Hepatitis C reinfection following successful direct-acting antiviral therapy among patients attending a multidisciplinary treatment centre for people who use drugs in Zurich, Switzerland.

BACKGROUND AND AIM: On-going risk-exposure followed by reinfection may jeopardize hepatitis C elimination efforts among people who use drugs. We estimated the HCV reinfection incidence in patients who successfully completed HCV therapy and attended a low-threshold access centre for comprehensive addiction medicine. METHODS: Retrospective chart review was undertaken, in a convenience sample of patients with opioid/cocaine use disorders who achieved sustained viral response (SVR) after direct-acting antiviral (DAA) therapy in Zurich, Switzerland between April 2015 and July 2019 (n = 153). HCV reinfection incidence in patients with and without on-going drug use was calculated. RESULTS: 79% of the patients were in opioid agonist treatment, and 19% were being managed for other medical or psychiatric conditions. 58% used drugs after SVR, of whom 49% injected. The follow-up period totalled 346 (median 2.1) person-years (py). Overall HCV reinfection incidence was 1.2 (CI-95: 0.3 to 3.0) per 100 py and 1.6 (0.2 to 5.8) in patients with drug use after SVR. CONCLUSION: The risk of HCV reinfection after DAA therapy in persons who use drugs can be low if, after SVR, patients remain in care in a well developed comprehensive harm reduction setting.

Immune recovery in HIV-infected patients after Candida esophagitis is impaired despite long-term antiretroviral therapy.

OBJECTIVE: Candida esophagitis belongs to the most common AIDS-defining diseases; however, a comprehensive immune pathogenic concept is lacking. DESIGN: We investigated the immune status of 37 HIV-1-infected patients from the Swiss HIV cohort study at diagnosis of Candida esophagitis, 1 year before, 1 year later and after 2 years of suppressed HIV RNA. We compared these patients with three groups: 37 HIV-1-infected patients without Candida esophagitis but similar CD4 cell counts as the patients at diagnosis (advanced HIV group), 15 HIV-1-infected patients with CD4 cell counts higher than 500 cells/µl, CD4 cell nadirs higher than 350 cells/µl and suppressed HIV RNA under combination antiretroviral therapy (cART) (early cART group) and 20 healthy individuals. METHODS: We investigated phenotype, cytokine production and proliferative capacity of different immune cells by flow cytometry and enzyme-linked immunosorbent spot. RESULTS: We found that patients with Candida esophagitis had nearly abolished CD4 cell proliferation in response to Candida albicans, significantly increased percentages of dysfunctional CD4 cells, significantly decreased cytotoxic natural killer cell counts and peripheral innate lymphoid cell counts and significantly reduced IFN-γ and IL-17 production compared with the early cART group and healthy individuals. Most of these defects remained for more than 2 years despite viral suppression. The advanced HIV group without opportunistic infection showed partly improved immune recovery. CONCLUSION: Our data indicate that Candida esophagitis in HIV-1-infected patients is caused by an accumulation of multiple, partly Candida-specific immunological defects. Long-term immune recovery is impaired, illustrating that specific immunological gaps persist despite cART. These data also support the rationale for early cART initiation to prevent irreversible immune defects.

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.

Immune Reconstitution After Allogeneic Hematopoietic Stem Cell Transplantation and Association With Occurrence and Outcome of Invasive Aspergillosis.

BACKGROUND: Invasive aspergillosis (IA) remains a leading cause of morbidity and mortality in patients receiving allogeneic hematopoietic stem cell transplantation (HSCT). To date, no reliable immunological biomarkers for management and outcome of IA exist. Here, we investigated reconstitution of antifungal immunity in patients during the first 12 months after HSCT and correlated it with IA. METHODS: Fifty-one patients were included, 9 with probable/proven IA. We determined quantitative and qualitative reconstitution of polymorphonuclear (PMN), CD4, CD8, and natural killer (NK) cells against Aspergillus fumigatus over 5 time points and compared the values to healthy donors. RESULTS: Absolute CD4 and CD8 cell counts, antigen-specific T-cell responses, and killing capacity of PMN against A. fumigatus were significantly decreased in all patients over 12 months. In patients with probable/proven IA, reactive oxygen species (ROS) production tended to be lower compared to patients without IA, and absolute NK-cell counts remained below 200 cells/µL. Patients with well-controlled IA showed significantly higher ROS production and NK-cell counts compared to patients with poor outcome. CONCLUSIONS: This study highlights the importance of functional PMN, T-cell, and NK-cell immunity for the outcome of IA. Larger multicenter studies should address the potential use of NK-cell counts for the management of antifungal therapy.

Multispecific Aspergillus T cells selected by CD137 or CD154 induce protective immune responses against the most relevant mold infections.

BACKGROUND: Aspergillus and Mucorales species cause severe infections in patients after hematopoietic stem cell transplantation (HSCT). Induction of antifungal CD4(+) T-helper type 1 (Th1) immunity is an appealing strategy to combat these infections. Immunotherapeutic approaches are so far limited because of a lack of antigens inducing protective T cells, their elaborate production, and the need of targeting a broad spectrum of pathogenic fungi. METHODS: We examined the response to different Aspergillus fumigatus proteins in healthy individuals and patients after HSCT and compared rapid selection protocols for fungus-specific T cells based on CD137 or CD154 expression. RESULTS: The A. fumigatus proteins Crf1, Gel1, and Pmp20 induced strong Th1 responses in healthy individuals. T cells specific for these antigens expanded in patients with active invasive aspergillosis, indicating their contribution to infection control. Th1 cells specific for the 3 proteins can be selected with similar specificity within 24 hours, based on CD137 or CD154 expression. These cells recognize naturally processed A. fumigatus and the multispecific T-cell lines, directed against all 3 proteins, especially those selected by CD154, additionally cross-react to different Aspergillus and Mucorales species. CONCLUSIONS: These findings may form the basis for adoptive T-cell transfer for prophylaxis or treatment in patients with these devastating infections.

Triple-combination rilpivirine, emtricitabine, and tenofovir (Complera™/Eviplera™) in the treatment of HIV infection.

The combination rilpivirine (RPV)/emtricitabine (FTC)/tenofovir (TDF) is a once-daily, single-tablet regimen (STR) containing one nonnucleoside reverse-transcriptase inhibitor associated with two nucleos(t)ide reverse transcriptase inhibitors. It is approved by regulatory agencies (eg, US Food and Drug Association, European Medicines Agency) in all countries in which it is manufactured, except Switzerland, as first-line highly active antiretroviral therapy (HAART) for the treatment of naïve patients with HIV infection and a viral load HIV-RNA level of ≤100,000 copies/mL. Two large trials (ECHO and THRIVE) comparing RPV with efavirenz, along with different background regimens, led to approval of the drug, while a more recent trial (STaR) explored the use of STR. RPV showed noninferiority to efavirenz in all the studies, including superiority as an STR in patients with HIV-RNA ≤100,000 copies/mL in the STaR study. A positive CD4 cell response was observed in all the studies, both in the RPV and efavirenz groups. The incidence of virologic failures was higher for RPV, but was mostly referred to patients with HIV-RNA >100,000 copies/mL. There were fewer adverse events (AEs) with the RPV-based regimens versus efavirenz-based regimens, with a lower discontinuation rate because of AEs, especially psychiatric-neurological AEs, and a significantly lower rate of blood-lipid abnormalities. In the SPIRIT study (a switch study), significantly greater improvements from baseline in serum total cholesterol, low-density lipoprotein cholesterol, and trygliceride were demonstrated in patients switching to RPV/FTC/TDF from a ritonavir-boosted protease inhibitor (PI/r)-based regimen, than in those who continued treatment with a PI/r regimen. RPV's better tolerability, associated with its once-daily STR formulation, is key to improving patients' adherence and quality of life, which are among the most important factors affecting the therapeutic efficacy of an antiretroviral regimen. In summary, RPV/FTC/TDF STR is a valuable treatment option for the majority of antiretroviral-naïve HIV-infected patients. Furthermore, the use of this STR in the therapeutic switch, like in the SPIRIT study, can result in another valuable option by which to reduce AEs and improve patients' quality of life.

Inflammation markers correlate with common carotid intima-media thickness in patients perinatally infected with human immunodeficiency virus 1.

OBJECTIVES: To investigate common carotid intima-media thickness in a cohort of patients who were vertically infected with human immunodeficiency virus 1 (HIV-1). METHODS: We conducted a cross-sectional observational study. Human immunodeficiency virus 1-infected patients were compared with age-, sex-, and body mass index-matched healthy participants. Common carotid intima-media thickness was measured in all participants on both sides of the neck, and the mean intima-media thickness was calculated. Metabolic parameters and markers of inflammation were measured only in HIV-1-infected patients. Statistical analysis was performed by multiple regression and by a matrix of Pearson correlation coefficients. The Student t test was used to compare mean common carotid intima-media thickness values between groups. RESULTS: Forty patients (21 female) with HIV-1 infection acquired from birth with a mean age ± SD of 16.3 ± 4.7 years and 27 healthy participants (11 female) with a mean age of 17.7 ± 4.6 years were included in the study. Mean common carotid intima-media thickness in the HIV-1-infected group (0.450 ± 0.088 mm) was significantly higher (P < .05) than in the control group (0.407 ± 0.079 mm). No significant association was found between intima-media thickness and a specific antiretroviral regimen, exposure to combined antiretroviral agents, and HIV status. In multiple regression analyses, higher levels of insulin (P= .007) and elevated levels of glycated hemoglobin (P= .01) were associated with intima-media thickness changes. CONCLUSIONS: Patients perinatally infected with HIV have increased common carotid intima-media thickness compared with healthy individuals. These changes were more pronounced with increasing age and inflammation markers. Interventions that improve cardiovascular risk profiles should be considered in HIV-infected young adults.

Migration patterns of HIV-1 subtype B virus in Northern Italy.

Gene flow analysis is used to identify the migration patterns of viruses within a geographical area and /or in different populations. 883 HIV-1 B subtype pol gene sequences were analyzed. The gene analysis among different geographical areas of the Bergamo district and from different transmission risk groups showed 25% of the observed gene flow was from people living in the north valleys to lowland and 40.5% from a heterosexual risk group to injecting drug users. Injecting drug users seem to be the central link, mercenary sex being the common route of transmission (and gene flow) between this group and both heterosexual and homosexual individuals.

Ultrasensitive assessment of residual low-level HIV viremia in HAART-treated patients and risk of virological failure.

BACKGROUND: Low-level viremia (LLV) is measurable, with enhanced assays, in many subjects with HIV RNA levels <50 copies per milliliter. The clinical consequences of LLV are unknown. METHODS: In a prospective study in HIV-1-infected adults, HIV RNA levels were determined with an ultrasensitive test (3 copies/mL) based on a real time polymerase chain reaction. The primary end point was to evaluate LLV prediction of virological failure, defined as a confirmed plasma HIV RNA level >50 copies per milliliter. RESULTS: One thousand two hundred fourteen patients were followed for (mean) 378 days. At baseline, 71.5% were <3 copies per milliliter below the limit of detection (BLD). The risk of failing highly active antiretroviral therapy in the following 4 months for patients BLD was 0.4% compared with a 3.2% risk for those with LLV (P < 0.0001; odds ratio: 7.52). There was a significant (P < 0.0001) linear relationship between the HIV RNA and the risk of virologic failure. LLV receiver operating curve analysis showed an area under the curve of 0.76 (95% confidence interval: 0.68 to 0.84) that significantly (P < 0.0001) predicted the risk of failure. The risk of an unconfirmed viral blip was higher in patients with LLV (3.9%) than in those BLD (1.1%) (P < 0.0001; odds ratio: 3.56). Longer exposure to antiretrovirals, current use of nonnucleoside reverse transcriptase inhibitors, longer time BLD, and current HIV RNA <3 copies per milliliter were independent predictors of a positive outcome. INTERPRETATION: Viral replication may be the cause of LLV, at least in some patients. A LLV >3 copies per milliliter is linked to a significant increment of risk of virological failure leading to drug resistance. Patients with measurable LLV should be managed to better evaluate, over time, the risk of failure and to limit its consequences.

Safety and efficacy of pegylated interferon and ribavirin in adolescents with human immunodeficiency virus and hepatitis C virus acquired perinatally.

Limited evidence is available currently regarding the efficacy and safety of pegylated interferon (PEG-IFN) and ribavirin in patients co-infected perinatally with human immunodeficiency virus (HIV) and hepatitis C virus (HCV). No information is available on whether or not these patients should be treated earlier for infection with HCV. This report describes four patients with HIV and HCV co-infection acquired perinatally, who were treated with PEG-IFN and ribavirin for chronic viral hepatitis caused by HCV.

Potential prodrugs of non-steroidal anti-inflammatory agents for targeted drug delivery to the CNS.

Recently non-steroidal anti-inflammatory drugs (NSAIDs) have been proposed to prevent or to cure Alzheimer's disease. In this respect, we synthesized new potential prodrugs of several NSAIDs in order to increase their access to the brain. The carboxylic group of NSAIDs was attached to the 1,4-dihydro-1-methylpyridine-3-carboxylate moiety, which acts as a carrier, via an amino alcohol bridge, according to the chemical delivery approach developed by Bodor. The lipophilicity of potential prodrugs was evaluated both via traditional experimental parameters, such as partition coefficient and chromatographic R(m) value, and by predictive computational methods. From experimental parameters, all prodrugs were more lipophilic when compared to their corresponding parent compounds and consequently a better blood brain barrier (BBB) penetration is hypothesised. Prodrug lipophilicity was correlated with a calculated log P value according to Kowwin's method. The correlation between experimental Rm0 and calculated log P, determined by PLS analysis, was good for all compounds with the exception of compound 7i. In addition the BBB permeation profile of our synthesized compounds was predicted using the BBB VolSurf model and seven of the synthesized prodrugs resulted in good candidates for BBB penetration.

Drugs and non-medical products sold in pharmacy: information and advertising.

This paper is the third part of a survey about patient information and the use of patient package leaflet. The aim of this research section is to analyse the role of the pharmacy and the pharmacist in the health-care field. By means of answers of interviewed people, informations were obtained about the purchase of drugs and other products in pharmacy, the consumer requirements, the non-medical products and self-medication channels of information, the patient-physician and patient-pharmacist quality of communication and the role of advertising for drugs and other products sold in pharmacy. From this survey, it emerged that most of the respondents go to pharmacy to purchase drugs exclusively and only a small number of people go to purchase other products. The pharmacist does not play a remarkable role in providing health information to the patient.