Long-term data on the efficacy and tolerability of lamivudine plus dolutegravir as a switch strategy in a multi-centre cohort of HIV-1-infected, virologically suppressed patients

BACKGROUND: Results from clinical trials and observational studies suggest that lamivudine plus dolutegravir (3TC+DTG) could be an effective and tolerated option for simplification in human immunodeficiency virus (HIV)-1-positive patients. MATERIALS AND METHODS: This observational study enrolled HIV-1-infected, virologically suppressed patients switching to 3TC+DTG. Kaplan-Meyer survival analysis was performed to evaluate time to virological failure (VF; defined by a single HIV-RNA determination ≥1000 copies/mL or by two consecutive HIV-RNA determinations ≥50 copies/mL) and time to treatment discontinuation (TD; defined as interruption of either 3TC or DTG), Cox regression was performed to assess predictors, and linear mixed model was performed for repeated measures to measure changes in immunological and metabolic parameters. RESULTS: Five hundred and fifty-six patients were eligible for analysis. Their median CD4+ count at baseline was 668 cells/mm3 and median time of virological suppression was 88 months. Estimated probabilities of maintaining virological suppression at 96 and 144 weeks of follow-up were 97.5% [standard deviation (SD) 0.8] and 96.5% (SD 1.0), respectively. Years since HIV diagnosis was the only predictor of VF. In patients with time of virological suppression <88 months, the rate of VF was higher in the presence of the M184V mutation. Estimated probabilities of remaining on 3TC+DTG at 96 and 144 weeks of follow-up were 79.2% (SD 1.9) and 75.2% (SD 2.2), respectively. A significant increase in CD4 cell count (+44 cells/mm3, P=0.015), CD4/CD8 ratio (+0.10, P=0.002) and high-density lipoprotein cholesterol (+5.4 mg/dL, P=0.036) was found at 144 weeks of follow-up; meanwhile, total cholesterol (-9.1 mg/dL, P=0.007) and triglycerides (-2.7, P=0.009) decreased significantly. CONCLUSIONS: These findings confirm the efficacy and tolerability of 3TC+DTG in virologically suppressed patients. Copyright © 2019 Elsevier Ltd. All rights reserved

A multicenter multinational study of abdominal candidiasis: epidemiology, outcomes and predictors of mortality

Abstract Purpose: Clinical data on patients with intra-abdominal candidiasis (IAC) is still scarce. Methods: We collected data from 13 hospitals in Italy, Spain, Brazil, and Greece over a 3-year period (2011\u20132013) including patients from ICU, medical, and surgical wards. Results: A total of 481 patients were included in the study. Of these, 27 % were hospitalized in ICU. Mean age was 63 years and 57 % of patients were male. IAC mainly consisted of secondary peritonitis (41 %) and abdominal abscesses (30 %); 68 (14 %) cases were also candidemic and 331 (69 %) hadconcomitant bacterial infections. The most commonly isolated Candida species were C. albicans (n = 308 isolates, 64 %) and C. glabrata (n = 76, 16 %). Antifungal treatment included echinocandins (64 %), azoles (32 %), and amphotericin B (4 %). Septic shock was documented in 40.5 % of patients. Overall 30-day hospital mortality was 27 % with 38.9 % mortality in ICU. Multivariate logistic regression showed that age (OR 1.05, 95 % CI 1.03\u20131.07, P\0.001), increments in 1-point APACHE II scores (OR 1.05, 95 % CI 1.01\u20131.08, P = 0.028), secondary peritonitis (OR 1.72, 95 % CI 1.02\u20132.89, P = 0.019), septic shock (OR 3.29, 95 % CI 1.88\u20135.86, P\0.001), and absence of adequate abdominal source control (OR 3.35, 95 % CI 2.01\u20135.63, P\0.001) wereassociated with mortality. In patients with septic shock, absence of source control correlated with mortality rates above 60 % irrespective of administration of an adequate antifungal therapy. Conclusions: Low percentages of concomitant candidemia and high mortality rates are documented in IAC. In patients presenting with septic shock, source control is fundamental

Virological efficacy of dual therapy with lamivudine and dolutegravir in HIV-1-infected virologically suppressed patients: long-term data from clinical practice

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HIV DNA Decay in a Treatment-Naive Patient Starting Dolutegravir Plus Lamivudine with Resistance Mutations to Integrase Inhibitors: A Case Report

Editor: Recent data from clinical trials highlight the efficacy of a two-drug strategy with lamivudine (3TC) plus dolutegravir (DTG) as first-line regimen in treatment-naive HIV-infected people living with HIV (PLWH).1 PLWH with transmitted resistance mutations, however, were not included in the two GEMINI trials and thus no data are available on the efficacy of such regimens in PLWH with primary resistances. In a recently published report,2 we described our initial experience in a small cohort of treatment-naive PLWH starting 3TC plus DTG in clinical practice. We would like to further analyze the case of a 23-year-old subject with Y188C and D232N resistance mutations starting 3TC+DTG. The D232N mutation, in particular, is a nonpolymorphic mutation selected in patients previously exposed to raltegravir3 and has been related to potential resistance to first-generation integrase inhibitors (INIs) raltegravir and elvitegravir. The subject was diagnosed with HIV infection in March 2019, with a peak HIV RNA value of 114,866 copies/mL and a nadir CD4+ cell count of 328 cell/mm3. Genotypic test was also performed, showing the mentioned resistance mutations. He subsequently started the two-drug regimen with a rapid decline in HIV RNA, reaching 48 copies/mL after 3 weeks from treatment initiation. His HIV RNA load became undetectable after 8 weeks and as of today, after 24 weeks, it is still undetectable. We also observed a steady improvement in immunological parameters; after 24 weeks his CD4+ cell count was 1,091 cell/mm3. Given the presence of the transmitted resistances, we further investigated the subject's virological status by evaluating total HIV-1 DNA levels, a marker of low-grade inflammation and viral reservoir dynamics.4 In our patient, baseline HIV-1 DNA quantification was 3.00 log10 copies/106 leukocytes. Initial decay was sharp, as HIV DNA levels decreased to 2.69 log10 copies/106 leukocytes after 4 weeks of treatment and to 2.37 log10 copies/106 leukocytes after 8 week

Reduced soluble CD14 levels after switching from a dual regimen with lamivudine plus boosted protease inhibitors to lamivudine plus dolutegravir in virologically suppressed HIV-infected patients

Background: HIV-induced systemic immune activation and inflammation have been associated with morbidity and mortality in virologically suppressed patients. Objective: To evaluate the impact of treatment switch from a dual regimen with lamivudine (3TC) plus ritonavir-boosted protease inhibitors (PI/r) to 3TC plus dolutegravir (DTG) on the monocyte activation marker soluble CD14 (sCD14) and other inflammatory biomarkers, interleukin-6 (IL-6), C-reactive protein (CRP), intestinal fatty acid–binding protein (I-FABP) and D-dimer. Methods: We performed a retrospective case-crossover study on integrase inhibitors-naïve virologically suppressed patients while on 3TC + PI/r dual maintenance therapy for ≥48 weeks who switched to 3TC + DTG and maintained this regimen for ≥48 weeks. Biomarkers plasma levels were tested by ELISA assays on stored samples at three time points: at switch (BL), 48 weeks before (−48 W) and 48 weeks after switch (+48 W). Results: A total of 67 patients were included. Median sCD14 levels were stable from −48 W to BL (from 6.07 to 6.04 log10 pg/mL, p = 0.235) but showed a statistically significant decrease after switch: from 6.04 (IQR 5.92-6.12) at BL to 5.95 (IQR 5.84–6.07) log10 pg/mL at + W48 (p < 0.001). Concurrently, an improvement in lipid profile was observed, even thought it was not correlated to the change in sCD14. The levels of IL-6, CRP, I-FABP and D-dimer remained stable before and after the switch to 3TC + DTG. Conclusions: In virologically suppressed HIV-infected patients on a 3TC + PI/r dual therapy, switching to 3TC + DTG was associated with a significant decline in sCD14. These data suggest reduced monocyte activation following substitution of boosted PI with DTG, which could have important clinical implications

Re: “No Significant Changes in Weight and Body Fat Mass in Suppressed HIV Infected Patients Switched to Dual Combination Lamivudine Plus Dolutegravir or Raltegravir” by Calza et al.

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Efficacy and safety of raltegravir in switch strategies in virologically suppressed patients: long-term data from clinical practice

Sir, We appreciated the recently published work by d\u2019Arminio Monforte et al.1 on the durability of integrase strand transfer inhibitors (INSTIs) in a large cohort of treatment-naive HIV-positive patients. Indeed, INSTI-based regimens have become the first choice for initial HIV therapy, but they are also very popular as part of three-drug or two-drug switching strategies. Eleven years have passed since the first-generation INSTI, raltegravir, was introduced. Despite the availability of the new INSTIs, such as dolutegravir (with higher genetic barrier) and elvitegravir (available as a single tablet regimen), raltegravir still plays an important role in combination ART (cART).2 The major advantages of using raltegravir are the virtual absence of potential interactions with concomitant drugs and its high bioavailability irrespective of food intake. To investigate the safety and efficacy of raltegravir in the setting of cART optimization, we performed a retrospective study enrolling HIV-1-infected, virologically suppressed (defined as HIV-RNA &lt;50\u2009copies/mL) patients switching to a raltegravir-containing dual or triple therapy. The study period ranged from September 2008 to May 2017. We evaluated the percentage of patients free from treatment discontinuation (TD; discontinuation of raltegravir for any reason regardless of whether the remaining antiretroviral drugs used in the combination had been stopped or not) and from virological failure (VF; defined as two consecutive counts of HIV-RNA 6550 copies/mL or one of 651000 copies/mL) at weeks 48, 96 and 144. Kaplan\u2013Meier curves and Cox regression models were performed to estimate the time to event and the predictors of TD and VF. Data analysed in the present study were selected from an internal observational database, which collects the main clinical and demographic characteristics of every patient who gave informed consent to personal data record since the time of HIV diagnosis. The creation of the database was approved by the Fondazione Policlinico Gemelli Ethics Committee (protocol number: 10978/15)

'How much raltegravir do you take?' The answer may not be so obvious: an accidental finding from clinical practice

It has been over a decade since the introduction of ralte-gravir, which has a well-established efficacy and tolera-bility profile . However, until recently, raltegravir hasonly been available as twice-daily formulations with, as aresult, a lower cumulative compliance to therapy and ahigher rate of discontinuation compared with the otheragents in the class .Following encouraging results from the ONCEMRK trial, a new raltegravir formulation of 1200 mg once dailywas introduced, and has been available in our centre sinceMay 2018. The new once-daily administration appearspromising in improving the compliance to raltegravir-con-taining regimens. However, during our routine clinicalactivity, we noticed that some of the patients recentlyswitched to raltegravir 1200 mg once daily were incor-rectly taking the drug. We then decided to investigate thisissue and to determine how widespread it was and pro-ceeded to recall all patients switched to this therapy in ourclinical centre between May 2018 and December 2018. Wethen asked our patients how they were taking raltegravirand collected their opinions on the ease of administrationof the new formulation and the onset of side effects