on days 1, 7, 14 and 42. Intra- and inter-subject dolutegravir concentrations and geometric means (GMs) were evaluated. RESULTS: Six of 10 participants on dolutegravir were randomized to receive valproic acid. During 14 days of valproic acid treatment, the GM total dolutegravir concentration decreased sharply from 1.36 mg/L on day 0 to 0.85, 0.31 and 0.20 mg/L on days 0, 1, 7 and 14, respectively, while total dolutegravir concentrations in the controls remained comparable during the same period: 1.27-1.49 mg/L. We observed a parallel increase in unbound dolutegravir fractions ranging from 0.39% to 0.58% during valproic acid administration, compared with 0.25% to 0.28% without valproic acid. Unbound dolutegravir concentrations were above the established in vitro EC90 value for unbound dolutegravir in 85% of the tested samples. CONCLUSIONS: This study confirms protein displacement as the main mechanism for this DDI, although additional mechanisms might be involved too. If dolutegravir is taken with food, this DDI is probably not clinically relevant.

Fendrix® compared to Engerix® in HIV-infected patients nonresponding to initial- and re-vaccination schedule.

BACKGROUND: In HIV-infected patients, the immunogenicity of hepatitis B vaccines is impaired. In this randomised controlled study (RCT), we investigated the effect of Fendrix® versus double-dose Engerix® vaccination in previously non-responsive HIV-infected subjects. METHODS: Patients included those who were HIV-infected and non-responders to a primary (single-dose hepatitis B (HBV) vaccination) and a subsequent double-dose HBV revaccination schedule. Subjects were randomised 1:1 to receive Fendrix® (t = 0, 4, 8, 24 weeks) or double-dose Engerix® (t = 0, 4, 24 weeks) vaccinations. Primary efficacy, defined as anti-HBs response ≥ 10 IU/l, was evaluated at week 28 in both study arms. RESULTS: A subset of 48 patients non-responsive to HBV vaccination was selected, from a cohort of patients at our institution, who underwent HBV vaccination unsuccessfully either in a previous RCT or through standard care. The anti-HBs ≥ 10 IU/l response rate at week 28 in the Fendrix® arm and the Engerix® arm were 85.7% and 65.0%, respectively (p = 0.09). There was no significant difference between the two used vaccine types in the anti-HBs levels reached. In our institution, the overall response rate after initial standard-dose vaccination schedule and double-dose revaccination in our cohort was 75%. In this study, combining the effects of Fendrix and Engerix resulted in a 75% response rate in the 25% remaining non-responders on initial and double-dose revaccination series. This yielded an absolute 19% increase and an overall response to HBV vaccination in HIV-infected patients of around 94% in our cohort. CONCLUSION: These results together, suggest that continuing HBV vaccination in non-responders to a first course of single-dose vaccine and a double-dose revaccination scheme is worth the effort. No superiority of one of the investigated hepatitis B vaccines was shown in this cohort but an appropriate number of patients needed to achieve reliable answers was not achieved.

Non-targeted HIV screening in emergency departments in the Netherlands.

BACKGROUND: In the Netherlands a substantial proportion of newly diagnosed human immunodeficiency virus (HIV) patients present late for care and an estimated 12-34% of people living with HIV are undiagnosed. Linkage to care of these patients is important to decrease HIV transmission and to improve individual patient outcomes. We investigated if non-targeted HIV testing in emergency departments is a useful and cost-effective way to identify these patients. METHODS: In a cross-sectional multicentre study, eligible adult patients who underwent phlebotomy were given an active choice to be additionally tested for HIV. In a subset of patients, risk factors for HIV infection were asked for. A cost-effectiveness analysis was conducted. RESULTS: Of 7577 eligible patients, 3223 patients were tested, and two new HIV infections were diagnosed (0.06%). Both patients had risk factors for HIV infection. Non-targeted HIV testing in the emergency department was not considered cost-effective, with a cost per quality adjusted life years gained of € 77,050, more than triple the Dutch cost-effectiveness threshold of € 20,000. CONCLUSION: Non-targeted HIV testing in emergency departments in the Netherlands had a low yield of newly diagnosed HIV infections and was not cost-effective. Our data suggest that targeted HIV testing may offer an alternative approach to decrease the number of undiagnosed people living with HIV.

Wild type and YMDD variant of hepatitis B virus: no difference in viral kinetics on lamivudine/tenofovir therapy in HIV-HBV co-infected patients.

Prolonged lamivudine therapy has been identified as the major risk for the development of resistance in HBV, with rates of 90% after 4 years of treatment. Tenofovir disoproxil fumarate showed activity against both wild type and lamivudine resistant HBV in HIV-HBV co-infected patients. In order to compare the efficacy of lamivudine/tenofovir treatment we investigated detailed HBV kinetics in 13 HIV-HBV co-infected patients with either wild type HBV or lamivudine resistant HBV. The viral strains in both patient groups showed a biphasic viral decline pattern. Only in the first phase of viral decay, which reflects the clearance rate of the free virus from plasma, there was a statistically significant response in favor of the wild type group. After the first phase we observed a similar viral decline till 24 weeks of both groups. This is reassuring for many pretreated co-infected patients harbouring mutant viruses.

[Severe hypokalemia with paralysis in a patient with distal renal tubular acidosis as an initial expression of Sjögren's syndrome]. / Ernstige hypokaliëmie met paralyse bij een patiënte met een distale renale tubulaire acidose als eerste uiting van het syndroom van Sjögren.

In a 33-year-old woman with a recent flaccid paralysis of the arms and legs, laboratory tests demonstrated a severe hypokalemia with hyperchloremic metabolic acidosis and abnormally acidified urine. The urinary anion gap was positive in the presence of acidosis, thus establishing the diagnosis of distal renal tubular acidosis. The patient made a full recovery after potassium and alkali replacement. Further investigation revealed Sjögren's syndrome as the underlying cause.