Ignacio Pérez-Valero

Protease inhibitor monotherapy.

Purpose of review The present review focuses on recent data about boosted protease inhibitor monotherapy for maintenance of HIV virological suppression. Recent findings Until recently most of the trials of boosted protease inhibitor monotherapy have studied lopinavir/ritonavir monotherapy. These trials showed a slightly inferior efficacy of lopinavir/ritonavir monotherapy than that of lopinavir/ritonavir and two nucleosides. Two clinical trials [Monotherapy in Europe with TMC114 (MONET) and Monotherapy inhibitor protease (MONOI)] have shown that darunavir/ritonavir monotherapy has also a slightly lower efficacy for maintenance of virological suppression than darunavir/ritonavir with two nucleosides. The risk of resistance development is minimal and patients who fail this strategy can be re-suppressed again by adding nucleosides or switching to a triple therapy regimen without having lost therapeutic options. MONOI has also shown limb fat recovery in patients receiving darunavir/ritonavir monotherapy and good penetration of darunavir in the seminal fluid. There are still conflicting views about the ability of boosted protease inhibitor to protect the central nervous system from HIV replication. There are no randomized clinical trials showing a higher risk of discordant HIV replication in the cerebrospinal fluid in patients exposed to monotherapy. There are insufficient data of monotherapy with atazanavir/ritonavir. Summary There currently is no consensus about the role of boosted protease inhibitor monotherapy for the treatment of HIV infection. It is clear that suppression can be maintained in a large proportion of patients without exposing patients to a substantial risk of resistance development, but the precise role of this strategy is still undefined.

Protease inhibitor monotherapy and the CNS: peace of mind?

Boosted protease inhibitor (bPI) monotherapy has demonstrated high efficacy for maintaining viral suppression in the blood. bPI monotherapy has the theoretical advantage of avoiding the long-term toxicity associated with the use of nucleoside reverse transcriptase inhibitors. Concern about the efficacy of bPI monotherapy in preventing HIV replication in the CNS is one reason that has precluded the widespread use of this therapeutic strategy. In several studies, a low CNS penetration-effectiveness (CPE) score has been associated with a higher risk of virological failure in the CNS and with neurocognitive impairment. Since the CPE score is substantially lower for bPI monotherapy than for triple-drug highly active antiretroviral therapy (HAART), it has been postulated that bPI monotherapy might have a higher risk for CNS virological failure and neurocognitive impairment. However, the available evidence, although limited, does no support this notion. Lopinavir and darunavir achieve CSF drug levels that are sufficient to fully suppress HIV replication. In clinical trials, when compared with triple-drug HAART, patients receiving bPI monotherapy with lopinavir and darunavir who maintain full virological suppression in plasma do not appear to be at a higher risk of discordant HIV replication in the CSF or of neuropsychiatric adverse events. It should be noted that several studies have suggested that nucleoside reverse transcriptase inhibitors might have neurotoxic effects and, consequently, bPI monotherapy might be able to avoid the CNS toxicity induced by nucleosides. It is clear that more studies including detailed neurocognitive testing are needed to completely establish the risk/benefit ratio of bPI monotherapy or triple-drug HAART for preserving neurocognitive function in HIV-infected patients.

Neurocognitive Impairment in Patients Treated with Protease Inhibitor Monotherapy or Triple Drug Antiretroviral Therapy

Background 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. Methods 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. Results 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). Conclusions 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.

A Prospective Cohort Study of Neurocognitive Function in Aviremic HIV-Infected Patients Treated With 1 or 3 Antiretrovirals

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.

Mortality risk factors in patients with zygomycosis: a retrospective and multicentre study of 25 cases.

AIM To investigate mortality risk factors in patients with zygomycosis. PATIENTS AND METHODS Retrospective case history review of patients diagnosed with proven zygomicosis in 17 centres in Spain. We compared demographics and risk factors in patients who survived, and in those who died. RESULTS We identified twenty-five patients with proven zygomycosis. The primary site of infection was rhino-orbito-cerebral (28%) and disseminated (20%) or cutaneous/soft infections (20%) of the patients. Eleven patients (44%) received preemptive or empirical antifungal treatment; of these patients, 4 received liposomal amphotericin B, 1 received amphotericin B lipid complex, and 6 received other antifungals. The overall mortality rate was 72%. In the univariate analysis factors associated with an increased risk of death were the presence of a haematological malignancy (P=.03), neutropenia (P=.03) and monocytopenia (P=.008). CONCLUSION Our study supports previous research that has documented a high mortality rate among patients with invasive zygomycosis, especially among those with an underlying haematological malignancy, and the need for a rapid initiation of an effective antifungal treatment.

Ictus and antiphospholipid syndrome: How much is enough?

Herein we report the case of a patient with antiphospholipid Syndrome (APS) and an ischemic stroke suffered while he was anticoagulated, and we discuss the usefulness of magnetic resonance angiography in the early diagnosis of such a complication. We also attempt to emphasize the great value of an individual risk evaluation when warfarin therapy is introduced. In fact, our case supports the importance of high-intensity anticoagulation in patients with multiple thrombotic recurrences, and the exceptional value that strict anticoagulation control has in this kind of patients.

Brief report: Differential effects of tenofovir, abacavir, emtricitabine, and darunavir on telomerase activity in vitro

Abstract: 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 &mgr;M 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 &mgr;M and 14% (IQR 10%–29%, P = 0.043) at 10 &mgr;M. 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.

Is etravirine and two nucleosides an option for HIV with an isolated K103N mutation

We report long-term virologic response to etravirine and tenofovir/emtricitabine in four HIV-1-infected patients who had prior standard genotypic resistance testing showing an isolated K103N mutation (three acquired, one transmitted). In three patients tested, the K103N mutation was detected in cellular HIV-1 DNA whereas remaining suppressed on etravirine plus tenofovir/emtricitabine.

Impact of Antiretroviral Treatment Containing Tenofovir Difumarate on the Telomere Length of Aviremic HIV-Infected Patients.

Objective: To evaluate the in vivo relevance of the inhibitory effect of tenofovir on 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 1 year). Methods: Telomere length in whole blood was measured by quantitative real-time polymerase chain reaction. 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% men, median age 49 (IQR 45–54.5), 103 with exposure to a TDF containing antiretroviral treatment (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), white race (P = 0.048), and longer time of known HIV infection (10–20 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.

Long-Term Control of Human Immunodeficiency Virus-1 Replication Despite Extensive Resistance to Current Antiretroviral Regimens: Clonal Analysis of Resistance Mutations in Proviral Deoxyribonucleic Acid

Archived resistance mutations compromise antiretroviral treatment. We have investigated 3 selected aviremic patients who had extensive historical resistance to their current regimen. All 3 patients underwent unstructured treatment interruptions associated to the re-emergence of wild-type virus before starting their current suppressive regimes. Almost all historical resistance mutations detected in plasma were found in circulating proviral deoxyribonucleic acid. None of the clones analyzed was fully resistant to the current antiretroviral regimen.