Switching from tenofovir disoproxil fumarate to tenofovir alafenamide or dual therapy-based regimens in HIV-infected individuals with viral load ≤50 copies/mL: does estimated glomerular filtration rate matter?

Our aim was to evaluate the association between recent eGFR values and risk of switching from TDF to TAF or dual therapy (DT) in real life. HIV-positive patients achieving HIV-RNA ≤50 copies/mL for the first time after starting a TDF-based regimen were included. Kaplan-Meier (KM) curves and Cox regression models were used to estimate the time from TDF to switch to TAF or DT. 1486 participants were included: median (IQR) age 36 (30-42) years; baseline CKD-EPI eGFR 99.92 (86.47-111.4) mL/min/1.73m2. We observed a consistently higher proportion of people with HIV-RNA ≤50 copies/mL who switched from TDF to TAF rather than to DT. By competing risk analysis, at 2 years from baseline, the probability of switching was 3.5% (95% CI 2.6-4.7%) to DT and 46.7% (42.8-48.5%) to TAF. A significantly higher probability of switching to TAF was found for patients receiving INSTI at baseline versus NNRTIs and PI/b [KM, 65.6% (61.7-69.4%) vs. 4.0% (1.8-6.1%) and 59.9% (52.7-67.2%), respectively; P < 0.0001]. eGFR <60 mL/min/1.73m2 both as time-fixed covariate at baseline or as current value was associated with a higher risk of switching to DT [aHR 6.68 (2.69-16.60) and 8.18 (3.54-18.90); P < 0.001] but not to TAF-based cART [aHR 0.94 (0.39-2.31), P = 0.897; and 1.19 (0.60-2.38), P = 0.617]. Counter to our original hypothesis, current eGFR is used by clinicians to guide switches to DT but does not appear to be a key determinant for switching to TAF.

Evolution of the prevalence of hepatitis C virus infection and hepatitis C virus genotype distribution in human immunodeficiency virus-infected patients in Italy between 1997 and 2015.

OBJECTIVES: To analyse the variation of hepatitis C virus (HCV) prevalence and genotype distribution and their determinants in people living with human immunodeficiency virus (HIV) who entered care between 1997 and 2015. METHODS: HIV-infected patients enrolled in ICONA who were tested for HCV antibodies (HCV-Ab) were included. RESULTS: Overall 3407 of 12 135 (28.1%) were HCV-Ab+; and 735 of 12 135 (6.1%) were HBsAg+. Among patients whose HCV genotype was known, the most represented were genotypes 1 and 3. The prevalence of HCV infection decreased from 49.2% (2565/5217) during 1997-2002 to 10.2% (556/5466) during 2009-2015. The frequency of genotype 1a increased from 29.0% (264/911) to 43.0% (129/300), whereas genotype 3 decreased from 38.5% (351/911) to 27.0% (81/300). Independent predictors of HCV-Ab+ status were being female (adjusted OR (AOR) 1.23, 95% CI 1.04-1.50, p = 0.01), risk category (versus injecting drug users: men who have sex with men AOR 0.01, 95% CI 0.01-0.01, p <0.001; heterosexuals AOR 0.01, 95% CI 0.01-0.01, p <0.001; other/unknown AOR 0.02, 95% CI 0.01-0.02, p <0.001), being cared for in Central Italy (versus being cared for in Northern Italy: AOR 0.85, 95% CI 0.73-0.98, p <0.001), being Italian-born (AOR 1.44, 95% CI 1.16-1.80, p = 0.001) and being enrolled in less recent calendar years (versus 1997-2002: 2009-2015 AOR 0.23, 95% CI 0.19-0.27, p <0.001; 2003-2008 AOR 0.49, 95% CI 0.41-0.61, p <0.001). CONCLUSIONS: The prevalence of HCV infection in HIV-infected patients entering into care in Italy significantly declined in more recent calendar years. After adjusting for risk factors and calendar years, HCV co-infection was more frequent in females and in those born in Italy.

Italian consensus statement on management of HIV-infected individuals with advanced disease naïve to antiretroviral therapy.

BACKGROUND: Individuals with advanced HIV infection naïve to antiretroviral therapy represent a special population of patients frequently encountered in clinical practice. They are at high risk of disease progression and death, and their viroimmunologic response following the initiation of highly active antiretroviral therapy may be more incomplete or slower than that of other patients. Infection management in such patients can also be complicated by underlying conditions, comorbidities, and the need for concomitant medications. AIM: To provide practical guidelines to those clinicians providing care to HIV-infected patients in terms of diagnostic assessment, monitoring, and treatment. CONCLUSIONS: The principals of antiretroviral treatment in asymptomatic naïve patients with advanced HIV infection are the same as those applicable to the general population with asymptomatic HIV infection. Naïve patients with advanced HIV infection and a history of AIDS-defining illnesses urgently need antiretroviral treatment, with the choice of antiretroviral regimen and timetable based on such factors as concomitant treatment and prophylaxis, drug interactions, and potential concomitant drug toxicity. Finally, an adequate counseling program - both before and after HIV-testing - that includes aspects other than treatment adherence monitoring is a crucial step in disease management.

ISSQoL: a new questionnaire for evaluating the quality of life of people living with HIV in the HAART era.

OBJECTIVE: To design a Health-related Quality of Life (HRQoL) instrument for HIV-infected people in the era of highly active antiretroviral therapy (HAART). METHODS: The self-administered questionnaire was developed by an Italian network including researchers, physicians, people living with HIV, national institutions and community-based organizations (CBO) through several steps: (1) review of existing HRQoL literature and questionnaires for HIV-infected people; (2) selection of relevant domains measuring HRQoL in HIV-infected people, and identification of new domains related to new aspects of HRQoL concerning HAART-treated individuals; (3) conduction of two pre-test analyses in independent groups of Italian HIV-positive people (n approximately =100) distributed throughout the country. The objectives of the first pre-test were to verify the usefulness of the questionnaire, to construct a form easily understandable by everyone, to define the domains and their significance; the second pre-test aimed at evaluating and reshaping the questionnaire based on a statistical analysis of the outcomes of first pre-test; (4) validation analysis. A large cohort of people with HIV infection was recruited for the last step. RESULTS: The internal consistence reliability (Cronbach's alpha) was >or=0.70 for all domains. Most domains had Cronbach's coefficient >0.80. All domains demonstrated convergent and discriminant validity. The final version of ISSQoL includes two sections: HRQoL Core Evaluation Form (9 domains) and Additional Important Areas for HRQoL (6 domains). The ISSQoL was administered together with two additional forms: a Daily Impact of Symptoms Form and a Demographic Information Form. The Additional Important Areas for HRQoL include social support, interaction with medical staff, treatment impact, body changes, life planning, and motherhood/fatherhood. CONCLUSION: The data reported in the present paper provide preliminary evidence of the reliability and validity of the ISSQoL questionnaire for the measurement of HRQoL in HIV-infected people. The direct involvement of HIV-positive people in all the phases of the project was a key aspect of our work.

Changes in hospital admissions across Europe: 1995-2003. Results from the EuroSIDA study.

OBJECTIVES: To describe changes in the proportions of patients admitted to hospital and the duration of admission during the month of March between 1995 and 2003 and to describe the factors related to admission for 9802 patients from EuroSIDA, a pan-European, observational cohort study. METHODS: Generalized estimating equations were used to determine changes over time in the proportion of patients admitted and the median duration of admission. Logistic regression was used to determine factors related to admission in March 1995, March 1998 and March 2001. RESULTS: The proportion of patients admitted during March declined from 7.4% in 1995 to 2.6% in 2003. After adjustment, the estimated reduction in the proportion of patients admitted was 5.5% per year [95% confidence interval (CI) 2.5-8.5%; P=0.0004], a 26% reduction. The median duration of hospital admission declined by 58% from 12 days in 1995 [interquartile range (IQR) 5-19 days] to 5 days in 2003 (IQR 3-12 days), a significant decline of 0.7 days per year after adjustment (95% CI 0.5-0.9 days; P=0.031). Patients with a lower CD4 lymphocyte count, and with an AIDS diagnosis made within the 3 months prior to March, all had increased odds of admission during March 1995, 1998 or 2001. In March 2001, patients whose treatment regimen was changed as a consequence of toxicities had increased odds of admission [odds ratio (OR) 2.34; 95% CI 1.26-4.37; P=0.0074]. In addition, patients who were hepatitis C virus-positive during March 2001 (OR 1.66; 95% CI 1.02-2.68; P=0.041) had increased odds of admission. CONCLUSIONS: There has been a considerable decline in both the proportion of patients admitted to hospital and the median duration of the stay. Patients with hepatitis C had increased odds of admission, but there was little evidence of an increase in admissions among patients taking highly active antiretroviral therapy (HAART) associated with serious adverse events, although longer follow up is required.

Declining levels of rescued lymphoproliferative response to human cytomegalovirus (HCMV) in AIDS patients with or without HCMV disease following long-term HAART.

OBJECTIVE: To investigate the lymphoproliferative response (LPR) to human cytomegalovirus (HCMV) in two groups of AIDS patients undergoing long-term highly active antiretroviral therapy (HAART): group 1 ( n = 22) with nadir CD4(+) cell count <50/microl and no HCMV disease; group 2 ( n = 16) with <50/microl CD4(+) T-cell count and HCMV disease. All patients had previously undergone antiretroviral monotherapy or dual therapy before initiating HAART. STUDY DESIGN AND METHODS: The two groups of patients were tested prospectively for CD4(+) T cell count, HIV RNA load, HCMV viremia, and LPR to HCMV at baseline, and then after 3 and 4 years of HAART. A control group of 13 recently diagnosed treatment-naive AIDS patients with CD4(+) T-cell counts <100/microl was also investigated. RESULTS: No LPR to HCMV was found in any of the treatment-naive patients nor in any patient of the two groups examined at baseline, when HCMV viremia was 13.6% in the patient group without disease and 87.5% in the group with disease ( p <.0001). After 3 years of HAART, the frequency of patients who recovered an LPR to HCMV was not significantly different (81.8% in the group without HCMV disease, and 68.7% in the group with HCMV disease), whereas, compared with baseline, the HIV load decreased and the CD4(+) T-cell count increased significantly and to a comparable extent in the two groups of patients. In addition, the frequency of patients with HCMV viremia, although reduced, became comparable in both groups. After 4 years of HAART, the frequency of responders to HCMV without and with HCMV disease dropped to comparable levels (50.0 vs. 56.3%, respectively) in association with high median CD4(+) T-cell counts and low median HIV RNA plasma levels. In parallel, the frequency of patients with HCMV viremia did not change significantly. In addition, after between 3 and 4 years of HAART, although the frequency of stable responders and nonresponders remained unchanged (50%) in both groups, most of the remaining patients showed declining levels of responsiveness to HCMV. Although some patients from both groups were found to have CD4(+) T-cell counts >150/microl in the absence of LPR to HCMV, thus suggesting dissociation of specific and nonspecific immune reconstitution, a significant correlation was found between CD4(+) T-cell count and LPR to HCMV (r = 0.44; p <.001). From a clinical standpoint, anti-HCMV therapy could be safely discontinued in 8 patients with HCMV retinitis showing CD4(+) T-cell counts >150/microl, recovery of HCMV LPR, and no HCMV viremia. CONCLUSIONS: Declining levels of the previously recovered LPR to HCMV are often observed after long-term HAART. However, because the role of LPR in the evolution of HCMV infection and disease during HAART remains to be defined, the clinical impact of the declining LPR to HCMV must still be clarified in long-term prospective studies.

Changes in lymphocyte subsets in depressed HIV-infected patients without antiretroviral therapy.

The authors studied the effects of major depression on lymphocyte subsets by comparing depressed and matched control subjects in a population of HIV-seropositive outpatients not treated with antiretroviral therapy. Twelve patients with major depression, as determined by the Structured Clinical Interview for DSM-III-R, were assessed in comparison with 15 matched nondepressed control subjects. Flow cytometric analysis of peripheral blood lymphocyte subsets together with immunological parameters were performed. In HIV-infected patients, major depression was significantly (P=0.001) associated with a reduction in natural killer cell absolute count and percentage. This report suggests that depression may alter the natural killer cell population that provides a cytotoxic defense against HIV infection.

Cidofovir added to HAART improves virological and clinical outcome in AIDS-associated progressive multifocal leukoencephalopathy.

OBJECTIVES: To analyse the virological and clinical efficacy of cidofovir combined with highly active antiretroviral therapy (HAART) in AIDS-related progressive multifocal leukoencephalopathy (PML). DESIGN: Multicentre observational study of consecutive HIV-positive patients with histologically or virologically-proven PML. Group A, 26 patients treated with HAART; group B, 14 patients treated with HAART plus cidofovir 5 mg/kg intravenously per week for the first 2 weeks and alternate weeks thereafter. JC virus DNA was quantified in cerebrospinal fluid (CSF) by PCR. RESULTS: Baseline virological, immunological and clinical characteristics were homogeneous between the groups. In one case cidofovir was discontinued because of severe proteinuria. There was no significant difference in HIV RNA responses and changes in the number of CD4 cells between group A and B. After 2 months of therapy, five out of 12 (42%) patients from group A and seven out of eight (87%) from group B reached undetectable JC virus DNA in the CSF (Chi-square P = 0.04); moreover, 24% of group A and 57% of group B patients showed neurological improvement or stability (P = 0.038). One-year cumulative probability of survival was 0.67 with cidofovir and 0.31 without (log-rank test, P = 0.01). Variables independently associated with longer survival were the use of cidofovir, HAART prior to the onset of PML, a baseline JC virus DNA load in CSF < 4.7 log10 copies/ml, and a baseline Karnofsky performance status > or = 60. CONCLUSIONS: In AIDS-related PML, cidofovir added to HAART is associated with a more effective control of JCV replication, with improved neurological outcome and survival compared with HAART alone.

The effect of potent antiretroviral therapy and JC virus load in cerebrospinal fluid on clinical outcome of patients with AIDS-associated progressive multifocal leukoencephalopathy.

A multicenter analysis of 57 consecutive human immunodeficiency virus-positive patients with progressive multifocal leukoencephalopathy (PML) was performed, to identify correlates of longer survival. JC virus (JCV) DNA was quantified in the cerebrospinal fluid (CSF) by polymerase chain reaction. Two months after therapy, 4% of the patients without highly active antiretroviral therapy (HAART) and 26% with HAART showed neurologic improvement or stability (P=.03), and 8% and 57%, respectively, reached undetectable JCV DNA levels in the CSF (P=.04). One-year probability of survival was.04 without HAART and.46 with HAART. HAART and lack of neurologic progression 2 months after diagnosis were independently associated with longer survival. Among HAART-treated patients, a baseline JCV DNA <4.7 log, and reaching undetectable levels after therapy predicted longer survival. Survival of AIDS-related PML is improved by HAART when JCV replication is controlled.

Influence of age on rates of new AIDS-defining diseases and survival in 6546 AIDS patients.

It has consistently been reported that older AIDS patients have a shortened survival compared with younger patients. The aim of the present study was to investigate whether this difference in survival is caused by differences in the pattern of the complicating diseases. Information on patient follow-up after the AIDS diagnosis was obtained by retrospective case note review. The 6,546 patients were followed from the time of AIDS diagnosis as part of the multicentre AIDS in Europe study, which examined AIDS cases diagnosed at 52 centres in 17 European countries between 1979 and 1989. Occurrence of AIDS-defining events and demographic variables were recorded for all patients, and CD4 lymphocyte count at the time of AIDS diagnosis for approximately half the patients. After adjusting for imbalances in other variables, persons > or = 50 years of age had a significantly higher risk of contracting AIDS wasting syndrome, AIDS dementia complex and oesophageal candidiasis after the initial AIDS diagnosis, compared with age group 30-39 years [relative risk (RR) 95% confidence interval (CI)], 3.23 (2.70-3.75 CI); 2.48 (2.16-2.80 CI); 1.55 (1.26-1.83 CI), respectively]. Shortened survival after the time of AIDS diagnosis was associated with older age. After adjusting for pattern of complicating diseases, the age effect remained unchanged. Older age predisposes to AIDS-related wasting syndrome, AIDS dementia complex and oesophageal candidiasis. Independent of these differences, older age is significantly associated with shortened survival, suggesting that factors such as severity of complicating diseases or the capability of handling serious infections, rather than disease pattern, are responsible for the shortened survival.

Polymerase chain reaction on cerebrospinal fluid for diagnosis of virus-associated opportunistic diseases of the central nervous system in HIV-infected patients.

OBJECTIVE: To assess the diagnostic reliability of polymerase chain reaction (PCR) on cerebrospinal fluid (CSF) for virus-associated opportunistic diseases of the central nervous system (CNS) in HIV-infected patients. DESIGN: CSF samples from 500 patients with HIV infection and CNS symptoms were examined by PCR. In 219 patients the PCR results were compared with CNS histological findings. METHODS: Nested PCR for detection of herpes simplex virus (HSV) type 1 or 2, varicella zoster virus (VZV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), human herpesvirus 6 (HHV-6), and JC virus (JCV) DNA. Histopathological examination of CNS tissue obtained at autopsy or on brain biopsy. RESULTS: DNA of one or more viruses was found in CSF in 181 out of 500 patients (36%; HSV-1 2%, HSV-2 1%, VZV 3%, CMV 16%, EBV 12%, HHV-6 2%, and JCV 9%). Among the 219 patients with histological CNS examination, HSV-1 or 2 was detected in CSF in all six patients (100%) with HSV infection of the CNS, CMV in 37 out of 45 (82%) with CMV infection of the CNS, EBV in 35 out of 36 (97%) with primary CNS lymphoma, JCV in 28 out of 39 (72%) with progressive multifocal leukoencephalopathy. Furthermore, HSV-1 was found in one, VZV in four, CMV in three, EBV in three, HHV-6 in seven, and JCV in one patient without histological evidence of the corresponding CNS disease. CONCLUSIONS: CSF PCR has great relevance for diagnosis of virus-related opportunistic CNS diseases in HIV-infected patients as demonstrated by its high sensitivity, specificity, and the frequency of positive findings.

Ganciclovir therapy for cytomegalovirus (CMV) infection of the central nervous system in AIDS patients: monitoring by CMV DNA detection in cerebrospinal fluid.

Seven AIDS patients with central nervous system (CNS) disease and cytomegalovirus (CMV) DNA in cerebrospinal fluid (CSF) were evaluated before and 3 weeks after standard ganciclovir treatment by nested polymerase chain reaction (PCR) on limiting dilutions and by quantitative PCR. After therapy, PCR CSF was negative for CMV in 3 patients with low baseline levels of CMV DNA and positive with decreased DNA titers in 4 patients with higher baseline levels. CMV pp65 antigen in polymorphonuclear leukocytes was found in 6 of 7 patients before therapy and in none of 5 after therapy. At autopsy, CMV was found in the CNS of the 4 cases examined, including 3 whose CSF was continuously positive by PCR. Quantitative PCR of CSF is useful for monitoring ganciclovir treatment in CMV infection of the CNS. In AIDS patients, standard ganciclovir treatment seems effective in reducing but not suppressing viral replication in severe cases of CMV infection of the CNS.

Cytomegalovirus infection of the central nervous system in patients with AIDS: diagnosis by DNA amplification from cerebrospinal fluid.

A nested polymerase chain reaction (PCR) was evaluated for the detection of cytomegalovirus (CMV) DNA in cerebrospinal fluid (CSF). CSF and serum samples from 19 AIDS patients with intracerebral CMV infection diagnosed at autopsy were retrospectively examined. As controls, CSF and serum samples from 15 AIDS patients with only extracerebral CMV involvement at autopsy, from 10 AIDS patients without CMV infection at autopsy, and from 10 anti-human immunodeficiency virus-negative patients without ongoing CMV infection, were studied. CMV DNA was detected from patients with intracerebral CMV infection in 9 of 9, 5 of 6, and 1 of 4 CSF samples collected, respectively, 1-30, 30-90, and 90-300 days before death. Twelve of 13 sera from these patients were CMV PCR-positive. None of the control patients had CMV DNA in CSF. PCR was positive in 6 of 8 sera from AIDS patients with only extracerebral CMV infection and in serum from 1 AIDS patient without CMV involvement at autopsy. CMV PCR on CSF is highly sensitive and specific. It should be considered a rapid and reliable diagnostic method for CMV infection of the central nervous system.

Mother-to-child transmission of hepatitis C virus detected by nested polymerase chain reaction.

Serum samples from eight pregnant women and their offspring were studied by nested polymerase chain reaction (PCR) for detection of hepatitis C virus (HCV) RNA to evaluate mother-to-child transmission of this virus. The mothers were all infected with human immunodeficiency virus (HIV); none showed symptoms of HCV infection. Anti-HCV antibodies were tested for by recombinant immunoblot assay. HCV viral sequences were found in five of the mothers and four of eight children, three of them at birth. Viremia was persistent in one infant who had chronic transaminase elevation and persistently remained anti-HCV-positive. The other three babies had intermittent viremia; all were asymptomatic and lost anti-HCV antibodies during follow-up. This loss of antibodies was also observed in PCR-negative infants. Thus, these results demonstrate transmission of HCV from mother to child by women coinfected with HCV and HIV. They indicate the usefulness of PCR for direct and early detection of HCV viremia in neonates.

[Prevalence of HBsAg and anti-HBs in hospital personnel]. / Prevalenza di HBsAg e anti-HBs nel personale ospedaliero.

The prevalence of serum HBsAg and Anti-HBs was studied in 201 staff members from two Renal Dialysis Units, one Medical and one Dermatological Division from two Hospitals in the Milano area. The overall prevalence of HBsAg was significantly greater among staff members (8.9%) as compared to controls (4.9%). On the contrary, the prevalence of Anti-HBs was only slightly higher in hospital personnel than in controls. Non-medical staff members (nurses, technicians) showed a prevalence of HBV markers (HBsAg and/or Anti-HBs) twice as high as medical staff members (46.1% vs 23.2%). When the prevalence of HBV markers was correlated to the duration of work in the hospital, a steady increase in the prevalence of Anti-HBs was observed. On the contrary, the prevalence of HBsAg rose in the first 3 years and remained constant thereafter. The prevalence of HBV markers was significantly higher among staff members from Renal Dialysis Units (HBsAg+ and/or Anti-HBs+:50%) than in the personnel from the Medical and Dermatological Divisions (32.4%). However, the difference was solely related to a higher prevalence of Anti-HBs in the former (42% vs 23%). This may reflect a higher risk of infection in Dialysis Units as compared to other Hospital Divisions. However, the difference might be magnified by the frequent use of HBIG in the Dialysis Units personnel.