Paola Cicconi

Insights into reasons for discontinuation according to year of starting first regimen of highly active antiretroviral therapy in a cohort of antiretroviral‐naïve patients

The aim of the study was to determine whether the incidence of first‐line treatment discontinuations and their causes changed according to the time of starting highly active antiretroviral therapy (HAART) in an Italian cohort.

Is moderate HIV viremia associated with a higher risk of clinical progression in HIV-infected people treated with highly active antiretroviral therapy: evidence from the Italian cohort of antiretroviral-naive patients study.

Objective: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. Design: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. Methods: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. Results: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 VL >10,000 copies/mL. For each year longer spent on HAART with a VL >100,000 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 suppression <1.5 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 of >3 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. Conclusions:Virologic failure to antiretroviral drugs is common. The risk of CP may remain low despite a low but detectable level of HIV viremia.

Occult hepatitis B virus infection in a Cohort of HIV-positive patients: Correlation with hepatitis C virus coinfection, virological and immunological features

Background:An evaluation of the prevalence of occult hepatitis B virus (HBV) infection in HIV-positive individuals is important as HBV infection may have an impact on the outcome of the liver disease in these patients.Materials and Methods:Of the 1,593 HIV-positive subjects enrolled in the Italian Cohort Naïve Antiretroviral (ICONA) program, 175 (10.9%) were selected for inclusion in the study on the basis of hepatitis B surface antigen (HBsAg) negativity and antibody to hepatitis B core antigen (anti- HBc) positivity; 101/175 (58%) were also anti-hepatitis C virus (HCV) positive. HBV-DNA was detected in plasma using a highly sensitive PCR assay (detection limit: 2.6 copies/ml). Two different genomic regions were assayed. Quantification was performed by real-time PCR. The HBV genotype was determined in 20 cases with occult HBV infection. Data on the antiretroviral therapy (ART) regimen was obtained in 169 individuals: 53 (31.4%) patients were ART-naive, 46 (27.2%) were under ART without lamivudine or tenofovir, and the remaining 70 (41.4%) were under ART including lamivudine or tenofovir.Results:27/175 (15%) patients had detectable HBV-DNA in their plasma: 21/101 (21%) were anti-HCV positive and 6/74 (8%) were anti-HCV negative. Genotype D was invariably found in the 20 cases analyzed. Occult HBV infection was significantly higher in HCV-coinfected subjects: adjusted OR 5.02, 95% CI 1.31–19.26, p = 0.02. The value was not associated with immune status, HIV load, or ART regimen.Conclusions:In relation to the high prevalence of occult HBV infection, particularly in HIV/HCV-coinfected individuals, it is necessary to clarify the clinical impact of this cryptic infection by monitoring HBV-DNA in plasma using the correct approach. Similarly to HBsAg-positive individuals of the Mediterranean area, HBV genotype D is invariably detected in this cohort of HIV-infected patients with occult HBV infection.

Genetic polymorphisms differently influencing the emergence of atrophy and fat accumulation in HIV-related lipodystrophy

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 γ gene, the Adrenergic β3 Receptor (ARβ3) codon 64 TC variant, and two polymorphisms in the Adrenergic β2 Receptor (ARβ2) 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], ARβ3 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 ARβ2 codon 27 CC genotype resulted protective (ARR 0.21, 95% CI 0.08–0.51 vs CG/GG, P = 0.0006), whereas the ARβ2 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 ARβ2 in fat accumulation.

Evaluation of glomerular filtration rate in HIV-1-infected patients before and after combined antiretroviral therapy exposure*

The prevalence and factors associated with an increased risk of renal dysfunction in HIV‐infected patients receiving or not receiving antiretroviral therapy (ART) have been poorly evaluated in observational settings.

Is the increased risk of liver enzyme elevation in patients co-infected with HIV and hepatitis virus greater in those taking antiretroviral therapy?

Objectives:To investigate if the risk of liver enzyme elevation (LEE) in HIV/hepatitis B or C (HBV, HCV) co-infection is altered by HAART (two or more drugs). Methods:Analysis comprised HIV-positive patients in the ICoNA study without acute hepatitis who had ≥ 1 positive HCV antibody test and > 1 positive HBV surface antigen test. LEE was defined as > 5× baseline alanine aminotransferase (ALT) or > 3.5× baseline if the baseline was > 40 IU/l. Analysis used Poisson regression with generalized estimating equation correction to examine HBV or HCV co-infection, use of HAART, baseline ALT and demographics as LEE predictors. Results:Of the 5272 patients, 47.6% were co-infected with HCV/HBV; 29.9% were female and 39% were intravenous drug users. There were 275 episodes of LEE during 18 259 person-years follow up. Taking HAART did not significantly increase risk of LEE [adjusted relative risk (RR), 1.19; 95% confidence interval (CI), 0.81–1.75; P = 0.37]. Co-infection increased the risk of LEE (adjusted RR, 5.07; 95% CI, 3.47–7.48; P < 0.001), with no significant differences if taking HAART (adjusted RR, 4.99; 95% CI, 3.38–7.37) or not (adjusted RR, 6.02; 95% CI, 2.02–17.98) (P = 0.74 for interaction). Females were at lower risk of LEE than males (adjusted RR, 0.59; 95% CI, 0.42–0.83; P = 0.02). Conclusions:HIV and HBV/HCV co-infection per se is associated with increased risk of LEE that is not modified by HAART. The recommendation for caution in HAART use in co-infected patients, simply based on a high rate of LEE in people on therapy, may be questionable.

Viral interference between hepatitis B, C, and D viruses in dual and triple infections in HIV-positive patients.

Objective:To investigate the reciprocal inhibitory effects of hepatitis B virus (HBV)/hepatitis C virus (HCV)/hepatitis D virus (HDV) infections in naive and previously antiretroviral-experienced HIV-positive patients. Design:This retrospective study involved 72 consecutive patients of the Italian Cohort Naive Antiretroviral cohort: 21 coinfected with HBV/HCV (group 1BC), 18 infected with HBV (group 2B), and 33 infected with HCV (group 3C). Methods:Viral interference between HBV and HCV was assessed by means of the qualitative detection, quantification, and genotyping of each virus; HDV infection was assessed by means of genomic amplification. Results:Univariate analysis showed that HBV DNA was less frequently detected in group 1BC than in group 2B (16 of 21 vs 18 of 18; P = 0.02), their HBV load was significantly lower (median 3.9 vs 5.4 log10 HBV DNA copies/mL; P = 0.002), and they more frequently carried HBV genotype D (12 of 13 vs 4 of 11; P = 0.0071). HCV RNA was less frequently detected in group 1BC than in group 3C (12 of 21 vs 33 of 33; P < 0.0001), and HDV RNA was more frequently detected in group 1BC than in group 2B (9 of 21 vs 2 of 18; P = 0.028). Multivariate analysis of the HBV-infected subjects showed that the risk of HCV coinfection was associated with older age [relative risk 0.28, 95% confidence interval (CI): 0.09 to 0.90; P = 0.033 for every 10 years older] and intravenous drug use (relative risk 73, 95% CI: 2.4 to >999.999; P = 0.013). The only predictor of HBV coinfection in HCV-infected individuals was a lower HCV load (relative risk 0.30, 95% CI: 0.11 to 0.79 for every additional log10 HCV RNA; P = 0.015). Conclusion:HBV and HCV showed alternative dominant replication in the I.Co.N.A. cohort, with HBV having a more unfavorable effect on HCV replication.

Inconsistent condom use among HIV-positive women in the ‘‘Treatment as Prevention Era’’: data from the Italian DIDI study

Translation of the evidence regarding the protective role of highly active antiretroviral therapy (HAART) on HIV sexual transmission rates into sexual behaviour patterns of HIV‐infected subjects remains largely unexplored. This study aims to describe frequency of self‐reported condom use among women living with HIV in Italy and to investigate the variables associated with inconsistent condom use (ICU).

Duration of first-line antiretroviral therapy with tenofovir and emtricitabine combined with atazanavir/ritonavir, efavirenz or lopinavir/ritonavir in the Italian ARCA cohort

OBJECTIVES To explore the durability of three first-line tenofovir/emtricitabine-based regimens in combination with atazanavir/ritonavir, efavirenz or lopinavir/ritonavir in HIV-1-infected patients. PATIENTS AND METHODS A retrospective, longitudinal, multicentre analysis of adult patients enrolled in the Antiretroviral Resistance Cohort Analysis (ARCA), a national prospective observational cohort of HIV-1-infected patients followed up at more than 100 clinical and laboratory units in Italy. Patients eligible were those starting first-line antiretroviral therapy between 1 June 2004 and 15 April 2011 and who were followed up for at least 6 months. The primary endpoint was durability, defined as the time from antiretroviral therapy initiation to first treatment modification. Time-dependent events were analysed by the Kaplan-Meier approach and the Cox proportional hazard model. RESULTS There are 26,000 HIV-infected patients in the ARCA database, of whom 1654 met study inclusion criteria. Six hundred and thirty-nine (38.6%) received efavirenz, 321 (19.4%) received atazanavir/ritonavir and 694 (41.9%) received lopinavir/ritonavir as a first-line regimen. Over a total observation period of 88 months, equivalent to more than 2805 person-years of follow-up, 618 patients underwent treatment modification. Lopinavir/ritonavir, given twice daily, was associated with a higher discontinuation rate than efavirenz- and atazanavir-based regimens [hazard ratio (HR) 1.83, 95% confidence interval (CI) 1.56-2.15, P = 0.001]. Comparing the once-daily regimens, the rate of discontinuation of efavirenz was higher than that of atazanavir/ritonavir (HR 1.39, 95% CI 1.06-1.83, P = 0.016). CONCLUSIONS Significant differences in treatment duration were observed among the three studied regimens. Once-daily regimens exhibited greater durability than the twice-daily regimen. Among the specific regimens examined, tenofovir/emtricitabine plus atazanavir/ritonavir showed the greatest durability.

Recent acquired STD and the use of HAART in the Italian Cohort of Naive for Antiretrovirals (I.Co.N.A): analysis of the incidence of newly acquired hepatitis B infection and syphilis.

Objective:To estimate the incidence of newly acquired syphilis (n-syphilis) and hepatitis B infection (n-hepatitis B) in I.Co.N.A. and to evaluate the impact of HAART, calendar date and risk group.Methods:Cohort study: Incidence was calculated by person–years analyses. Poisson regression was used for the multivariate model.Results:The rate of n-syphilis was 23.4/1,000 PYFU and it increased over time; HIV transmission risk was the most important predictor: men who have sex with men (MSM) had a considerable higher risk (RR 5.92, 95% CI 2.95–12.13 vs IDU/exIDU, p < 0.0001). The rate of n-hepatitis B was 12.2/1,000 PYFU; it declined in recent years and halved per 10 years age. Patients with HIV-RNA < 500 copies/ml had a 60% reduced risk of n-hepatitis B if they were treated with HAART compared with not treated individuals.Conclusions:In our population, the use of HAART was not associated with a higher risk of newly acquired sexually transmitted diseases (STD). Suppressive HAART was associated with a lower risk of HbsAg seroconversion. Incidence of n-hepatitis B has recently been declining possibly due to herd immunity provided by vaccination policies. The risk of acquiring n-syphilis has increased over time and it is higher in the population of MSM compared with other categories of HIV exposure.