Risk of Cardiovascular Events in People with HIV (PWH) Treated with Integrase Strand-Transfer Inhibitors: The Debate Is Not Over; Results of the SCOLTA Study.

Cardiovascular disease (CVD) is common in people with HIV (PWH), and has great impact in terms of morbidity and mortality. Several intertwined mechanisms are believed to play a role in determining the increased risk of CVD, including the effect of certain antiretrovirals; among these, the role of integrase strand-transfer inhibitors (INSTIs) is yet to be fully elucidated. We conducted a multicenter, observational study comprising 4984 PWH evaluating the antiretroviral therapy (ART)-related nature of CVD in real life settings, both in naïve vs. treatment-experienced people. A comparison was conducted between INSTIs vs. either protease inhibitors (PIs) or non-nucleoside reverse transcriptase inhibitors (NNRTIs) considering demographic, baseline clinical characteristics, incidence of CVD in both 2-year and complete follow-up periods. Among 2357 PWH exposed to INSTIs, 24 people experienced CVD; the corresponding figure was 12 cases out of 2599 PWH exposed to other ART classes. At univariate and multivariate analysis, a tendency towards an increased risk of CVD was observed in the 2-year follow-up period in PWH exposed to INSTIs in the absence, however, of statistical significance. These findings leave open the hypothesis that INSTIs may play a role, albeit minimal, in determining an increased risk of CVD in PWH.

People with HIV pioneers of injectable cabotegravir and rilpivirine long acting in Italy: who are they?

Injectable cabotegravir and rilpivirine long-acting therapy is a revolutionary new antiretroviral treatment (ART) option for HIV infection in virologically suppressed adults on a stable ART. The aim of this study from SCOLTA multicenter observational prospective database is to describe the first people living with HIV (PWH) who started this regimen in Italy, assessing adherence to eligibility criteria, describing clinical-epidemiological characteristics compared to registration trials-population and describe early treatment-discontinuations.

Lipids and Transaminase in Antiretroviral-Treatment-Experienced People Living with HIV, Switching to a Doravirine-Based vs. a Rilpivirine-Based Regimen: Data from a Real-Life Setting.

Doravirine (DOR) is a newly approved non-nucleoside reverse transcriptase inhibitor (NNRTI). We aimed to investigate, in a real-life setting, how switching to a DOR-based regimen rather than a rilpivirine (RPV)-based regimen impacted metabolic and hepatic safety. The analysis included 551 antiretroviral treatment (ART)-experienced people living with HIV (PLWH), starting RPV-based or DOR-based regimens with viral load < 200 copies/mL, baseline (T0), and at least one control visit (6-month visit, T1). We enrolled 295 PLWH in the RPV and 256 in the DOR cohort. At T1, total cholesterol (TC), low-density lipoprotein-C (LDL-C), and triglycerides significantly decreased in both DOR and RPV cohorts, while high-density lipoprotein-C (HDL-C) only decreased in RPV-treated people. Consistently, the TC/HDL-C ratio declined more markedly in the DOR (-0.36, p < 0.0001) than in the RPV cohort (-0.08, p = 0.25) (comparison p = 0.39). Similar trends were observed when excluding the PLWH on lipid-lowering treatment from the analysis. People with normal alanine aminotransferase (ALT) levels showed a slight ALT increase in both cohorts, and those with baseline ALT > 40 IU/L experienced a significant decline (-14 IU/L, p = 0.008) only in the DOR cohort. Lipid profile improved in both cohorts, and there was a significant reduction in ALT in PLWH with higher-than-normal baseline levels on DOR-based ART.

Unexpected effects of COVID-19 outbreak: adaption of Anti-Retroviral Therapy (ART) delivery policies improved adherence in a population of People Living With HIV (PLWH).

Background: Adherence to Anti-Retroviral Therapy (ART) is crucial for People Living With HIV (PLWH). In Italy, ART is delivered by Hospital Pharmacies, on a renewable prescription from the hospital physician. The measurement of package-refill (the rate of ART packages actually collected out of those to be collected in order to comply with therapy) is an effective tool to evaluate the adherence.During COVID-19 outbreak, at "D. Cotugno" hospital in Naples, Italy, the ART delivery policies have been adapted, in order to reduce the number of patients' access. We analysed the impact of these changes on the pill-refill of ART in January-August 2020, compared with 2018-2019. Methods: "D. Cotugno" hospital is a mono-specialistic Infectious Diseases hospital, caring for about 2500 PLWH. Since February 2020, the hospital was almost entirely dedicated to COVID-19 patients. All out-patient activities were interrupted, except for those dedicated to HIV/AIDS patients.In this preliminary study we included all patients assigned to one of the three Medical Divisions dedicated to HIV, who were already under treatment since at least 2017. Rate of package-refill was obtained by the Hospital Pharmacy registry, demographic and clinical data were derived from clinical database.During COVID-19, many measures were adopted in order to increase safety of PLWH attending to hospital. Among these, medical prescription validity increased from 4 to 6 months, and number of packages to be collected increased from 2 to 4, adopting a multi-month dispensing strategy.Package-refill is adequate if at least 95% of ART have been actually collected; partial and inadequate if 75%-94% or less than 75% of ART, respectively, have been collected. Package-refill was measured during the first year of COVID-19 (March 2020 - February 2021), compared to the same period in the two years before. Results: A total of 594 PLWH were included. PLWH with optimal pill-refill significantly increased in 2020-21 compared to 2018-2020 (62% vs 55%, p 0.013). Discussion: Due to COVID-19, we would have expected a reduction in ART deliveries. Surprisingly, the opposite occurred. The increase of pill-refill rates may be due to different reasons, but we hypothesized that the adaption of delivery policies, with a higher number of packages allowed to be collected, strongly contributed to this result. This study suggests that multi-month dispensing policies may contribute to the improvement of adherence among PLWH.

Does COVID-19 Vaccination with BNT162b2 Influence HIV-Related Immunological and Virological Markers? Data from 235 Persons Living with HIV at Cotugno Hospital, Naples, Italy: Immune Response After Second and Third Doses, and Influence on Immunovirological Markers.

Few data are available on the impact of COVID-19 vaccination on CD4 counts and HIV-RNA in persons living with HIV (PLWH). We present the data of 235 PLWH who were vaccinated with BNT162b2 in March 2021-February 2022 at the "Cotugno" hospital in Naples. PLWH treated at the "Cotugno" hospital, who were vaccinated at the hospital vaccination center, without prior COVID-19 and for whom immunological/virological data were available in the last 12 months and in the 6 months after vaccination were included. Antispike Ab were available for 187 and 64 PLWH after the second and third doses: PLWH with antispikes >33 binding antibodies units (BAU)/mL increased from 91% to 98%. Antinucleocapsid Ab performed in 147 and 56 patients identified 19 (13%) asymptomatic/paucisymptomatic COVID-19 infections after the second dose and an additional 15 (27%) after the third dose. Immunological/virological data were collected before vaccination (T0), after the second dose (T1), and after the third dose (T2). The absolute number of CD4 increased after the third dose (median 663, 657, and 707 at T0, T1, and T2; p < 0.000 T0 vs. T2). The proportion of patients with HIV-RNA <50 copies/mL increases significantly after the second dose (73%; 85.7%; 87.7%; p < 0.000 T0 vs. T2). The presence of COVID-19 asymptomatic/paucisymptomatic infections (demonstrated by the presence of antinucleocapsid Ab) significantly increases SARS-CoV-2 antispike Ab after second dose, but not after third dose. Asymptomatic/paucisymptomatic COVID-19 infections do not have influence on CD4 cell number and HIV-RNA level. Similarly, the presence of not-controlled HIV-RNA (HIV-RNA >50 copies/mL) does not influence antispike Ab response. According to our data, the response to SARS-CoV2 vaccination is effective in people living with HIV. Vaccination against COVID-19 appears to positively affect immunological and virological levels in people living with HIV.

Adherence to antiretroviral therapy thought package-refill among HIV+ persons at "D. Cotugno" hospital, Naples, Italy.

Background: A gold-standard for the measurement of adherence to antiretroviral therapy (ART) is lacking. Aim of this study is to verify the feasibility of a package-refill-based measurement of ART at "D. Cotugno" hospital, Naples, Italy, and the factors associated to adherence. Methods: In the period January 2018-August 2020, we calculated the package-refill as the ratio between ART-packages actually withdrawn, and the ART packages needed to regularly take ART. Adherence was associated, trough a univariate e multivariate logistic regression, to demographical, behavioural and clinical factors. Results: 1140 HIV+ subjects were included. At univariate logistic regression inadequate package-refill-based adherence is associated with HIV-RNA higher than 50 copies/mmL (OR 3.77-IC95% 2.76-5.13) and with HIVRNA higher than 200 copies/mmL (OR 3.98-IC95% 2.69-5.90). Being not-Italian and Injective-drug-user are associated with low adherence, having HIV/AIDS for more than 8 years is associated with better adherence. Conclusions: Package-refill is a suitable method for measuring adherence and is associated with the condition of viral failure.

Evolving epidemiology of HIV/AIDS in Campania region, 2011-2018: Is HIV/AIDS population in Campania different?

Objectives: Data on HIV/AIDS cases in Italy are collected using a standardised form. Regional epidemiology may vary. We described the epidemiological and clinical characteristics of newly diagnosed persons with HIV in the 'Cotugno' hospital in Naples during 2011-2018 and compared them with national data to identify similarities and differences. Methods: Data source for the Campania region is the data collection forms sent to the national surveillance system. The data source for the national data is from the periodic annual bulletins on HIV/AIDS published by the National Institute of Health. Results: In all, 1149 persons with HIV were diagnosed in 'Cotugno' (69.7% of those diagnosed in Campania). Persons with HIV in Campania showed many similarities with the Italian population: men were in the majority in both groups (about 75%), foreign origin was about 30%, heterosexuals were the most represented risk group, followed by men who have sex with men and injecting drug use in both samples. Some notable differences are also present. Among the risk factors for HIV acquisition, injecting drug use is significantly more common in Campania. Among the reasons for testing, significant differences are evident for almost all reasons, with screening activities (testing for concurrent diseases, for diagnosis of sexually transmitted diseases, screening in hospital during maternity care and screening in drug-addition services or prisons) being more common at the national level. The Campania population has a more severe disease pattern, with a significantly higher proportion of patients diagnosed with less than 200 CD4 cells/µL and AIDS. For each variable, we compared trends in the Campania region and in Italy using Spearman's correlation coefficient. Almost all trends show a weak correlation. Conclusion: In conclusion, the prevalence of injecting drug use is still consistent, and requires specific campaigns. The reasons for testing are different: screening activities work less in Campania than in Italy. This untimely approach contributes to a more severe clinical picture in Campania.

Different Cell Cycle Modulation in SKOV-3 Ovarian Cancer Cell Line by Anti-HIV Drugs.

Antiretroviral drugs used for the treatment of human immunodeficiency virus (HIV) have proven to be effective even against cancer. Drawing from this background, the aim of our research project was to evaluate the effects of anti-HIV drugs that belong to the nucleoside and nucleotide reverse transcriptase inhibitor [NRTI; abacavir (ABC) and tenofovir (TDF)], nonnucleoside reverse transcriptase inhibitor [NNRTI; efavirenz (EFV) and etravirine (ETR)], and protease inhibitor [PI; darunavir (DRV)] categories on ovarian adenocarcinoma cell line SKOV-3. Using FACS analysis, we observed that treatment with NRTIs and NNRTIs showed a block in the G0/G1 phase. In particular, ETR displayed a relevant block in the progression of the G0/G1 phase of the cell cycle compared with the other examined drugs, and it also induced differentiation of SKOV-3 cells. In contrast, FACS analysis demonstrated that ABC and the PI inhibitor DRV showed no effect on the proliferation of cancer cells. DAPI (4',6-diamidino-2-phenylindole) staining demonstrated that cells treated with NNRTIs (EFV and ETR) presented more DNA damage compared with other treatments. Immunoblotting analysis demonstrated that TDF, EFV, and ETR were able to obtain a reduction in the expression of cyclin D1 and Rb hypophosphorylation, and an increase in p21 concentration. Finally, we observed that ETR also induced differentiation, as demonstrated by Western blot, with high levels of E-cadherin expression. Therefore, our study provides additional evidence supporting the in vitro cytotoxic effects of ETR and EFV. Furthermore, it promotes the hypothesis for their potential use as therapeutic agents in ovarian cancer.

HIV positive patient with HSV-2 encephalitis: case report.

Incidence of brain infections in Human Immunodeficiency Virus (HIV) positive patients is reduced after the availability of current high active antiretroviral therapy (HAART). Herpes Simplex Virus type 2 (HSV-2) is an infrequent cause of encephalitis in HIV patients despite it is frequently involved in sexual transmitted infections. Here, we report a case of HSV-2 encephalitis occurring in a patient without full suppression of HIV replication within the brain. A 38 year-old HIV infected man was admitted to our department because of recurrent generalized seizure and fever during the previous 24 hours. Eight months before our observation the patient was switched from a protease inhibitor based regimen to a rilpivirine-based regimen without any evidence of HIV-RNA replication in the plasma. When the patient was admitted in our hospital, he was febrile and moderately confused, no deficit of cranial nerves was reported, motility was conserved, but he was unable to walk. Laboratory examinations performed at admission demonstrated an increase of cerebrospinal fluid (CSF) protein and cells with lymphocyte prevalence, and normal CSF glucose. HSV-2-DNA and HIV-RNA were present within CSF at admission. Nuclear Magnetic Resonance imaging of the brain revealed lesions of the medial part of both temporal lobes including hippocampus without any sign of bleeding. A 21-day course of acyclovir therapy was administered with consistent improvement of clinical findings and disappearance of HSV-2-DNA within CSF. After the episode, HAART was switched to a regimen with high CSF penetrability containing abacavir, lamivudine, darunavir and ritonavir. Twelve months after HSV-2 encephalitis neurologic evaluation was normal, but symptoms of depression were reported, HIV-RNA remained undetectable both in the plasma and CSF, and CD4+ lymphocytes were above 500/µL. No opportunistic infection was reported. Patients switched to regimen well tolerated such those containing rilpivirine, that have poor drug concentration within CSF could be considered at risk for opportunistic infection of the brain. Further larger investigation needs to confirm this finding.

Aortic Valve Endocarditis Caused by Abiotrophia defectiva: Case Report and Literature Overview.

UNLABELLED: Abiotrophia defectiva or nutritionally variant Streptococcus (NVS) are a rare but important cause of infectious endocarditis, with high rates of bacteriological failure and mortality. We report the case of a 74-year-old man admitted for fever, fatigue and general malaise in the absence of any underlying cardiac, immunosuppressive illness and previous dental manipulations. Transthoracic and transesophageal echocardiogram revealed bacterial vegetation and significant aortic stenosis and regurgitation. Initial blood culture reported gram-positive cocci in chains, subsequently identified as A. defectiva. The patient completed 6 weeks of antibiotic therapy with ampicillin, with a significant decrease of serum inflammatory markers. He refused cardiac surgery and had relapsing endocarditis with positive blood culture for the same pathogen. The patient was then submitted to double-valve cardiac surgery, obtaining a prompt resolution of clinical signs and symptoms, without other relapse or any complications. CONCLUSION: Infectious diseases caused by A. defectiva are extremely rare illnesses. Due to the difficult isolation of the pathogen and the slow clinical progression, clinicians should be aware of this bacterium when dealing with blood culture-negative infective endocarditis.

Different Impact Of Antiretroviral Drugs On Bone Differentiation In An In Vitro Model.

Recently increasing emphasis is placed on preventive health and management of chronic comorbidities avoiding long-term toxicities of antiretroviral therapy (ART). Drawing from this background we decided to use the Saos-2, osteosarcoma cell line, as a cellular model, to evaluate the effects of some antiretroviral drugs such as abacavir (ABC), tenofovir (TDF), efavirenz (EFV), etravirine (ETR), and darunavir (DRV), on bone differentiation related pathways. According to our observation, treatment with TDF and ABC affects the ability of the cells to produce calcium deposits with a reduced expression of type I collagen gene and p21 mRNA, also increasing the activity of Wnt3a related pathway. On the other hand treatment with EFV and DRV was not related to any significant reduction of calcium deposits but displayed a decrease in the expression of Wnt3a at day 14 and Type I Collagen at day 7 compared with untreated cells, even if this last down regulation was not confirmed at day 14. Instead ETR administration to Saos-2 cells increases the calcium deposits collagen type I production, as a result of Wnt3a mRNA overexpression, and of an upregulation of collagen type I expression, being also the only drug able to increase the expression of p21 cdk inhibitor as further marker of terminal differentiation. In summary these data suggest the potential negative interference of TDF and ABC on bone differentiation. DRV and EFV partially affect collagen type I production, instead ETR facilitates a positive bone balance as a result of an increased osteoblasts terminal differentiation.

Different impact of anti-retroviral regimen containing protease inhibitors on development of HIV-related Kaposi sarcoma.

BACKGROUND: The incidence of Kaposi's sarcoma (KS), an AIDS-related malignancy, has dramatically decreased in the Highly Active Anti-retroviral Therapy (HAART) era. However, KS remains the second most frequent tumor in HIV-infected patients worldwide and has become the most common cancer in the sub-Saharan Africa. Experimental studies have demonstrated a direct anti-neoplastic effect of HAART, and overall of protease inhibitors (PIs), on KS. CASE REPORT: We describe five cases of KS in HIV-infected patients on HAART regimen, containing PIs as atazanavir/r (ATV/r), darunavir/r (DRV/r), lopinavir/r (LPV/r) and fosamprenavir (fAMP/r). CONCLUSION: Clinical and experimental observations support the hypothesis that PIs may play an important role in prevention and treatment of KS. In our study, the treatment with PIs of recent generation was not protective against the development of KS. Therefore, it could be necessary to re-evaluate the therapeutic effects of PIs and their role in the development and treatment of KS in HIV-infected patients.

Interferon gamma release assays and tubercolin skin test performance in different settings of HIV immunodeficiency.

BACKGROUND/AIM: HIV infection is a risk factor for re-activation of latent tubercolosis infection (LTBI). In recent years new blood tests for the detection of TB infection have been developed: Quantiferon TB Gold in Tube and TSPOT TB, which are interferon-γ releasing assays (IGRAs), have improved the identification of LTBI. In our study we have compared IGRAs and TST in HIV-positive patients with different settings of immunodeficiency. PATIENTS AND METHODS: 98 consecutive HIV patients were recruited. They underwent a blood draw, a chest radiography and a tuberculin skin test. The HIV infection setting was detected and IGRAs were carried-out. Five patients showed a complete correspondence of TST, TSPOT-TB and QFT-IT. Discordant results were observed in patients testing positive to IGRAs but negative to TST. Only 2 patients showed positive TST and negative IGRAs. CONCLUSION: Our study showed a poor concordance between tuberculin skin test and IGRAs, mainly in patients with a low CD4 cell count.

In vivo antiviral activity of telbivudine against HIV-1: a case report.

The treatment of HBV infection in patients with HIV co-infection presents several peculiar features: some drugs active against HBV are also active against HIV. This precludes their use in monotherapy in HIV-HBV co-infected patients due to the potential risk of selecting HIV-resistant strains. Telbivudine seemed to be a candidate for exclusive anti-HBV therapy because it exerts no significant in vitro activity against HIV. In this context, we describe the case of a HIV-HBV co-infected patient who presented indication for treatment only for HBV infection. After a short course of interferon treatment withdrawn due to adverse events, adefovir monotherapy was started. Since no significant viral drop was achieved during adefovir treatment, telbivudine was added. This treatment was associated with a complete virological response on HBV. It is noteworthy that after two months of this treatment even the HIV viral load presented a significant reduction. Our findings pose concerns of possible antiviral activity of telbivudine against HIV and therefore of selecting resistant mutations.

Hepatitis B in pregnancy.

Chronic hepatitis B virus (HBV) infection affects about 350 million individuals worldwide. Management of HBV infection in pregnancy is difficult because of several peculiar and somewhat controversial aspects. The aim of the present review is to provide a tool that may help physicians to correctly manage HBV infection in pregnancy. This review focuses on (1) the effect of pregnancy on HBV infection and of HBV infection on pregnancy; (2) the potential viral transmission from mother to newborn despite at-birth prophylaxis with immunoglobulin and vaccine; (3) possible prevention of mother-to-child transmission through antiviral drugs, the type of antiviral drug to use considering their efficacy and potential teratogenic effect, and the timing of their administration and discontinuation; and (4) the evidence for the use of elective caesarean section vs vaginal delivery and the possibility of breastfeeding.

The efficacy and safety of telaprevir - a new protease inhibitor against hepatitis C virus.

IMPORTANCE OF THE FIELD: Hepatitis C virus (HCV) is the main agent of chronic hepatitis, liver cirrhosis and hepatocellular carcinoma in the western world. It affects more than 170 million people worldwide. HCV treatment, based on the combination of Peg-interferon and ribavirin, is effective in about 50% of treated patients. Therefore, there is a need to develop new drugs active against HCV. AREAS COVERED IN THIS REVIEW: Data were obtained by searching for all full articles on Medline and abstracts presented at major international congresses on viral hepatitis. WHAT THE READER WILL GAIN: A review of clinical data about the efficacy and safety of telaprevir (VX-950), the HCV protease inhibitor that is in the most advanced phase of clinical development. TAKE HOME MESSAGE: Telaprevir has an acceptable pharmacokinetic profile and seems to be a potent antiviral drug against HCV, although, owing to a low genetic barrier, resistant variants emerge within a few days when used in monotherapy, thereby decreasing its efficacy. Consequently, telaprevir has been combined with pegylated-interferon and ribavirin in clinical trials. This triple combination is more effective but has a higher rate of adverse events (notably rash) than the standard of care, despite the shorter duration of therapy.

Tenofovir and its potential in the treatment of hepatitis B virus.

Recent literature is reviewed about treatment of chronic hepatitis B virus (CHB), focusing on tenofovir disoproxil fumarate (TDF; Viread((R))), among the nucleotide and nucleoside analogs. TDF pharmacokinetics and pharmacodynamics, activity in respect of hepatitis B virus (HBV) multi-drug-resistant mutations, efficacy in treatment-naïve and treatment-experienced patients, and side effects are described. The most predictive response factors to TDF therapy are discussed and all available combination therapies to optimize clinical outcome in the various patient profiles are analyzed, such as compensated and/or decompensated cirrhotic patients. The use of TDF in pregnancy, and prophylaxis after exposure to HBV and post-liver transplantation are also evaluated.