Antiviral Therapy

An increase in pretreatment drug resistance (PDR) to first-line antiretroviral therapy (ART) in low-income countries has been recently described. Herein we analyse the prevalence of PDR and risk of virological failure (VF) over time among migrants to Italy enrolled in ARCA.

HIV-1 sequences from ART-naive patients of non-Italian nationality were retrieved from ARCA database from 1998 to 2017. PDR was defined by at least one mutation from the reference 2009 WHO surveillance list.

Protease/reverse transcriptase sequences from 1,155 patients, mainly migrants from sub-Saharan Africa (SSA; 42%), followed by Latin America (LA; 25%) and Western countries (WE; 21%), were included. PDR was detected in 8.6% of sequences (13.1% versus 5.8% for B and non-B strains, respectively; P<0.001), 2.1% of patients carried a PDR for protease inhibitors (PIs; 2.1% versus 2.3%; P=0.893), 3.9% for nucleoside/ nucleotide reverse transcriptase inhibitors (NRTIs; 6.8% versus 2.1%; P<0.001) and 4.3% for non-nucleoside/ nucleotide reverse transcriptase inhibitors (NNRTIs; 6.3% versus 3.1%; P=0.013).

Overall, prevalence of PDR over the years remained stable, while it decreased for PIs in LA (P=0.021) and for NRTIs (P=0.020) among migrants from WE.

Having more than one class of PDR (P=0.015 versus absence of PDR), higher viral load at diagnosis (P=0.008) and being migrants from SSA (P=0.001 versus WE) were predictive of VF, while a recent calendar year of diagnosis (P<0.001) was protective for VF.

PDR appeared to be stable over the years in migrants to Italy enrolled in ARCA; however, it still remains an important cause of VF together with viral load at diagnosis.

In patients treated for HCV infection, potential drug–drug interactions (DDIs) can occur among direct-acting antiviral drugs (DAAs) and comedications used. The real-life effectiveness and safety of elbasvir/grazoprevir (ELB/GZR) among co-medicated HCV patients was evaluated.

We prospectively evaluated consecutive patients from 15 clinical centres participating in PITER who were treated with ELB/GZR and had been followed for at least 12 weeks after treatment. Data were prospectively collected on the use of comedications (including discontinuation, dose modification and addition of drugs) and potential DDIs with DAAs.

Of the 356 patients with at least 12-week post-treatment follow-up (median age 67, range 50–88 years), 338 (95%) achieved sustained virological response. Of these, 219 (60%) had at least one comorbidity (median 2, range 1–6); information on comedication was available for 212 of them. Of 190 comedications used, 15 (8%) drugs were modified during ELB/GZR therapy, specifically in 9 (4%) patients they were interrupted, in 2 (1%) of whom, the comedication was interrupted before the DAA therapy because of potential DDI (that is, patients treated with carbamazepine); in 12 (6%) patients the comedications were modified in terms of dosage. In 29 (14%) patients, the comedications required monitoring when used with ELB/GZR, as well as with all available DAAs. Of the 190 drugs, 27 (14%) used in 67% of patients were free of DDIs when used with ELB/GZR, whereas they required monitoring if used with other DAA regimens.

The results of this prospective study support findings that ELB/GZR is effective and safe in most treated patients.

Neuropsychiatric AEs (NPAEs) leading to dolutegravir (DTG) discontinuation were seen more frequently in real-world use than in randomized clinical trials (RCTs). The recently approved fixed-dose combination bictegravir plus emtricitabine and tenofovir alafenamide (BIC/F/TAF) has shown comparable NPAE rates but some favourable patient-reported outcomes in RCTs compared with DTG. We were interested in its neuropsychiatric tolerability in clinical practice.

All patients starting BIC/F/TAF from June 2018 in a single centre (two subcentres) were followed retrospectively. Discontinuation rates due to any AEs and NPAEs were compared with those of patients initiating DTG-based regimens.

As of May 2019, a total of 943 patients (852 males, 76 females, 15 transgender and gender diverse) initiated BIC/F/TAF outside RCTs. After a median follow-up of 6.2 months, 50 (5.3%) and 31 (3.3%) patients had discontinued BIC/F/TAF due to any AEs or to NPAEs, respectively. In multivariate analysis, a pre-existing depression and subcentre remained predictive for NPAEs, but not age, gender, ethnicity or prior DTG-related AEs. Compared with 1,043 patients treated with DTG-based regimens, the estimated NPAE-related discontinuation rate with BIC/F/TAF was comparable during the first 6 months (P=0.36). Cross-intolerance was low, and only 5/55 patients with prior DTG intolerability had to discontinue BIC/F/TAF due to NPAEs.

Short-term tolerability of BIC/F/TAF was comparable to DTG-containing regimens. As seen with DTG, discontinuation rates were higher than in RCTs. A pre-existing depression but also physician's awareness may have an impact on tolerability and continuation of BIC/F/TAF. In contrast, prior intolerability of DTG was of limited predictive value.

Cofactors associated with persistently abnormal CD4⁺:CD8⁺ T-cell ratio in people with HIV (PWH) on antiretroviral treatment (ART) might change over time as the population of people with HIV ages or as new ART drugs become available. The main objective of our study was to determine the long-term associations of baseline factors, including the CD4⁺ T-cell count and ratio, with ratio normalization (≥1). In addition to this, we explored whether the ratio remained associated with the risk of both AIDS and non-AIDS events among individuals on suppressive ART.

Clinic-based study in a tertiary, university hospital in Madrid. People with HIV starting a first-line ART regimen (January 2006–June 2017) were included in a prospective national multicentre cohort (CoRIS). People with controlled HIV-infection within the first year of ART initiation and complete CD4⁺ and CD8⁺ T-cell records were selected. Cox proportional hazard (PH) regression models were used to estimate the cumulative incidence of ratio normalization and to examine associations with socio-demographic and clinical variables. To investigate factors independently associated with the development of AIDS and non-AIDS events we used a time updated Poisson regression model.

The study included 557 subjects. During follow-up (median 5.24 years), 44% of participants achieved a ratio of 1 within a median of 1.49 years. In a multivariate PH model, pre-ART factors negatively associated with ratio normalization were the pre-ART CD4⁺:CD8⁺ T-cell ratio and mode of HIV acquisition. For the secondary analysis, 1.3 events/100 person years of follow-up were observed. After adjustment, older age, HIV RNA >200 copies/ml and CD4⁺:CD8⁺ T-cell ratios over follow-up, remained significantly associated with the development of AIDS and non-AIDS events. In contrast, pre-ART ratio was not associated with the risk of AIDS and non-AIDS events.

In summary, our study showed that higher pre-ART CD4⁺:CD8⁺ T-cell ratio is associated with rates of ratio normalization ≥1. In addition, the risk of AIDS and non-AIDS events seems to be predicted by the time updated CD4⁺:CD8⁺ T-cell ratio not by the pre-ART CD4⁺:CD8⁺ T-cell ratio. Therefore, CD4⁺:CD8⁺ T-cell ratio should be considered as a dynamic marker for translation into clinical practice.

Daclatasvir has potent antiviral activity against HCV infection when used in combination with sofosbuvir, however, its pharmacokinetics have not been described in adolescents. The aim is to determine the pharmacokinetic parameters of daclatasvir in adolescents, and to develop a population pharmacokinetic (PopPK) model.

Seventeen adolescent patients with genotype-4 chronic HCV infection received once daily oral daclatasvir 60 mg in combination with 400 mg sofosbuvir for 12 weeks. Steady state concentrations were determined. Non-compartmental and population PK were determined.

The average PK parameters calculated by non-compartmental analysis (NCA): maximum plasma concentration (C_max), area under the curve (AUC), apparent oral volume of distribution (V/F), apparent oral clearance (CL/F) and half-life (T_1/2) were 1,092 ng/ml, 11,178 ng/ml•h, 55 l, 4.5 l/h and 8.5 h, respectively. Daclatasvir was best described by one compartment structural PK model with zero order absorption and first-order elimination. The absorption rate constant (K₀), V/F, and CL/F of the final PopPK model of daclatasvir were 1.5/h, 52 l and 4.7 l/h, respectively. Body weight and serum albumin had significant effect on the V/F parameter.

Body weight and serum albumin were the major determinants of daclatasvir V/F in this population. PK parameters were comparable to those reported in adult HCV patients, demonstrating that 60 mg daclatasvir is an appropriate dose for adolescents. ClinicalTrials.gov NCT03540212.

Pharmacokinetic (PK) changes can affect antiretroviral (ARV) systemic exposure for critically ill patients living with HIV (CI-PLWH). Studies to guide ARV adjustments in this population are limited.

A PK analysis was conducted in a 44-year-old CI-PLWH who presented for a heart and lung transplant on veno-arterial extracorporeal membrane oxygenation (VA ECMO). Home ARV therapy (ART) of co-formulated abacavir/lamivudine/dolutegravir (ABC/3TC/DTG) was continued. ARV serum concentrations were obtained during and after VA ECMO. Two blood levels were drawn at 1 h, for maximum serum concentration (C_max) and a serum trough (C_t). ARVs were given as a single tablet crushed via nasogastric tube.

Area under the concentration–time curve (AUC_0–t) was calculated using non-compartmental analysis. C_max and AUC_0–t were higher during VA ECMO compared with post-decannulation. The C_max of ABC was >2.5-fold higher than the mean in the reference. C_max and C_t post VA ECMO were within range of referenced literature for all ARVs. C_max and AUC_0–t of DTG post VA ECMO was approximately four- to fivefold lower than referenced literature. HIV virological suppression was maintained throughout the hospitalization.

ART adjustments would not be required for this patient. Additional studies are needed to assess effects of VA ECMO and crushed tube administration of ARVs in CI-PLWH.