Andrea Giacomelli

Effect of Cobicistat on Tenofovir Disoproxil Fumarate (TDF): What Is True for TAF May Also Be True for TDF

Background: The dose of tenofovir alafenamide is reduced from 25 to 10 mg daily when given with boosting agents. However, such dose reduction has never been adopted for tenofovir disoproxil fumarate (TDF). In this study, we aim to quantify the effect of cobicistat (COBI) both on tenofovir concentrations and TDF durability in real life setting. Methods: HIV-positive patients receiving TDF-containing antiretroviral therapies with at least 1 assessment of tenofovir plasma trough concentrations were included in the study. Univariate and multivariate regression analyses were performed considering tenofovir concentration as the dependent variable and clinical characteristics as independent covariates. Subsequently, survival and Cox analyses were performed considering as the primary outcome TDF discontinuation for any reasons. Results: Patients were given TDF with protease inhibitors/ritonavir (n = 212), non–nucleoside reverse transcriptase inhibitors (n = 176), integrase inhibitors (dolutegravir or raltegravir, n = 46), or with elvitegravir/COBI (ELV/COBI) (n = 76). By multivariate analysis, concomitant antiretroviral therapies resulted significantly associated with tenofovir levels, with the highest drug concentrations measured in patients given ELV/COBI. By survival analysis, we found that patients given TDF with ELV/COBI had the lowest rate of drug durability. Overall, these patients had a 2.3-fold increased risk to experience TDF discontinuation. Conclusions: Coadministration with COBI resulted in significantly higher tenofovir concentrations and higher TDF discontinuation compared with other antiretroviral regimens. Accordingly, the possibility that the lack of proper dose adjustment for TDF when given with COBI might have biased the safety comparisons with tenofovir alafenamide during registrative trials cannot be ruled out.

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

Abstract 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.

Clinical and genetic determinants of nevirapine plasma trough concentration

Background: Only few data are available on the influence of CYP2B6 and CYP3A4/A5 polymorphisms on nevirapine plasma concentrations in the Caucasian population. Our aim was to assess the impact of CYP2B6 and CYP3A4/A5 polymorphisms on nevirapine plasma concentrations consecutively collected. Methods: We retrospectively analyzed clinical data of all HIV-positive patients who were followed at the Infectious Diseases Unit, DIBIC Luigi Sacco, University of Milan between January 2000 and December 2015. All patients with at least one nevirapine plasma trough concentration (NVP Cmin) determination were tested for CYP2B6 c.516 G>T, CYP3A4*22C>T and CYP3A5*3 A>G polymorphisms. Univariate and multivariate regression analyses were carried out considering NVP Cmin as the dependent variable and genetic polymorphisms and clinical characteristics as independent variables. Results: A total of 143 patients were evaluated. Most of them were males (61.5%) and Caucasian (92.3%). Overall, NVP Cmin varied from 1571 to 14,189  ng/mL (median  =  5063  ng/mL, interquartile range  =  3915–6854). The median NVP Cmin significantly differed in patients with different CYP2B6 genotypes, but did not vary in those with different CYP3A phenotypes. In the final general linear model, factors significantly associated with a higher NVP Cmin were each extra unit of T alleles of CYP2B6 rs3745274 (β  =  0.328, 95% confidence interval  =  0.172–0.484; p  <  0.0001), older age (β  =  0.362, 95% confidence interval  =  0.193–0.532; p  <  0.0001) and hepatitis C virus coinfection (β  =  0.161, 95% confidence interval  =  0.006–0.315; p  <  0.041). Conclusion: Our study, conducted in a prevalent Caucasian population, highlighted the importance of CYP2B6 genetic variants in influencing nevirapine plasma trough concentration. Furthermore, older age and hepatitis C virus coinfection significantly increase exposure to nevirapine.

Loss of Control of HIV Viremia With OTC Weight-Loss Drugs: A Call for Caution?: Antiretroviral and Weight-Loss Drug Interactions

Improved survival achieved by HIV‐infected patients has complicated their medical care, as increasing numbers of comorbidities have led to polypharmacy and a higher risk of drug–drug interactions. Here, evidence is provided that weight‐loss drugs should be used with caution in HIV‐infected patients treated with lipophilic antiretroviral drugs because of the risk of virologic failure. This is particularly relevant considering that these agents are available on the market as over‐the‐counter medications, thus escaping the control of the physician.

RNA Viruses and Autoimmunity: A Short Overview

RNA viruses are a large group of widespread and extremely prevalent pathogens capable of eliciting a broad spectrum of innate and adaptive immune responses. Additionally, persistent infection by some RNA viruses can induce or enhance accelerated immune activation. The hypothesis that molecular mimicry is implicated in autoimmunity was first proposed in 1987. Since then, a growing evidence from medical literature of a possible role for viral infection in autoimmunity has risen. In particular, enteroviruses have been investigated as possible causes of type 1 diabetes. Some hypotheses have put forward the possible implication of hepatitis A virus in autoimmune phenomena. The two most prevalent RNA viruses causing chronic infection, hepatitis C virus and human immunodeficiency virus type 1 (HIV-1), are both associated with autoimmune disorders. HCV can trigger and sustain a clonal B-cell expansion which causes a wide spectrum of autoimmune/lymphoproliferative disorders, through a multistep process. Similarly, HIV is responsible for derangement of the immune regulation and is associated with some autoimmune disorders, such as autoimmune thrombocytopenia. Nevertheless, a formal scientific demonstration of an etiological relationship between any RNA virus and a major autoimmune disease has not yet been obtained.

Factors involved in continuance of atazanavir-based regimens: Results from a cohort of HIV1-positive patients.

We evaluated predictive factors involved in durability and therapeutic failure of atazanavir (ATV)-based antiretroviral regimens with or without ritonavir (r) in real life setting. This retrospective study of HIV-1-positive patients evaluated the factors related to ATV continuance and the time-dependent probability of therapeutic failure (HIV-RNA >200 copies/mL and concomitant discontinuation of ATV). We also investigated the rate of therapeutic failure and the variations in total bilirubin levels from starting unboosted ATV-based regimens. The study involved 1030 patients: 183 treatment-naïve patients (17.8%) started ATV/r (17 subsequently switched to unboosted ATV); 653 (63.4%) switched to ATV/r from previous antiretroviral regimens (121 subsequently switched to unboosted ATV); and 194 (18.8%) switched to unboosted ATV from previous ATV-free regimens. The median ATV follow-up was 28 months (interquartile range 7-56). The risk of ATV discontinuation was significantly lower in patients switched to unboosted ATV from ATV/r (HR 0.45; p < 0.0001). The discontinuation of ATV correlated with female gender (HR 1.26; p = 0.035), use of a zidovudine/didanosine/stavudine containing backbone (HR 1.8; p = 0.004), and a baseline CD4+ cell counts of <200/μL (HR 1.54; p = 0.003), the last of which was also associated with a higher risk of therapeutic failure (HR 2.42; p = 0.001). Total bilirubin levels were significantly lower in the patients switching from ATV/r to unboosted ATV. Unboosted ATV-based therapies are safe and effective options in patients whose immuno-virological conditions are stable, and allow the long-term survival of ATV-containing regimens.

Factors involved in treatment durability and immunological recovery in a cohort of HIV-positive patients receiving atazanavir-based regimens.

Since antiretroviral therapy must be taken lifelong, persistence and safety have become the goals to achieve. Protease inhibitors, in particular atazanavir (ATV) with or without ritonavir (r), represent a highly prescribed class in real life long‐term treatment.

Predictive factors of therapeutic success of a HAART regimen including atazanavir with or without ritonavir in HIV-infected patients

To evaluate the factors that may influence the persistence and the virological failure of an atazanavir (ATV)‐containing antiretroviral regimen. We conducted a retrospective cohort study in HIV‐positive patients (pts) who were being followed at the Infectious Diseases Division, University of Milan. Data regarding viral load, CD4 lymphocytes and the blood chemistry parameters were collected at 1st, 3rd, 6th months from the beginning of therapy and then every six months. Factors related to persistence of therapy with ATV and virological failure (HIV‐RNA>50cp/mL after six months) were evaluated with Kaplan‐Meier curve, Cox model and logistic regression. 574 pts were evaluated: 480 experienced therapy with ATV with ritonavir (ATV/r) (80 naïve), 218 with unboosted ATV (5 naïve) and 124 with both regimens. At baseline: median age of 43 years (IQR 39–48), CD4+median count 418 cell/mm3 (IQR 277–606), VL<50cp/mL in 370 pts (54.4%), and median duration of infection 12 years (IQR 6–18). The median duration of therapy was 21 months (IQR 7–49) in pts treated with ATV/r and 22 months (IQR 8–44) with unboosted ATV. We observed a borderline significant difference for the persistence of the regimen between the two groups (p=0.05) that disappears after removing the suspensions for simplification. Pts treated with ritonavir (OR=1.563; 95% CI 1.058–2.308, p=0.025) and with a backbone containing AZT‐ddI‐d4T (OR=3.34; 95% CI 1.873–5.956, p<0.001) had an increased risk of therapy suspension, whereas starting therapy with ATV in recent years resulted protective (OR=0.741; 95% CI 0.678–0.809, p<0.001). The suspension for toxicity was not significantly different between pts treated with ATV/r and unboosted ATV. No significant difference between the two therapies was observed regarding virological failure. Of note, pts with an elevated VL at baseline (OR 1.234; 95% CI 1.065–1.429, p=0.005) and male gender (OR 1.667; 95% CI 1.06–2.621, p=0.027) were at elevated risk of failure, whereas a backbone containing AZT‐ddI‐d4T (OR 0.356; 95% CI 0.196–0.638, p=0.001) and a recent year of starting ATV (OR 0.64; 95% CI 0.579–0.71, p<0.001) are protective factors. No significant difference between pts treated with ATV/r or unboosted was observed regarding the induction of hyperbilirubinemia of ACTG grade III and IV. Treatment with unboosted ATV can last longer than that with ATV/r without an increased risk of therapeutic failure. A comparable safety profile was seen for pts who received ATV/r or unboosted ATV.