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Objective: To compare the incidence of dyslipidemia in people with HIV receiving integrase inhibitors (INSTI) versus boosted protease inhibitors (PI/b) and nonnucleoside reverse transcriptase inhibitors (NNRTI) within RESPOND consortium of prospective cohorts. Methods: Participants were eligible if they were at least 18 years, without dyslipidemia and initiated or switched to a three-drug antiretroviral therapy (ART)-regimen consisting of either INSTI, NNRTI, or PI/b for the first time, between 1 January 2012 and 31 December 2018. Dyslipidemia was defined as random total cholesterol more than 240 mg/dl, HDL less than 35 mg/dl, triglyceride more than 200 mg/dl, or initiation of lipid-lowering therapy. Poisson regression was used to determine the adjusted incidence rate ratios. Follow-up was censored after 3 years or upon ART-regimen discontinuation or last lipid measurement or 31 December 2019, whichever occurred first. Results: Overall, 4577 people with HIV were eligible (INSTI = 66.9%, PI/b = 12.5%, and NNRTI = 20.6%), 1938 (42.3%) of whom were ART-naive. During 1.7 (interquartile range, 0.6 - 3.0) median years of follow-up, 1460 participants developed dyslipidemia [incidence rate: 191.6 per 1000 person-years, 95% confidence interval (CI) 182.0 - 201.7]. Participants taking INSTI had a lower incidence of dyslipidemia compared with those on PI/b (adjusted incidence rate ratio 0.71; CI 0.59 - 0.85), but higher rate compared with those on NNRTI (1.35; CI 1.15 - 1.58). Compared with dolutegravir, the incidence of dyslipidemia was higher with elvitegravir/cobicistat (1.20; CI 1.00 - 1.43) and raltegravir (1.24; CI 1.02 - 1.51), but lower with rilpivirine (0.77; CI 0.63 - 0.94). Conclusion: In this large consortium of heterogeneous cohorts, dyslipidemia was less common with INSTI than with PI/b. Compared with dolutegravir, dyslipidemia was more common with elvitegravir/cobicistat and raltegravir, but less common with rilpivirine.

Background: Although antiretroviral treatments have improved survival of persons living with HIV, their long-term use may limit available drug options. We estimated the prevalence of heavily treatment-experienced (HTE) status and the potential clinical consequences of becoming HTE. Setting: EuroSIDA, a European multicenter prospective cohort study. Methods: A composite definition for HTE was developed, based on estimates of antiretroviral resistance and prior exposure to specific antiretroviral regimens. Risks of progressing to clinical outcomes were assessed by Poisson regression, comparing every HTE individual with 3 randomly selected controls who never became HTE. Results: Of 15,570 individuals under follow-up in 2010-2016, 1617 (10.4%, 95% CI: 9.9% to 10.9%) were classified as HTE. 1093 individuals became HTE during prospective follow-up (HTE incidence rate 1.76, CI: 1.66 to 1.87 per 100 person-years of follow-up). The number of HTE individuals was highest in West/Central Europe (636/4019 persons, 15.7%) and lowest in East Europe (26/2279 persons, 1.1%). Although most HTE individuals maintained controlled viral loads (

OBJECTIVE: To evaluate time trends in pregnancies and pregnancy outcomes among women with HIV in Europe. DESIGN: European multicentre prospective cohort study. METHODS: EuroSIDA has collected annual cross-sectional audits of pregnancies between 1996 and 2015. Pregnancy data were extracted and described. Odds of pregnancy were modelled, adjusting for potential confounders using logistic regression with generalized estimating equations. RESULTS: Of 5535 women aged 16 to

Objective Zero risk of linked HIV transmission in serodiscordant couples when the HIV-infected partner had viral load less than 200 copies/ml ('U status') was found in observational studies. We aimed at estimating the proportion of time in which 'U status' was maintained and identifying factors associated with the risk of losing it. Design Observational cohort study. Methods We included participants in the ICONA cohort who had reached an established 'U status' (viral load ≤200 copies/ml for >6 months) as of December 2010. The outcome was the number of person-days of follow-up (PDFU) above a viral load greater than 200 copies/ml, relative to the total number of PDFU observed. A logistic regression model was used to identify factors independently associated with the risk of losing 'U status'. Results Eight thousand, two hundred and forty-one persons living with HIV were included in the analysis who contributed 2 670 888 PDFU. Of these, 1648 (20%) were women, 768 (9%) were people who inject drugs (PWID), and 2066 (25%) were foreign-born. The median of viral load measurements was 9 (IQR: 4-15). Overall, only 3.1% of PDFU were observed when viral load was above 200 copies/ml. The proportion of PDFU with viral load more than 200 copies/ml was higher than average in women (5.3%), unemployed (5.4%), PWID (4.7%), and in people with more than three previous virologic failures (6.3%). These variables were significant predictors of losing 'U status' in the multivariable logistic regression. Conclusion Our results reinforce the validity of the U=U message in real-world setting. However, we identified subsets of our study population at higher risk of losing the 'U status' for whom additional efforts are needed.

Objective: This study investigates the effectiveness and tolerability of switching to a darunavir/cobicistat (DRV/c)-based antiretroviral regimen from a ritonavir-boosted protease inhibitor (PI/r)-based regimen in virologically suppressed HIV-positive patients. DRV trough values were also investigated. Setting: Prospective, multicenter, single-country, noninterventional cohort study. Methods: This study included patients on a PI/r-based ART for at least 12 months having plasma HIV-1 RNA

Background: Efavirenz (EFV) association with neurocognitive impairment is debated. Whether switching away from EFV improves neurocognitive performances is still controversial.Methods:In a randomized open-label controlled trial, patients under effective treatment with tenofovir disoproxil-fumarate (TDF), emtricitabine (FTC) and EFV, who had altered neurocognitive assessment (z-transformed score below -1 in at least one cognitive domain), depression, anxiety or low sleep-quality, were randomized 1:1 to immediate or delayed (24-weeks) switch to TDF/FTC/rilpivirine (RPV). Treatment efficacy, neurocognitive function, symptoms and quality of life were evaluated 12, 24 and 48 weeks after randomization.Findings:Seventy-four patients were randomized to immediate (36 patients) or delayed switch (38 patients). At baseline, 63 and 25% of patients had z-scores below -1 in at least one or two neurocognitive domains, 31.1, 17.6 and 44.6% had significant depression or anxiety symptoms or low sleep quality. At week 24 (primary end-point), overall neurocognitive improvement was observed, with no statistically significant differences between arms, neither considering the global z score (between arms difference +0.1; P=0.458), nor domain-specific z scores. Patients switching away from EFV had significant greater improvement of sleep quality index (between-arm difference -1.5; P=0.011), self-reported cognitive failures (-6.2; P=0.001) and CNS symptoms score (-5; P=0.002), but not of anxiety or depression. No protocol defined virological failure, grade at least 3 lab abnormalities or drug-related serious adverse events were reported.Conclusion:Our results do not support the hypothesis that switching to RPV improves cognitive function in patient under stable treatment with EFV. Nonetheless, improvements in neuropsychiatric symptoms, sleep quality and self-perceived cognition were observed.

Supplemental Digital Content is available in the text, Introduction: HIV cohort data from high-income European countries were compared with the UNAIDS Spectrum modelling parameters for these same countries to validate mortality rates and excess mortality estimates for people living with HIV (PLHIV) on antiretroviral therapy (ART). Methods: Data from 2000 to 2015 were analysed from the Antiretroviral Therapy Cohort Collaboration (ART-CC) for Austria, Denmark, France, Italy, the Netherlands, Spain, and Switzerland. Flexible parametric models were used to compare all-cause mortality rates in the ART-CC and Spectrum. The percentage of AIDS-related deaths and excess mortality (both are the same within Spectrum) were compared, with excess mortality defined as that in excess of the general population mortality. Results: Analyses included 94 026 PLHIV with 585 784 person-years of follow-up, from which there were 5515 deaths. All-cause annual mortality rates in Spectrum for 2000–2003 were 0.0121, reducing to 0.0078 in 2012–2015, whilst the ART-CC's corresponding annual mortality rates were 0.0151 [95% confidence interval (95% CI): 0.0130–0.0171] reducing to 0.0049 (95% CI: 0.0039–0.0060). The percentage of AIDS-related deaths in Spectrum was 74.7% in 2000–2003, dropping to 43.6% in 2012–2015. In the ART-CC, AIDS-related mortality constitutes 45.3% (95% CI: 38.4–52.9%) of mortality in 2000–2003 and 26.7% (95% CI: 19–46%) between 2012 and 2015. Excess mortality in the ART-CC was broadly similar to the Spectrum estimates, dropping from 75.3% (95% CI: 60.3–95.2%) in 2000–2003 to 30.7% (95% CI: 25.5–63.7%) in 2012–2015. Conclusion: All-cause mortality assumptions for PLHIV on ART in high-income European settings should be adjusted in Spectrum to be higher in 2000–2003 and decline more quickly to levels currently captured for recent years.

OBJECTIVE Nelfinavir exhibits potent anticancer properties against a range of tumours. However, in 2006/2007, nelfinavir supplies were accidently contaminated with a carcinogen. This analysis investigated the association between nelfinavir use and cancer risk in HIV-positive persons. DESIGN Observational cohort study. METHODS D:A:D study data was analysed using Poisson regression models to examine associations between cancer incidence and cumulative nelfinavir exposure, current nelfinavir exposure, and exposure to nelfinavir between 1 July 2006-30 June 2007. RESULTS A total of 42 006 individuals (50% white, 73% male) contributed 303 005 person-years of follow-up between 1 January 2004 and 1 February 2014. At study enrolment, median age was 40 [interquartile range (IQR) 33-46] years and 8305 individuals had a history of nelfinavir use [median duration 1.7 (IQR 0.7-3.4) years]. During follow-up, nelfinavir was used by 2476 individuals for a median of 1.7 (IQR 0.7-3.8) years; 1063 were exposed to nelfinavir between 1 July 2006 and 30 June 2007. Overall, 2279 cancers were diagnosed at a rate of 0.75 [95% confidence interval (95% CI) 0.72-0.78] per 100 person-years. Neither greater cumulative exposure to nelfinavir [adjusted risk ratio (aRR) 0.93 for every additional 5 years, 95% CI 0.82-1.06, P = 0.26] nor current use of nelfinavir (aRR 0.98 vs other protease inhibitor use, 95% CI 0.68-1.41, P = 0.92) were associated with cancer risk. The adjusted risk of cancer for participants exposed to nelfinavir between 1 July 2006 and 30 June 2007 compared to those receiving other treatment over this period was 1.07 (95% CI 0.78-1.46, P = 0.68). CONCLUSION Nelfinavir use was not associated with a lower cancer incidence than other protease inhibitor regimens. As of February 2014, exposure to the 2006/2007 contamination of nelfinavir does not appear to be associated with increased cancer incidence.

HIV-infected individuals with incomplete CD4⁺ T-cell recovery upon combination antiretroviral therapy (cART) display high levels of immune activation and microbial translocation. However, whether a link exists between gut damage and poor immunological reconstitution remains unknown.Cross-sectional study of the gastrointestinal tract in late cART-treated HIV-infected individuals: 15 immunological nonresponders (CD4⁺350 cells/μl and/or delta CD4⁺ change from baseline30%); 15 full responders (CD4⁺350 cells/μl and/or delta CD4⁺ change from baseline30%).We assessed gut structure (junctional complex proteins in ileum and colon) and function (small intestine permeability/damage and microbial translocation parameters). The composition of the fecal microbiome and the size of the HIV reservoir in the gut and peripheral blood were investigated as possible mechanisms underlying mucosal impairment.Markers of intestinal permeability, damage, systemic inflammation, and microbial translocation were comparable in all study individuals, yet the expression of junctional complex proteins in gut biopsies was significantly lower in HIV-infected patients with incomplete CD4⁺ restoration and negatively correlated with markers of CD4⁺ reconstitution. Electron microscopy revealed dilated intercellular spaces in individuals lacking immunological response to cART, yet not in patients displaying CD4⁺ T-cell recovery. Analysis of the fecal microbiome revealed an overall outgrowth of Bacteroides-Prevotella spp. with no differences according to CD4⁺ T-cell reconstitution. Interestingly, HIV reservoirs in peripheral CD4⁺ T cells and intestinal tissue negatively correlated with immune recovery.These observations establish gut damage and the size of the HIV reservoir as features of deficient immunological response to cART and provide new elements for interventional strategies in this setting.

BACKGROUND The goal of antiretroviral therapy (ART) is to reduce HIV-related morbidity and mortality by suppressing HIV replication. The prognostic value of persistent low-level viremia (LLV), particularly for clinical outcomes, is unknown. OBJECTIVE Assess the association of different levels of LLV with virological failure, AIDS event, and death among HIV-infected patients receiving combination ART. METHODS We analyzed data from 18 cohorts in Europe and North America, contributing to the ART Cohort Collaboration. Eligible patients achieved viral load below 50 copies/ml within 3-9 months after ART initiation. LLV50-199 was defined as two consecutive viral loads between 50 and 199 copies/ml and LLV200-499 as two consecutive viral loads between 50 and 499 copies/ml, with at least one between 200 and 499 copies/ml. We used Cox models to estimate the association of LLV with virological failure (two consecutive viral loads at least 500 copies/ml or one viral load at least 500 copies/ml, followed by a modification of ART) and AIDS event/death. RESULTS Among 17 902 patients, 624 (3.5%) experienced LLV50-199 and 482 (2.7%) LLV200-499. Median follow-up was 2.3 and 3.1 years for virological and clinical outcomes, respectively. There were 1903 virological failure, 532 AIDS events and 480 deaths. LLV200-499 was strongly associated with virological failure [adjusted hazard ratio (aHR) 3.97, 95% confidence interval (CI) 3.05-5.17]. LLV50-199 was weakly associated with virological failure (aHR 1.38, 95% CI 0.96-2.00). LLV50-199 and LLV200-499 were not associated with AIDS event/death (aHR 1.13, 95% CI 0.81-1.68; and aHR 0.95, 95% CI 0.62-1.48, [corrected] respectively). CONCLUSION LLV200-499 was strongly associated with virological failure, but not with AIDS event/death. Our results support the US guidelines, which define virological failure as a confirmed viral load above 200 copies/ml.

Background: Hepatitisdelta virus(HDV) infection resultsin the mostaggressive formof chronic viral hepatitis. There is scarce information about the prevalence, epidemiology, virological profile and natural history of hepatitis delta in HIV patients. Methods: From 16597 HIV patients enrolled in EuroSIDA, 1319 (7.9%) have ever reported serum hepatitis B virus (HBV) surface antigen (HBsAg)-positive. At last followup, 1084 (6.5%) patients were HBsAg-positive. The HDV substudy was carried out in 422 individuals for whom stored sera were available at the time they were HBsAgpositive. Anti-HDV immunoglobulin G was assessed using a commercial enzyme immunoassay(EIA) and serumHDV-RNA was quantifiedusing a real-time PCR method. Results: A total of 61 of 422 HBsAg-positive carriers were anti-HDV-positive (prevalence: 14.5%). Hepatitis delta predominated in intravenous drug users and for this reason in south and/or east Europe. Serum HDV-RNA was detectable in 87% of tested anti-HDV-positive patients, with a median titer of 1.76 � 10 7 copies/ml. Overall, delta hepatitis patients showed lower serum HBV-DNA than the rest of HBsAg-positive carriers, although the inhibitory effect of HDV on HBV replication was not recognized in HBV genotype D patients. Whereas HDV was not associated with progression to AIDS, it significantly influenced the risk of death. Conclusion: The prevalence of anti-HDV in chronic HBsAg-positive/HIV carriers in EuroSIDA is 14.5%. Most of these patients exhibit detectable HDV viraemia. Viral interference between HBV and HDV is manifested in all but HBV genotype D carriers in whom overt coreplication of both viruses occurs which might result in enhanced liver damage. Overall, delta hepatitis increases the risk of liver-related deaths and overall mortality in HIV patients. 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins AIDS 2011, 25:1987‐1992

Objectives: To explore the relationship between elevated triglyceride levels and the risk of myocardial infarction (MI) in HIV-positive persons after adjustment for total cholesterol (TC), high-density lipoprotein–cholesterol (HDL-C) and nonlipid risk factors. Background: Although elevated triglyceride levels are commonly noted in HIVpositive individuals, it is unclear whether they represent an independent risk factor for MI. Methods: The incidence of MI during follow-up was stratified according to the latest triglyceride level. Multivariable Poisson regression models were used to describe the independent association between the latest triglyceride level and MI risk after adjusting for TC and HDL-C, nonlipids cardiovascular disease (CVD) risk factors, HIV and treatment-related factors. Results: The 33 308 persons included in the study from 1999 to 2008 experienced 580 MIs over 178 835 person-years. Unadjusted, the risk of MI increased by 67% [relative risk (RR) 1.67, 95% confidence interval 1.54–1.80] per doubling in triglyceride level. After adjustment for the latest TC and HDL-C level, the RR dropped to 1.33 (95% confidence interval 1.21–1.45); this effect was further attenuated by other CVD risk factors and the RR was reduced to 1.17 (95% confidence interval 1.06–1.29). In models that additionally adjusted for HIV and treatment factors, the risk was further diminished, although remained significant (RR 1.11, 95% confidence interval 1.01–1.23). Conclusion: Higher triglyceride levels were marginally independently associated with an increased risk of MI in HIV-positive persons, although the extent of reduction in RR after taking account of latest TC, latest HDL-C and other confounders suggests that any independent effect is small. 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins AIDS 2011, 25:1497–1504

OBJECTIVE: Analysis of functionally defined T-cell differentiation in HIV-infected patients with low CD4(+) on virologically suppressive HAART is crucial to design clinically efficacious treatments. METHODS: We cross-sectionally investigated the maturation (CD45RA/CCR7, CD7) and function [antigen-specific enzyme-linked immunosorbent spot assay (ELISPOT), interleukin-2 (IL-2)/interferon-gamma-producing cells] of CD4(+) and CD8(+) T cells in 34 HIV-infected immunological nonresponders (INRs): CD4(+) cell count less than or equal to 200 cells/microl, HIV-RNA 50 copies/ml or less, as compared to 20 full responders (CD4(+) > 500 cells/microl, HIV-RNA < 50 copies/ml). RESULTS: We describe skewed T-cell maturation in INRs with outgrowth of effector memory CD45RA(-)CCR7(-) CD4(+)/CD8(+) and Th2-committed CD7(-)CD4(+), and reduced unprimed-naive T cells (P = 0.001). Functionally, INRs display reduced Gag-specific ELISPOT (P = 0.04) and IL-2-secreting CD8(+) (P = 0.08) while showing CMV-specific responses comparable to full responders. CONCLUSION: CD4 lymphopenia on HAART results in skewed, senescent T-cell maturation profile, inefficient T-helper function and poor HIV-specific CD8(+) response. This delineates a functional/phenotypic T-cell pattern that correlates to unfavourable clinical outcome.

Objectives: CD4 cell count and plasma viral load are well known predictors of AIDS and mortality in HIV-1-infected patients treated with combination antiretroviral therapy (cART). This study investigated, in patients treated for at least 3 years, the respective prognostic importance of values measured at cART initiation, and 6 and 36 months later, for AIDS and death. Methods: Patients from 15 HIV cohorts included in the ART Cohort Collaboration, aged at least 16 years, anti retroviral-naive when they started cART and followed for at least 36 months after start of cART were eligible. Results: Among 14208 patients, the median CD4 cell counts at 0, 6 and 36 months were 210, 320 and 450 cells/mu l, respectively, and 78% of patients achieved viral load less than 500 copies/ml at 6 months. In models adjusted for characteristics at cART initiation and for values at all time points, values at 36 months were the strongest predictors of subsequent rates of AIDS and death. Although CD4 cell count and viral load at cART initiation were no longer prognostic of AIDS or of death after 36 months, viral load at 6 months and change in CD4 cell count from 6 to 36 months were prognostic for rates of AIDS from 36 months. Conclusions: Although current values of CD4 cell count and HIV-1 RNA are the most important prognostic factors for subsequent AIDS and death rates in HIV-1-infected patients treated with cART, changes in CD4 cell count from 6 to 36 months and the value of 6-month HIV-1 RNA are also prognostic for AIDS. (C) 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins

Patients with inefficient CD4+ T-cell recovery on virogically suppressive highly active antiretroviral therapy constitute a major clinical hurdle given the threat of HIV/AIDS disease progression. We show heightened circulating lipopolysaccharide associated with plasma enterobacterial DNA and highly activated Ki67+CD4+CD8+ in 24 immunologic-nonresponders (CD4+ T-cellor = 200; HIV-RNAor = 50) compared with 11 full responders (CD4+ T-cellor= 400; HIV-RNAor = 50). These data provide novel insight into INRs pathogenesis, since they correlate augmented systemic translocation of microbial bioproducts with T-cell hyperactivation.

OBJECTIVE AND DESIGN The present study aims at evaluating the influence of genetic polymorphisms on antiretroviral therapy (ART)-associated lipodystrophy. We included in the study 255 ICoNA. patients and we assessed the distribution of Fas -670 AG polymorphism, ApoC3 -455 CT and -482 CT polymorphisms, C161T silent substitution in the PPAR gamma gene, the Adrenergic beta3 Receptor (ARbeta3) codon 64 TC variant, and two polymorphisms in the Adrenergic beta2 Receptor (ARbeta2) codon 16 AG and codon 27 CG. Crude rates of lipoatrophy and fat accumulation and adjusted relative rates were calculated using Poisson regression. RESULTS In a multivariate model after adjusting for gender, HIV exposure, age, current viral load, hepatitis C virus (HCV) serology, nucleoside reverse-transcriptase inhibitor (NRTI) pair/'third drugs' currently used, months of pre-highly active antiretroviral therapy (HAART) exposures to NRTI, the following genotypes resulted protective against lipoatrophy: ApoC3 -455 CC genotype [adjusted relative risks (ARR) 0.2, 95% confidence interval (CI) 0.046-0.91 vs CT/TT, P = 0.037], ARbeta3 codon 64 TT genotype (ARR 0.39, 95% CI 0.14-1.06 vs TC/CC, P = 0.066), and Fas -670 GG genotype (ARR 0.51, 95% CI 0.26-1.01 vs AG/AA, P = 0.053). With regard to fat accumulation, in the multivariate model, the ARbeta2 codon 27 CC genotype resulted protective (ARR 0.21, 95% CI 0.08-0.51 vs CG/GG, P = 0.0006), whereas the ARbeta2 codon 16 AA genotype resulted associated with higher risk (ARR 3.72, 95% CI 1.58-8.76 vs AG/GG, P = 0.0026). CONCLUSION Our study suggests that genetic polymorphisms of genes involved in apoptosis and adipocyte metabolism are significantly related to ART associated lipodystrophy. Particularly, we evidenced a role for ApoC3 -455 in lipoatrophy and for the two variants of ARbeta2 in fat accumulation.

A substantial proportion of HIV-infected individuals do not present for HIV testing until late in infection; these individuals are often ill, have a high mortality risk, and are less likely to respond to treatment when initiated. Furthermore, late presentation means that opportunities to reduce onward transmission, either by reducing high-risk behaviours or by reducing an individual's infectivity, are missed. The proportion of HIV-infected individuals who present late has remained relatively stable over the past decade, despite several attempts to encourage earlier diagnosis. Late presenters tend to be those at lower perceived risk of infection, those who are not routinely offered HIV testing, and are often from marginalized groups. Strategies that encourage earlier testing, including routine HIV testing in healthcare settings where high-risk individuals attend frequently, the availability of HIV testing services in non-medical settings, and partner notification schemes or peer-led projects to encourage high-risk individuals to attend for testing, may all increase the proportion of HIV-infected individuals who are aware of their HIV status, thus helping to control the spread of the epidemic. This review summarizes recent evidence on the epidemiology of late presentation and its impact on clinical progression, and describes several key strategies that may encourage earlier diagnosis.

Background: Changes in virologic response to initial combination antiretroviral therapy (cART) over calendar time may indicate improvements in cART or emergence of primary resistance. Regional variations may identify differences in available antiretroviral drugs or patient management.Methods: Virologic response (viral load < 500 copies/mL) 6 to 12 months after starting cART was analyzed in antiretroviral-naive EuroSIDA patients. Analyses were stratified by region (south, central west, north, east) or time started cART (early, 1996-1997; mid, 1998-1999; late, 2000-2004).Results: Virologic suppression was achieved by 60% of 2102 patients: 57% south (n = 560), 61% central west (n = 466), 63% north (n = 606), 58% east (n = 470) (P = 0.091). An increase was observed over time: 2% early cART, 56% mid cART, 69% late cART (P < 0.001). Overall, there were significant effects of region (P = 0.026) and time (P < 0.001) on virologic response after adjustment for confounders. Stratified by period, regional differences were less evident (early cART, P = 0.967; mid cART, P = 0.291; late cART, P = 0.163). Stratified by region, temporal changes were observed (south, P 0.061; central west, P < 0.001; north: P = 0.070; east, P = 0.001).Conclusions: There was some evidence of regional differences in initial virologic response to cART. Improvements over time were observed, suggesting that so far,the effect of primary resistance has not been of sufficient magnitude to prevent increasing suppression rates.

To assess the risk of clinical progression (CP) according to the duration of time spent without complete viral load (VL) suppression compared with that associated with periods of stably suppressed viremia in HIV-infected people who started highly active antiretroviral therapy (HAART) when previously naïve to antiretrovirals.A cohort study of patients having started HAART after enrollment in the Italian Cohort of Antiretroviral-Naive Patients (ICoNA) and being followed for at least 6 months.Person-years spent in different categories according to the VL level and the change in VL from the most recent value before the initiation of HAART were calculated. A multivariable Poisson regression model, including potential confounders, was constructed.A total of 3023 patients were studied. The overall rate of CP was 13.4 per 1000 person-years. Evidence for a higher risk of CP was observed for people with a current VL10,000 copies/mL. For each year longer spent on HAART with a VL100,000 copies/mL, a 5-fold increased risk was observed (relative risk [RR] = 5.34, 95% confidence interval [CI]: 2.83 to 1.08; P = 0.0001). An increased risk of CP in patients with current suppression1.5 log10 copies/mL (RR = 2.34, 95% CI: 1.16 to 4.74; P = 0.02) and in those with no suppression or a VL higher than their set point (RR = 2.39, 95% CI: 1.17 to 4.89; P = 0.02) was observed compared with those with suppression of3 log10 copies/mL, although it was not significant. Longer duration on HAART with a VL suppressed below set point seemed to confer protection against CP.Virologic failure to antiretroviral drugs is common. The risk of CP may remain low despite a low but detectable level of HIV viremia.

Dynamics of human immunodeficiency virus type 1 (HIV-1) tropism after antiretroviral therapy (ART) initiation and their association with disease progression are poorly investigated. This was a cohort study on subjects from the ICONA cohort receiving ART with persistently detectable (PD) or persistently undetectable (PU) viral load (VL) and with stored plasma or peripheral blood mononuclear cell (PBMC) samples at 2 time-points (T1, T2) after ART initiation. HIV-1 co-receptor tropism was determined by V3-loop sequencing and the geno2pheno algorithm. A switch in viral tropism was defined if the tropism classification at T2 differed from that observed at T1. Time to disease progression, defined as the occurrence of a new acquired immune deficiency syndrome (AIDS)-defining event/death from T2, was also evaluated. One hundred ninety-five patients were analyzed (124 PD, 71 PU). Over a median follow-up of 22.6 (19.8–28.1) months, PD and PU patients showed similar rates (95% confidence interval) of switch to a non-R5 virus [PD: 6.9 (3.7–11.2)/100-person-years of follow-up (PYFU); PU: 8.0 (3.4–14.5)/100-PYFU; P = 0.63] and of switch to a R5 virus [PD: 15.4 (7.3–26.4)/100-PYFU; PU: 8.1 (2.5–16.7)/100-PYFU; P = 0.38]. Switch to non-R5 virus was predicted by nadir CD4+ before T1. Twenty-two (18%) PD and 4 (6%) PU subjects experienced disease progression (P = 0.02). The risk of disease progression was independently associated with a switch in co-receptor tropism (adjusted hazard ratio = 4.06, 95% CI: 1.20–13.80, P = 0.03) as well as age, AIDS diagnosis, nadir CD4+ before T2, current CD4+, and VL. Switch of HIV-1 tropism under ART occurs in both directions, with similar rates in subjects with PD or PU VL and it might be predictive of future unfavorable clinical outcome.

Objective: To investigate the impact of 215 HIV-1 revertants on the risk of virological failure of the first thymidine analog-containing highly active antiretroviral therapy (HAART).Design: The study included 491 HIV-1 subjects of the Italian Cohort Naive for Anti retrovirals, 405 of whom received a genotypic assay before therapy and had a virological follow-up.Methods: Pre-treatment genotypic resistance was assessed by sequencing of the whole protease (PR) and reverse transcriptase (RT) region.Results: Three (3.2%) and 13 (3.3%) individuals with recent (n = 95) and chronic (n = 396) HIV-1 infection carried an HIV-1 strain with 215 revertants (215D/C/E/A/V), respectively. In contrast, nucleoside associated mutations were higher in the former (15.8%) compared with the latter group (6.8%) (P = 0.005). A multivariable regression model, considering pre-HAART viral load levels, use of saquinavir-hard gel as the only PI, use of zidovudine, number of other RT and PR mutations, indicated that patients carrying 215 revertants had an increased risk of virological failure compared with those not carrying such mutants (adjusted relative hazard = 2.97 95% confidence interval, 1.11-7.94, P = 0.03). Among patients with 215 revertants, who experienced virological failure, four out of seven showed the emergence of the 215Y resistant mutation. The probability of 215Y occurrence was different between patients carrying 215 revertants compared with those who did not carried these mutants (P = 0.006).Conclusions: HIV-1 215 revertants with an increased ability for selecting 215Y mutation are associated with a higher risk of virological failure and may lead to the appearance of virus carrying 215Y/F mutation in vivo. These findings suggest that 215 revertant viruses may compromise the efficacy of the first thymidine analog-containing regimen. (C) 2004 Lippincott Williams Wilkins.

The difference between adherence to non- nucleoside reverse transcriptase inhibitor (NNRTI) and protease inhibitor (PI)-based regimens was investigated. Better adherence was found in NNRTI-treated patients, especially when efavirenz was included in the regimen, compared with single PI-treated patients and in those with CD4 cell counts less than 200 x 10(6)/l. By contrast, younger age, self-report of active drug use, fatigue or vomiting negatively affected adherence. Self-reported sexual dysfunction was significantly associated with non-adherence only in PI-treated individuals.

Affective disorders have been reported as the most common mental health problem in persons with HIV infection. Depression has a significant impact on the quality of life of persons living with HIV and AIDS and is associated with HIV disease progression and mortality, even after controlling for sociodemographic and clinical characteristics and substance abuse. Depression has been also reported as one of the main causes of poor adherence with antiretroviral regimens. However, no published investigation has specifically focused on the relationship between depression and adherence to antiretroviral therapy. Nonetheless, information on the association between depressive symptoms and adherence may be gathered from investigations carried out to explore determinants of adherence with antiretroviral therapy. Findings from available studies show a substantial and consistent relationship between adherence to antiretroviral regimens and depression. Early recognition and proper management of depressive comorbidity could be an effective intervention strategy to improve adherence and may make a difference in the quality of life, social functioning, and disease course of people with HIV.

Objective: To evaluate the prevalence of HIV-related central nervous system (CNS) lesions (HIV-encephalitis and/or HIV-leukoencephalopathy: HIV-E/L) with and without concomitant opportunistic diseases in a large autopsy series, and to correlate it with the changes in antiretroviral treatment that have occurred since the beginning of the epidemic. Methods: We reviewed 1597 consecutive autopsies of HIV-positive patients performed between 1984 and 2000, and divided into four time periods on the basis of the therapeutic regimens available: 1984-1987, no therapy; 1988-1994, monotherapy (zidovudine); 1995-1996, dual combination therapy with nucleoside reverse transcriptase inhibitors (NRTI); and 1997-2000, triple combination therapy including two NRTI and at least one protease inhibitor or non-NRTI. The data concerning the treatment actually received were collected only for the patients who died during the last period. The X 2 -test was used to assess the significance of the differences in prevalence. Results: The CNS of 1210 patients (76%) was affected by opportunistic diseases, HIV-related lesions or both. The prevalence of HIV-related lesions in the four periods was respectively 54%, 32%, 18% and 15%; this reduction was statistically significant (P < 0.000001). During the last period, however, differences in HIV-E/L between treated and untreated patients were not statistically significant, although there were fewer than expected cases among the treated patients (six instead of eight) and more than expected among the untreated patients (10 instead of eight). Conclusions: These neuropathological data from a large autopsy series confirm clinical observations concerning the efficacy of antiretroviral treatment in reducing the frequency of HIV-related CNS lesions in AIDS patients.

OBJECTIVES: The causes of death among HIV-positive patients may have changed since the introduction of highly active antiretroviral therapy (HAART). We investigated these changes, patients who died without an AIDS diagnosis and factors relating to pre-AIDS deaths. METHODS: Analyses of 1826 deaths among EuroSIDA patients, an observational study of 8556 patients. Incidence rates of pre-AIDS deaths were compared to overall rates. Factors relating to pre-AIDS deaths were identified using Cox regression. RESULTS: Death rates declined from 15.6 to 2.7 per 100 person-years of follow-up (PYFU) between 1994 and 2001. Pre-AIDS incidence declined from 2.4 to 1.1 per 100 PYFU. The ratio of overall to pre-AIDS deaths peaked in 1996 at 8.4 and dropped to < 3 after 1998. The adjusted odds of dying following one AIDS defining event (ADE) increased yearly (odds ratio, 1.53; P < 0.001), conversely the odds of dying following three or more ADE decreased yearly (odds ratio, 0.79; P < 0.001). The proportion of deaths that followed an HIV-related disease decreased by 23% annually; in contrast there was a 32% yearly increase in the proportion of deaths due to known causes other than HIV-related or suicides. Injecting drug users (IDU) were significantly more likely to die before an ADE than homosexuals (relative hazard, 2.97; P < 0.0001) and patients from northern/eastern Europe (relative hazard, 2.01; P < 0.0001) were more likely to die pre-AIDS than southern patients. CONCLUSIONS: The proportion of pre-AIDS deaths increased from 1994 to 2001; however, the incidence of pre-AIDS deaths and deaths overall declined. IDU and subjects from northern/eastern Europe had an increased risk of pre-AIDS death. HIV-positive patients live longer therefore it is essential to continue to monitor all causes of mortality to identify changes.

Objective: To assess the prevalence of mutations in the reverse-transcriptase (RT) and protease (PR) region in a cohort of chronically-infected HIV-positive patients requiring highly active antiretroviral therapy (HAART). Methods: The study included 347 patients enrolled in the Italian Cohort of Antiretroviral Naive patients (I.CO.NA) who had to initiate HAART. The whole PR-region, and aminoacids 1-320 of RT-region were sequenced from plasma samples at baseline. Results: Median CD4-lymphocytes and HIV-RNA at baseline were 231 × 10 6 cells/l and 4.89 log 10 copies/ml; 307 of 347 (88.5%) patients carried no mutations in the RT region, whereas 40 (11.5%) carried one or more mutations associated with resistance to nucleoside-RT inhibitor (NRTI) (7.8%), or non-nucleoside-RTI (NNRTI) (4.9%), with four patients carrying mutations to both classes. Among mutations associated with high-level resistance to RTI, T215Y was found in only two patients, M184V in two cases, T69D and T215C in other two cases (one each), and K103N in only one patient, for a total of six patients (one carrying both T215Y and M184V) (1.7%). Seventy-six patients (21.9%) carried no mutations in the PR region, whereas 271 (78.1%) had one or more mutations. Primary mutations associated with substantial resistance to protease inhibitors were found in only five of 347 patients (1.4%) (M46V/L, 154V, V82A/l); all the other patients carried only secondary mutations (L10F/I/V, M36I, L63P, A71T/V, V77I). Conclusions: Prevalence of mutations associated with high-level resistance to antiretroviral drugs is low in HIV-infected patients with long-term infection. This suggests no preclusion in principle to any antiretroviral drug at the time of decision of the first therapeutic regimen.

To compare the response to highly active antiretroviral therapy (HAART) in individuals starting HAART at different CD4 cell counts.The mean increase in CD4 cell count and rate of virological failure after commencing HAART were measured in antiretroviral-naive patients (1421) in a large, non-randomized multicentre, observational study in Italy (ICONA). Clinical endpoints were also evaluated in a subset of patients who started HAART with a very low CD4 cell count.After 96 weeks of therapy, the mean rise in CD4 cell count was 280, 281 and 186 x 10(6) cells/l in patients starting HAART with a CD4 cell count200, 201--350 and350 x 10(6) cells/l, respectively. Patients starting HAART with a CD4 cell count200 x 10(6) cells/l tended to have a higher risk of subsequent virological failure [relative hazard (RH), 1.15; 95% confidence interval (CI), 0.93--1.42] compared with patients starting with350 x 10(6) cells/l. There was no difference in risk between the 201--350 and the350 x 10(6) cells/l groups (RH, 1.0; 95% CI, 0.79--1.29). The incidence of new AIDS-defining diseases/death in patients who started HAART with a CD4 count50 was 0.03/person-year (95% CI, 0.10--0.33) during the time in which the patient's CD4 cell count had been raised to200 x 10(6) cells/l.There was no clear immunological or virological advantage in starting HAART at a CD4 cell count350 rather than at 200--350 x 10(6) cells/l. The increase in CD4 cells restored by HAART is meaningful in that they are associated with reduced risk of disease/death.

Context: According to recent studies, women have lower plasma HIV RNA concentrations than men. However, these studies did not take into account the duration of HIV infection. Objectives: To analyze the relationship between viral load and gender among individuals with known date of seroconversion. Setting: Sixty infectious disease clinics in Italy. Design: Cross-sectional analysis of data collected at enrollment in a cohort study. Participants: Injecting drug users and heterosexual contacts naive to antiretroviral therapy at enrollment (245 men; 170 women). Main Outcome Measures: Plasma HIV RNA concentrations, measured using quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) or signal amplification b-DNA assays before antiretroviral therapy. Results: Plasma HIV RNA concentrations were similar by age and exposure category (p = .80 and p = .39, respectively). Median viral load among women was roughly half that of men (p = .002). The association between viral load and gender remained significant after fitting a two-way analysis of variance (p = .03) and after adjusting for CD4 count, modality of HIV transmission, and age at enrollment in a regression model. Viral load was 0.27 log 10 copies/ml (95% confidence interval, 0.05-0.40; p = .01) lower in women (i.e., 50% lower in the raw scale). Conclusions: Plasma HIV RNA concentrations were found to be lower among women, even when considering the duration of HIV infection. Compared with men, it is possible women should be given highly aggressive antiretroviral therapy at lower HIV-RNA concentrations.

The outcome of second-line protease inhibitor (PI)-containing highly active antiretroviral therapy (HAART) was investigated in 263 patients who were failed by (n = 148) or intolerant of (n = 115) a first HAART regimen. The endpoints were virologic failure (decline in HIV RNA 34 years versus less than or equal to 34 years: 95% CI, 0.42-0.88), a saquinavir-containing first HAART (HR 0.57 versus indinavir: 95% CI, 0.34-0.93) and change due to intolerance/toxicity (HR 0.58 versus failure: 95% CI, 0.35-0.98). The independent variables predictive of discontinuation due to intolerance/toxicity were the reason for switching (HR 1.79 intolerance versus failure: 95% CI, 1.02-3.16) and the first protease inhibitor (PI) regimen (HR 0.42 ritonavir versus indinavir: 95% CI, 0.22-0.80). Given that patients who are failed by a first regimen are at high risk of having rescue therapy fail as well, second-line regimens including therapies directed by testing of drug resistance patterns of clinical viral isolates are warranted. Patients experiencing toxicity due to a first PI-containing regimen are at risk of toxicity to other PIs and should be addressed to PI-sparing HAART.

The authors enrolled 1,029 patients with CD4 counts/= 200/microL and no CNS AIDS-defining events (CNS-AIDS) between January 1993 and December 1998. The primary end point was the first appearance of CNS-AIDS. Three different periods and different antiretroviral regimens were considered. During the median follow-up of 329 days, 144 patients (9.5%) developed CNS-AIDS. The independent predictors were CD4 counts and therapy. All regimens decreased the risk of CNS-AIDS. Highly active antiretroviral therapy led to a 95% risk reduction in comparison with untreated patients.

Objective: To evaluate the frequency of discontinuation of the first highly active antiretroviral regimen (HAART) and the factors predictive of discontinuing for toxicity and failure in a population-based cohort of HIV-positive individuals in Italy, naive from antiretrovirals at enrolment.Methods: The study population consisted of individuals who initiated HAART and had at least one follow-up visit. The primary end-points were discontinuation of any component of HAART for drug toxicity and discontinuation for failure. Survival analyses were performed to identify predictive factors for reaching the two end points.Results: Eight hundred and sixty-two individuals initialed HAART; in 727 of them (84.3%) this consisted of two nucleoside reverse transcriptase inhibitors (NRTI) and one protease inhibitor (PI). Over a median follow-up of 45 weeks, 312 patients (36.2%) discontinued therapy: 182 (21.1%) discontinued due to toxicity, 44 (5.1%) due to failure. The probability of discontinuing HAART at 1 year was 25.5% [95% confidence interval (Cl), 21.9-28.9] due to toxicity and 7.6% (95% Cl, 4.9-10.3) due to failure. Independent factors associated with discontinuation for toxicity were: gender [relative hazard (RH) = 0.51; 95% Cl, 0.32-0.80 for men versus women], type of treatment (indinavir-containing regimens, RH = 1.94; 95% Cl, 1.10-3.41 and ritonavir-containing regimens, RH = 3.83; 95% Cl, 2.09-7.03 versus hard-gell saquinavir) and time spent on treatment (RH = 0.89; 95% Cl, 0.80-0.98 for each additional month). Discontinuation due to failure was independently associated with the most recent HIV-RNA (RH = 3.20; 959/0 Cl, 1.74-5.88 for log(10) copies/ml higher), and with type of treatment (indinavir-containing regimens, RH = 0.21; 95% Cl, 0.06-0.78 and ritonavir-containing regimens, RH = 0.23; 95% Cl, 0.04-1.26 Versus hard-gell saquinavir).Conclusions: If the current HAART regimen caused no toxicity, less than 10% of naive patients discontinue their first HAART regimen because of failure after 1 year from starting therapy. (C) 2000 Lippincatt Williams & Wilkins.

Objectives: To describe changes in haemoglobin over time and to determine the joint prognostic value of the current haemoglobin, CD4 lymphocyte count and viral load among patients from across Europe. Patients: The analysis included 6725 patients from EuroSIDA, an observational, prospective cohort of patients with HIV from across Europe. Methods: Normal haemoglobin was defined as haemoglobin greater than 14 g/dl for men and 12 g/dl for women; mild anaemia was 8-14 g/dl for men and 8-12 g/dl for women; severe anaemia was defined as less than 8 g/dl for both males and females. Linear regression techniques were used to estimate the annual change in haemoglobin; standard survival techniques were used to describe disease progression and risk of death. Results: At recruitment to the study, 40.4% had normal levels of haemoglobin, 58.2% had mild anaemia and 1.4% had severe anaemia. At 12 months after recruitment, the proportion of patients estimated to have died was 3.1% [95% confidence interval (CI) 2.3-3.9] for patients without anaemia, 15.9% for patients with mild anaemia (95% Cl 14.5-17.2) and 40.8% for patients with severe anaemia (95% CI 27.9-53.6; P < 0.0001). In a multivariate, time-updated Cox proportional hazards model, adjusted for demographic factors, AIDS status and each antiretroviral treatment as time-dependent covariates, a 1 g/dl decrease in the latest haemoglobin level increased the hazard of death by 57% [relative hazard (RH) 1.57; 95% Cl 1.41-1.75; P < 0.0001], a 50% drop in the most recent CD4 lymphocyte count increased the hazard by 51% (RH 1.51; 95% Cl 1.35-1.70; P < 0.0001) and a log increase in the latest viral load increased the hazard by 37% (RH 1.37; 95% Cl 1.15-1.63; P = 0.0005). Conclusions: Severe anaemia occurred infrequently among these patients but was associated with a much faster rate of disease progression. Among patients with similar CD4 lymphocyte counts and viral load, the latest value of haemoglobin was a strong independent prognostic marker for death.