Transformation of Cancer Care during and after the COVID Pandemic, a point of no return. The Experience of Italy.

Policymakers everywhere struggle to introduce therapeutic innovation while controlling costs, a particular challenge for the universal Italian National Healthcare System (SSN), which spends only 8.8% of GDP to care for one of the world's oldest populations. Oncology provides a telling example, where innovation has dramatically improved care and survival, transforming cancer into a chronic condition. However, innovation has also increased therapy duration, adverse event management, and service demand. The SSN risks collapse unless centralized cancer planning changes gear, particularly with Covid-19 causing treatment delays, worsening patient prognosis and straining capacity. In view of the 750 billion Euro "Next Generation EU", released by the European Union to relieve Member States hit by the pandemic, the SSN tapped a multidisciplinary research team to identify key strategies for equitable uptake of innovations in treatment and delivery, with emphasis on data-driven technological and managerial advancements - and lessons from Covid-19.

Effect of suppressing HIV viremia on the HIV progression of patients undergoing a genotype resistance test after treatment failure.

BACKGROUND: Treatment guidelines for multi-experienced HIV patients have recently evolved from aiming to preserve immunity to achieving virological success, largely due to the availability of new antiretroviral drugs and drug classes. To assess the role of viral suppression on clinical progression following a genotypic resistance test (GRT), we have examined a database on patients failing to respond to combined antiretroviral therapy (cART). METHODS: Patients undergoing a GRT after failure to respond to cART between January 1999 and May 2006 were followed up to December 2006. Time-to-death or a new AIDS event/death were considered to be analysis end-points. Viral suppression (< 50 copies/ml [c/ml]) after GRT, a time-dependent covariate, was tested as predictor of disease progression. RESULTS: Overall, 1,389 patients were included in this observational study. After the GRT, patients were followed up to 72 months (median 28 months, IQ range 13-51 months). During the follow-up, 124 patients (9%) died, and 86 (6%) experienced a new AIDS event. 774 patients (56%) achieved < 50 c/ml HIV-RNA. The results of an adjusted Cox model showed that undetectable HIV-RNA after the GRT was significantly associated with a lower risk of death (hazard ration [HR] 0.46, 95% confidence interval [CI] 0.27-0.76) and AIDS/death (HR 0.43, 95% CI 0.28-0.65). The adjusted hazard ratios suggested a twofold risk reduction. A threefold risk reduction of death related to achieved undetectable viral load was found in patients with resistance to more than one drug class and with CDC-C diagnosis; a fourfold reduction was found in patients with < 200 CD4+/mm(3). CONCLUSIONS: Maximal viral suppression has a large impact on HIV progression, particularly in heavily pre-treated individuals. Our findings support the latest treatment guidelines, which have rapidly evolved from an initial lack of indication to suggestions, and finally to strong recommendations for achieving the goal of suppressing viremia.

An IL-15 dependent CD8 T cell response to selected HIV epitopes is related to viral control in early-treated HIV-infected subjects.

In some early-treated HIV-positive patients, Structured Treatment Interruption (STI) is associated to spontaneous control of viral rebound. Thus, in this clinical setting, we analyzed the immunological parameters associated to viral control. Two groups of early treated patients who underwent STI were retrospectively defined, according to the ability to spontaneously control HIV replication (Controller and Non-controller). Plasma cytokine levels were analyzed by multiplex analysis. CD8 T cell differentiation was determined by polychromatic flow cytometry. Antigen-specific IFN-gamma production was analyzed by ELISpot and intracellular staining after stimulation with HIV-peptides. Long-term Elispot assays were performed in the presence or absence of IL-15. Plasma IL-15 was found decreased over a period of time in Non-Controller patients, whereas a restricted response to Gag (aa.167-202 and 265-279) and Nef (aa.86-100 and 111-138) immunodominant epitopes was more frequently observed in Controller patients. Interestingly, in two Non-Controller patients the CD8-mediated T cells response to immunodominant epitopes could be restored in vitro by IL-15, suggesting a major role of cytokine homeostasis on the generation of protective immunity. In early-treated HIV+ patients undergoing STI, HIV replication control was associated to CD8 T cell maturation and sustained IL-15 levels, leading to HIV-specific CD8 T cell responses against selected Gag and Nef epitopes.

Effects of zidovudine in 30 patients with mild to end-stage AIDS dementia complex.

OBJECTIVE: Zidovudine (ZDV) is an inhibitor of HIV replication that may have a beneficial effect on patients with AIDS dementia complex (ADC). However, little is known about the association between long-term ZDV treatment and severity of ADC, ZDV dose or clinical and laboratory response to therapy. DESIGN: An open study on ZDV administration in 30 consecutive patients with ADC. SETTING: An infectious diseases hospital. PATIENTS: Thirty consecutive patients followed-up for 12 months. INTERVENTIONS: Three oral ZDV doses were used: 1000 mg (nine patients), 750 mg (eight patients) and 500 mg (13 patients) per day, depending on haematological status. MAIN OUTCOME MEASURES: Clinical and neurological examinations, neuropsychological evaluations, high-field brain magnetic resonance imaging (MRI) and 99mTc-HM-PAO single photon emission computerized tomography (SPECT). RESULTS: A favourable clinical response, defined as reversal to a less severe ADC stage (Price and Brew's criteria), was observed after 1, 3, 6, 9 and 12 months in 15, 22, 25, 19 and 14 patients, respectively. Neither severity of ADC at entry nor ZDV dose correlated with response to treatment. Seven patients died during the 12-month follow-up. The only factor associated with longer survival was ADC severity at entry (12-month survival, 0.94 and 0.53, in patients in stages 1 or 2 and in stages 3 or 4, respectively; P < 0.01). After 6-12 months of ZDV treatment six patients who initially responded to therapy showed a relapse in initial ADC stage, and two patients a less severe neurological deterioration. Neuropsychological evaluations showed significant improvement in the Wisconsin Card-Sorting test (P = 0.006 for categories, P = 0.029 for perseverative errors), which is particularly sensitive to cognitive and frontal-lobe type functions. Brain MRI revealed a reduction of the extent of white matter lesions in six out of 13 patients, who also showed clinical improvement. SPECT scanning revealed a reduction in the extent of uptake defects concomitant with clinical response in nine out of 14 patients. CONCLUSIONS: ZDV is effective in most patients with mild to end-stage ADC, although the benefit is sometimes only transient; several relapses and deaths occurred after the sixth month of treatment.

Positive and sustained effects of highly active antiretroviral therapy on HIV-1-associated neurocognitive impairment.

OBJECTIVES: To determine whether highly active antiretroviral therapy (HAART) is effective in HIV-associated neurocognitive impairment. DESIGN: An open label, prospective, observational study. METHODS: Since April 1996, 116 patients with advanced HIV infection, reverse transcriptase inhibitor (nRTI) experienced but protease inhibitor (PI) naive, were screened for the presence of neurocognitive impairment. Ninety patients with confounding neurological illness, opportunistic infections or drug abuse were excluded. The remaining 26 patients underwent comprehensive neuropsychological testing, and laboratory measures before, after 6 and after 15 months of treatment with one PI plus two nRTI. RESULTS: The prevalence of neurocognitive impairment decreased from 80.8% (baseline) to 50.0% (P<0.05) (sixth month) and to 21.7% (P<0.001) (15th month). Among the functions explored, the impairment of concentration and speed of mental processing decreased from 65.4 to 21.7% (P<0.01) and of memory impairment from 50 to 8.7% (P<0.01). Comparing baseline with the sixth and 15th month raw scores, a statistically significant improvement was seen in measures exploring concentration and speed of mental processing (P<0.05), mental flexibility (P<0.05), memory (P<0.05), fine motor functions (P<0.05) and visuospatial and constructional abilities (P<0.01). After 6 months of HAART patients with a normal neuropsychological examination had lower mean plasma viraemia (2.95 versus 3.97 log copies/ml, P<0.05) and greater mean log plasma HIV RNA changes from baseline (-1.84 versus -0.83 log copies/ml, P<0.05) than neuropsychologically impaired subjects. CONCLUSION: HAART produces a positive and sustained effect on neurocognitive impairment in HIV-infected patients. A reduction of plasma viral load was associated with the regression of neuropsychological test abnormalities.

Female sex and the use of anti-allergic agents increase the risk of developing cutaneous rash associated with nevirapine therapy.

To identify factors associated with cutaneous rash, we performed a retrospective multicentre analysis of HIV outpatients starting a highly active antiretroviral therapy regimen containing nevirapine. A total of 62 cutaneous adverse events were observed in 429 patients. Rash hazard was increased in women, by the prophylactic use of glucocorticoids or antihistaminics, and was reduced by escalating the initial dose of nevirapine. Women receiving glucocorticoids had a 3 month cumulative probability of rash of 0.41.

Acute disseminated encephalomyelitis as manifestation of primary HIV infection.

The authors report a 27-year-old woman with clinical, MRI, virologic, and CSF findings consistent with acute disseminated encephalomyelitis as a manifestation of primary HIV infection. Improvements in the clinical and MRI findings and a reduction in HIV RNA levels, both in plasma and in the CSF, were observed during highly active antiretroviral therapy.

Decay of HIV type 1 DNA and development of drug-resistant mutants in patients with primary HIV type 1 infection receiving highly active antiretroviral therapy.

The present study was aimed at describing the effect of highly active antiretroviral therapy (HAART) in 10 patients with primary HIV infection (PHI). Clearance rates of HIV RNA and HIV DNA in peripheral blood as well as the preexistence and the emergence of drug-resistant strains of HIV were determined over 52 weeks of treatment. The data indicate that HAART is able to induce a suppression of plasma viral load together with a significant decrease, but not a suppression, of peripheral blood mononuclear cell-associated proviral DNA in PHI subjects. Analysis of drug-resistant strains revealed that three PHI patients, showing a complete virologic response, developed mutations in the pol gene, thus suggesting that a persistent residual virus replication exists despite a sustained suppression of plasma viremia.

Metabolic and morphologic disorders in patients treated with highly active antiretroviral therapy since primary HIV infection.

UNLABELLED: Our objective was to describe morphologic and metabolic disorders in patients treated with highly active antiretroviral therapy (HAART) since primary HIV infection (PHI). Our method was prospective evaluation of patients with PHI initiating HAART at the time of diagnosis. Outcome measures were: development of hyperglycemia, hypercholesterolemia, hypertriglyceridemia, and of body shape abnormalities indicative of lipodystrophy, assessed through self-reported questionnaires and physical examination. RESULTS: From May 1997 to April 2001, 41 patients (35 males) with PHI presented at the National Institute for Infectious Diseases "Lazzaro Spallanzani" in Rome, Italy. A protease inhibitor-including regimen was started in 30 patients, and a nonnucleoside reverse transcriptase-inhibitor in 11. Median interval between enrollment and treatment initiation was 30 days (mean 39, range 10-150). Median HAART duration was 19 months (mean 21.2, range 3-47). Thirty-eight patients had undetectable (less than 80 cp/mL) HIV RNA after a median of 3 months (mean 4.1, range 1-15). Mean CD4 cells count increased from 632/mmc at baseline to 936/mmc at the last follow up. No cases of hyperglycemia (glucose level greater than 110 mg/dL) were observed. After a median of 6 months on HAART, 10 patients developed beyond grade 2 (greater than 240 mg/dL) hypercholesterolemia, 5 developed beyond grade 2 (greater than 400 mg/dL) hypertrygliceridemia, and two developed both. Body mass index did not change significantly. Five patients (12.2%) developed lipodystrophy after a median of 14.5 months (mean 15.3, range 2-30), with an incidence of 7.3 per 100 patient-years. CONCLUSIONS: Dyslipidemia and lipodystrophy can occur in patients treated with HAART since PHI. This risk of should be taken into account when considering this early antiretroviral treatment of HIV infection.

Alteration of thymidine kinase activity in cells treated with an antiviral agent.

A lymphoblastoid cell line, CEM, was rendered resistant to zidovudine (AZT) in vitro by exposure to low but gradually increasing concentrations of the drug. This type of cellular resistance seems to be due to a defect of thymidine kinase (TK) activity that is acquired by cells grown in the presence of AZT. In fact, enzymatic studies with extracts from AZT-resistant cells (CEMazt), have shown that the value of the maximum velocity (Vmax) of TK activity measured with AZT and for deoxythymidine (dThd) is decreased as compared to sensitive CEM cells. Furthermore, the enzyme affinity for AZT and dThd is reduced in CEMazt. Further experiments have shown that such cells do not show resistance to other nucleoside analogs, such as ddI, ddC, AraT and D4T, suggesting that the phosphorylation pathways different from those involving TK are unaltered. Ex vivo experiments performed by using peripheral blood mononuclear cells (PBMC) from HIV infected individuals revealed that a prolonged treatment with AZT may modify the affinity of TK for dThd, thus suggesting that the aforementioned phenomenon may occur also in vivo.

Significant reduction in HIV-1 plasma viral load but not in proviral infected cells during sub-optimal antiretroviral therapy.

Attempts to eradicate HIV infection through highly active antiretroviral therapy (HAART) in the very early stages of the infection have failed due to the resumption of viral replication from unknown reservoirs. It has been postulated that antiretroviral therapy capable of suppressing viral replication, as shown by reduction of HIV-RNA copies in plasma and lymph nodes, should have less effect on the number of HIV-DNA carrying cells in the same districts. To test this hypothesis, plasma viremia and the proportion of provirally infected cells in peripheral blood and in lymph nodes were measured in patients at 3 and 6 months of treatment with zidovudine plus lamivudine. All patients showed a significant decrease in plasma viremia at 3 months that was maintained at 6 months (mean values of 1.6 +/- 0.6 log10 from baseline). Conversely the proportion of HIV-DNA carrying cells slightly declined at 3 months but remained substantially stable thereafter both in peripheral blood and in lymph nodes. Taken together these data suggest that this therapeutic regimen, although sub-optimal, is effective in significantly reducing the virus production by productively infected cells but does not seem to substantially affect the load of provirally infected cells.

Neurocognitive impairment influences quality of life in HIV-infected patients receiving HAART.

The objective of the study was to determine the association of neurocognitive impairment with health-related quality of life (HRQoL) in patients receiving highly active antiretroviral therapy (HAART). Seventy subjects were cross-sectionally analysed with a standardized neuropsychological test battery and a questionnaire including an Italian translation of the MOS-HIV Health Survey. The presence of neurocognitive impairment was significantly associated with lower HRQoL scores: pain (P = 0.03), physical functioning (P = 0.01), role functioning (P = 0.01), social functioning (P = 0.029), mental health (P = 0.001), energy (P = 0.036), health distress (P = 0.002), cognitive functioning (P = 0.05), current health perception (P <0.001), physical health summary score (PHS) (P = 0.005), mental health summary score (MHS) (P = 0.002). Years of education (odds ratio [OR] 0.79; 95% confidence interval [CI] 0.65-0.96), PHS (OR 0.71; 95% CI 0.54-0.95) and MHS (OR 0.67; 95% CI 0.51-0.88) were also associated with cognitive impairment. Neurocognitive impairment in patients receiving HAART was associated with reduced HRQoL. Identifying cognitive impairment may provide motivation for additional treatment to help patients to compensate for deficits in functioning.

[Guidelines for the management of HCV infection in HIV-infected patients. Istituto Nazionale per le Malattie Infettive Lazzaro Spallanzani]. / Linee-guida per la gestione clinica della infezione/malattia da HCV nei pazienti con infezione da HIV.

It is crucial to ensure an optimal clinical management of HCV infection in HIV-co-infected persons. The reasons for the development of guidelines on HCV-infection treatment in HIV-infected persons arise from the need for a standardised management of HIV/HCV coinfection in our Institute. The aim of these guidelines are: to clarify principles of clinical management of HCV infection in HIV-infected patients to care-providers; to improve the awareness of HIV-infected patients cared for our Institute on current management of HCV infection; to improve the quality of care on this topic. These guidelines, based on Evidence based Medicine principles, have been developed by a panel of experts, who conducted a systematic review of the literature, mainly taking into account current international recommendations. In the present document, the most frequent clinical presentation occurring in the management of HIV/HCV co-infected patients at our Institution are discussed. The adherence to present guidelines and their effectiveness at our Institution, outcome indicators will be evaluated. The present guidelines cannot entirely substitute the judgement of an expert clinician. However, adherence to these guidelines will contribute to the improvement of the standard of care of HIV/HCV-co-infected persons.

Cost of surgical intervention for reconstructive therapy of HIV-associated facial lipoatrophy.

This study aims to assess direct cost of reconstructive interventions with facial fillers for treatment of HIV (human immunodeficiency virus)-associated facial lipoatrophy (FLA). Evaluation was performed on data from patients enrolled in one arm of a comparative study of immediate versus delayed reconstructive treatment of facial lipoatrophy. Median costs were standardized for efficacy, estimated using data reported by physicians and patient reported outcomes. The variations of the results were evaluated with a sensitivity analysis. Evaluation was performed on 66 patients characterized by significant differences in terms of severity of FLA. Total cost resulted of €140,416.15, with a median cost per patient of €2126.04 (interquartile range [IQR]: 1599-2822). Taking into consideration severity of disease, median costs were €1641.67 (IQR: 1326.67-2126.04) and 2557.12 (IQR: 1939.34-2872.04) (P = 0.0) respectively for patients with low and high severity scores at baseline. Significant differences in term of cost-effectiveness ratios were also found between patients with different severity of FLA, and sensitivity analysis showed that these ratios increase with higher severity scores at baseline and vary widely depending on the costs of filler. Although these results cannot be considered representative because of important limitations, the present study suggests the severity of disease as an important determinant of costs.

T20QoL: an observational multicenter cohort study to evaluate the quality of life in HIV-patients treated with enfuvirtide (ENF, T-20) in combination with an optimized background therapy.

AIM: To evaluate the impact of health-related quality of life (HRQoL) enfuvirtide-based (ENF-based) salvage regimens of treatment-experienced HIV patients, in an observational multicenter cohort study. METHODS: HRQoL was measured in a cohort of 16 patients over a 6-month follow-up using 2 instruments: the ISSQoL (Istituto Superiore di Sanità Quality of Life), a recently validated HIV-specific questionnaire; the EQ-5D (EuroQol), a generic widely used instrument. ENF was given at standard dosage along with an optimized background regimen. RESULTS: Most of HRQoL dimensions showed improvement in ENF-treated patients at the post-baseline time points. Social functioning was the only dimension showing a negative effect. Monthly care costs of antiretroviral drugs for HIV patients taking ENF plus an optimized background regimen were approximately euro2,348 per patient-month (range euro382-euro2,940). CONCLUSION: Our results show that the addition of ENF to an optimized background salvage-HAART may positively affect HRQoL not only in clinical trials but also in a sample population of patients used in a routine clinical practice.

Persistent productive HIV infection in EBV-transformed B lymphocytes.

The susceptibility to HIV infection of 14 B-cell lines established from five healthy HIV seronegative and from six HIV seropositive subjects by lymphocyte transformation with EBV and/or by lymphocyte cultivation with cyclosporin A was studied. Although the cell lines contained different proportions of CD4-positive cells, as shown by flow cytometry, all of them could be infected with the SF-2 strain of HIV. Infection was blocked by a monoclonal antibody directed against the viral attachment site of the CD4 molecule, even in a line that lacked demonstrable CD4 receptors. B-cell lines with high proportions of CD4-expressing cells produced HIV p24 antigen more rapidly and at higher concentrations than cell lines with low CD4 expression. Although HIV infection resulted in some cytopathic effects, it was possible to cultivate the infected cells for more than 8 months without refeeding the cultures with uninfected cells. Even in long-term cultures, there was a continuous production of infectious HIV, as detected by transfer of culture supernatants to other susceptible cell lines. The production of viral antigens was consistently more pronounced in the B-cell line with the highest CD4 positivity than it was in a permissive T-cell line (HUT-78) infected in the same manner. These results indicate that HIV can chronically and productively infect transformed B cells via interaction with CD4 molecules. Thus it is possible that B cells may constitute a source of infectious virus in HIV-infected EBV-positive individuals.