Highlights ► Safety and immunogenicity of HIV/AIDS MVA-B. ► This first phase I trial with candidate MVA-B in healthy volunteers showed that this immunogen was safe and well tolerated. ► This vaccine ...elicited strong and durable T-cell responses in 75% of volunteers. ► This vaccine elicited antibody responses against HIV-1 Env in 95% of volunteers and 33% generated neutralizing antibodies ► These data support further exploration of MVA-B as an HIV-1 vaccine candidate.
There are few studies comparing the safety and immunogenicity of the same HIV immunogen in healthy volunteers and HIV-infected individuals. We analyzed demographics, adverse events (AEs), and ...immunogenicity against vaccinia virus in preventive (RISVAC02,
= 24 low-risk HIV-negative volunteers) and therapeutic (RISVAC03,
= 20 successfully treated chronically HIV-1-infected individuals) vaccine phase-I clinical trials that were performed with the same design and the same immunogen (modified vaccinia virus Ankara-B: MVA-B). Total AEs were significantly higher in HIV-infected patients (mean AEs/patient 6.6 vs. 12.8 (
< 0.01)). Conversely, the number of AEs related to vaccination (AEsRV) was similar between both groups. No grade III or IV AEsRV were observed in either clinical trial. Regarding the immunogenicity, the proportion of anti-vaccinia virus antibody responders was similar in both studies. Conversely, the magnitude of response was significantly higher in HIV-infected patients (median binding antibodies at w8 267 vs. 1600 U/mL (
= 0.002) and at w18 666 vs. 3200 U/mL (
= 0.003)). There was also a trend towards higher anti-vaccinia virus neutralizing activity in HIV-infected individuals (proportion of responders 37% vs. 63% (
= 0.09); median IC50 32 vs. 64 (
= 0.054)). This study confirms the safety of MVA-B independent of HIV serostatus. HIV-infected patients showed higher immune responses against vaccinia virus.
The safety, immunogenicity, impact on the latent reservoir and rebound of viral load after therapeutic HIV-1 vaccination with recombinant modified vaccinia Ankara-based (MVA-B) HIV-1 vaccine ...expressing monomeric gp120 and the fused Gag-Pol-Nef polyprotein of clade B with or without a drug to reactivate latent HIV-1 (disulfiram) were assessed.
HIV-1-infected patients were randomized to receive three injections of MVA-B (n = 20) or placebo (n = 10). Twelve patients (eight who received vaccine and four who were given placebo) received a fourth dose of MVA-B followed by 3 months of disulfiram. Combined ART (cART) was discontinued 8 weeks after the last dose of MVA-B. Clinical Trials.gov identifier: NCT01571466.
MVA-B was safe and well tolerated. A minor, but significant, increase in the T cell responses targeting vaccine inserts of Gag was observed a median of 290, 403 and 435 spot-forming-cells/10(6) PBMCs at baseline, after two vaccinations and after three vaccinations, respectively; P = 0.02 and P = 0.04. After interruption of cART, a modest delay in the rebound of the plasma viral load in participants receiving vaccine but not disulfiram was observed compared with placebo recipients (P = 0.01). The dynamics of the viral load rebound did not change in patients receiving MVA-B/disulfiram. No changes in the proviral reservoir were observed after disulfiram treatment.
MVA-B vaccination was a safe strategy to increase Gag-specific T cell responses in chronically HIV-1-infected individuals, but it did not have a major impact on the latent reservoir or the rebound of plasma viral load after interruption of cART when given alone or in combination with disulfiram.
Abstract Background Pandemic 2009 influenza A/H1N1 (H1N1v) is resistant to adamantanes, leaving neuraminidase inhibitors as the only therapeutic option. Other mutations are considered to be ...associated with virulence and clinical severity. However, out of the surveillance programs, few studies analyze the presence of resistance/virulent H1N1v variants in certain clinical circumstances. Objectives To define the frequency and role of resistance and virulence mutations in a specific clinical circumstance—in patients with persistent infection by H1N1v. Study design Observational study of patients with persistent H1N1v infection admitted to our hospital. Results NAI-resistance mutations were detected in 14.3% of cases with persistent infection (2/14), and in none of the non-persistent controls (0/15). These cases were initially infected with susceptible variants that acquired resistance at different time-points after therapy with oseltamivir (OTV). The first case (case 2) was an HIV-positive patient who rapidly acquired resistance 9 days after diagnosis (6 days on OTV) and whose infection resolved after standard OTV therapy. The second case (case 3) was a patient with acute myeloid leukemia and the longest viral persistence (59 days). The resistance mutation was detected in the specimen taken on day 37 after diagnosis (30 days on OTV). Once the resistance mutation was identified, OTV was substituted by zanamivir and the infection resolved. In addition to mutations encoding resistance, variants associated with virulence were also sought. The D225G mutation was not found in any case, whereas the D225E variant was identified in three persistent cases but also in two non-persistent ones. In one patient, the D225E substitution coincided with the H275 resistant mutation. Conclusions NAI-resistance mutations were detected, at rather different paces, in non-severe immunosuppressed cases with persistent infection by influenza A/H1N1v.
: We report the long-term outcomes, changes in laboratory parameters, the incidence of secondary nosocomial infections and treatment cost of a Spanish cohort of patients with severe COVID-19 that ...received tocilizumab (TCZ).
: Retrospective cohort of PCR confirmed adult patients who received TCZ from March 1 to 24, 2020 in a tertiary hospital was analyzed. Patients were followed up until 10 May 2020.
: We included 162 patients (median age 64 years; 70.4% male). At time of TCZ administration, 48.1% of patients were on invasive mechanical ventilation (IMV). Over a median follow-up of 53 days, 46.9% of patients were discharge in good conditions and 19.8% were still hospitalized. The overall mortality was 33.3%, being higher in patients on IMV than those who did not (46.2% vs 26.7%, P < 0.001). A significant improvement in the lymphocyte count, C-reactive protein, lactate dehydrogenase, and D-dimer was observed. Overall, 43.2% patients presented nosocomial infections, causing death in 8%. Infections were more prevalent in ICU units (63.0% vs 17.1%, P < 0.001). The total cost of TCZ was €371,784.
: Among the patients who used TCZ, one third died, regardless the improvement in some inflammatory biomarkers. The incidence of secondary nosocomial infections was high.
Abstract
Objectives
To assess the effectiveness and tolerability of dolutegravir (DTG)/lamivudine (3TC) among treatment-naive and virologically suppressed treatment-experienced individuals in the ...multicentre cohort of the Spanish HIV/AIDS Research Network (CoRIS) during the years 2018–2021.
Methods
We used multivariable regression models to compare viral suppression (VS) HIV RNA viral load (VL) <50 copies/mL and the change in CD4 cell counts at 24 and 48 (±12) weeks after initiation with dolutegravir/lamivudine or other first-line ART regimens.
Results
We included 2160 treatment-naive subjects, among whom 401 (18.6%) started with dolutegravir/lamivudine. The remaining subjects started bictegravir (BIC)/emtricitabine (FTC)/tenofovir alafenamide (TAF) (n = 949, 43.9%), DTG + FTC/tenofovir disoproxil fumarate (TDF) (n = 282, 13.1%), DTG/3TC/abacavir (ABC) (n = 255, 11.8%), darunavir (DRV)/cobicistat(COBI)/FTC/TAF (n = 147, 6.8%) and elvitegravir (EVG)/COBI/FTC/TAF (n = 126, 5.8%). At 24 and 48 weeks after starting dolutegravir/lamivudine, 91.4% and 93.8% of the subjects, respectively, achieved VS. The probability of achieving VS with dolutegravir/lamivudine was not significantly different compared with any other regimen at 24 or 48 weeks, with the exception of a lower chance of achieving VS at 24 weeks for DRV/COBI/FTC/TAF (adjusted OR: 0.47; 95% CI: 0.30–0.74) compared with dolutegravir/lamivudine.
For the analysis of treatment-experienced virally suppressed subjects we included 1456 individuals who switched to dolutegravir/lamivudine, among whom 97.4% and 95.5% maintained VS at 24 and 48 weeks, respectively. During the first 48 weeks after dolutegravir/lamivudine initiation, 1.0% of treatment-naive and 1.5% of treatment-experienced subjects discontinued dolutegravir/lamivudine due to an adverse event.
Conclusions
In this large multicentre cohort, effectiveness and tolerability of dolutegravir/lamivudine were high among treatment-naive and treatment-experienced subjects.
We conducted a retrospective, multicenter study evaluating the safety of discontinuing maintenance therapy for cryptococcal meningitis after immune reconstitution. Inclusion criteria were a previous ...definitive diagnosis of cryptococcal meningitis, a CD4 cell count of >100 cells/µL while receiving highly active antiretroviral therapy (HAART), and the subsequent discontinuation of maintenance therapy for cryptococcal meningitis. The primary end point was relapse of cryptococcal disease. As of July 2002, 100 patients were enrolled. When maintenance therapy was discontinued, the median CD4 cell count was 259 cells/µL and the median plasma virus load was <2.30 log10 copies/mL, and serum cryptococcal antigen was undetectable in 56 patients. During a median follow-up period of 28.4 months (range, 6.7–64.5; 262 person-years), 4 events were observed (incidence, 1.53 events per 100 person-years; 95% confidence interval, 0.42–3.92). Three of these patients had a CD4 cell count of >100 cells/µL and a positive serum cryptococcal antigen test result during the recurrent episode. In conclusion, discontinuation of maintenance therapy for cryptococcal meningitis is safe if the CD4 cell count increases to >100 cells/µL while receiving HAART. Recurrent cryptococcal infection should be suspected in patients whose serum cryptococcal antigen test results revert back to positive after discontinuation of maintenance therapy.
Effective two-drug regimens could decrease long-term drug exposure and toxicity with HIV-1 antiretroviral therapy (ART). We therefore aimed to evaluate the efficacy and safety of a two-drug regimen ...compared with a three-drug regimen for the treatment of HIV-1 infection in ART-naive adults.
We conducted two identically designed, multicentre, double-blind, randomised, non-inferiority, phase 3 trials: GEMINI-1 and GEMINI-2. Both studies were done at 192 centres in 21 countries. We included participants (≥18 years) with HIV-1 infection and a screening HIV-1 RNA of 500 000 copies per mL or less, and who were naive to ART. We randomly assigned participants (1:1) to receive a once-daily two-drug regimen of dolutegravir (50 mg) plus lamivudine (300 mg) or a once-daily three-drug regimen of dolutegravir (50 mg) plus tenofovir disoproxil fumarate (300 mg) and emtricitabine (200 mg). Both drug regimens were administered orally. We masked participants and investigators to treatment assignment: dolutegravir was administered as single-entity tablets (similar to its commercial formulation, except with a different film colour), and lamivudine tablets and tenofovir disoproxil fumarate and emtricitabine tablets were over-encapsulated to visually match each other. Primary endpoint was the proportion of participants with HIV-1 RNA of less than 50 copies per mL at week 48 in the intention-to-treat-exposed population, using the Snapshot algorithm and a non-inferiority margin of −10%. Safety analyses were done on the safety population. GEMINI-1 and GEMINI-2 are registered with ClinicalTrials.gov, numbers NCT02831673 and NCT02831764, respectively.
Between July 18, 2016, and March 31, 2017, 1441 participants across both studies were randomly assigned to receive either the two-drug regimen (n=719) or three-drug regimen (n=722). At week 48 in the GEMINI-1 intention-to-treat-exposed population, 320 (90%) of 356 participants receiving the two-drug regimen and 332 (93%) of 358 receiving the three-drug regimen achieved plasma HIV-1 RNA of less than 50 copies per mL (adjusted treatment difference −2·6%, 95% CI −6·7 to 1·5); in GEMINI-2, 335 (93%) of 360 in the two-drug regimen and 337 (94%) of 359 in the three-drug regimen achieved HIV-1 RNA of less than 50 copies per mL (adjusted treatment difference −0·7%, 95% CI −4·3 to 2·9), showing non-inferiority at a −10% margin in both studies (pooled analysis: 655 91% of 716 in the two-drug regimen vs 669 93% of 717 in the three-drug regimen; adjusted treatment difference −1·7%, 95% CI −4·4 to 1·1). Numerically, more drug-related adverse events occurred with the three-drug regimen than with the two-drug regimen (169 24% of 717 vs 126 18% of 716); few participants discontinued because of adverse events (16 2% in the three-drug regimen and 15 2% in the two-drug regimen). Two deaths were reported in the two-drug regimen group of GEMINI-2, but neither was considered to be related to the study medication.
The non-inferior efficacy and similar tolerability profile of dolutegravir plus lamivudine to a guideline-recommended three-drug regimen at 48 weeks in ART-naive adults supports its use as initial therapy for patients with HIV-1 infection.
ViiV Healthcare.
We compared the baseline characteristics, effectiveness, and tolerance of direct-acting antiviral drug (DAA)-based regimens taken by hepatitis C virus (HCV)-monoinfected and HCV/HIV-coinfected ...individuals in clinical practice.
We performed a prospective observational study in two tertiary centres in Madrid, Spain, which included all HCV-monoinfected and HCV/HIV-coinfected patients undergoing HCV treatment with all-oral DAA regimens in a routine clinical setting, from April 2015 to November 2015. We evaluated sustained virological response 12 weeks after the end of therapy (SVR12), adverse events, and baseline and treatment characteristics.
The study population comprised 1634 patients: 1152 HCV-monoinfected patients (70%) and 482 HCV/HIV-coinfected patients (30%). Fifty percent had cirrhosis, and 47% were peginterferon/ribavirin-experienced. HCV/HIV-coinfected patients were younger median age (interquartile range) 51 (48-54) years vs. 59 (50-68) years; P < 0.001), more frequently male (76 vs. 54%; P < 0.001), and infected with genotypes 1a (37 vs. 17%; P < 0.001), 3 (15 vs. 7%; P < 0.001), and 4 (23 vs. 4%; P < 0.001). One of every three patients took ribavirin. SVR12 was 94% (95% confidence interval 91.7-96%) and 97% (95% confidence interval 95.7-99.4%) in coinfected and monoinfected patients, respectively, with no significant differences between the groups after adjustment for cirrhosis, genotype, and DAA combination. DAA-based regimens were well tolerated, and only 1% of patients had severe adverse events, with no differences between the populations.
HCV/HIV-infected patients treated with all-oral DAA combinations achieved high rates of SVR12 that were similar to those of HCV-monoinfected patients under real-life conditions. Safety and tolerance were excellent, even in patients with end-stage liver disease.
PDF
