Association of HIV Infection with Epilepsy and Other Comorbid Conditions.

Here, we aimed to investigate the associations of comorbidities in HIV patients given antiepileptic drugs. HIV patients given antiepileptic drugs for at least 6 months were considered. Comorbidities of the epileptic, HIV-positive patients were stratified according to patients' age and causes of epilepsy. Seventy-four of the 97 HIV patients identified had at least one comorbidity. Patients more than 50-years old had more comorbidities (1.9 ± 1.5 vs. 1.1 ± 1.2, p < 0.01) compared with younger subjects. The distribution of the psychiatric disorders was comparable between age-related categories. A marginally significant trend for higher frequency of psychiatric disorders was observed in patients with idiopathic epilepsy versus other causes of epilepsy (43% vs. 24%), Because the presence of comorbid disorders is a major driver for premature mortality both in HIV infection and epilepsy, strategies aimed at favoring prevention, early identification, and adequate treatment in these clinical settings should be pursued at all levels of care.

Polypharmacy and Aging in People Living with HIV: 6 Years of Experience in a Multidisciplinary Outpatient Clinic.

BACKGROUND: Despite the availability of potent antiretroviral drugs, the management of human immunodeficiency virus (HIV) infection still presents some important challenges, especially in older patients who often experience age-related comorbidities and complex polypharmacy. OBJECTIVE: To describe the results of our 6 year experience with the outpatient clinic [Gestione Ambulatoriale Politerapie (GAP)] for the management of polypharmacy in people living with HIV (PLWH). METHODS: Demographic characteristics, antiretroviral regimens, and number and type of comedications were collected in all PLWH included in the database of GAP from September 2016 to September 2022. Therapies were stratified based on the number of anti-HIV drugs (dual versus triple regimens) and on the presence of pharmacokinetic boosters (ritonavir or cobicistat). RESULTS: A total of 556 PLWH were included in the GAP database. Overall, the enrolled patients were administered 4.2 ± 2.7 drugs (range 1-17) in addition to antiretroviral therapies. The number of comedications greatly increased with age (3.0 ± 2.2 versus 4.1 ± 2.5 versus 6.3 ± 3.2 in PLWH aged < 50 versus 50-64 versus > 65 years; p < 0.001 for all comparisons). PLWH on dual antiretroviral therapies were significantly older (58 ± 9 versus 54 ± 11 years; p < 0.001) and were concomitantly treated with more drugs (5.1 ± 3.2 versus 3.8 ± 2.5; p < 0.001) compared with those on triple therapies. A significant reduction of boosted antiretroviral regimens (53% versus 23%; p < 0.001) and in the number of comedications (4.0 ± 2.9 versus 3.1 ± 2.2 drugs; p < 0.001) was observed in the subgroup of patients (n = 198) with two GAP visits. CONCLUSIONS: The high prevalence of polypharmacy in PLWH, especially among older adults, place these patients at high risk for clinically relevant drug-drug interactions (DDIs). A multidisciplinary approach involving physicians and clinical pharmacologists could help to optimize medication regimens associated with reduced risk.

Evaluation of the concentrations of psychotropic drugs in HIV-infected versus HIV-negative patients: Potential implications for clinical practice.

Objectives: The management of psychiatric illness in HIV-infected patients is clinically challenging because of the risk of potential drug-drug interactions. Here, we aimed to measure the antidepressant and/or antipsychotic drug concentrations in HIV-infected patients during routine outpatient visits.Methods: Six hundred HIV-infected patients were screened during the first 15 months after the introduction of our outpatient polytherapy management service in a search for subjects treated with psychotropic drugs for at least 3 months. The distribution of psychotropic drug concentrations in HIV-infected patients was compared with that observed in a control group of HIV-negative patients monitored over the same period.Results: The search identified 82 HIV-infected patients concomitantly receiving antiretroviral and psychotropic drug treatment, 55% of whom had plasma psychotropic drug concentrations that were below minimum effective levels. The same result was found in only 26% of the samples taken from HIV-negative patients. These results were not affected by patients' gender, age, adherence to therapies or drug-drug interactions.Conclusions: A higher rate of sub-therapeutic antidepressant and/or antipsychotic drugs concentrations were found in HIV-infected patients. The creation of multidiscliplinary specialist teams may contribute to improving the management of such complex patients.

Assessment of Antiepileptic Drug Concentrations in HIV-Infected versus HIV-Negative Patients: A Retrospective Analysis.

INTRODUCTION: A higher rate of subtherapeutic psychotropic drug concentrations was recently found in HIV-infected versus HIV-negative patients. In this study, we sought to investigate if this trend could also apply to antiepileptic drugs. METHODS: Overall, 700 HIV-infected patients were screened during the first 2 years after the introduction of our outpatient polytherapy management service (Gestione Ambulatoriale Politerapie [GAP]) in the search for subjects with antiepileptic drug trough concentration assessments. The distribution of such concentrations was compared with that in HIV-negative patients monitored over the same period. RESULTS: The search identified 97 HIV-infected patients concomitantly receiving antiretroviral and antiepileptic drugs, for a total of 310 drug measurements. Overall, 30%, 64% and 6%, versus 28%, 65% and 7%, of the antiepileptic concentrations measured in HIV-infected versus HIV-negative patients (1090 patients, for a total of 3488 antiepileptic concentrations measured) were below, within, or above the therapeutic targets, respectively. The antiepileptic drug valproate was associated with the highest risk of subtherapeutic drug concentrations, with 57% and 46% of determinations below the therapeutic range in HIV-positive and HIV-negative patients, respectively. Remarkably, the concentrations of valproate were significantly lower in HIV-infected versus HIV-negative patients (47.9 ± 21.2 versus 53.9 ± 21.6 mg/L; p < 0.05). CONCLUSION: In our retrospective study, most HIV-infected patients had antiepileptic drug concentrations falling within the therapeutic targets, with the exception of valproate, which was associated with a higher rate of subtherapeutic concentrations compared with other antiepileptic drugs.

Pharmacokinetic drug evaluation of dolutegravir plus rilpivirine for the treatment of HIV.

INTRODUCTION: The search for simple, potent, metabolic-friendly and nucleoside/nucleotide sparing antiretroviral regimens has led clinical investigators to move steps towards dual therapies. Among these the association of rilpivirine and dolutegravir is emerging as a twin randomized clinical trial (SWORD1&2) and at least three observational cohort describe it as a safe and highly effective regimen for switch from other therapies Areas covered: We review the evidence supporting the use of dolutegravir plus rilpivirine for the treatment of HIV in virologically suppressed patients taking other antiretroviral regimens. The reasons for the switch in clinical practice may range from simplification to tolerability/toxicity issues, to the prevention of future metabolic damage, to predicted drug-drug interactions when treatment of HCV co-infection is planned. Articles searchable on MEDLINE/PubMed and from the main international congresses in the field of HIV therapy were reviewed to provide context for use of dolutegravir plus rilpivirine Expert opinion: This treatment is highly effective in maintaining HIV-1 RNA <50 copies/mL. Although the studies up to date requested patient to switch to drugs they had no experience of, a predictable 'radical change' effect did not impact negatively on the results. Further data from these studies may help elucidate the possible advantage in terms of safety and metabolic effect in the next few months.

Cost-effectiveness analysis of antiretroviral therapy in a cohort of HIV-infected patients starting first-line highly active antiretroviral therapy during 6 years of observation.

OBJECTIVES: Costs may play a role in deciding how and when to start highly active antiretroviral therapy (HAART) in a naïve patient. The aim of the present study was to assess the cost- effectiveness of treatment with HAART in a large clinical cohort of naïve adults to determine the potential role of single-tablet regimens in the management of patients with human immunodeficiency virus (HIV). An incremental cost-effectiveness ratio analysis was performed, including a quality-adjusted life year approach. RESULTS: In total, 741 patients (females comprising 25.5%) were retrospectively included. The mean age was 39 years, the mean CD4 cell count was 266 cells/µL, and the mean viral load was 192,821 copies/mL. The most commonly used backbone was tenofovir + emtricitabine (77.6%); zidovudine + lamivudine was used in 10%, lamivudine + abacavir in 3%, and other nucleoside reverse transcriptase inhibitor (NRTI) or NRTI-free regimens in 9.4% of patients. NNRTIs were used in 52.8% of cases, boosted protease inhibitors in 44.1%, and unboosted protease inhibitors and integrase inhibitors in 0.7% and 2.4%, respectively. Starting therapy at CD4 >500 cells/µL and CD4 351-500 cells/µL rather than at <201 cells/µL was the more cost-effective approach. The same consideration was not true comparing current indications with the possibility to start HAART at any CD4 value (eg, >500 cells per µL); in this case, the incremental cost-effectiveness ratio value was €199,130 per quality-adjusted life year gained, a higher value than the one suggested in guidelines. The single-tablet regimen (STR) invariably dominated any other therapeutic approach. Sensitivity analysis was performed, and starting right away with an STR was cost-effective even when compared with therapeutic strategies contemplating STR as simplification. CONCLUSION: By integrating clinical data with economic variables, our study offers an estimate of the cost-effectiveness of the various first-line treatment strategies for patients infected with HIV and provides significant evidence to be used in future prospective pharmacoeconomic evaluations.

Risk of Liver Enzyme Elevation During Treatment With Ritonavir-Boosted Protease Inhibitors Among HIV-Monoinfected and HIV/HCV-Coinfected Patients.

BACKGROUND: The risk of liver enzyme elevation (LEE) after different ritonavir-boosted protease inhibitors (PI/r) has not been fully assessed in real-life settings and in populations with high rates of hepatitis C virus (HCV) coinfection. METHODS: Patients introducing a new PI/r between 1998 and 2012 were included, if transaminases and HCV antibody (Ab) were assessed before treatment initiation. Time to grade 3 and 4 LEE were assessed using univariable and multivariable conditional Cox analyses, stratified by HCV serostatus. RESULTS: A total of 6193 HIV-infected patients (3242 HCV-Ab negative and 2951 HCV-Ab positive) were included. Incidence of grade 3 LEE was 1.05, 7.66, and 8.08 per 100 patient-years of follow-up among HCV-Ab negative, HCV-Ab-positive and HCV-RNA-positive patients, respectively. Among HCV-Ab-negative patients, no differences were detected between different PI/r. Use of darunavir/ritonavir was not associated with LEE among HCV-coinfected patients. Atazanavir/ritonavir use was associated with grade 3 LEE but only among HCV-Ab-positive patients (versus LPV/r, hazard ratio: 1.39; 95% confidence interval: 1.1 to 1.75). This risk was not confirmed in a subanalysis restricted to HCV-RNA-positive patients (versus LPV/r, hazard ratio: 1.16; 95% confidence interval: 0.87 to 1.55). Other independent predictors of grade 3 LEE among HCV-Ab-positive patients were older age, male gender, being treatment naive, nonnucleoside reverse transcriptase inhibitor coadministration, increased aspartate aminotransferase at baseline, overweight, positive HCV-RNA, and advanced estimated liver fibrosis. CONCLUSIONS: Occurrence of hepatotoxicity was a rare finding among HCV-Ab-negative patients and was not influenced by the type of PI/r. In particular, the use of darunavir/ritonavir, previously linked with severe cases of hepatotoxicity, was not associated with a greater risk of LEE, irrespective from HCV serostatus.

Single-Tablet Regimens in HIV Therapy.

Combined antiretroviral therapy (cART) has evolved considerably over the past decades leading to a better control of human immunodeficiency virus replication. Recently, regimens have evolved so as to simplify dosing frequency and reduce pill burden to improve adherence. Several national and international guidelines suggest antiretroviral (ARV) regimen simplification as a method of improving adherence. Decreased cART adherence has been associated with both patient-related factors and regimen-related factors. Adherence rates are statistically higher when simpler, once-daily (OD) regimens are combined with smaller daily regimen pill burdens. The avoidance of selective non-adherence, where a patient takes part of a regimen but not the full regimen, is a further potential benefit offered by single-tablet regimens (STRs). Simplification of cART has been associated with a better quality of life (QoL). Although tempered by other factors, better adherence, higher QoL and patients' preferences are all key points which might combine to assure long-lasting efficacy and durability of cART. All studies underlined the favorable tolerability profile of newer STRs. Three STRs are currently available. Tenofovir (TDF) plus emtricitabine (FTC)/efavirenz (EFV) was the first OD complete ARV regimen available as a STR. TDF plus FTC/rilpivirine is a second-generation STR. The most recently approved STR, TDF plus FTC/cobicistat/elvitegravir, is the first non-nucleoside reverse transcriptase inhibitor-based STR. All of them have shown excellent efficacy; safety and tolerability have been improved by more recent formulations. Several other STRs are anticipated both combining completely different drugs, abacavir (ABC) plus lamivudine (3TC)/dolutegravir, utilizing innovative formulations of older drugs, tenofovir alafenamide fumarate, or taking advance of bioequivalent drugs, lamivudine (3TC) plus ABC/EFV. The future challenge would be to develop completely alternative STRs (including for example protease inhibitors or new molecules) to extend the advantages of simplicity to heavily pre-treated individuals.

Switching from an EFV-based STR to a RPV-based STR is effective, safe and improves HIV patients health status.

INTRODUCTION: TDF/FTC/RPV has been shown effective in both naïve and PI-pre-treated patients. Less is known about a switch strategy in subjects receiving EFV. MATERIALS AND METHODS: We evaluated viro-immunologic outcomes, Quality of Life (QoL) and costs of an unselected cohort of patients switching from a TDF/FTC/EFV STR (≥6 months duration) to a TDF/FTC/RPV STR. The considered outcome measures were quality-adjusted life years (QALYs) as measured with the EQ5D questionnaire and the overall direct health costs. 64 patients with a baseline viral load<50 copies/mL were randomized to immediately switch therapy or to continue TDF/FTC/EFV for four months and then switch to TDF/FTC/RPV. Six patients in the deferred switch group did not actually change cART. RESULTS: Patients were mostly males (73.4%) with a mean age of 46 years, a baseline mean HIV-RNA of 6.4 copies/mL and a mean baseline CD4 count of 588 cells/µL. For the considered follow-up period, the mean cost per patient resulted 2,563 for TDF/FTC/RPV and 2,572 for TDF/FTC/EFV. Viremia remained undetectable and CD4 stable in all patients. Over time the mean QoL increased in the RPV arm ad slightly decreased in the EFV arm, after four months the mean per patient QALYs was 0.849 for RPV and 0.841 for EFV, respectively (Figure 1). A sharp increment of QoL was observed in the deferred-switch arm after switch, too. VAS analysis of health status perception also increased overall from 82.78 to 83.79 due to the improvement in the RPV arm. Mean cholesterol levels improved in the RPV arm from 203 to 170 mg/dL, while an increment from 190 to 207 mg/dL was observed in the EFV arm. HDL levels lowered from 49 to 45 and rose from 53 to 54 mg/dL in the RPV and EFV arms, respectively. Triglycerides levels improved both in the RPV arm (from 138 to 112 mg/dL) and in the EFV arm (from 110 to 103 mg/dL). CONCLUSIONS: Switching from TDF/FTC/EFV to TDF/FTC/RPV is a safe, well tolerated strategy that improves the overall health status of HIV-treated patients. The switch does not expose patients to a risk of virologic failure due to possible PK interactions of the drugs. RPV compared to EFV proved to be cost-effective showing lower cost and higher outcome measure values.

Early clinical response and presence of viral resistant minority variants: a proof of concept study.

INTRODUCTION: Traditional genotyping assays detect viral variants present in at least 15-25% of the entire virus population. We tested the Next generation GS Junior System (NGS) setted with a detection limit of 0.05% and evaluated the clinical relevance of low prevalent mutations. METHODS: NGS was performed on the plasma of 26 infected individuals who started a TDF/FTC/RPV (15 subjects) or TDF/FTC/EFV (11 subjects) cART after a routine HIV-1 drug-resistance negative test by Viroseq HIV-1 Genotyping System. Amplicon Sequencing of HIV-1 RT and PR Plate (Roche) was performed following the manufacturer's instructions. HIV-1 variants were analyzed by a specific HIV-1 tool by AVA software v. 2.7. The updated IAS resistance mutations list (March 2013) was considered for the analysis of resistance positions. Patients were followed testing viral load and immunologic parameters. RESULTS: Twenty four males and two females with a mean age of 43 years were included. Twenty-one were nave for cART. At baseline, median HIV-RNA was 4.57 log copies/mL (range 2.15-6.57) and CD4 count 315 cells/mcL (range 16-648). In 18 patients, NGS did not detect any additional variant relevant for the selected cART compared to population genotyping. In the remaining eight patients resistance conferring mutations to part of the ongoing regimen were detected. Single mutations E138K (two cases) and M184V in three distinct patients and V90I+G190E; M184V+A98S; Y215F+V118I+T215I; L210S+T215I+F227L; and A62V+D67G+K70N+188H in the remaining five subjects. In all cases, the mutation prevalence was inferior to 5%. The mean daily reduction of VL was -3759 copies/mL in patients without NGS detected mutations and -1045 copies/mL in those with mutations. The median KM estimates for reaching an HIV-RNA blood level <50 copies/mL were 127 days and 161 days, respectively. One patient without baseline resistance selected for M184I+E138K+T215I (NGS) after four months of TDF/FTC/RPV therapy. CONCLUSIONS: NGS detected low-frequency HIV-1 variants harbouring RT drug resistance mutations that could have affected the therapy outcome. However, viral decay in an early cART phase was not affected by the presence of resistant minority variants. The low prevalence of the detected mutation, the limited effect on the combination regimen and the potency of cART components could be possible explanations of our findings. Longer follow-up and larger casuistries are needed to determine the clinical relevance of NGS in routine clinical practice and eventually define a clinically relevant mutations' prevalence.

Long-term effect of a four-drugs induction regimen for patients with high baseline viral load.

INTRODUCTION: The long-term effects of an intensified induction regimen are unknown. In this pilot, randomized, prospective study we evaluate the effect of a short-term four-drugs induction regimen in patients with high baseline viral load. METHODS: Naive patients with HIV-RNA>100.000 copies/ml receiving TDF+FTC+EFV+RAL (group ER) for 4 months and were then simplified to TDF+FTC+EFV. Two randomized control groups treated ab-initio with TDF+FTC+EFV (E) or TDF+FTC+RAL (R) were used. RESULTS: 19 patients with a mean age of 38 years and mean baseline CD4 count of 334 (SD 216) cells/mcL and HIV-RNA of 5.47 log (SD 0.32) copies/mL were enrolled. No baseline significant difference was observed among groups. Early HIV-RNA reduction was significantly higher in ER compared to the other groups from week 1 to week 4 (P from 0.026 to 0.003) (figure 1), thereafter HIV-RNA values were comparable among the groups. At week 96, all patients had an HIV-RNA < 50 copies/mL, however only patients in the ER group had in all cases an HIV-RNA level < 3 copies/mL with a statistically significant difference compared to E (60%; P=0.038) and R (50%; P=0.020). At 96 weeks, CD4 cell median counts were 765 cells/mcL for ER, 600 cells/mcL for E and 771 for R (P=0.16), however patients in the ER group presented a lower proportion of activated CD4+CD38+HLADR+ cells (1.9% versus 3.9 and 3.8%) and CD8+CD38+HLADR+ cells (10.3% versus 16.8 and 16.5%) and a significantly better CD4/CD8 ratio (0.98 versus 0.53 and 0.61; P=0.03). CONCLUSIONS: A four-drug regimen in naive patients with high pre-therapy viral load improves early virologic response. A quick drop of HIV-RNA seems to correlate with a sustained virologic response. Although limited in time (four months), the four-drug regimens correlates with an improved immunological response as measured by the CD4/CD8 ratio or the percentage of activated CD4+ and CD8+ cells. The reasons why this happens deserve further studies. This study highlights the importance of a personalised therapy especially in high risk patients.