Predictors of incomplete viral response and virologic failure in patients with acute and early HIV infection. Results of Italian Network of ACuTe HIV InfectiON (INACTION) cohort.

OBJECTIVES: The aim of this study was to evaluate the factors that can influence an incomplete viral response (IVR) after acute and early HIV infection (AEHI). METHODS: This was a retrospective, observational study including patients with AEHI (Fiebig stages I-V) diagnosed between January 2008 and December 2014 at 20 Italian centres. IVR was defined by: (1) viral blip (51-1000 HIV-1 RNA copies/mL after achievement of < 50 HIV-1 RNA copies/mL); (2) virologic failure [> 1000 copies/mL after achievement of < 200 copies/mL, or ≥ 200 copies/mL after 24 weeks on an antiretroviral therapy (ART)]; (3) suboptimal viral response (> 50 copies/mL after 48 weeks on ART or two consecutive HIV-1 RNA levels with ascending trend during ART). Cox regression analysis was used to calculate the hazard ratios (HRs) and 95% confidence intervals (95% CIs) for IVR. RESULTS: In all, 263 patients were studied, 227 (86%) males, with a median [interquartile range (IQR)] age of 38 (30-46) years. During a median follow-up of 13.0 (5.7-31.1) months, 38 (14.4%) had IVR. The presence of central nervous system (CNS) symptoms was linked to a higher risk of IVR (HR = 4.70, 95% CI: 1.56-14.17), while a higher CD4/CD8 cell count ratio (HR = 0.13, 95% CI: 0.03-0.51 for each point increase) and first-line ART with three-drug regimens recommended by current guidelines (HR = 0.40, 95% CI: 0.18-0.91 compared with other regimens including four or five drugs, older drugs or non-standard backbones) were protective against IVR. CONCLUSIONS: Patients with lower CD4/CD8 ratio and CNS symptoms could be at a higher risk of IVR after AEHI. The use of recommended ART may be relevant for improving short-term viral efficacy in this group of patients.

Week 96 efficacy and safety of darunavir/ritonavir monotherapy vs. darunavir/ritonavir with two nucleoside reverse transcriptase inhibitors in the PROTEA trial.

OBJECTIVES: PROTEA is a randomized controlled trial to assess the efficacy and safety of darunavir/ritonavir (DRV/r) monotherapy as an alternative to triple therapy. METHODS: Patients fully suppressed on first-line antiretrovirals (viral load < 50 HIV-1 RNA copies/mL) were switched to DRV/r 800/100 mg once daily, either as monotherapy (n = 137) or with two nucleoside reverse transcriptase inhibitors (NRTIs) (n = 136). Treatment failure was HIV-1 RNA level ≥ 50 copies/mL at week 96 or discontinuation of study treatment [Food and Drug Administration (FDA) snapshot algorithm]. RESULTS: Patients were mainly male and white, with mean age 44 years. In the primary efficacy analysis, the percentage of patients with HIV-1 RNA < 50 copies/mL by week 96 [intent to treat (ITT)] was lower in the DRV/r monotherapy arm (103 of 137 patients; 75%) than in the triple therapy arm (116 of 136 patients; 85%) [difference -10.1%; 95% confidence interval (CI) -19.5, -0.7%]. In the switch-included analysis, monotherapy was noninferior to triple therapy. In a post hoc analysis, for patients with nadir CD4 count ≥ 200 cells/µL, rates of HIV-1 RNA suppression were 82 of 96 patients (85%) in the DRV/r monotherapy arm and 88 of 106 patients (83%) in the triple therapy arm. No treatment-emergent primary protease inhibitor mutations were detected in either arm. The frequency of adverse events was similar in the two arms; however, one patient in the monotherapy arm was hospitalized with HIV encephalitis and elevated cerebrospinal fluid HIV-1 RNA. CONCLUSIONS: In this study, in patients with HIV-1 RNA < 50 copies/mL at baseline, switching to DRV/r monotherapy showed lower efficacy vs. triple therapy at week 96 in the primary ITT switch-equals-failure analysis, particularly in patients with CD4 counts < 200 cells/µL.

Ageing with HIV: a multidisciplinary review.

INTRODUCTION: After the introduction of highly active antiretroviral treatment, the course of HIV infection turned into a chronic disease and most of HIV-positive patients will soon be over 50 years old. MATERIAL AND METHODS: This paper reviews the multiple aspects that physicians have to face while taking care of HIV-positive ageing patients including the definitions of frailty and the prevalence and risk factors of concomitant diseases. From a therapeutic point of view pharmacokinetic changes and antiretroviral-specific toxicities associated with ageing are discussed; finally therapeutic approaches to frailty are reviewed both in HIV-positive and negative patients. CONCLUSION AND DISCUSSION: We conclude by suggesting that the combined use of drugs with the least toxicity potential and the promotion of healthy behaviours (including appropriate nutrition and exercise) might be the best practice for ageing HIV-positive subjects.

Investigating coping and stigma in people living with HIV through narrative medicine in the Italian multicentre non-interventional study DIAMANTE.

Antiretroviral therapy (ART) significantly reduced Human Immunodeficiency Virus (HIV) morbidity and mortality; nevertheless, stigma still characterises the living with this condition. This study explored patients' coping experience by integrating narrative medicine (NM) in a non-interventional clinical trial. From June 2018 to September 2020 the study involved 18 centres across Italy; enrolled patients were both D/C/F/TAF naïve and previously ART-treated. Narratives were collected at enrolment (V1) and last visit (V4) and then independently analysed by three NM specialist researchers through content analysis. One-hundred and fourteen patients completed both V1 and V4 narratives. Supportive relationships with clinicians and undetectable viral load facilitated coping. Conversely, lack of disclosure of HIV-positive status, HIV metaphors, and unwillingness to narrate the life before the diagnosis indicated internalised stigma. This is the first non-interventional study to include narratives as patient reported outcomes (PROs). Improving HIV awareness and reducing the sense of guilt experienced by patients helps to overcome stigma and foster coping.

HIV-HCV co-infection: epidemiology, pathogenesis and therapeutic implications.

Hepatitis C virus (HCV) is the cause of more than three-quarters of liver-related deaths in HIV-seropositive individuals and it is remarkable that today approximately one-quarter of HIV-infected individuals in Europe and the USA have a HCV coinfection. HIV/HCV coinfected patients were more likely to develop cirrhosis, had an increased risk of developing AIDS, of HIV-related disease and of overall mortality. How HCV may affect the course of HIV infection is not well known even if it was suggested that HCV co-infection is able to increase immune activation and to sensitize CD4+ T-cells towards apoptosis in the absence of HIV therapy. There are many evidences that the simultaneous presence of HIV infection accelerates the liver damage from HCV favouring the evolution to cirrhosis in co-infected patients. HIV increasing of TNF alpha liver production and of HCV replication in peripheral blood lymphomonocytes are the mechanisms at the basis of this phenomenon. HAART had a positive effect on HIV/HCV co-infection, otherwise it does not appear to fully correct the adverse effect of HIV infection on HCV-related outcomes. Traditional treatment with pegilated Interferon plus ribavirin have low rates of sustained virological response in co-infected patients especially if infected with HCV genotype 1, and better results were often obtained in patients in which the use of antiretroviral treatment was avoided to reduce the occurrence of adverse effects. The recent preliminary results on the use of anti-HCV protease inhibitor drugs, boceprevir and telapravir, in co-infected people seems to demonstrate an enhanced antiviral efficacy in the HIV/HCV co-infected population of triple anti-HCV treatment even is some important limitation as interactions with antiretroviral agents and selection of HCV drug resistance, lead to consider the need for further studies designed to assess the best therapeutic strategies.

Causes of death and risk factors among HIV-infected persons in the HAART era: analysis of a large urban cohort.

OBJECTIVE: We aimed to examine the clinical outcome in HIV-1-infected patients after more than 10 years of highly active antiretroviral therapy (HAART). METHODS: We analyzed data from 1,236 treatment-naïve adults who had started HAART. The primary endpoint was the yearly prevalence of death for AIDS-related causes (ARC) or for non-AIDS related causes (non-ARC). The data from our cohort were compared with that of the general population (GP) of our region. RESULTS: We observed that 116 patients died, and 58.6% of deaths were non-ARC. The death incidence decreased from 18.8% in 1998-1999 to 1.2% in 2008-2009. The leading causes of death were malignancies (35.3%), infections (21.6%), end-stage liver diseases (18.1%), and cardiovascular diseases (CVD) (6.9%). Yearly death rates were similar in the HIV-infected cohort and in the crude GP (odds ratio [OR] 1.1, 95% confidence interval [CI] 0.5-2.5), but when adjusted for age, HIV-infected patients showed a greater risk (OR 7.4, 95% CI 4.1-13.4). The difference was still highly significant when the analysis was restricted to non-ARCs (OR 4.3, 95% CI 2.07-9.2). Overall, malignancies (OR 5.7, 95% CI 2.6-12.8) and end-stage liver diseases (OR 35.0, 95% CI 15.5-78.8) were significantly more frequent than in the age-adjusted GP. CONCLUSIONS: Despite HAART, HIV-infected patients are at greater risk of death compared to a reference uninfected population.

Cutaneous mucormycosis by Rhizopus arrhizus treated with isavuconazole as first line therapy: A case report.

Mucormycosis are a group of infections that affect principally immunocompromised host and have a high mortality. Liposomal amphotericin B is the first-line treatment with combined surgical removal of the infectious focus. We report the case of 67-year-old man with idiopathic granulocytic aplasia and a cutaneous lesion caused by Rhizopus arrhizus treated with isavuconazole. Its safety profile and spectrum of activity make it an important therapeutic option.

Determination of dose rates from natural radionuclides in dental materials.

Different types of materials used for dental prosthetics restoration, including feldspathic ceramics, glass ceramics, zirconia-based ceramics, alumina-based ceramics, and resin-based materials, were investigated with regard to content of natural radionuclides by means of thermoluminescence beta dosimetry and gamma spectrometry. The gross beta dose rate from feldspathic and glass ceramics was about ten times higher than the background measurement, whereas resin-based materials generated negligible beta dose rate, similarly to natural tooth samples. The specific activity of uranium and thorium was significantly below the levels found in the period when addition of uranium to dental porcelain materials was still permitted. The high-beta dose levels observed in feldspathic porcelains and glass ceramics are thus mainly ascribable to (40)K, naturally present in these specimens. Although the measured values are below the recommended limits, results indicate that patients with prostheses are subject to higher dose levels than other members of the population. Alumina- and zirconia-based ceramics might be a promising alternative, as they have generally lower beta dose rates than the conventional porcelain materials. However, the dosimetry results, which imply the presence of inhomogeneously distributed clusters of radionuclides in the sample matrix, and the still unsuitable structural properties call for further optimization of these materials.

A non-derivative, non-surgical tracheostomy: the translaryngeal method.

OBJECTIVE: To present a new technique for non-surgical tracheostomy. DESIGN: An open, clinical trial on patients requiring elective tracheostomy. SETTING: Intensive care unit of a community hospital. PATIENTS: 95 adults, mean age 60 years, and 14 infants and children, mean age 26 months (2 months-7 years) with common indications for tracheostomy. INTERVENTION: Through a needle inserted in the trachea, a guidewire is pushed out of the mouth against the usual direction and attached to a special device formed by a flexible plastic cone with a pointed metal tip joined to an armoured tracheal cannula. This device is then pulled back through the oral cavity, larynx and trachea and outwards across the neck wall by the operator applying traction on the wire with one hand and counterpressure on the neck wall with the fingers of the other hand. When the cone and a part of the cannula have emerged, the cannula is cut off from the cone, straightened perpendicular to the skin, rotated and advanced caudally to its final position. RESULTS: The cone-cannula passed smoothly through the vocal cords. The metallic point perforated the neck easily. The dilation did not present any risk of tracheal wall damage because the direction of the manoeuvre was from the inside to the outside of the neck. The tissues tightly adhered to the cannula, thus avoiding infection and bleeding. The use of ventilation systems permitted utilization of translaryngeal tracheostomy (TLT) even in patients for whom apnoea might have carried some risk, because there is no interruption of respiratory assistance during the procedure. Follow-up showed no late obstructive complication at the level of the tracheostoma. CONCLUSIONS: By virtue of its greater safety and less trauma to tissues than percutaneous techniques, TLT can also be carried out in infants and children (an important benchmark for any tracheostomy technique) and in very difficult patients from whom other techniques have serious drawbacks.

Long-term clinical benefit after highly active antiretroviral therapy in advanced HIV-1 infection, even in patients without immune reconstitution.

Our objective was to assess, in the clinical setting, the predictors of immune reconstitution (IR) and its relation with long-term clinical benefit, in HIV patients with advanced disease after highly active antiretroviral therapy (HAART) through an observational study. A retrospective cohort study in a clinical setting of 383 consecutive adult patients with advanced HIV infection (CD4+ cells <200/mm(3) at baseline), starting their first protease inhibitor (PI)-containing regimen was observed. Immune reconstitution was defined as CD4 count >200 cells/mm(3) and an increase > or =100 cells from baseline, anytime since starting HAART. Clinical benefit was defined as decreased mortality and reduction in AIDS-defining events, AIDS-related complex (ARC) events, major infections and hospitalization (days spent in hospital). During a mean follow-up of 808 days, 261 patients (68.1%) achieved IR. About 50% of these patients reached this result within one year after starting HAART. In multivariate analysis, predictors of immune recovery were sex (female) and baseline CD4 count higher than 50 cells/mm(3). The group of patients with IR had greater clinical benefit with lower mortality, fewer AIDS-defining events, shorter lengths of stay in hospital, fewer ARC events and fewer major infections during all the follow-up (P < 0.0001, tests for trends). However, although they did less remarkably than the first group of patients, even those patients who did not achieve IR experienced a significant decrease in the incidence of all the above events, as compared with the first and sometimes the second trimester after starting their HIV therapy. About 70% of HIV patients with advanced disease achieved IR after starting HAART. Such a benefit is a time-dependent effect and may even take more than 2 years to occur. Predictors of IR were sex (female) and higher baseline CD4 count (>50 cells/mm(3)). The patients who achieved immune recovery performed clinically better than patients who did not. Also the patients who failed to gain such a strong immunological recovery experienced a long-term clinical benefit. This suggests that PI-containing regimens, in advanced HIV disease, may produce a significant clinical benefit, at least temporary, even for patients who do not achieve a substantial immune response.

Severe lactic acidosis and thiamine administration in an HIV-infected patient on HAART.

Severe lactic acidosis has been increasingly reported as a potentially fatal complication of HIV treatment. We report on an asymptomatic HIV-infected woman treated with stavudine, lamivudine and indinavir for one year. She was hospitalized because of progressive dispnoea, oedema, cyanosis and severe lactic acidosis. Arterial blood pH was 6.98, bicarbonate 4.4 mmol/l (normal value 22-26), blood lactate: 29.7 mmol/l (normal value <2.2). Hepatic function was normal. She had an impressively rapid response (within a few hours) to empirical treatment with thiamine (100 mg i.v.). No evidence of sepsis or malabsorption were identified and vitamin B1 level was not tested before thiamine infusion. Three months later she was re-started successfully on nelfinavir plus nevirapine. The rapid response to thiamine infusion deserves a careful attention and such an approach should be considered in similar cases as a support treatment of this potentially life-threatening complication of HIV therapy.

Changing patterns of HIV transmission and better targeting for intervention strategies.

We considered the HIV population of our area, comparing demographic characteristics between 2 consecutive 6-year periods to assess the current patterns of HIV transmission. All HIV-positive patients referred to our hospital from January 1985 to December 1996 were included in the study and were classified into 2 periods: A (January 1985 to December 1990) and B (anuary 1991 to December 1996). The variables analysed were: sex, age at first visit, HIV risk category. A total of 4284 HIV subjects were observed, 2306 in period A vs 1978 in period B (P=ns). Males were 76.3% vs 75.2% (P=ns). Mean age for males was 27.4 vs 32.4 years (P < 0.001) and for females 25.4 vs 30.1 years (P < 0.001). Intravenous drug users (IVDUs) were 88.4% vs 65.4% (P < 0.001), 'heterosexuals' 14.3% vs 24.8% (P < 0.001), 'men who have sex with men' 2.4% vs 4.8% (P < 0.001). Mean age by the main risk groups was: IVDUs 25.9 vs 29.7 years (P < 0.001); heterosexuals 30.4 vs 36 years (P=0.007); 'men who have sex with men' 35 vs 35 years. In conclusion, our study confirms the emerging role of heterosexuals in the current HIV epidemic. People older than teenagers seem to have misperceived their own risk of HIV infection, given the increase in the mean age occurred in the most recent years. This trend suggests the need for prevention strategies focusing more on heterosexual transmission and older people.

[Cholestatic liver disease and thrombocytopenia associated with long exposure to ticlopidine]. / Colestasi epatica e trombocitopenia associate a trattamento protratto con ticlopidina.

A 45-year-old woman was admitted to the hospital because of cholestatic liver disease and severe thrombocytopenia following a 4-day history of fever and malaise. In her childhood the patient suffered from acute rheumatic fever with secondary mitral stenosis. Three years before admission, an atrial fibrillation had been diagnosed for which the patient was put on ticlopidine, 250 mg daily, that was taken regularly, without any adverse event. The patient had no history of cholestatic hepatitis or biliary colic. The abdominal ultrasonography was negative for biliary tract diseases and histological features were compatible with drug induced hepatotoxicity. Laboratory tests for viral and bacterial infection were negative. No other medications, apart from 2 doses of nimesulide, had been taken by the patient in the previous days. Ticlopidine was discontinued on admission and both bilirubin and platelet count rapidly normalized. We think that, in our patient, ticlopidine may be responsible of concomitant hematologic and hepatic toxicity and the trigger event might have been the reduced renal excretion of the drug following acute renal failure.

Factors influencing the normalization of CD4+ T-cell count, percentage and CD4+/CD8+ T-cell ratio in HIV-infected patients on long-term suppressive antiretroviral therapy.

We evaluated factors associated with normalization of the absolute CD4+ T-cell counts, per cent CD4+ T cells and CD4+/CD8+ T-cell ratio. A multicentre observational study was carried out in patients with sustained HIV-RNA <50 copies/mL. Outcomes were: CD4-count >500/mm(3) and multiple T-cell marker recovery (MTMR), defined as CD4+ T cells >500/mm(3) plus%CD4 T cells >29%plus CD4+/CD8+ T-cell ratio >1. Kaplan-Meier survival analysis and Cox regression analyses to predict odds for achieving outcomes were performed. Three hundred and fifty-two patients were included and followed-up for a median of 4.1 (IQR 2.1-5.9) years, 270 (76.7%) achieving a CD4+ T-cell count >500 cells/mm(3) and 197 (56%) achieving MTMR. Using three separate Cox models for both outcomes we demonstrated that independent predictors were: both absolute CD4+ and CD8+ T-cell counts, %CD4+ T cells, a higher CD4+/CD8+ T-cell ratio, and age. A likelihood-ratio test showed significant improvements in fitness for the prediction of either CD4+ >500/mm(3) or MTMR by multivariable analysis when the other immune markers at baseline, besides the absolute CD4+ count alone, were considered. In addition to baseline absolute CD4+ T-cell counts, pretreatment %CD4+ T cells and the CD4+/CD8+ T-cell ratio influence recovery of T-cell markers, and their consideration should influence the decision to start antiretroviral therapy. However, owing to the small sample size, further studies are needed to confirm these results in relation to clinical endpoints.

Anatomical particularities and difficulties in tracheostomy: three case reports.

Three tracheostomies conducted using Fantoni's translaryngeal technique (TLT) are described in patients with particular anatomical conditions of the trachea and neck. The first case is of a patient with tracheal stenosis, which is known to be problematic with regard to gaining adequate endoscopic control, assuring effective ventilation during maneuvers and ensuring the safety of the walls of the trachea. The second case is with regard to a patient with a voluminous thyroid goiter that displaced the trachea to the right, making it difficult to appreciate the tracheal lumen during needle introduction. The third case is of a patient with spastic tetraparesis due to asphyxia neonatorum and kyphoscoliorachitis, which made ventilation and access to the trachea difficult. The peculiarity of the technique and the constitutive elements of the TLT kit were invaluable for the resolution of the problems that occurred during the procedure. In particular, the tracheoscope with a rigid optical lens inside allowed for better protection of the trachea by offering optimal endoscopic vision. The three tracheostomies were performed without intraprocedural or long term complications.

[Tracheostomy in pediatrics patients]. / Tracheostomia in et pediatrica.

This is a case study of 79 children who under-went a tracheostomy with three different techniques, used in succession on three different groups of patients: surgical, percutaneous with progressive probes and translaryngeal technique. The pediatric patient, only under the age of 10, starts showing clear-cut anatomical differences compared to an adult, which gradually become more marked the younger the patient is. The causes of increased difficulties that can normally be found in these patients are obviously due to the reduced diameter of the airway and, above all, the high degree of pliability of the cartilaginous frame. After the discovery that even minimal external pressure can cause the collapse of the tracheal walls, it was decided to adopt the systematic use of a rigid bronchoscope, in order to be able to offer internal support to the anterior wall. The following advantages were obtained in the various techniques: In surgery it permitted the reduction, through the protrusion of the trachea, of the size of the operatory field, of the tracheal opening and consequently of the local trauma. It also caused less bleeding and reduced the risk of lesion to the pleural dome which are very frequent when a bronchoscope is not used. In the percutaneous method the bronchoscope allowed the application of the technique without complications, even in infants of only a few months' old, because it eliminated tracheal squashing, caused by the introduction of the needle, dilators and especially cannula, and the relative danger of lesion to the posterior wall of the trachea. This complication which was always impending in the original technique, which does not involve the use of a rigid bronchoscope, is the main reason which lead to the ban on PDT for patients younger than 16-18. In the translaryngeal method the advantages are of minor importance because they are limited to the initial stage of the procedure, the introduction of the needle and guide wire which are quicker and more precise. As regard the dilation, the TLT mode has a high level of intrinsic safety and is perfectly suitable to the anatomy of the child. In fact it is carried out from the inside towards the outside, causing a tendency to evertion of the tracheal wall which the physician must even limit with external pressure. It is remarkable that this contrast in pressure and the resulting compression of the peristomal tissues creates advantages, which are essential in younger children, that cannot be found in other tracheal techniques. These advantages are the complete absence of loss of blood, minimal local trauma and a perfect adherence of the stoma to the cannula, particularly effective at level of the tracheal wall.

An unusual aspect of tracheal stenosis. Case report.

lnjury of the tracheal mucosa at the decubitus site of the endotracheal tube cuff during prolonged endotracheal intubation and resulting fibrin deposits may predispose for the development of tracheal stenosis. Frequent endoscopic control examinations, following the increased use of dilation tracheostomy techniques, have revealed a considerable number of these once misrecognized complications in laryngeal and tracheal structures alike. The case reported here appears to confirm this sequence of events. Timely operative endoscopy using a pair of pincers mounted on a rigid endoscope permitted the removal of the fibrin membrane causing the tracheal lumen stenosis and allowed us to achieve complete and definitive recalibration of the trachea, with restoration of spontaneous breathing. Cortisone therapy prolonged for 5 days probably prevented recurrence of the stenosis. Follow-up was carried out in 3 phases. The 1(st) phase included early control using tracheal endoscopy; 2(nd) comprised neck CT scan to examine the tracheal lumen 15 days after endoscopic control, and the 3rd phase involved medical examination after about 3 months and neck radiography in 2 projections.