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R Bucciardini1, M Massella1, A Corpolongo2, P Narciso2, V Fragola1, M Mirra1, S Donnini1, O Viganò3, S Costarelli4, V Tozzi21Istituto Superiore di Sanità, Rome, Italy; 2IRCCS L. Spallanzani, Rome, Italy; 3Ospedale L. Sacco, Milan, Italy; 4Spedali Civili di Brescia, Brescia, ItalyAim: 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 €2,348 per patient-month (range €382– €2,940).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.Keywords: enfuvirtide, HRQoL, HIV

Background: There are few data comparing patient-reported outcomes (PROs) in randomized trials of initial antiretroviral therapy. We present results from a substudy of the NEAT001/ANRS143 trial., Methods: The randomized trial compared first-line DRV/r 800/100 mg once daily plus RAL 400 mg twice daily and DRV/r plus TDF/FTC 245/200 mg once daily. Changes in PROs were assessed with 3 questionnaires: EuroQoL 5 domains (EQ-5D), Center for Epidemiologic Studies Depression (CES-D) scale, and HIV Treatment Satisfaction Questionnaire. Major depressive disorder (MDD) was defined as CES-D ≥ 16. General estimating equations were used to model change over 96 weeks in PROs from baseline., Results: Of the 805 participants, 797 (99%) contributed to the substudy. Baseline PRO data were similar for the 2 randomized groups. Health status improved over time with a mean increase in EQ-5D visual analogue scale (VAS) of 8.0 by W96 [95% confidence interval (CI): 6.5 to 9.4; P < 0.001], and no statistically significant differences between groups (difference of 0.3 on VAS score (95% CI: -1.7 to 2.3); P = 0.7, global P value ≥0.05 for all domains over follow-up). There was no significant difference between groups on CES-D [difference of -0.1 (95% CI: -1.3 to 1.1); P = 0.9], or MDD during follow-up, adjusted for baseline MDD (odds ratio = 0.98, 95% CI: 0.82 to 1.18; P = 0.9). RAL + DRV/r group had lower level of convenience (P = 0.03) and fitted less well into patients' lifestyle (P = 0.007) than the TDF/FTC + DRV/r regimen, and was associated with lower treatment satisfaction [median score: 53 RAL + DRV/r vs 55 TDF/FTC + DRV/r (P = 0.001)]., Conclusion: PROs improved after starting antiretroviral therapy, with no statistically significant difference between groups. The lower satisfaction with RAL + DRV/r may be explained by twice-daily administration.

Introduction: Ethiopia has experienced rapid expansion of antiretroviral therapy (ART). However, as long-term retention in ART therapy is key for ART effectiveness, determinants of attrition need to be identified so appropriate interventions can be designed., Methods: We used data from the 'Cohort of African people Starting Antiretroviral therapy' (CASA) project, a prospective study of a cohort of HIV-infected patients who started ART in seven health facilities (HFs). We analysed the data of patients who had started first-line ART between January 2013 and December 2014. The Kaplan-Meier method was used to estimate the probability of retention at different time points. The Cox proportional hazards model was used to identify factors associated with attrition., Results: A total of 1198 patients were included in the study. Kaplan-Meier estimates of retention in care were 83.9%, 82.1% and 79.8% at 12, 18 and 24 months after starting ART, respectively. Attrition was mainly due to loss to follow-up, transferred-out patients and documented mortality. A multivariate Cox proportional hazard model showed that male sex, CD4 count <200 cells/µL and the type of HF were significantly associated with attrition., Conclusions: The observed attrition differences according to gender suggest that separate interventions designed for women and men should be explored. Moreover, innovative strategies to increase HIV testing should be supported to avoid CD4 levels falling too low, a factor significantly associated with higher attrition in our study. Finally, specific studies to analyse the reasons for different levels of attrition among HFs are required., Competing Interests: Competing interests: None declared.

There is limited information on the variations of HIV-1 DNA mutation profile in reverse transcriptase (RT) and protease (PR) genes during suppressive antiretroviral treatment (plasma HIV-1 RNA continuously <50 copies/ml) with raltegravir (RAL)-based regimens in patients with baseline RT/PR resistant HIV. Twelve multidrug resistant (RT: 12/12, PR: 8/12) HIV-infected patients were followed during effectively suppressive RAL-based therapy. Total and integrated HIV-1 DNA were assessed by real time PCR at baseline and every 6 months. Ultrasensitive (threshold: 2.5 copies/ml) plasma HIV-1 RNA and genotypic analysis of RT and PR in proviral DNA were performed at baseline and at 24 months. Half of the patients had full viral suppression (plasma HIV-RNA < 2.5 copies/ml) at month 12. Total HIV-1 DNA declined significantly after 12 months of therapy (from 249.2 to 145.7 copies/10 6 cells, P = 0.023), and remained stable until 24 months, when total HIV-1 DNA levels raised, concomitantly with a less stringent suppression of HIV-1 RNA (81.8% of patients with >2.5 copies/ml). Integrated HIV-1 DNA did not show fluctuations during the study period. Sequencing of the PR and RT regions from HIV-1 DNA revealed changes in the resistance mutation profile in five patients. Total HIV-1 DNA declined after the introduction of RAL-based therapy, with a rebound after 2 years. No changes were observed in levels of integrated DNA, suggesting limited effect on archived HIV. The RT and PR sequence changes in archived HIV-1 DNA suggest that variation of the mutation profile can occur even in the absence of detectable HIV-1 RNA. J. Med. Virol. 88:2115-2124, 2016. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Background: To describe the development and the psychometric properties of the Istituto Superiore di Sanità-HIV symptoms scale (lSS-HIV symptoms scale)., Methods: The ISS-HIV symptom scale was developed by an Italian working team including researchers, physicians and people living with HIV. The development process went through the following steps: (1) review of HIV/AIDS literature; (2) focus group; (3) pre-test analysis; (4) scale validation., Results: The 22 symptoms of HIV-ISS symptoms scale were clustered in five factors: pain/general discomfort (7 items); depression/anxiety (4 items); emotional reaction/psychological distress (5 items); gastrointestinal discomfort (4 items); sexual discomfort (2 items). The internal consistence reliability was for all factors within the minimum accepted standard of 0.70., Conclusions: The results of this study provide a preliminary evidence of the reliability and validity of the ISS-HIV symptoms scale. In the new era where HIV infection has been transformed into a chronic diseases and patients are experiencing a complex range of symptoms, the ISS-HIV symptoms scale may represent an useful tool for a comprehensive symptom assessment with the advantage of being easy to fill out by patients and potentially attractive to physicians mainly because it is easy to understand and requires short time to interpret the results.

Introduction: Although Ethiopia has been scaling up the antiretroviral therapy (ART) services, low retention in care of patients remains one of the main obstacles to treatment success. We report data on retention in care and its associated determinants in Tigray, Ethiopia., Methods: We used data from the CASA project, a prospective observational and multi-site study of a cohort of HIV-infected patients who initiated ART for the first time in Tigray. Four participating health facilities (HFs) located in the South of Tigray were considered for this study. Patients were followed for one year after ART initiation. The main outcome measure was represented by the current retention in care, defined as the proportion of patients who were alive and receiving ART at the same HF one year after ART initiation. Patients who started ART between January 1, 2013 and December 31, 2013 were included in this analysis. Patients were followed for one year after ART initiation. The determinants of retention were analysed using univariate and multivariate Cox Proportional Hazards model with robust sandwich estimates to account for within HF correlation., Results: The four participating HFs in Tigray were able to retain overall 85.1% of their patients after one year from starting ART. Loss to follow-up (5.5%) and transfers to other HF (6.6) were the main determinant of attrition. A multivariate analysis shows that the factors significantly associated with retention were the type of HF, gender and active TB. Alamata health center was the HF with the highest attrition rate (HR 2.99, 95% CI: 2.77-3.23). Active TB (HR 1.72, 95% CI: 1.23-2.41) and gender (HR 1.64, 95% CI: 1.10-2.56) were also significantly associated with attrition., Conclusions: Although Ethiopia has significantly improved access to the ART program, achieving and maintaining a satisfactory long-term retention rate is a future goal. This is difficult because of different retention rates among HFs. Moreover specific interventions should be directed to people of different sex to improve retention in care in male population.

HIV-associated lipodystrophy commonly presents with fat loss in the face, buttocks, arms and legs, hypocomplementaemia, glomerulonephritis, and autoimmune disorders. The exact mechanism of HIV-associated lipodystrophy is not fully elucidated. There is evidence indicating that it can be caused by both antiretroviral medications and HIV infection in the absence of antiretroviral medication. Lipodystrophy seems to be mainly due to HIV-1 protease inhibitors. Interference with lipid metabolism is postulated as pathophysiology. Also, the development of lipodystrophy is associated with specific nucleoside reverse transcriptase inhibitors (NRTI). Mitochondrial toxicity is postulated to be involved in the pathogenesis associated with NRTI. Here, we analyse the side effects and examine the impact of the highly active antiretroviral therapy (HAART) regimen including raltegravir, lamivudine, darunavir and ritonavir in an HIV-1 infected patient with severe lipodystrophy after six years of antiretroviral therapy.

Residual HIV viremia, defined by low levels of plasma HIV RNA with enhanced-sensitivity assays, may persist even in the presence of successful antiretroviral therapy, but little is known about its determinants. Our objective was to evaluate the rate and determinants of residual viremia in patients who show stable undetectable plasma HIV-1 RNA with conventional assays. Forty-four multidrug-experienced patients with undetectable levels of HIV RNA for at least 2 years under raltegravir-based regimens were evaluated. An ultrasensitive (2.5 copies/ml) real-time PCR method was used to quantify plasma HIV RNA. After 12 months of salvage treatment, 48.3% of the patients had residual viremia between 2.5 and 37 copies/ml. The proportion of patients with plasma HIV RNA below 2.5 copies/ml decreased from 51.7% at 12 months to 30.8% at 24 months. The presence of residual viremia was not associated with levels of viremia before starting raltegravir. Considering CD4 counts, hepatitis B or C virus (HBV or HCV) coinfection, or other demographic characteristics, for the time interval between HIV diagnosis and initiation of antiretroviral therapy, patients with a longer interval (>1 year) were significant less likely to have RNA levels below 2.5 copies/ml at 12 months compared to patients who started therapy within 1 year of HIV diagnosis (28.6% vs. 73.3%, p=0.027). Half of the patients showing undetectable HIV viremia with conventional assays had low-level viremia with ultrasensitive assays, with no predictive role of viroimmunological status at the start of the regimen. The potential influence of the interval between HIV diagnosis and initiation of treatment should be confirmed in subjects with a known date of seroconversion.

In this case report, we examine the impact of a simplified two-drug highly active antiretroviral therapy (HAART) regimen of raltegravir and lamivudine in a patient co-infected with human immunodeficiency virus (HIV) and hepatitis C, D and B viruses (HCV/HDV/HBV) under immunosuppressive therapy after liver transplantation. Pharmacokinetic interactions between integrase inhibitors and immunosuppressant drugs are described. Raltegravir, the first integrase inhibitor, associated with lamivudine, was introduced because its metabolism does not interfere with immunosuppressant therapy. During post-orthotopic liver transplantation follow-up, the patient's transaminases level increased and his antiretroviral therapy (HAART) of tenofovir/emtricitabine and fosamprenavir was changed, due to suspected drug toxicity. After seven months of follow-up, the patient showed good tolerance, good viro-immunological control with undetectable HIV viraemia and stable concentrations of immunosuppressive drugs. This case indicates that the combination of raltegravir and lamivudine is an optimal and effective strategy because it resulted in an important reduction of hepatic transaminases in a patient with very critical clinical conditions.

Background: Health-related quality of life (HRQoL) has been recognized as a central measure of the overall health status in HIV patients. With the availability of different highly effective drug combinations, maximizing quality-adjusted survival has become a major target of HIV treatment. Although the association of HIV RNA and CD4 cell count with clinical HIV progression has been well established, the relation between these markers and HRQoL measures is still unclear., Method: This cross-sectional study investigated the relationship linking HIV RNA and CD4 to HRQoL measures in 181 triple-class-experienced patients with advanced HIV disease. The instrument used was the ISSQoL, a self-administered and HIV-specific HRQoL questionnaire., Results: Data showed no correlation between HRQoL measures and CD4 counts. Higher HIV RNA levels were, however, associated with poor HRQoL scores in 3 out of 9 scales of social functioning, depression and anxiety, and satisfaction with quality of life. In multivariable analyses, only the satisfaction with quality of life mean score remained significantly lower for the HIV RNA ≯100,000 copies/mL group compared to the HIV RNA 50 to 10,000 copies/mL group., Conclusions: Although other determinants of HRQoL in people with HIV should also be considered, this finding suggests a negative impact of high viral load on perceived HRQoL that adds to other described determinants of lower quality of life in people with HIV, such as lower social support and self-reported symptoms.

The purpose of this investigation was to determine the impact on human immunodeficiency virus (HIV) tropism of uncontrolled virus exposure during 2 years of intermittent highly active antiretroviral therapy (HAART). The Istituto Superiore di Sanità-Pulsed Antiretroviral Therapy (ISS-PART) randomized study compared the outcome of 2 years of structured treatment interruptions (STIs) versus standard continuous treatment in first-line HAART responder subjects. The STI schedule consisted of five STIs of 1, 1, 2, 2, and 3 months, respectively, separated by four periods of 3-month therapy. In the present study, coreceptor tropism was assessed in 12 patients of the STI arm at different time points over a period of 2 years. Tropism was determined on DNA and RNA by V3 loop region sequencing. The Geno2pheno algorithm (false-positive rate, FPR: 20%) was used for data interpretation. At baseline, 9/12 subjects (75.0%) had CCR5-tropic viruses in their HIV. Three had a CXCR4-tropic virus. Ten patients maintained the same coreceptor in DNA after 2 years, whereas in two patients, a shift occurred (one R5-X4, one X4-R5). In a patient with an R5 virus at baseline, a transient change to X4 tropism was seen in the rebounding virus during STI. Changes in tropism were not associated with the amplitude and duration of virus exposure during STIs, residual viremia at baseline, or the development of resistance mutations in the RT region. Our preliminary results suggest that viral replication, observed after short periods of treatment interruption, is not enough to drive the evolution of HIV tropism.

Background: There is no consensus on darunavir (DRV) target levels in plasma for clinical use, and information about variability in plasma concentrations is limited., Aim: : To investigate the variability in DRV plasma trough concentrations in the clinical setting, evaluating interindividual and intraindividual variabilities of plasma drug levels among HIV-infected patients receiving ritonavir (RTV)-boosted DRV (DRV/r) within salvage regimens, and evaluate the potential correlation between variability and virological response., Methods: Sixty-two patients taking DRV/r (600/100 mg twice a day) were evaluated for trough plasma concentrations and immunovirological parameters after 6 months from the start of the regimen. A subgroup of patients (n = 21) was also evaluated for intraindividual variability (expressed as coefficient of variation) on 2 samples taken at different time points. Drug concentrations were assayed by high-performance liquid chromatography with ultraviolet detection, and the values were expressed as medians with interquartile range (IQR). Genotypic sensitivity score and genotypic inhibitory quotient were calculated., Results: DRV/r was used with a median of 3 other antiretroviral drugs (raltegravir use 88.7%). Median plasma concentrations were 3.22 mcg/mL (IQR, 2.04-5.69) for DRV and 0.44 mcg/mL (IQR, 0.21-0.70) for RTV. Both drugs showed a high interindividual variability in plasma concentrations (61% and 99.3%, respectively). Only 3 patients (4.8%) had undetectable DRV plasma levels. DRV plasma concentrations showed a significant positive correlation with age (r = 0.298, P = 0.019), but no significant correlation between DRV genotypic inhibitory quotient and HIV-RNA plasma levels (P = 0.614) was found. Intraindividual coefficients of variation were 58.4% for DRV and 47.1% for RTV. Patients with undetectable HIV-RNA showed a trend for lower intraindividual coefficients of variation compared with patients with detectable HIV-RNA (55.9% versus 83.8%, P = 0.156). No major interaction effects with other antiretroviral drugs were found., Conclusions: In a context of salvage therapy, both DRV and RTV plasma levels showed high interindividual and intraindividual variabilities. Lower intraindividual variability could be beneficial in maintaining viral suppression.

Objectives: To define the impact of coinfection with hepatitis B virus (HBV) or hepatitis C virus (HCV) on viroimmunological response to raltegravir-based salvage regimens that also include new HIV inhibitors such as maraviroc, darunavir and etravirine., Methods: We used data from a national observational study of patients starting raltegravir-based regimens to compare virological suppression and CD4 cell change from baseline in patients with and without concomitant HBV or HCV infection., Results: Overall, 275 patients (107 coinfected and 168 non-coinfected) were evaluated. Coinfected patients were more commonly former intravenous drug users and had a longer history of HIV infection and higher baseline aminotransferase levels. Both HIV-RNA and CD4 response were similar in the two groups. Mean time to first HIV-RNA copy number <50 copies/mL was 4.1 months (95% CI 3.5-4.6) in non-coinfected patients and 3.9 months (95% CI 3.3-4.5) in coinfected patients (hazard ratio 1.039, 95% CI 0.761-1.418, P = 0.766, log-rank test). The risk of developing new grade 3-4 hepatic adverse events was significantly higher in coinfected patients (hazard ratio 1.779, 95% CI 1.123-2.817, P = 0.009). The two groups of coinfected and non-coinfected patients had similar rates of interruption of any baseline drug (hazard ratio 1.075, 95% CI 0.649-1.781, P = 0.776) and of raltegravir (hazard ratio 1.520, 95% CI 0.671-3.447, P = 0.311). Few AIDS-defining events and deaths occurred., Conclusions: Viroimmunological response to regimens based on raltegravir and other recent anti-HIV inhibitors is not negatively affected by coinfection with HBV or HCV. Liver toxicity, either pre-existing or new, is more common in coinfected patients, but with no increased risk of treatment interruption.

Background: The HIV integrase inhibitor raltegravir (RAL) can exacerbate autoimmune diseases in genetically predisposed mice. To evaluate whether this may occur in clinical practice, we clinically monitored HIV-positive patients treated with RAL and measured a panel of autoantibodies (auto-Abs) during the first year of RAL treatment., Methods: This was a longitudinal study in 109 antiretroviral-experienced patients who started a RAL-based regimen and were followed up for more than 2 years. A total of 45 patients were tested at baseline (before starting RAL) and after 12 months for the presence of the following auto-Abs: anti-nuclear antibodies, anti-double-stranded DNA, anti-smooth-muscle antibodies, anti-thyreoglobulin and anti-thyroid peroxidase antibodies, anti-cardiolipin immunoglobulin G and immunoglobulin M and anti-nuclear extractable antigens, including anti-SM ribonucleoprotein antigen, anti-Ro antigen and anti-La antigen., Results: A low rate of clinically relevant autoimmune diseases was observed at study entry (3/109; 2.8%; 95% CI 0.004, 0.059). No exacerbations were observed during follow-up. During the second year of RAL-based therapy a previously healthy patient developed psoriasis. At baseline, 17/45 (37.8%) patients tested for the presence of auto-Abs were positive. Most patients (n=13) were positive for anti-cardiolipin. After 12 months of RAL exposure, 9/45 patients were positive (20%; P=0.063). A positive correlation was found between HIV-1 RNA and anti-cardiolipin antibody concentration (P=0.010)., Conclusions: According to these results, RAL does not promote antibody-mediated immune disorders, at least not in the mid-term. A prolonged follow-up and an extension of the panel of auto-Abs are recommended to support these results.

Sustained increase of serum creatine phosphokinase (CPK) concentrations and muscle abnormalities have been reported in patients taking raltegravir (RAL). In this report, we describe a case of sustained and asymptomatic increase of serum CPK concentrations associated with raltegravir, zidovudine, and lamivudine in an HIV-1 experienced patient with intolerance to protease inhibitor, abacavir and penicillin during 32 weeks of continuous drug monitoring.

The use of new antiretroviral drugs in HIV infection is particularly important in patients with intolerance or resistance to other antiretroviral agents. Raltegravir and maraviroc represent new, important resources in salvage regimens. A reduced grade of liver fibro-steatosis after a combination of raltegravir and maraviroc (second-line) has not been studied and the mechanism by which these new drug classes induced a marked reduction of grade of liver diseases is currently unknown. In the present case report, nested in an ongoing multicentre observational study on the use of new antiretroviral inhibitors in heavy treatment-experienced HIV patients, we evaluated the correlation between a "short therapeutic regimen" raltegravir maraviroc and fosamprenavir and liver diseases. The aim of this report is to describe the use of a three-drug regimen based on two novel-class antiretroviral agents (raltegravir and maraviroc) plus the protease inhibitor fosamprenavir, in an experienced HIV-infected patient with chronic progressive hepatitis C complicated by liver fibrosis; an overwhelming increased serum creatine kinase level occurred during treatment, and is probably related to integrase inhibitor administration. At present no information is available regarding this correlation.

We evaluated rates and determinants of virological failure in triple-class experienced patients receiving raltegravir-based regimens from a national observational study over 48 weeks, defined by any one of the following: (1) no HIV-RNA suppression to undetectable levels (<50 copies/mL) during follow-up; (2) detectable viral load after obtaining undetectable levels; and (3) leaving the study before 48 weeks. Among 101 eligible patients, 26 (25.7%; 95% CI 17.2-34.2) had virological failure. No significant differences between patients with and without virological failure were observed for gender, age, route of transmission, baseline CD4/HIV-RNA, CDC group, hepatitis B or C co-infections, resistance (based on the last genotype available), type and number of concomitant drug classes, concomitant use of darunavir, atazanavir, etravirine, enfuvirtide or maraviroc, and health-related quality-of-life measures. A high rate of treatment response was observed. The analyses did not identify any baseline factor associated with failure, including resistance status. Even if we cannot exclude the presence of pre-existing minority resistant variants not captured by genotypic tests, the lack of baseline predictors of failure suggests the need to monitor patients closely during follow up for other factors, such as potential drug interactions and reduced levels of adherence, which may favour virological failure.

Objectives: To evaluate the evolution of HIV-1 coreceptor tropism in proviral DNA of patients during maraviroc-based therapy., Methods: Fourteen heavily high active antiretroviral therapy (HAART)-treated patients with a CCR5 Trofile profile were monitored over a 24 month period from the start of maraviroc therapy. Whole-blood samples were obtained at different timepoints, and coreceptor tropism was determined for proviral DNA from the V3-loop region sequence using the Geno2Pheno algorithm [false positive rate (FPR): 20%]., Results: At the start of maraviroc treatment, 13/14 patients were viraemic (median: 4.33 log copies/mL). Concordance in R5 tropism (R5/R5) was observed between circulating HIV-RNA (Trofile) and HIV-DNA provirus in 10/14 patients (median FPR = 54.0%), while 4 patients showed a CXCR4-tropic R5/X4 variant in their provirus (FPR: 5.8%, 5.7%, 16.6% and 1.1%, respectively). All R5/R5 patients showed a stable HIV-1 DNA coreceptor usage. Two out of four R5/X4 patients showed a tropism shift in their archived provirus and, after 6 months a prevalence of R5-tropic virus was detected in DNA. The other two R5/X4 patients harboured the 11/25 genotype, and maintained X4 tropism in provirus during the study. Virological response did not reveal differences in RNA decay and CD4+ cell recovery in patients with discordant tropism., Conclusions: A relatively good correlation between RNA and DNA tropism was observed at baseline. Proviral DNA tropism remained stable over 24 months of maraviroc-based therapy, indicating that determination of proviral DNA V3 sequence could be used in tropism prediction in clinical practice. The data also confirm the importance of the 11/25 rule in predicting viral tropism.

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.

Emergence of resistance is one of the drawbacks associated with treatment interruptions (TI), especially when regimens include nonnucleoside reverse transcriptase inhibitors (NNRTIs), because of their long half-life. ISS-PART was a randomized trial comparing a continuous treatment arm with a TI arm in which 136 patients underwent five treatment interruptions, each followed by 3 months of therapy, over 2 years. To minimize the potential risk of developing resistance, patients on NNRTIs were requested, at each TI, to interrupt nevirapine (NVP) or efavirenz (EFV) 3 or 6 days before the other drugs, respectively. To determine if a difference in drug levels existed during TIs between patients with and without resistance we compared NNRTI concentrations in the 12 patients (6 on NVP and 6 on EFV) who developed NNRTI mutations during TIs with those of 20 patients (10 on NVP and 10 on EFV) who retained a wild-type virus. Genotypic resistance and drug concentrations were analyzed on plasma samples collected 15 days after each drug interruption. Overall, EFV was quantifiable in 28% (16/57) and NVP in 22.9% (14/61) of evaluable samples collected during TIs, with no difference between patients with and without mutations. Median EFV or NVP concentrations at each TI were not significantly different between patients with and without mutations. Although the staggered stop strategy was not completely effective in preventing exposure to suboptimal levels, no evident correlation was found between NNRTI concentrations and the emergence of resistance, suggesting that other factors (such as the presence of drug-resistant minority variants) could also play an important role in these patients.

Objectives: The Italian National Institute of Health Quality of Life - Core Evaluation Form (ISSQoL-CEF) is a specific questionnaire measuring health-related quality of life for human immunodeficiency virus-infected people in the era of highly active antiretroviral therapy. The main goal of this study was to examine the construct validity of this questionnaire by confirmation of its hypothesized dimensional structure., Methods: Baseline quality of life data from four clinical studies were collected and a confirmatory factor analysis of the ISSQoL-CEF items was carried out. Both first-order and second-order factor models were tested: Model 1 with nine correlated first-order factors; Model 2 with three correlated second-order factors (Physical, Mental, and Social Health); Model 3 with two correlated second-order factors (Physical and Mental/Social Health); Model 4 with only one second-order factor (General Health)., Results: A total of 261 patients were surveyed. Model 1 had a good fit to the data. Model 2 had an acceptable fit to the data and it was the best of all hierarchical models. However, Model 2 fitted the data worse than Model 1., Conclusions: The findings of in this study, consistent with the results of previous study, pointed out the construct validity of the ISSQoL-CEF.

We assessed the safety and efficacy of reconstructive therapy with facial fillers for the treatment of HIV-associated facial lipoatrophy (FLA) through a randomized, controlled, open-label single-center study. A total of 134 HIV-infected patients with severe FLA were randomly assigned to receive immediate (67 patients) or delayed (67 patients) facial injections of poly-l-lactic acid (PLA) or polyacrylamide gel (PAIG). Outcome measures included changes in physician and patient FLA severity scale, adverse events, and changes in health-related quality of life (HRQoL) and anxiety using validated measures. The mean average study follow-up was 27 weeks for the immediate and 25 weeks for the delayed subjects. Adverse events were mild and resolved after a mean of 4 days. Compared to patients randomized to the delayed treatment group, patients assigned to the immediate treatment group had significantly lower physician-rated (0.0 versus -3.0; p < 0.0001) and patient-rated (0.1 versus -1.8; p < 0.0001) FLA severity scores. By contrast, measures exploring HRQoL and anxiety did not show any significant difference between patients randomized to the immediate and deferred groups. Reconstructive therapy with facial fillers was effective and safe and led to significant improvements in FLA severity. However, no significant gains in HRQoL, relational and psychological consequences of body changes, and anxiety-related concerns were observed. Studies should be performed to identify patients who could maximally benefit from filling interventions for FLA.

Objectives: The aim of the study was to determine the modifications of the mutational archive in proviral HIV-1 DNA occurring during 24 months of intermittent or continuous highly active antiretroviral therapy (HAART)., Methods: The study population included subjects enrolled in the Istituto Superiore di Sanità Pulsed Antiretroviral Therapy (ISS PART) clinical trial. All of these patients were on first-line HAART and had plasma HIV-1 RNA below 50 HIV-1 RNA copies/mL. A genotypic resistance test was performed on HIV-1 DNA extracted from peripheral blood mononuclear cells (PBMC) at baseline and after 24 months of follow-up. Resistance-associated mutations (RAMs) were defined according to the International AIDS Society (IAS) USA classification., Results: Sixty-nine subjects were included in the study [36 enrolled in arm A of the ISS PART (continuous HAART) and 33 enrolled in arm B (intermittent HAART)]. No major modifications of the mutational archive were found in either group after 24 months of follow-up, in terms of both the proportion of subjects with mutations and the total number of mutations., Conclusions: In this patient population, the mutational archive in HIV-1 DNA extracted from PBMC was stable for 24 months, irrespective of HAART modality, whether continuous or intermittent.

Residual viraemia is detectable in the majority of human immunodeficiency virus (HIV)-infected subjects with plasma HIV-1 RNA <50 copies ml(-1). In the present study, the impact of repeated treatment interruptions on residual HIV-1 viraemia was investigated in 58 subjects enrolled in the ISS-PART, a multicentre, randomized clinical trial comparing 24 months of continuous (arm A) and intermittent (arm B) highly active antiretroviral therapy (HAART). Residual viraemia was measured by a modified Roche Amplicor HIV-1 RNA assay (limit of detection 2.5 copies ml(-1)). At baseline, the median value of residual viraemia was 2.5 copies ml(-1) in both arms; after 24 months, the median value was 2.5 in arm A and 8.3 in arm B. The median change from baseline to month 24 was significantly different between patients under continuous or intermittent HAART: 0 copies ml(-1) (range -125.2 to +82.7) of HIV-1 RNA in arm A versus 2.1 copies ml(-1) (range -80 to +46.8) in arm B (P=0.024). These results suggest that intermittent HAART tends to modify HIV-1 viraemia set point even if a virological response is achieved after HAART reinstitution.

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.

The health-related quality of life (HRQoL) outcomes in HIV-infected, treatment-naive patients starting different HAART regimens in a 3-year, randomized, multinational trial were compared. HRQoL was measured in a subgroup of patients enrolled in the INITIO study (153/911), using a modified version of the MOS-HIV questionnaire. The regimens compared in the INITIO trial were composed by two NRTIs (didanosine + stavudine) plus either an NNRTI (efavirenz) or a PI (nelfinavir), or both (efavirenz + nelfinavir). Primary HRQoL outcomes were Physical and Mental Health Summary scores (PHS and MHS, respectively). During follow-up, an increase of PHS score was observed in all treatment arms. The MHS score remained substantially unchanged with the four-drug combination and showed with both NNRTI- and PI-based three-drug regimens a marked trend toward improvement, which became statistically significant when a multiple imputation method was used to adjust for missing data. Overall, starting all the combination regimens compared in the INITIO study was associated with a maintained or slightly improved HRQOL status, consistently with the positive immunological and virological changes observed in the main study. The observed differences in the MHS indicate a possible HRQoL benefit associated to the use of three-drug, two-class regimens and no additional benefit for the use of four-drug, three-class regimens, confirming that three-drug, two-class regimens that include two NRTIs plus either an NNRTI or a PI should be preferred as initial treatment of HIV infection.

Background: Factors influencing the outcome of structured treatment interruptions (STIs) in HIV chronic infection are not fully elucidated., Methods: In ISS-PART, 273 subjects were randomly assigned to arm A (137 assigned to continuous highly active antiretroviral therapy [HAART]) and arm B (136 assigned to 5 STIs of 1, 1, 2, 2, and 3 months' duration, each followed by 3 months of therapy). Main outcome measures were the proportion of subjects with a CD4 count >500 cells/mm3, the rate of virologic failure, and the emergence of resistance at 24 months., Results: The proportion of subjects with a CD4 count >500 cells/mm3 was higher in arm A than in arm B (86.5% vs. 69.1%; P = 0.0075). Pre-HAART CD4 cell count and male gender were independent predictors of a CD4 count >500 cells/mm3 in arm B. The overall risk of virologic failure was not increased in arm B; however, it was higher in the 38 subjects who had resistance mutations in the rebounding virus. Archived mutations at baseline and the use of a regimen that included an unboosted protease inhibitor (PI), compared with nonnucleoside reverse transcriptase inhibitor-based HAART, independently predicted the emergence of plasma mutations during STI (P = 0.002 for DNA mutations and P = 0.048 for PI-based HAART)., Conclusions: Our results suggest that patients with preexisting mutations and treated with unboosted PI-based HAART should not be enrolled in studies of time-fixed treatment interruptions, being at higher risk of developing plasma mutations during STI and virologic failure at therapy reinstitution.

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.

Objective: To determine factors associated with < 2.5 copies/ml plasma HIV RNA in subjects treated with highly active antiretroviral therapy (HAART) and with viraemia < 50 copies/ml., Design: Cross-sectional analysis of 84 HIV-positive patients taking HAART with plasma HIV RNA < 50 copies/ml for at least 6 months and no history of virological failure., Methods: Current HAART therapy was based on a non-nucleoside reverse transcriptase inhibitor (NNRTI) in 66%, a protease inhibitor in 26% and nucleoside reverse transcriptase inhibitors in 7%. Viraemia levels were measured using a modified ultrasensitive Roche Amplicor HIV-1 Monitor test able to quantify plasma HIV RNA to a lower limit of 2.5 copies /ml; proviral DNA was measured with a real-time polymerase chain reaction assay. Analysis of variance and multiple logistic regression analysis were utilized to test for associations between residual replication and other variables., Results: Residual HIV viraemia > 2.5 copies/ml was found in 50% of subjects; 94% of subjects had detectable proviral DNA (>or= 20 copies/10(6) peripheral blood mononuclear cells) and 21% had archived mutations. Usage of a NNRTI-based HAART was the only independent predictor of viral suppression below the cut-off value of the modified ultrasensitive assay., Conclusions: In our population, NNRTI-based HAART seems to have a stronger impact on residual replication than protease inhibitor-based HAART. This finding may be considered in therapeutic decisions such as the choice of initial HAART regimen and the interruption or simplification of treatment.

Background: Most of the studies evaluating rash in HIV-positive patients have focused on nonnucleoside reverse transcriptase inhibitors (NNRTI), particularly nevirapine, and little is known about the occurrence of rash and the risk factors for its development in patients receiving regimens not based on NNRTI., Methods: We evaluated all cases of rash observed during a 48-week randomized multicentre trial in 1251 nucleoside-experienced patients who started treatment with protease inhibitors (ritonavir or indinavir) at CD4 counts below 50 cells/microL. Incidence rates for rash were calculated according to gender, clinical status, age, use of highly active antiretroviral therapy (HAART), Pneumocystis carinii pneumonia (PCP) prophylaxis and use of individual antiretroviral drugs at enrollment. Differences between groups defined according to the above characteristics were tested for statistical significance using the log-rank test in a Kaplan-Meier survival analysis. All factors that gave results in the univariate analyses below the significance level of 0.05 were included in a multivariate analysis using a Cox regression model., Results: During a follow-up period of 9690 person-months, 66 patients (5.3%) developed rash (0.68 events/100 person-months). In the univariate analyses, risk of rash did not differ with trial treatment (indinavir or ritonavir), clinical status, PCP prophylaxis, or age. During follow-up, rash was observed in 7.5% of enrolled women and in 4.5% of enrolled men (P=0.03). Serious rash occurred in 4.5% of enrolled women and in 1.6% of enrolled men (P=0.003). Use of HAART (P<0.001) and inclusion of zidovudine and of zalcitabine in the prescribed regimen (P=0.02) appeared to be associated with a lower risk of rash. In the multivariate analysis, the variables that remained significantly predictive of rash were gender (risk for women compared to men: 1.65, 95% confidence interval (CI): 1.00-2.72, P=0.048) and use of a non-HAART regimen (risk for non-HAART patients compared to HAART: 2.73, 95% CI: 1.49-5.02, P=0.001)., Conclusions: In our study, about 5% of HIV-positive patients who started treatment with protease inhibitors at very low CD4 counts developed rash, generally in the first few weeks after treatment. Risk was significantly higher in women and in patients who did not receive a HAART regimen. Our data indicate that women have a higher risk of rash than men, also with regimens that do not include NNRTI.

Background: AIDS defining events occur infrequently in the presence of CD4 counts above 200 cells/microL. It is, however, uncertain for most of the AIDS defining conditions whether this threshold can be considered equally safe in patients with a previously very low CD4 nadir., Methods: We evaluated in detail all the AIDS defining events observed during a 48-week clinical trial in 1251 nucleoside reverse transcriptase inhibitor-experienced patients who started protease inhibitors (PIs) at CD4 counts below 50 cells/microL. The type of event, immunological status at the moment of event and time between start of PI treatment and event occurrence were analysed cumulatively and by event type; event rates were calculated., Results: Concomitant data on CD4 counts were available for 338 AIDS defining events (81% of total events). Median time between start of treatment with PI and event was 94.5 days and median absolute CD4 value at the occurrence of event was 20 per microL. Only 14 events (in 12 patients) were observed above the threshold of 200 CD4 cells/microL. An analysis of the 67 deaths with concomitantly available CD4 counts (57%) showed a median CD4 count of 10 cells/microL, with only four deaths occurring in the presence of a CD4 count above 100 cells/microL., Conclusions: Very few clinical AIDS defining conditions were observed in patients who start PIs at very low CD4 counts and with treatment restore absolute values in CD4 counts above 200 cells/microL. This threshold can therefore be considered a clinically effective goal of treatment with respect to occurrence of all AIDS defining conditions in patients starting PIs in very advanced HIV disease.

ISS-IP1, a multicenter, randomized, 48-week open trial, was designed to compare the introduction of ritonavir or indinavir in patients with previous nucleoside experience and CD4+ cell counts below 50/mm3. Concomitant antiretroviral treatment with nucleoside analogs was allowed. Primary efficacy measures were survival and time to a new AIDS-defining event or death, analyzed through the whole period of observation by the intention-to-treat approach. Primary toxicity measures were time to treatment discontinuation and adverse events, grade at least 3/serious, analyzed by an on-treatment approach. Evaluation-of efficacy also included CD4+ cell and RNA response. The trial enrolled 1251 patients in 5 months. At baseline, mean CD4+ cell count was about 20 cells/mm3 and mean HIV RNA copy number was 4.9 log10/ml in both groups. Overall, 402 patients in the ritonavir group and 250 patients in the indinavir group permanently discontinued the assigned treatment (relative risk, 1.96; 95% CI, 1.68-2.30; p = 0.0001), with most of this difference dependent on a higher number of discontinuation for adverse events in the ritonavir group. After a mean follow-up of 307 days (ritonavir, 304; indinavir, 309), 124 deaths (ritonavir, 61; indinavir, 63; relative risk, 0.96; 95% CI, 0.67-1.36; p = 0.80) and 330 new AIDS-defining events (ritonavir, 170; indinavir, 160; relative risk, 1.05; 95% CI, 0.85-1.31; p = 0.60) were observed. CD4+ cell counts increased in both groups in patients still receiving treatment, with about 100 cells gained by week 24 and 150 cells gained by week 48. Body weight also increased over time in both groups. Analysis of RNA response showed a decrease of 1.5 log10 or higher in both treatment groups. Overall, 400 patients in the ritonavir group and 338 patients in the indinavir group developed at least one grade 3/serious new adverse event during follow-up (relative risk, 1.48; 95% CI, 1.28-1.72; p = 0.0001). Favorable CD4+ cell and RNA responses at 24 and 48 weeks were observed in both groups of patients remaining on treatment. Indinavir showed slightly better effects in sustaining RNA, CD4+ cell, and body weight responses. Ritonavir and indinavir results were comparable in terms of clinical outcome (survival and AIDS-defining events).

Objectives: To evaluate the quality of life outcomes in antiretroviral-naive patients randomized to zidovudine plus didanosine versus zidovudine plus didanosine plus nevirapine for treatment of advanced HIV disease (the Istituto Superiore di Sanità 047 trial)., Design: A 48-week randomized, double-blind trial., Methods: Sixty patients were enrolled and evaluated over 24 weeks. Quality of life was assessed using a modified version of the Medical Outcomes Study-HIV Health Survey. For analysis, we calculated two summary scores reflecting the physical (PHS) and the mental (MHS) components of health., Results: Although the three-drug combination was superior at inducing immunologic and virologic responses, the two-drug regimen was superior for both PHS and MHS, especially at week 8 where differences were both statistically and clinically significant (5.8 and 9.2 points, respectively, P< 0.02 for both). Quality of life changes paralleled trends in body weight and Karnofsky performance status score., Conclusion: Although a three-drug antiretroviral therapy regimen was superior in terms of short term virologic/immunologic response, the two-drug regimen was better in terms of quality of life. In general, triple therapy remains the most effective treatment option. However, quality of life assessments can yield results that may be discordant with and complementary to those obtained using conventional endpoints. Comparative trials should collect a comprehensive range of outcome measures, including patient-reported quality of life, in order to provide clinicians and patients with additional information that may influence treatment decisions.