This update to the document on antiretroviral therapy (ART) in adults, which has been prepared jointly by GeSIDA and the Spanish National AIDS Plan for the last two decades, supersedes the document ...published in 2017.1 The update provides physicians treating HIV-1-infected adults with evidence-based recommendations to guide their therapeutic decisions. The main difference with respect to the previous document concerns recommended initial ART regimens, only three of which are maintained as preferential. All three include dolutegravir or raltegravir, together with emtricitabine/tenofovir alafenamide or abacavir/lamivudine. Other differences concern the section on switching ART in patients with suppressed viral replication, which now includes new two- and three-drug regimens, and the antiretroviral drugs recommended for pregnant women and patients with tuberculosis. A recommendation has also been added for patients who present with acute HIV infection after pre-exposure prophylaxis.
Esta actualización del documento sobre el tratamiento antirretroviral (TAR) en adultos que GeSIDA y el PNS elaboran desde hace 2 décadas, reemplaza a la de 20171. Su objetivo es proporcionar a los clínicos que tratan a adultos con infección por el VIH-1 recomendaciones basadas en evidencias científicas para guiar sus decisiones terapéuticas. El principal cambio respecto al documento previo incumbe a los regímenes recomendados para el TAR de inicio, solo 3 de los cuales se mantienen como preferentes, incluyendo todos ellos dolutegravir o raltegravir junto con emtricitabina/tenofovir alafenamida o abacavir/lamivudina. Otros cambios conciernen al apartado de cambio del TAR en pacientes con replicación viral suprimida, en el que se han incluido nuevos regímenes de 2 y 3 fármacos, y a los antirretrovirales recomendados en embarazadas o en pacientes con tuberculosis. Se ha añadido también una recomendación para personas que habiendo realizado profilaxis pre-exposición al VIH presentan una infección aguda por dicho virus.
Due to their suppressive capacity, the adoptive transfer of regulatory T cells (Treg) has acquired a growing interest in controlling exacerbated inflammatory responses. Limited Treg recovery and ...reduced quality remain the main obstacles in most current protocols where differentiated Treg are obtained from adult peripheral blood. An alternate Treg source is umbilical cord blood, a promising source of Treg cells due to the higher frequency of naïve Treg and lower frequency of memory T cells present in the fetus' blood. However, the Treg number isolated from cord blood remains limiting. Human thymuses routinely discarded during pediatric cardiac surgeries to access the retrosternal operative field has been recently proposed as a novel source of Treg for cellular therapy. This strategy overcomes the main limitations of current Treg sources, allowing the obtention of very high numbers of undifferentiated Treg. We have developed a novel good manufacturing practice (GMP) protocol to obtain large Treg amounts, with very high purity and suppressive capacity, from the pediatric thymus (named hereafter thyTreg). The total amount of thyTreg obtained at the end of the procedure, after a short-term culture of 7 days, reach an average of 1,757 x10
(range 50 x 10
- 13,649 x 10
) cells from a single thymus. The thyTreg product obtained with our protocol shows very high viability (mean 93.25%; range 83.35% - 97.97%), very high purity (mean 92.89%; range 70.10% - 98.41% of CD25
FOXP3
cells), stability under proinflammatory conditions and a very high suppressive capacity (inhibiting in more than 75% the proliferation of activated CD4
and CD8
T cells
at a thyTreg:responder cells ratio of 1:1). Our thyTreg product has been approved by the Spanish Drug Agency (AEMPS) to be administered as cell therapy. We are recruiting patients in the first-in-human phase I/II clinical trial worldwide that evaluates the safety, feasibility, and efficacy of autologous thyTreg administration in children undergoing heart transplantation (NCT04924491). The high quality and amount of thyTreg and the differential features of the final product obtained with our protocol allow preparing hundreds of doses from a single thymus with improved therapeutic properties, which can be cryopreserved and could open the possibility of an "off-the-shelf" allogeneic use in another individual.
Little is known about the impact of baseline resistance-associated mutations (RAMs) on the outcomes of alternative therapeutic strategies such as dual regimens. We assessed the efficacy of boosted ...darunavir plus raltegravir (DRV + RAL) dual regimen as a simplification strategy in virologically suppressed patients with protease inhibitors RAMs.
Retrospective, multicentre study on the evolution of 228 heavily pretreated patients who switched to boosted DRV + RAL according to genotypic sensitivity score (GSS). Patients were classified as full susceptible (GSS = 2;
= 177), or with reduced darunavir susceptibility (GSS < 2;
= 51).
Median (range) number of prior antiretroviral regimens was 9 (6-14), with a median (range) of 2 (1-3), 4 (3-6), and 5 (2-9) major mutations to non-nucleoside reverse transcriptase inhibitors, nucleoside reverse transcriptase inhibitors, and protease inhibitors, respectively. The median time of virological suppression before simplification was 49 months (IQR 39.8-63.5). Patients with reduced darunavir GSS showed a higher number of protease inhibitors-RAMs (9.3 vs 4.5,
< .01) and were suppressed for longer time (median, 61 months). At week 96, the rate of virological failure was low (two cases, 0.9%; 95% confidence interval, CI, 0.4-2.7%), and the efficacy, excluding non-virological reasons, was 96.8% (95%CI, 90.2-98.4%), without differences according to GSS or protease inhibitors-RAMs. Furthermore, significant improvements in CD4+ counts and CD4/CD8 ratio were observed (
< .01) in both groups.
Treatment simplification to a dual regimen of boosted DRV + RAL after long-term virological suppression was not associated with a high risk of treatment failure, even in patients harbouring protease inhibitors-resistant HIV infection.
Antiretroviral therapy (ART) is recommended for all patients infected by HIV-1. The objective of ART is to achieve an undetectable plasma viral load (PVL). Initial ART should be based on a ...combination of 3 drugs, including 2 nucleoside reverse transcriptase inhibitors (tenofovir in either of its two formulations plus emtricitabine or abacavir plus lamivudine) and another drug from a different family. Four of the recommended regimens, all of which have an integrase inhibitor as the third drug (dolutegravir, elvitegravir boosted with cobicistat or raltegravir), are considered preferential, whereas a further 3 regimens (based on elvitegravir/cobicistat, rilpivirine, or darunavir boosted with cobicistat or ritonavir) are considered alternatives. We present the reasons and criteria for switching ART in patients with an undetectable PVL and in those who present virological failure, in which case salvage ART should include 3 (or at least 2) drugs that are fully active against HIV. We also update the criteria for ART in specific situations (acute infection, HIV-2 infection, pregnancy) and comorbidities (tuberculosis or other opportunistic infections, kidney disease, liver disease and cancer).
Tenofovir DF in rescue regimens López Bernaldo de Quirós, Juan Carlos
Enfermedades infecciosas y microbiología clínica
26 Suppl 8
Journal Article
Recenzirano
As with other nucleoside analogues, tenofovir (TDF) can be affected by several mutations in the reverse transcriptase gene. Most nucleoside analogue mutations (NAMs) are not induced specifically by ...TDF, although they can affect the activity of this drug. The impact of thymidine analogue mutations (TAMs) on tenofovir varies and, as with the remaining nucleoside analogue reverse transcriptase inhibitors, largely depends on the type and number present. Thus, the greater the number of TAMs, and the greater the number of type 1 TAMs, the more TDF activity will be affected. The 41L and 210W mutations have the greatest effect. The incidence of the 65R mutation was slight before the clinical introduction of TDF. This mutation was selected by treatments with zalcitabine monotherapy. However, after TDF came on to the market, the 65R mutation began to be more frequently reported and is currently the signature mutation of this drug. TDF has been shown to be safe and effective in patients with prior virological failure and resistance mutations in the reverse transcriptase gene. In these patients, the presence of the 41L and 210W mutations is associated with a worse response to rescue therapy containing TDF. In contrast, the presence of type 2 TAMs (67N, 70R and 219Q/E/N) has little effect on TDF activity in these patients. Importantly, in TDF therapy, the presence of the 184V mutation is associated with a more favorable virologic response than the absence of this mutation, with any of the distinct combinations of mutations present.
Interleukin-2 (IL-2) is a T cell derived cytokine that leads to a sustained expansion of the CD4+ T cell pool when given as 5-day cycles approximately every 8 weeks. An extensive series of phase I/II ...studies have been carried out and have leaded to the initiation of two phase III trials that are currently enrolling patients in 23 countries. Studies of the mechanisms of action have revealed that IL-2 is capable of inducing the polyclonal proliferation of CD4+ and CD8+ T cells, even in the absence of expression of the high affinity IL-2 receptor. While IL-2 leads to a 6-fold increase in T cell proliferation and a 2-fold increase in T cell death, the primary mechanism of action leading to expansion of the CD4+ T cell pool appears to be an increase in CD4+ T cell survival. While early work focused on the ability of IL-2 to exert these effects in patients with relatively early stages of HIV infection, more recent work, in the setting of HAART, indicates that these effects may be seen at all stages of HIV disease. The results of the phase III studies should provide an answer to the question of whether or not this is a strategy that will be of clinical benefit.
Summary Objective To study the effect of age on several outcomes among 187 antiretroviral-naive infected patients who started highly active antiretroviral therapy (HAART) with ≤200 CD4+ /μl. Methods ...We carried out a retrospective study to determine the hazard ratio (HR) to reach an outcome in patients who experienced a change from the baseline in CD4+ counts of at least +100, +200, +300, +400 and +500 cells/μl at any moment during the follow-up and the odds ratio (OR) of achieving and maintaining a CD4+ value above a certain setpoint during at least 6, 12 or 18 months. Results The adjusted HR for an increase of +400 CD4+ /μl and +500 CD4+ /μl were 1.3 (95% CI: 1.1; 1.5) and 1.3 (95% CI: 1.1; 1.6) times slower for each additional 5 years of age at baseline. In addition, for every 5 years of extra age, the adjusted OR to achieve an absolute CD4+ cell count >500/μl at 6, 12 and 18 months after the initiation of HAART were 2.2 (95% CI: 1.5; 3.2), 1.8 (95% CI: 1.2; 2.6), and 1.8 (95% CI: 1.2; 2.9) times less likely, respectively. We also found that patients ≥45 years old had worse complete CD4+ recovery (CD4+ > 500 cells/μl) than patients <45 years old. Conclusion The CD4+ recovery after HAART is a prolonged and continuous process which extends for several years. Age at baseline is inversely correlated with the magnitude and speed of CD4+ recovery among HIV-1 infected patients.
In 2009 a deep change in ARV treatment took place in Spain with the introduction of new ARV drugs. The principal objective of the study was to determine the clinical situation of the patients in ...which DRV/r was introduced in the ARV therapy.
Observational, cross sectional and multicentre study in which 91 reference hospitals participated. Patient's enrollment was carried out between 2008 and 2009. Data were collected retrospectively considering standard clinical practice.
719 medical records were reviewed. Patients had a different clinical situation compared to nowadays with predominance of multiresistant virus which leaded to virologic failure. The principal reason for introducing DRV/r in the ARV regimen was the virologic failure (54.2%).
Considering this situation, DRV/r became a therapeutic option which represented a change in the ARV paradigm in that period.
The common response to stopping anti-HIV treatment is an increase of HIV-RNA load and decrease in CD4+, but not all the patients have similar responses to this therapeutic strategy. The aim was to ...identify predictive markers of CD4+ cell count declines to < 350/microL in CD4-guided antiretroviral treatment interruptions.
27 HIV-infected patients participated in a prospective multicenter study in with a 24 month follow-up. Patients on stable highly active antiretroviral therapy (HAART), with CD4+ count > 600/microL, and HIV-RNA < 50 copies/ml for at least 6 months were offered the option to discontinue antiretroviral therapy. The main outcome was a decline in CD4+ cell count to < 350/microL.
After 24 months of follow-up, 16 of 27 (59%) patients (who discontinued therapy) experienced declines in CD4+ cell count to < 350/microL. Patients with a CD4+ nadir of < 200 cells/microL had a greater risk of restarting therapy during the follow-up (RR (CI95%): 3.37 (1.07; 10.36)). Interestingly, lymphoproliferative responses to Mycobacterium tuberculosis purified protein derivative (PPD) below 10000 c.p.m. at baseline (4.77 (1.07; 21.12)), IL-4 production above 100 pg/mL at baseline (5.95 (1.76; 20.07)) in PBMC cultured with PPD, and increased IL-4 production of PBMC with p24 antigen at baseline (1.25 (1.01; 1.55)) were associated to declines in CD4+ cell count to < 350/microL.
Both the number (CD4+ nadir) and the functional activity of CD4+ (lymphoproliferative response to PPD) predict the CD4+ decrease associated with discontinuation of ART in patients with controlled viremia.
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