Laura Sighinolfi

One-pill once-a-day HAART: a simplification strategy that improves adherence and quality of life of HIV-infected subjects

Objective: The aim of the ADONE (ADherence to ONE pill) study was to verify the effect of a reduced number of pills on adherence and quality of life (QoL) in HIV-infected patients on highly active antiretroviral therapy (HAART). Design: Prospective, multicenter, study. Methods: Patients chronically treated with emtricitabine (FTC) + tenofovir (TDF) + efavirenz (EFV) or lamivudine (3TC) +TDF +EFV and with a HIV-RNA < 50 copies/mL were switched to the single-pill fixed-dose regimen (FDR) of FTC +TDF +EFV. Data were collected with SF-36 using visual analog scales. Results of the final (6 months) primary as-treated analysis are reported. Results: 212 patients (77.4% males) of mean age 45.8 years were enrolled; 202 completed the study. One month post switch to FDR the adherence rate increased significantly to 96.1% from a baseline value of 93.8% (P < 0.01). The increase was steadily maintained throughout the study (96.2% at 6 months). QoL improved over time from 68.8% to 72.7% (P = 0.042) as well, and was significantly associated with the perception of health status, presence of adverse events (AEs) and number of reported AEs (P < 0.0001). QoL significantly influenced adherence (P < 0.0001). During FDR use the mean CD4 count increased from 556 to 605 cells/μL (P < 0.0001). At the end of follow-up 98% of patients maintained HIV-RNA level < 50 copies/mL and 100% <400 copies/mL. Four patients stopped therapy because they were lost to follow-up and 6 because of AEs (insomnia/nervousness 4, allergy 1, difficulties swallowing pills 1). Conclusion: By substituting a one-pill once-a-day HAART, we observed an improvement of both adherence and QoL while maintaining high virologic and immunologic efficacy. HAART simplicity is an added value that favors adherence and may improve long-term success.

Therapeutic immunization with hiv-1 tat reduces immune activation and loss of regulatory t-cells and improves immune function in subjects on HAART

Although HAART suppresses HIV replication, it is often unable to restore immune homeostasis. Consequently, non-AIDS-defining diseases are increasingly seen in treated individuals. This is attributed to persistent virus expression in reservoirs and to cell activation. Of note, in CD4+ T cells and monocyte-macrophages of virologically-suppressed individuals, there is continued expression of multi-spliced transcripts encoding HIV regulatory proteins. Among them, Tat is essential for virus gene expression and replication, either in primary infection or for virus reactivation during HAART, when Tat is expressed, released extracellularly and exerts, on both the virus and the immune system, effects that contribute to disease maintenance. Here we report results of an ad hoc exploratory interim analysis (up to 48 weeks) on 87 virologically-suppressed HAART-treated individuals enrolled in a phase II randomized open-label multicentric clinical trial of therapeutic immunization with Tat (ISS T-002). Eighty-eight virologically-suppressed HAART-treated individuals, enrolled in a parallel prospective observational study at the same sites (ISS OBS T-002), served for intergroup comparison. Immunization with Tat was safe, induced durable immune responses, and modified the pattern of CD4+ and CD8+ cellular activation (CD38 and HLA-DR) together with reduction of biochemical activation markers and persistent increases of regulatory T cells. This was accompanied by a progressive increment of CD4+ T cells and B cells with reduction of CD8+ T cells and NK cells, which were independent from the type of antiretroviral regimen. Increase in central and effector memory and reduction in terminally-differentiated effector memory CD4+ and CD8+ T cells were accompanied by increases of CD4+ and CD8+ T cell responses against Env and recall antigens. Of note, more immune-compromised individuals experienced greater therapeutic effects. In contrast, these changes were opposite, absent or partial in the OBS population. These findings support the use of Tat immunization to intensify HAART efficacy and to restore immune homeostasis. Trial registration ClinicalTrials.gov NCT00751595

Treatment-related factors and highly active antiretroviral therapy adherence.

Summary: Adherence to highly active antiretroviral therapy (HAART) plays a critical role in the effectiveness of HIV treatment. Nevertheless, the complexity of regimens and frequent side effects make HAART extraordinarily difficult to take, and many HIV‐infected persons fail to adhere. The current study offers an overview of the relationship between adherence and antiretroviral treatment‐related variables. As for other chronic diseases, medication regimen complexity also has an impact on adherence in the management of HIV infection. In particular, the authors discuss the effect of pill burden, dosing frequency, dietary instructions, number and type of different medications prescribed, short‐ and long‐term side effects, convenience, and ability to incorporate the treatment regimen into a daily routine. Medication side effects are common in HAART‐treated persons and are associated with concurrent and future nonadherence. Simplification of regimens, adjustment of the drug schedule to the patients specific lifestyle, and anticipation and self‐management of side effects are treatment‐based strategies to optimize HAART adherence and ensure the most effective, convenient, safe, and well‐tolerated antiretroviral treatment.

A novel methodology for large-scale phylogeny partition

Phylogenetic analysis is used to identify transmission chains, but no software is available for the automated partition of large phylogenies. Prosperiet al. apply a new search algorithm to identify transmission clusters within the phylogeny of HIV-1gene sequences linking molecular and epidemiological data. Supplementary information The online version of this article (doi:10.1038/ncomms1325) contains supplementary material, which is available to authorized users.

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.

Patients presenting with AIDS in the HAART era: a collaborative cohort analysis

Objective:Many patients infected with HIV still present with an AIDS diagnosis. The aim of this study was to evaluate the virological, immunological and clinical outcomes of HAART in these patients. Design:The present study was a multi-cohort study. All patients with an AIDS diagnosis between 30 days before and 14 days after HIV diagnosis, recruited between 1997 and 2004 from eight hospital cohorts, were evaluated. Results:A total of 760 patients were included [268 (35.3%) had pneumocystis and 168 (22.1%) tuberculosis]. Six hundred and twenty-four patients (82.1%) started HAART a median of 31 days after HIV diagnosis. One hundred and fifty-three patients started a nonnucleoside transcriptase inhibitor-based regimen (20.1%), 409 a protease inhibitor-based regimen (53.8%) and 62 other regimens (8.2%). In adjusted analyses, HAART was started sooner in more recent years, in patients with lower CD4 cell count and in those with Kaposis sarcoma, whereas it was started later in those with tuberculosis. Five hundred and five patients (89%) attained a viral load of less than 500 copies/ml. The factors associated with a better virological response were later calendar year, lower initial viral load and cytomegalovirus disease. Virological rebound was more common in those receiving nucleoside reverse transcriptase inhibitor-based regimens, in those with tuberculosis and in earlier calendar years. One hundred and twenty-five (16%) patients died; 61 had received HAART (48.6%). Mortality was more likely in those who were older, those with a higher viral load at diagnosis, those with nonsexual HIV risks and those with lower CD4 cell count and haemoglobin levels over follow-up. Conclusion:Virological suppression was achieved in most AIDS patients, though mortality remains high in these individuals.

Suicide probability and psychological morbidity secondary to HIV infection: a control study of HIV-seropositive, hepatitis C virus (HCV)-seropositive and HIV/HCV-seronegative injecting drug users

BACKGROUND Suicide ideation and psychological morbidity among HIV-positive patients has been the object of intense research. No study has investigated this area among injecting drug users (IDUs) infected with HIV and those infected with the hepatitis C virus (HCV), which has the same patterns of transmission of the HIV and may favour HIV replication and, possibly, HIV disease progression. METHODS In order to examine the prevalence and characteristics of suicide ideation and psychological morbidity associated with HIV and HCV infection in IDUs, a sample of HIV+ (n=81), HIV-/HCV+ (n=62) and HIV-/HCV- (n=152) subjects completed the Suicide Probability Scale (SPS), The Brief Symptom Inventory (BSI) and the Hospital Anxiety and Depression Scale (HADS). RESULTS No difference was found between the groups as far as the mean scores on SPS and the risk of suicide (no-low risk category: 70.7% HIV+, 56.09% HCV+, 65.6% HIV-/HCV-). Estimated psychological morbidity (BSI) (26.9% HIV+, 27.1% HCV+, 25.4% of HIV-/HCV-) and BSI and HADS scores were comparable across the groups. CONCLUSIONS Suicide ideation, psychological morbidity and anxiety and depression symptoms seemed not to be directly influenced by HIV-serostatus. Careful assessment of psychological symptoms and suicide ideas among IDUs, as a vulnerable segment of population at risk of HIV and HCV infections, needs to be routinely carried out in clinical settings.

A randomized, pilot trial to evaluate glomerular filtration rate by creatinine or cystatin C in naive HIV-infected patients after tenofovir/emtricitabine in combination with atazanavir/ritonavir or efavirenz

BackgroundGlomerular filtration rate (GFR) estimated by Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation based on creatinine or cystatine C may be more accurate methods especially in patients without chronic kidney disease. There is lack of data on GFR estimated by these methods in patients on highly active antiretroviral therapy. MethodsAntiretroviral-naive HIV-infected patients were randomized to tenofovir/emtricitabine in association with atazanavir/ritonavir (ATV/r) or efavirenz (EFV) Patients had to have an actual creatinine clearance >50 mL/minute (24-hour urine collection) and were followed for 48 weeks. ResultsNinety-one patients (48 ATV/r, 43 EFV) were recruited. Using the CKD-EPI creatinine formula, there was a significant decrease in GFR up to week 48 in patients receiving ATV/r (4.9 mL/minute/m2, P = 0.02) compared with a not statistically significant increment in patients prescribed EFV. Using the cystatin C–based equation, we found greater decrease in GFR in both arms, although, in the EFV arm, the decrease was not statistically significant (5.8 mL/minute/m2, P = 0.92). At multivariable analysis, ATV/r was a significant predictor of greater decrease in estimated glomerular filtration rate (eGFR) (P = 0.0046) only with CKD-EPI creatinine. ConclusionsATV/r plus tenofovir caused greater GFR decreases compared with EFV. The evaluation of eGFR by cystatin C confirmed this result, but this method seemed to be more stringent, probably precluding the possibility to detect a significant difference in the pattern of eGFR evolution between the two arms over time. More studies are needed to understand the clinical relevance of these alterations and whether cystatin C is a more appropriate method for monitoring GFR in clinical practice.

Emotional Stress, Psychosocial Variables and Coping Associated with Hepatitis C Virus and Human Immunodeficiency Virus Infections in Intravenous Drug Users

Background: The increasing health problem of hepatitis C virus (HCV) infection has only recently attracted the attention of psychosocial research, especially among subjects at higher risk (e.g. intravenous drug users; IDUs). The aim of the present study was to compare emotional stress symptoms, psychosocial variables (i.e. social support, external locus of control and emotional repression) and coping strategies in HCV-seropositive, human immunodeficiency virus (HIV)-seropositive and HCV/HIV-noninfected IDUs. Methods: IDUs followed by the Infectious Diseases Outpatient clinic were enrolled in the study over a period of 1 year. HCV-positive (n = 62) and HIV-positive (n = 76) IDUs and HCV/HIV-seronegative IDUs (n = 152) completed the Brief Symptom Inventory, the Social Provision Scale, the Locus of Control scale and the affective inhibition scale of the Illness Behavior Questionnaire. Coping with illness among HCV-positive and HIV-positive subjects was assessed through a modified version of the Mental Adjustment to Cancer Scale. Results: No significant differences were found between the samples with respect to individual and interpersonal variables. HCV-positive subjects showed higher scores on several psychological stress dimensions (i.e. obsessive-compulsive, phobic anxiety, paranoid ideation, psychoticism) and lower scores on fighting spirit, hopelessness and anxious preoccupation towards illness than HIV-positive patients. HCV-positive and HCV/HIV-seronegative IDUs reported comparable scores on most of the psychological measures. Conclusions: The findings indicate that routine assessment of psychosocial variables and coping mechanisms should be integrated into all HCV and HIV services, especially those dedicated to treatment of patients with substance abuse, as a vulnerable segment of the population at risk for life-threatening physical illness such as HCV and HIV infections.

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

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