Analysing the efficacy and tolerability of dolutegravir plus either rilpivirine or lamivudine in a multicentre cohort of virologically suppressed PLWHIV.

OBJECTIVES: We aimed to investigate and compare the efficacy and safety of two dolutegravir-based two-drug regimens: dolutegravir + lamivudine versus dolutegravir + rilpivirine. METHODS: We analysed a cohort of people living with HIV (PLWHIV) switching to dolutegravir + lamivudine or dolutegravir + rilpivirine. We excluded from the analysis PLWHIV with no available pre-switch genotypic test or with a known resistance mutation to one of the study drugs. We evaluated incidence of virological failure (VF) and treatment discontinuation (TD), as well as changes in immunological and metabolic parameters. RESULTS: We enrolled 592 PLWHIV: 306 in the lamivudine group and 286 in the rilpivirine group. We observed nine VFs in the lamivudine group [1.4 VF per 100 patient-years of follow-up (PYFU)] and four VFs in the rilpivirine group (0.6 VF per 100 PYFU). Subsequent genotypic analysis showed no acquired resistance-associated mutations in those experiencing VF. Estimated probability of maintaining virological suppression at 144 and 240 weeks were 96.6% and 92.7%, respectively, in the lamivudine group and 98.7% and 98.7%, respectively, in the rilpivirine group (log-rank P = 0.172). The estimated probability of maintaining study regimen at Week 240 was 82.3% in the lamivudine group and 85.9% in the rilpivirine group (log-rank P = 0.018). We observed a significant improvement in CD4+ cell count at Week 240 in the lamivudine group (P = 0.012); in the rilpivirine group we registered a significant increase in CD4/CD8 ratio (P = 0.014). CONCLUSIONS: Both analysed strategies are effective and safe as switch strategies in clinical practice, with a low incidence of VF and a favourable immunological recovery, even in the long term.

Efficacy and safety of switching to dolutegravir plus emtricitabine/tenofovir disoproxil fumarate (TDF) or elvitegravir/cobicistat/emtricitabine/TDF in virologically suppressed HIV-infected patients in clinical practice: results from a multicentre, observational study.

OBJECTIVES: The aim of the study was to compare the efficacy and tolerability of switching antiretroviral therapy to dolutegravir + emtricitabine/tenofovir disoproxil fumarate (TDF) with those of switching to elvitegravir/cobicistat/emtricitabine/TDF in clinical practice. METHODS: In a multicentre real-life observational study, we analysed data for HIV-infected patients on antiretroviral treatment with viral load < 50 HIV-1 RNA copies/mL switching to dolutegravir + emtricitabine/TDF (dolutegravir group) or elvitegravir/cobicistat/emtricitabine/TDF (elvitegravir group). Follow-up was censored at 48 weeks. RESULTS: The 48-week estimated proportion maintaining virological efficacy was 96.1% with dolutegravir (n = 123) and 95.4% with elvitegravir (n = 186; P = 0.941). Patients in the dolutegravir group showed more treatment discontinuations, but these were mainly as a result of simplification. The elvitegravir group showed more discontinuations because of renal adverse events (2.7% versus 0% with dolutegravir). Interestingly, no difference was observed between the two regimens in central nervous system toxicity-related discontinuations. Switching to dolutegravir was associated with a better blood lipid profile. CONCLUSIONS: Switching to dolutegravir + emtricitabine/TDF was associated with similar efficacy and tolerability to switching to elvitegravir/cobicistat/emtricitabine/TDF in virologically suppressed patients in clinical practice, although reasons for discontinuation showed differences between regimens. These results should be interpreted with caution, as this is a nonrandomized comparison.

Efficacy and tolerability of lamivudine plus dolutegravir as a switch strategy in a multicentre cohort of patients with suppressed HIV-1 replication.

OBJECTIVES: We evaluated the efficacy and tolerability of lamivudine + dolutegravir in a cohort of HIV-1 infected, treatment-experienced patients with undetectable HIV-RNA. METHODS: Time to treatment discontinuation (TD) and virological failure (VF) and their predictors were assessed in a multicenter cohort of HIV-1 infected patients, starting lamivudine + dolutegravir after reaching viral suppression. Secondary objective was the evaluation of changes in lipid profile, renal and immunological functions at week 48. RESULTS: We enrolled 206 patients (72.8% male, with 51 years median age), who mainly switched their antiretroviral therapy for simplification (32.5%) or drug toxicity (54.5%). The estimated probability of maintaining virological suppression at 48 and 96 weeks was 98.2% and 95.1%, respectively. VF was independently predicted by cumulative time on antiretroviral therapy. The estimated probability of remaining on lamivudine plus dolutegravir was 86.7% and 80.5% at week 48 and 96, respectively. A significant improvement in immunological function (CD4 count and CD4/CD8 ratio) was evidenced at week 48, as well as a decrease in total cholesterol/HDL ratio, triglycerides and estimated glomerular filtration rate. CONCLUSIONS: Lamivudine plus dolutegravir was effective in maintaining viral suppression in our cohort and led to an improvement in metabolic and immunologic functions.

Reduced risk of Efavirenz Discontinuation in Naïve Patients Starting First-Line Antiretroviral Therapy with Single Tablet versus dual Tablet Regimen.

OBJECTIVES: Despite not being approved in Europe as first-line therapy, the efavirenz (EFV)-containing single tablet regimen (STR) is frequently used in clinical practice in naïve patients but few data are available on this strategy. In our study, we aimed to assess the risk of EFV discontinuation in patients starting antiretroviral therapy with STR vs. nonSTR. METHODS: This was a multicentre study retrospectively enrolling naïve patients starting EFV+TDF+FTC. Patients were followed from the time of treatment initiation to the discontinuation of the EFV-containing regimen, comparing STR vs. nonSTR. Two different analyses were performed: (A) nonSTR patients censored at the last observation (switch to STR not considered as the end of observation); (B) nonSTR patients censored at the time of switch to STR. RESULTS: The study included 235 patients, of whom 74 (31.5%) directly started STR. Among patients starting nonSTR, 108 (67.1%) switched to STR after a median period of 6 months. Forty-four EFV discontinuations were observed (13 among STR vs. 31 among nonSTR patients). The overall estimated probability of discontinuation was 30% at 5 years, about half (14.8%) of these occurring during the first year. Analysis A did not show significant differences between STR and nonSTR regarding the probability of efavirenz discontinuation (19.9% vs. 24.7% at 5 years, P = 0.630). In contrast, Analysis B showed that the probability of EFV discontinuation was similar (8.3%) between STR and nonSTR patients up to 8 months. Thereafter, a significantly higher rate of discontinuation was observed in nonSTR patients (47.5% vs. 19.9% at 5 years, P = 0.034). CONCLUSIONS: Our data suggest that an early switch to STR during the first months of treatment could reduce the risk of EFV discontinuation.

Genotypic resistance profiles associated with virological failure to darunavir-containing regimens: a cross-sectional analysis.

INTRODUCTION: This study aimed at defining protease (PR) resistance mutations associated with darunavir (DRV) failure and PR resistance evolution at DRV failure in a large database of treatment-experienced human immunodeficiency virus (HIV) patients. RESULTS: Overall, 1,104 patients were included: 118 (10.7%) failed at a median observation time of 16 months. The mean number of PR mutations at baseline was 2.7, but it was higher in patients who subsequently failed DRV. In addition, the number of PR mutations increased at failure. The increase in the mean number of mutations was completely related to mutations considered to be associated with DRV resistance following the indications of the main DRV clinical trials. DISCUSSION: The higher statistical difference at baseline between failing versus non-failing patients was observed for the V32I and I84V mutations. At DRV failure, the major increase was still observed for V32I; I54L, V11I, T74P and I50V also increased. Despite the increment in the mean number of mutations per patient between baseline and failure, in 21 patients (17.8%) at baseline and 36 (30.5%) at failure, no PR mutation was detected. CONCLUSION: The HIV-DB interpretation algorithm identified few patients with full DRV resistance at baseline and few patients developed full resistance at DRV failure, indicating that complete resistance to DRV is uncommon.

Viro-immunological efficacy and tolerability of dolutegravir-based regimens compared to regimens based on other integrase strand inhibitors, protease inhibitors or non-nucleoside reverse transcriptase inhibitors in patients with acute HIV-1 infection: A multicenter retrospective cohort study.

OBJECTIVES: The aim of this study was to compare the tolerability and viro-immunological efficacy of dolutegravir-based regimens (DTG group) with regimens based on EVG, RAL, PI or NNRTI (NODTG group) in patients with acute HIV-1 infections (AHI). METHODS: All patients diagnosed with AHI and on antiretroviral therapy (ART) between January 2015 and December 2017 from five centers in Italy were included and followed-up to 30th April 2018. AHI was defined by the presence of the positive p24 antigen with negative or indeterminate western blot. RESULTS: Forty-three patients were enrolled: 20 in the DTG group, 23 in the NODTG group. Nine patients (20.9%; four in the DTG group, five in the NODTG group) were prescribed a four-drug regimen. In the cohort, 81.4% were Italian and 83.7% were male, with a median age of 41 years (interquartile range [IQR] 31-48). Median time between HIV diagnosis and ART initiation was 12 days (IQR 5-28). Seven patients harbored a virus with transmitted mutations at baseline (16.2%), all were in the DTG group (P=0.005). All patients had undetectable HIV-RNA at the end of follow-up except two patients, one of whom had 57 copies and one who was lost to follow-up. In Kaplan-Meier analysis, time to virological suppression was similar in the two groups (log rank: P= 0.7155). After achieving virological suppression, four patients stopped ART because of toxicity: two on DTG, two on EVG for neurological and gastrointestinal toxicity, respectively. CONCLUSION: In our setting, ART in AHI is started very early. DTG showed good viro-immunological efficacy even in the presence of NRTI-transmitted mutations. DTG interruptions were rare.

Effectiveness, safety, durability and immune recovery in a retrospective, multicentre, observational cohort of ART-experienced, HIV-1-infected patients receiving maraviroc.

The aim of this retrospective, multicentre, observational study was to assess the durability, safety, immune recovery and effectiveness on viral suppression of antiretroviral therapy (ART) in a maraviroc (MVC)-based cohort. We collected clinical, demographical, immunological and virological parameters of adult HIV patients who were infected by CCR5-tropic virus and started an ART regimen containing MVC from 2005 to 2012. We created a longitudinal mixed model to assess the change over time of data. We enrolled 126 drug-experienced patients; the median duration of MVC treatment was 25 months. The probability of stopping ART at one year was 13.3%, and at three years was 27.3%. Statistically significant changes were observed for CD4+ cell count increase ( p < 0.001), HIV-RNA decrease ( p < 0.001) and total cholesterol decrease ( p = 0.005). Ninety-four patients (79.7%) had CD4 ≥ 200 cells/mm3 at baseline while nine of them reached this threshold at nine months (7.6%), 17 (13%) after nine months and six (5%) remained below 200 cells/mm3 at the end of the study. Overall, 114 patients (90.5%) achieved an HIV-RNA ≤ 50 cp/ml. A majority of patients maintained CD4 cell counts of ≥ 200 cells/mm3 and achieved an undetectable HIV viral load within three months. MVC-containing regimens are safe and appear to be a feasible therapeutic option for ART.

Down-regulation of secondary in vitro antibody responses by suppressor T cells of mice treated with a tolerogenic conjugate of ovalbumin and monomethoxypolyethylene glycol, OVA(mPEG)13.

In previous studies from this laboratory it was shown that OVA(mPEG)n conjugates induced: (i) tolerance in mice with respect to IgG and IgE antibody responses to dinitrophenylated OVA (DNP-OVA); and (ii) OVA-specific suppressor T (Ts) cells which could down-regulate a primary immune response in vivo. For the present study, we have developed an in vitro culture system for assessing the activity of Ts cells of mice tolerized by an OVA(mPEG)13 conjugate. Spleen cells from mice which had been primed with DNP4-OVA in Al(OH)3 gel were cultured with DNP4-OVA to induce a secondary antibody response in vitro. After 6 days, cells secreting anti-DNP antibodies of the IgG1 class were enumerated by an immunoenzymatic plaque-forming cell assay. Addition to the culture of T cells from mice treated with 3 i.p. injections of 500 micrograms of OVA(mPEG)13 resulted in a 29-61% reduction in the number of IgG1 anti-DNP antibody-forming cells, in comparison with the effect of T cells from mice treated with PBS. It was concluded that this tolerogenic conjugate induced splenic Ts cells which were capable of suppressing secondary in vitro anti-DNP responses.

Persistent damage to Enterocytozoon bieneusi, with persistent symptomatic relief, after combined furazolidone and albendazole in AIDS patients.

AIM: To investigate morphological changes in Enterocytozoon bieneusi and the duration of symptomatic relief after combination treatment with furazolidone and albendazole in AIDS patients. METHODS: Four severely immunocompromised AIDS patients with symptomatic E bieneusi infection of the gut received an 18 day course of combined furazolidone and albendazole (500 + 800 mg daily). All patients were monitored for parasite shedding in stool by light microscopy at the end of treatment and monthly during follow up. At the end of treatment, duodenal biopsy specimens obtained from three patients were studied by transmission electron microscopy by two pathologists blind to the patients' treatment or clinical outcome. Duodenal biopsy specimens obtained from one of the patients two months after completion of treatment were also studied electronmicroscopically. RESULTS: All patients had long lasting symptomatic relief, with a major decrease--or transient absence--of spore shedding in stools from completion of treatment. After treatment, changes in faecal spores were persistently found by light microscopy in all cases, and there was evidence of both a substantial decrease in the parasite load and ultrastructural damage in the parasite in all biopsy specimens. The treatment was well tolerated, and no patient had clinical or parasitological relapse during follow up (up to 15 months). CONCLUSIONS: The long lasting symptomatic relief observed in all four treated patients correlated with the persistent decrease in parasite load both in tissue and in stool, and with the morphological changes observed in the life cycle of the protozoan. These data suggest that combined treatment with furazolidone and albendazole is active against E bieneusi and may result in lasting remission even in severely immunocompromised patients.

Chronic cryptosporidiosis in patients with AIDS: stable remission and possible eradication after long-term, low dose azithromycin.

AIMS: To investigate the effectiveness of long term, low dose azithromycin treatment for chronic cryptosporidiosis in patients with AIDS. METHODS: Azithromycin was administered as initial daily treatment to 13 patients with AIDS: 6 patients received 500 mg for 30 to 40 days (mean 35); 3 patients received 1000 mg for 21 to 50 days (mean 37); and 4 patients received 1500 mg for 20 days. Nine of the 13 patients were also given low dose maintenance treatment with different schedules of azithromycin for 30 to 360 days (mean 129). Patients were monitored, during and after treatment, for parasite shedding in stool and for daily stool frequency and body weight. All but one patient had severe immunodeficiency. RESULTS: Long term, low dose maintenance treatment was associated with major clinical and parasitological benefits: there was probable eradication of infection in 2 patients, and 7 patients showed a complete response with persistent high decrease (5 patients) or clearance (2 patients) of parasite in stool. The drug was well tolerated, and there was no relapse either during treatment or during follow up (up to 21 months). These results were more impressive than those observed after the short term initial course of azithromycin, which was unable at any tested dose to achieve parasite clearance in stool (except in the patient with less advanced immunodeficiency) or to prevent relapse in 3 patients who discontinued treatment. Reversible side effects occurred with the 1500 mg daily dose. CONCLUSIONS: Long term, low dose azithromycin is well tolerated and may induce stable remission of chronic cryptosporidiosis in patients with AIDS. It may lead to probable eradication of the infection in some patients, even those with severe immunodeficiency.

Enterocytozoon bieneusi in AIDS: symptomatic relief and parasite changes after furazolidone.

AIMS: To investigate changes in morphology of the developmental stages of Enterocytozoon bieneusi and symptomatic relief observed in AIDS patients after treatment with furazolidone. METHODS: Six AIDS patients with symptomatic E bieneusi infection of the small intestine were treated with a course of furazolidone. All patients had a weekly monitoring of parasite shedding in stool by light microscopy during and after treatment. At the end of the treatment, duodenal biopsy specimens obtained from three patients were studied by transmission electron microscopy by two pathologists who were unaware of the patients' treatment. RESULTS: All patients showed both clinical and parasitological response with transient clearance or decrease of spore shedding in stool. After treatment, alterations in faecal spores were observed in all patients by light microscopy, and ultrastructural changes in E bieneusi at all stages of the life cycle were demonstrated in biopsy specimens of the three patients who underwent post-treatment endoscopy. CONCLUSIONS: The clinical benefit seen after treatment with furazolidone in six AIDS patients with E bieneusi intestinal infection may be due to damage to the developmental stages causing a partial inhibition to reproduction of the parasite.

Aortic connective tissue in atherosclerotic aorta--a biochemical study.

Biochemical analysis of the extracellular matrix of human aortas was performed on samples of ascending and descending aortas affected by atherosclerosis in comparison with a control group of nonatherosclerotic aortas. Ulcerated or heavily calcified atheromas were excised and excluded from the analysis in order to differentiate biochemical alterations leading to the formation of atheromas from those due to complications of already formed atheromas. Our results show that the development of atheromas brings about an extensive destruction of elastic fibers and muscular cells, and their place is occupied by other components of the extracellular matrix, most notably, collagen, non-uronic sugars, water, and lipids, which were found significantly increased.

Biochemical analysis of dermal connective tissue in subjects affected by primary uncomplicated varicose veins.

Biochemical analysis of dermal connective tissue was carried out in 14 subjects affected by primary uncomplicated varicose veins and 14 controls. Skin samples were taken, according to fixed criteria, from operation pieces of total mastectomy for breast cancer. The results suggest that the dermal tissue in these subjects is just thinner than that of controls, confirming previous similar clinical findings. The elective reduction of the collagen content observed, unassociated with changes of other components of the dermal connective tissue, brings evidence for a systemic biochemical defect of the extracellular matrix i.e. a collagen defect affecting the entire body structure and not only the varicose or pre-varicose veins of the lower limbs.

Aortic connective tissue in ageing--a biochemical study.

The biochemical analysis of samples of aortic connective tissue was carried out in 22 subjects from 9 to 84 years old. Aortic samples were taken at necropsy performed after sudden or, more often, traumatic death. The results suggest that aging of the aorta is accompanied by an increase both in collagen content and in total sugar content when expressed as mg/cm2 while the elastin content, when expressed in the same way, does not undergo any variation.

Human papilloma virus type 16 E6 gene expression in oral exophytic epithelial lesions as detected by in situ rtPCR.

OBJECTIVE: We adopted an in situ reverse transcriptase polymerase chain reaction method of detecting and determining the frequency of early (E6) gene expression of human papilloma virus type 16 at the individual cell level in a sample of oral exophytic lesions with various degrees of epithelial hyperplasia and dysplasia in immunosuppressed and immunocompetent patients. STUDY DESIGN: The significance of differences between the study groups was determined by Mantel-Haenszel chi-square analysis and calculation of odds ratios, accounting for immunosuppression and degree of dysplasia, respectively. RESULTS: Grouped together, the lesions of dysplasia (mild to severe) and squamous cell carcinoma were found to be 16 times more likely to express human papilloma virus E6 mRNA than the benign lesions (P = .0013); in the lesions of immunosuppressed patients, human papilloma virus 16 E6 was roughly 10 times more likely to be expressed than in those of the immunocompetent patients (P = .0008, accounting for dysplasia). CONCLUSIONS: Our data indicate that human papilloma virus 16 E6 gene expression, and perhaps integration of the virus in the host genome, might play a role in the development of oral neoplasia in association with immunosuppression.

[Azithromycin combined with pyrimethamine in the treatment of neurotoxoplasmosis, in an AIDS patient]. / Azitromicina in associazione a pirimetamina nel trattamento della neurotoxoplasmosi, in un paziente con AIDS.

We report one case of successful treatment of cerebral toxoplasmosis in acquired immunodeficiency syndrome (AIDS) with azithromycin combined with pyrimethamine. Toxoplasmic encephalitis had been diagnosed on the basis of multiple lesions exhibiting ring like contrast enhancement on double contrast Computed Tomographic (CT) scan of the brain. Thereby our patient had been treated with pyrimethamine 25 mg/die, after an attack dose of 100 mg in the first day, and clindamycin 2400 mg/die, because of sulfa-drug allergy, but clindamycin had to be discontinued because of rash development. At this point azithromycin, at a dose of 1000 mg/die for 21 days and 1500 mg a week for the following 50 days of follow-up, was added to pyrimethamine. Follow-up CT scan after 20 days of treatment (10 with clindamycin+pyrimethamine and 10 with azithromycin+pyrimethamine) revealed partial resolution of the brain lesions and subsequently (after 50 and 80 days of treatment) complete resolution.

[Progressive paralysis. A case report]. / Paralisi progressiva. Descrizione di un caso.

STUDY OBJECTIVE: A fairly uncommon case of neurosyphilis is reported in a not immunocompromised patient. CASE REPORT: A case of general paresis in a 40 year-old male with the recent onset of mania is described. Psychiatric anamnesis was negative. Neurologic examination was negative. Laboratory tests were performed and serologic tests for syphilis were positive. Cerebrospinal fluid (CSF) examination showed 80 leukocytes/mm3, a reactive Venereal Disease Research Laboratory (VDRL) and normal protein concentration. CSF gamma globulin with an oligoclonal pattern and abnormal IgG index were found. A test for antibodies to Human Immunodeficiency Virus (HIV) was negative. The patient underwent a high dose intravenous penicillin G regimen for two weeks. A follow-up six months later showed a normal CSF even though the IgG index was still abnormal and the mental status was unchanged. CONCLUDING REMARKS: The authors suggest that patients with neurologic and/or psychiatric symptoms with a recent onset and a reactive VDRL should undergo a CSF examination to exclude a possible neurosyphilis.

Use of furazolidone for the treatment of microsporidiosis due to Enterocytozoon bieneusi in patients with AIDS.

The efficacy of furazolidone for treatment of intestinal microsporidiosis due to Enterocytozoon bieneusi was studied in three patients with AIDS. All patients had chronic diarrhoea and weight loss. Mean CD4 cell count was 34.6/mm3. A course of furazolidone (100 mg orally four times a day) was given for 20 days. The drug was well tolerated and neither side effects nor alterations in the laboratory parameters were noted. Diarrhoea ceased within a mean of 12 days of starting treatment and clearance of microsporidian shedding in stool was observed. In one of the patients, however, symptomatic microsporidiosis recurred. Therefore furazolidone seems to have a transient but significant effect on intestinal infection due to Enterocytozoon bieneusi.

[Intestinal mycobacterial infections in AIDS. Clinical course and treatment of infections caused by Mycobacterium avium, Mycobacterium kansasii, Mycobacterium genavense]. / Micobatteriosi intestinali in AIDS. Clinica e terapia delle infezioni da Mycobacterium avium, Mycobacterium kansasii, Mycobacterium genavense.

Digestive apparatus is a common target of atypical mycobacteriosis in AIDS patients (at least 50% of patients with CD4+ lymphocytes < 50/mm3). We describe the clinical-histological features of two cases of Whipple-like syndrome likely caused by Mycobacterium avium (MAI) (study performed by light and electron microscopy), of one case of infection caused by two morphological variants of a MAI strain with a different sensitivity to antibiotics, of one case of M. kansasii infection and of two cases of M. genavense infection accompanied by sensitivity tests to antibiotics (as far as we know, these are the first described quantitative sensitivity tests of M. genavense to antibiotics). In conclusion, we discuss the present therapeutical outlines for M. kansasii and avium, together with the teramporary pharmacological options for M. genavense as suggested by antibiotic sensitivity tests performed on the strains isolated from the studied patients.