In patients who remain virologically suppressed in plasma with triple-drug ART a switch to protease inhibitor monotherapy maintains high rates of suppression; however it is unknown if protease ...inhibitor monotherapy is associated to a higher rate of neurocognitive impairment.
In this observational, cross-sectional study we included patients with plasma virological suppression (≥ 1 year) without concomitant major neurocognitive confounders, currently receiving for ≥ 1 year boosted lopinavir or darunavir as monotherapy or as triple ART. Neurocognitive impairment was defined as per the 2007 consensus of the American Association of Neurology. The association between neurocognitive impairment and protease inhibitor monotherapy, adjusted by significant confounders, was analysed.
Of the 191 included patients--triple therapy: 96, 1-2 years of monotherapy: 40 and >2 years of monotherapy: 55--proportions (95% CI) with neurocognitive impairment were: overall, 27.2% (20.9-33.6); triple therapy, 31.6% (22.1-41.0); short-term monotherapy, 25.0% (11.3-38.7); long-term monotherapy: 21.4% (10.5-32.3); p = 0.38. In all groups, neurocognitive impairment was mildly symptomatic or asymptomatic by self-report. There were not significant differences in Global Deficit Score by group. In the regression model confounding variables for neurocognitive impairment were years on ART, ethnicity, years of education, transmission category and the HOMA index. Adjusted by these variables the Odds Ratio (95% CI) for neurocognitive impairment of patients receiving short-term monotherapy was 0.85 (0.29-2.50) and for long-term monotherapy 0.40 (0.14-1.15).
Compared to triple drug antiretroviral therapy, monotherapy with lopinavir/ritonavir or darunavir/ritonavir in patients with adequate plasma suppression was not associated with a higher rate of asymptomatic neurocognitive impairment than triple drug ART.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Tenofovir is a potent inhibitor of human telomerase. The clinical relevance of this inhibition is unknown.
A prospective cohort of human immunodeficiency virus (HIV)-infected participants with ...suppressed virological replication was recruited to compare whole-blood telomere length (measured by quantitative multiplex polymerase chain reaction analysis) in participants with current exposure to tenofovir disoproxil fumarate (TDF) to that in participants never exposed to TDF.
A total of 172 participants were included: 67 were in the TDF group, and 105 were in the non-TDF group (75 were receiving 2 nucleosides of whom 69 were receiving abacavir, 25 were receiving a nucleostide reverse transcriptase inhibitor N{t}RTI-sparing regimen, and 5 were receiving lamivudine as the only nucleoside). After 2 years, the mean blood telomere length increased significantly in the whole cohort. The TDF group had significantly smaller gains in telomere length than the non-TDF group. In the analysis restricted to participants receiving N(t)RTIs, TDF exposure was not associated with an independent negative effect. In the non-TDF group, participants treated with 2 nucleosides also had significantly smaller gains in telomere length than those receiving N(t)RTI-sparing regimens or lamivudine as the only nucleoside.
In HIV-infected adults with prolonged virological suppression, treatment with TDF or abacavir was associated with smaller gains in blood telomere length after 2 years of follow-up.
OBJECTIVE:To evaluate the in vivo relevance of the inhibitory effect of tenofovir upon telomerase activity observed in vitro.
DESIGN:Cross sectional study of HIV-infected patients with suppressed ...virological replication (HIV RNA < 50 copies/mL for more than one year) MethodsTelomere length in whole blood was measured by quantitative real time PCR. We performed a multivariate analysis to elucidate variables associated with telomere length and also evaluated the association between telomere length and use of tenofovir difumarate (TDF) adjusted by significant confounders
RESULTS:200 patients included, 72% male, median age 49 (IQR 45-54.5), 103 with exposure to a TDF containing ART regimen (69.9% for more than 5 years) and 97 never exposed to a TDF containing ART regimen. In the multivariate analysis significant predictors of shorter telomere length were older age (p = 0.008), parental age at birth (p = 0.038), Caucasian race (p = 0.048) and longer time of known HIV infection (10-20 years and ≥20 years compared with <10 years, p = 0.003 and p = 0.056 respectively). There was no association between TDF exposure and telomere length after adjusting for possible confounding factors (age, parental age at birth, race and time of HIV infection). Total time receiving ART and duration of treatment with nucleoside reverse transcriptase inhibitors were associated with shorter telomere length but these associations were explained by time of known HIV infection
CONCLUSIONS:Our data do not suggest that telomerase activity inhibition caused by TDF in vitro, leads to telomere shortening in peripheral blood of HIV infected patients.
Background:
An increasing number of women living with perinatally acquired HIV are reaching adulthood and becoming pregnant. Achieving viral suppression is challenging in this population frequently ...exposed to numerous antiretroviral regimens. This study describes the long-term outcomes of pregnant women living with perinatally acquired HIV in Spain.
Methods:
Descriptive, retrospective, multicenter study of the women living with perinatally acquired HIV who gave birth between January 2000 and December 2019 in Madrid. Epidemiological, clinical, and HIV-related data were collected from the first delivery to the end of the study period, including antiretroviral therapy, prevention strategies, and outcomes.
Results:
Sixty-three live births in 33 women were included. The mean number of pregnancies per women was 1.9 (range: 1–6). At first delivery, women's median age was 20 years (interquartile range: 18–23), 11 (33.3%) had been previously diagnosed with AIDS and 6 (18%) with mental health disorders. Forty percent became pregnant unsuppressed, whereas 81% achieved viral suppression at delivery. Treatment interruptions were common after delivery, as were losses to follow-up, with no positive effect of pregnancy on retention to care or the immune virological situation. Five women (15%) experienced a new AIDS event, and there were 2 deaths (6%) during follow-up. There was 1 case of mother-to-child transmission in a nonadherent woman in whom preventive measures could not be implemented.
Conclusions:
Pregnancy in this unique population of women living with perinatally acquired HIV poses particular challenges. Specific strategies, including a multidisciplinary approach, are needed to minimize perinatal transmission risks and improve outcomes during the postpartum period.
Background. The evolution of neurocognitive performance in aviremic human immunodeficiency virus (HIV)-positive patients treated with <3 antiretrovirals is unknown. Methods. We prospectively included ...aviremic (≥1 year) HIV-positive patients, without concomitant major neurocognitive confounders, currently receiving boosted lopinavir or darunavir as monotherapy (n = 67) or triple antiretroviral therapy (ART) (n = 67) for ≥1 year. We evaluated neurocognitive function (7 domains) at baseline and after 1 year. We performed analysis of covariance to evaluate if 1 additional year of exposure to monotherapy compared with triple ART had an effect on Global Deficit Score (GDS) changes after adjustment for potential confounders. We also compared the evolution of neurocognitive performance and impairment rates. Results. Intention-to-treat analysis showed that monotherapy did not influence 1-year GDS change after adjustment for significant confounders (age, ethnicity, duration of therapy, hepatitis C virus status, and HOMA-IR index); the adjusted effect was −0.04 (95% confidence interval, −.14 to .05; P = .38). Neurocognitive stability was observed with monotherapy and triple therapy (GDS crude mean change, −0.09 95% confidence interval, −.16 to −.01 vs −0.08 −.14 to −.02, after 1 year of follow-up, similar proportions of patients changed neurocognitive status from impaired to unimpaired (monotherapy, 4 of 18 22.2%; triple therapy, 4 of 19 21.1%; P = .91) and vice versa (monotherapy, 5 of 44 10.2% and triple therapy, 3 of 45 6.3%; P = .48). Similar results were observed in an on-treatment analysis and with use of clinical ratings instead of GDS changes. Conclusions. The number of antiretrovirals included in the ART regimen does not seem to influence the evolution of neurocognitive function in HIV-infected patients with suppressed plasma viremia.
In vitro, tenofovir and abacavir induced a significant dose-dependent inhibition of telomerase activity at therapeutic concentrations in peripheral blood mononuclear cells of healthy subjects. Median ...inhibition of telomerase activity by tenofovir at 0.5 and 1 μM was 29% Interquartile range (IQR) 29%–34%, P = 0.042 and 28% (IQR 28%–41%, P = 0.042), respectively. Abacavir inhibition was 12% (IQR 9%–13%, P = 0.043) at 3 μM and 14% (IQR 10%–29%, P = 0.043) at 10 μM. Tenofovir and abacavir did not change human telomerase reverse transcriptase (hTERT) levels or mRNA levels of other telomerase complex genes. Exposure to emtricitabine or darunavir did not affect telomerase activity, hTERT protein levels, or mRNA levels of telomerase/shelterin genes.
Abstract
Background
We compared the efficacy of the antiviral agent, remdesivir, versus standard-of-care treatment in adults with severe coronavirus disease 2019 (COVID-19) using data from a phase 3 ...remdesivir trial and a retrospective cohort of patients with severe COVID-19 treated with standard of care.
Methods
GS-US-540–5773 is an ongoing phase 3, randomized, open-label trial comparing two courses of remdesivir (remdesivir-cohort). GS-US-540–5807 is an ongoing real-world, retrospective cohort study of clinical outcomes in patients receiving standard-of-care treatment (non-remdesivir-cohort). Inclusion criteria were similar between studies: patients had confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, were hospitalized, had oxygen saturation ≤94% on room air or required supplemental oxygen, and had pulmonary infiltrates. Stabilized inverse probability of treatment weighted multivariable logistic regression was used to estimate the treatment effect of remdesivir versus standard of care. The primary endpoint was the proportion of patients with recovery on day 14, dichotomized from a 7-point clinical status ordinal scale. A key secondary endpoint was mortality.
Results
After the inverse probability of treatment weighting procedure, 312 and 818 patients were counted in the remdesivir- and non-remdesivir-cohorts, respectively. At day 14, 74.4% of patients in the remdesivir-cohort had recovered versus 59.0% in the non-remdesivir-cohort (adjusted odds ratio aOR 2.03: 95% confidence interval CI: 1.34–3.08, P < .001). At day 14, 7.6% of patients in the remdesivir-cohort had died versus 12.5% in the non-remdesivir-cohort (aOR 0.38, 95% CI: .22–.68, P = .001).
Conclusions
In this comparative analysis, by day 14, remdesivir was associated with significantly greater recovery and 62% reduced odds of death versus standard-of-care treatment in patients with severe COVID-19.
Clinical Trials Registration
NCT04292899 and EUPAS34303.
In this comparative analysis, remdesivir was associated with significantly lower mortality and higher recovery than standard-of-care treatment without remdesivir in patients with severe COVID-19. Ongoing studies will further determine the utility of remdesivir for the treatment of severe COVID-19.
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