Efficacy and tolerability of switching to a dual therapy with darunavir/ritonavir plus raltegravir in HIV-infected patients with HIV-1 RNA <= 50 cp/mL

Background: Nucleos(t)ide reverse transcriptase inhibitors (NRTI) toxicity may represent a threat for long-term success of combined antiretroviral therapy. Some studies have suggested a possible improvement of NRTI-related toxicity after switching to NRTI-sparing regimens. Objectives: We aimed to explore the efficacy and tolerability of switching to darunavir/ritonavir (DRV/r) plus raltegravir (RAL) while having a viral load (VL) ≤50 copies/mL in the clinical setting. Study design: Treatment-experienced HIV 1-infected patients enrolled in the ICONA Foundation Study cohort were included if they switched their current regimen to DRV/r + RAL with a HIV-RNA ≤50 copies/mL. Different definitions of virological failure (VF) and treatment failure (TF) were employed. Kaplan–Meier curves and Cox regression models were performed to estimate time to event probability. Results: We included 72 HIV-infected patients, 22 (31%) of these were female, 31 (43%) men who have sex with men (MSM) amd 15 (21%) had hepatitis co-infections. Median age was 44 (IQR: 35-50) years amd CD4 count was 389 (IQR 283-606) cells/mmc. Median follow-up time for TF was 24 (IQR 9–31) months. Twenty-five discontinuations occurred (60% simplifications); only 2 (8%) were toxicity-driven (lipid elevations). The probability of VF (confirmed VL >50 copies/mL) was estimated at 7% [95% confidence interval (CI) 1–13%] by 12 and 9% (95% CI 2–16%) by 24 months. When considering TF, we found a probability of stop/intensification/single VL > 200 copies/mL of 13% (95% CI 1–17%) and 22% (95% CI 11–33%) by 12 and 24 months. Female gender (adjusted relative hazard, ARH = 0.10; 95% CI 0.01–0.74; p = 0.024) and older age (AHR = 0.50 per 10 years older; 95% CI 0.25–0.99; p = 0.045) were associated with a lower risk of TF. A previous PI failure was strongly associated with TF (AHR = 52.6, 95% CI 3.6–779; p = 0.004). Conclusions: DRV/r + RAL is a valuable NRTI-sparing option, especially in female and older patients, with a relatively low risk of VF and good tolerability after 2 years since start in an ART-experienced population. However, previous PI-failure should be a limiting factor for this strategy

No impact of previous NRTIs resistance in HIV positive patients switched to DTG+2NRTIs under virological control: Time of viral suppression makes the difference

The accumulation of drug-resistance mutations on combined antiretroviral regimens (ART) backbone could affect the virological efficacy of the regimen. Our aim was to assess the impact of previous drug resistance to nucleoside reverse transcriptase inhibitors (NRTIs) on the probability of virological failure (VF) in patients, under virological control, who switched to dolutegravir (DTG)+2NRTIs regimens. All HIV-1 positive drug-experienced patients who started a regimen composed by DTG+2NRTIs [abacavir/lamivudine or tenofovir disoproxil fumarate (TDF) or tenofovir alafenamide (TAF)/emtricitabine (FTC)] in the ARCA collaborative group with HIV-RNA &lt;50 cp/mL were included in the analysis. Patients with a previous VF to integrase inhibitors were excluded. The impact of single and combined NRTIs mutations on the probability of VF (defined as 2 consecutive HIV-RNA &gt;50 copies/mL or one HIV-RNA &gt;1000 copies/mL) was assessed by Kaplan Meier curves. A multivariable Cox regression analysis was constructed to assess factors potentially related to VF. Five hundred and eighty-eight patients were included in the analysis with a median time of viral suppression before the switch of 37 months (IQR 12-78), of whom 148 (25.2%) had at least one previous NRTIs resistance mutation. In the multivariable model no association was observed between NRTIs mutations and VF. Conversely, the duration of viral suppression before switch resulted associated with a lower risk of VF (for 1 month increase, adjusted 0.98, 95%CI 0.96-0.99; p=0.024). Previous NRTIs mutations appeared to have no impact on the risk of VF in patients switched to DTG+2NRTIs, whereas a longer interval on a controlled viremia decreased significantly the risk of VF

Atazanavir-induced severe episodes of kidney stones in an HIV-1-infected subject characterized by a CYP3A poor metabolizer phenotype

Background: Atazanavir, an antiretroviral drug of the protease inhibitor class, is coadministered with ritonavir to inhibit atazanavir metabolism and decrease pharmacokinetic variability. Atazanavir is metabolised mainly by CYP3A4/5 enzymes. High CYP3A intersubject variability has been documented in most cases on a genetic basis. The CYP3A5*3 allele affects splicing defect and protein truncation. Recently a new intronic variant, CYP3A4*22, was found associated with reduced CYP3A4 activity. To assess whether an altered CYP3A activity impairs the metabolism of atazanavir, we investigated the two functional polymorphisms. To the best of our knowledge, this is the first case report showing that overexposure to ATV is associated with CYP3A poor phenotype and nephrolithiasis. Further study is needed in order to confirm this interesting observation. Case Presentation: We describe the case of a 43 year-old HIV-1-infected man treated with atazanavir/ritonavir plus lamivudine who experienced early and recurrent severe episodes of kidney stones. Atazanavir plasma trough concentrations showed a value higher than the normal range, thus we investigated the two polymorphisms that are known to affect CYP3A4/5 activity. This analysis revealed that our patient was a CYP3A poor metabolizer since he carried CYP3A4*1/*22 and CYP3A5*3/*3 genotypes. Conclusion: We suggest that screening of CYP3A functional variants is an appropriate approach, helping in treatment choice and potential dosage adjustment of protease inhibitors

Local epidemics gone viral: Evolution and diffusion of the Italian HIV-1 recombinant form CRF60_BC

The molecular epidemiology of HIV-1 in Italy is becoming increasingly complex, mainly due to the spread of non-B subtypes and the emergence of new recombinant forms. We previously characterized the outbreak of the first Italian circulating recombinant form (CRF60_BC), occurring among young MSM living in Apulia between the years 2009 and 2011. Here we show a 5-year follow-up surveillance to trace the evolution of CRF60_BC and to investigate its further spread in Italy. We collected additional sequences and clinical data from patients harboring CRF60_BC, enrolled at the Infectious Diseases Clinic of the University of Bari. In addition to the 24 previously identified sequences, we retrieved 27 CRF60_BC sequences from patients residing in Apulia, whose epidemiological and clinical features did not differ from those of the initial outbreak, i.e., the Italian origin, young age at HIV diagnosis (median: 24 years; range: 18-37), MSM risk factor (23/25, 92%) and recent infection (from 2008 to 2017). Sequence analysis revealed a growing overall nucleotide diversity, with few nucleotide changes that were fixed over time. Twenty-seven additional sequences were detected across Italy, spanning multiple distant regions. Using a BLAST search, we also identified a CRF60_BC sequence isolated in United Kingdom in 2013. Three patients harbored a unique second generation recombinant form in which CRF60_BC was one of the parental strains. Our data show that CRF60_BC gained epidemic importance, spreading among young MSM in multiple Italian regions and increasing its population size in few years, as the number of sequences identified so far has triplicated since our first report. The observed further divergence of CRF60_BC is likely due to evolutionary bottlenecks and host adaptation during transmission chains. Of note, we detected three second-generation recombinants, further supporting a widespread circulation of CRF60_BC and the increasing complexity of the HIV-1 epidemic in Italy

Polyclonal serum-free light chains elevation in HIV-infected patients.

We investigated the association between polyclonal serum-free light chains and prognostic biomarkers routinely used in the setting of HIV infection. For this purpose serum samples of 182 HIV-infected patients from the Italian Cohort of Antiretroviral Naive Patients foundation cohort were analysed. We found that polyclonal serum free light chains above the upper normal limit are strongly correlated in HIV-infected patients with advancing age, shorter time of undetectable HIV viremia, higher viral load and with lower CD4 cell count at sample

Predicting 2-drug antiretroviral regimen efficacy by genotypic susceptibility score: results from a cohort study

Background: HIV drug resistance has a deleterious effect on the virological outcome of antiretroviral therapy (ART). The aim of the study was to evaluate the ability of genotypic susceptibility score (GSS) to predict virological outcome following an ART switch to a 2-drug regimen in virosuppressed HIV-1 infected patients. Material and methods: From the ARCA database we selected HIV-1 infected patients virologically suppressed switching to 2-drug ART (2006-2018, time of switch=baseline), with pre-baseline resistance genotype and at least one HIV-1 RNA determination during follow up. Primary endopoint was virological failure (VF: an HIV-RNA, VL, ≥ 200 cps/mL or 2 consecutive ≥ 50 cps/mL). Survival analysis was used to investigate predictors of VF. The GSS predicted by the latest and the cumulative genotype (CGSS) was calculated using the Stanford hivdb (v.8.5) with respect to the 2-drug regimen started. CD4 changes from baseline at weeks 24, 48 and 96 were assessed using Student’s t-test for paired samples. Results: We included 773 patients: 522 (68%) were males, 186 (24%) heterosexuals, with median age of 50 years (IQR, 43-56), 10 years of HIV (5-20), 7 years of ART (4-15) and 5 (3-8) previous antiretroviral (ARV) lines. At baseline patients had been virologically suppressed for 6.4 years (2.5-14), allowing isolated blips. The median zenith VL was 4.9 log10 (4.4-5.5), CD4 cells count at nadir 222 (108-324) and at baseline 640 (477-860). Median GSS was 2 (1.5-2), with GSS &lt;2 in 213 (28%) pts, median CGSS was 2 (1-2), with CGSS &lt;2 in 250 (33%). The previous ARV classes used were NRTI in 770 patients (99%), NNRTI in 416 (54%), boosted PI in 639 (83%) and INSTI in 218 (28%). Current ARV regimens included: PI+3TC in 455 pts (59%), of which 3TC+ ATV unboosted or ATV/r or ATV/c in 181 (23%) and DRV/r or DRV/c in 274 (36%), DTG+3TC in 260 (34%) and DTG+RPV in 58 (7%). During a median observation time of 75 wks (IQR 37-120) the estimated probability of VF at 48 weeks was 6% (95% CI 5-7) among patients with GSS=2, 4% (3-5) among patients with GSS 1-1.99 and 11% (4-18) among those with GSS &lt;1 (Log Rank p=0.21). According to CGSS, the estimated probability of VF at 48 weeks was 5% (95% CI 1-6) among patients with CGSS =2, 6% (4-8) among patients with CGSS 1-1.99 and 8% (3-13) among those with CGSS &lt;1 (Log Rank p=0.006) (Fig 1). Observed median changes of CD4+ counts from baseline were +24 cells/μL (IQR -67;+132) at 24 weeks, +49 cells/μL (IQR -31;+159) at 48 weeks and +74 cells/μL (IQR -30; +197) at 96 weeks (p&lt;0.001 for all comparisons). At multivariate analysis, adjusting for years of ART, CD4 cell count at nadir and at baseline, CGSS strata, number of previous ARV lines, only longer time since last VL&gt;50 cps/mL was associated with lower risk of VF (+ 1 year, aHR 0.89, 95% CI 0.82-0.98; p=0.01). Conclusions: Despite an effect of CGSS, the duration of virosuppression was the only independent predictor of virological efficacy of switching to 2-drug regimens

Real-Life Impact of Drug Toxicity on Dolutegravir Tolerability: Clinical Practice Data from a Multicenter Italian Cohort

Dolutegravir (DTG) is currently one of the most used Integrase inhibitors (INI) in antiretroviral therapies (ARV) in both naïve and experienced people living with HIV (PLWHIV). We analyzed a multicenter cohort of PLWHIV, both naïve and experienced, starting an ARV including DTG. We enrolled 3775 PLWHIV: 2763 (73.2%) were males, with a median age of 50 years. During 9890.7 PYFU, we observed 930 discontinuations (9.4 per 100 PYFU). Estimated probabilities of maintaining DTG at three and five years were 75.1% and 67.2%, respectively. Treatment-naïve pts showed a lower probability of maintaining DTG at three and five years compared to treatment-experienced PLWHIV (log-rank p &lt; 0.001). At a multivariate analysis, a longer time of virological suppression (aHR 0.994, p &lt; 0.001) and having experienced a previous virological failure (aHR 0.788, p = 0.016) resulted protective against DTG discontinuation. Most discontinuations (84.0%) happened within the first 12 months of DTG initiation, in particular, 92.2% of discontinuations due to neuropsychiatric toxicity were observed in the first year. Our data confirm the overall good tolerability of DTG in clinical practice, with a low rate of discontinuations. CNS toxicity resulted the main reason for DTG discontinuation, with most related interruptions happening in the first year from DTG introduction

Risk of Severe Non AIDS Events Is Increased among Patients Unable to Increase their CD4+ T-Cell Counts >200+/μl Despite Effective HAART

Immunological non-response (INR) despite virological suppression is associated with AIDS-defining events/death (ADE). Little is known about its association with serious non-AIDS-defining events (nADE)

Improvement of lipid profile after switching from efavirenz or ritonavir-boosted protease inhibitors to rilpivirine or once-daily integrase inhibitors: Results from a large observational cohort study (SCOLTA)

Background: Dyslipidemia represents a significant non-infectious comorbidity among people living with HIV. The aim of this study is to evaluate the impact on lipid profile of switches from an efavirenz (EFV) or protease inhibitor/ritonavir (PI/r)-based regimen to a rilpivirine (RPV) or a once-daily integrase inhibitor-based regimen. Methods: We analyzed data from SCOLTA prospective database. All patients with HIV-RNA &lt; 50 copies/ml in therapy with two NRTI + EFV or PI/r were included if they switched from EFV to dolutegravir (group EFV-DTG), elvitegravir (EFV-EVG), or RPV (EFV-RPV) and from PI/r to DTG (PI/r-DTG), PI/r to EVG (PI/r-EVG), or PI/r to RPV (PI/r-RPV). Total cholesterol (TC), TC/HDL ratio, LDL-cholesterol (LDL) and triglycerides (TG) were compared at baseline, six months and one year. Comparisons among groups were performed by a general linear model. Results: Four hundred and ninety patients were enrolled, 24.9% female, mean age 47.3 years (\ub110.1). According to ART switch, 11.4% were classified in group EFV-DTG, 3.9% in EFV-EVG, 23.9% in EFV-RPV, 17.6% in PI/r-DTG, 17.8% in PI/r-EVG, and 25.5% in PI/r-RPV. After adjusted analysis, TC significantly decreased in all groups but EFV-EVG, TC/HDL in all but EFV-DTG and EFV-EVG, while the reduction of TG was significant only in switches to RPV (EFV-RPV and PI/r-RPV). The one year decrease of TC, TC/HDL, LDL and TG was higher in patients with higher baseline levels of the same variable (p &lt; .0001 for all). Conclusions: In SCOLTA, all switches from PI/r regimens gave advantages on lipid profile, while stopping EFV had consistently favorable lipid effects only if replaced by RPV