Alessandro Cozzi Lepri

Insights into the reasons for discontinuation of the first highly active antiretroviral therapy (HAART) regimen in a cohort of antiretroviral naive 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, naïve 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 initiated 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 (CI), 21.9–28.9] due to toxicity and 7.6% (95% CI, 4.9–10.3) due to failure. Independent factors associated with discontinuation for toxicity were: gender [relative hazard (RH) = 0.51; 95% CI, 0.32–0.80 for men versus women], type of treatment (indinavir-containing regimens, RH = 1.94; 95% CI, 1.10–3.41 and ritonavir-containing regimens, RH = 3.83; 95% CI, 2.09–7.03 versus hard-gell saquinavir) and time spent on treatment (RH = 0.89; 95% CI, 0.80–0.98 for each additional month). Discontinuation due to failure was independently associated with the most recent HIV-RNA (RH = 3.20; 95% CI, 1.74–5.88 for log10 copies/ml higher), and with type of treatment (indinavir-containing regimens, RH = 0.21; 95% CI, 0.06–0.78 and ritonavir-containing regimens, RH = 0.23; 95% CI, 0.04–1.26 versus hard-gell saquinavir). Conclusions:If the current HAART regimen caused no toxicity, less than 10% of naïve patients discontinue their first HAART regimen because of failure after 1 year from starting therapy.

Reasons for modification and discontinuation of antiretrovirals: results from a single treatment centre.

ObjectiveTo describe the reasons for, and factors associated with, modification and discontinuation of highly active antiretroviral therapy (HAART) regimens at a single clinic. SubjectsA total of 556 patients who started HAART at the Royal Free Hospital were included in analyses. Modification was defined as stopping or switching any antiretrovirals in the regimen, whereas discontinuation was defined as the simultaneous stopping of all antiretrovirals included in the initial regimen. Reasons were classified as immunological/virological failure (IVF) and toxicities and patient choice/poor compliance (TPC). ResultsThe median CD4 count at starting HAART was 171 × 106 cells/l and viral load 5.07 log copies/ml. During a median follow-up of 14.2 months, 247 patients (44.4%) modified their HAART regimen, 72 due to IVF (29.1%) and 159 due to TPC (64.4%) and a total of 148 patients (26.6%) discontinued HAART. Older patients were less likely to modify HAART [relative hazard (RH), 0.73 per 10 years;P = 0.0008], as were previously treatment-naive patients (RH, 0.65;P = 0.0050), those in a clinical trial (RH, 0.64;P = 0.027) and those who started nelfinavir (RH, 0.57;P = 0.035). Patients who started with four or more drugs (RH, 2.21, P < 0.0001), who included ritonavir in the initial regimen (RH, 1.41;P = 0.035) or who had higher viral loads during follow-up (RH per log increase, 1.51;P < 0.0001) were more likely to modify HAART. ConclusionsThere was a high rate of modification and discontinuation of HAART regimens in the first 12 months, particularly due to toxicities, patient choice or poor compliance.

RISK FACTORS FOR CENTRAL VENOUS CATHETER-RELATED INFECTIONS IN SURGICAL AND INTENSIVE CARE UNITS

OBJECTIVE To identify avoidable risk factors for central venous catheter (CVC) infections in patients undergoing short-term catheterization. DESIGN Prospective multicenter cohort study. SETTING Two university teaching hospitals and five large nonteaching hospitals. PATIENTS Patients admitted to intensive care units or surgical units and exposed to short-term CVCs. RESULTS Of 623 catheterization episodes, 9.3% were associated with catheter-related infections (CRI). The skin at the catheter site was frequently colonized (16.2%) and was the potential source of infection in 56.1% of the cases, mostly local infections. The hub was colonized less frequently (3.5%) but was responsible for systemic infections more frequently. The following variables were independently associated with CRI: duration of catheterization (for 7 to 14 days, odds ratio [OR], 3.9; 95% confidence interval [CI]95, 1.4 to 10.7; and for > 14 days, OR, 5.1; CI95, 1.7 to 15.4), coronary care unit service (OR, 6.7; CI95, 1.1 to 42.9) or surgery service (OR, 4.4; CI95, 1.03 to 18.5), second episode of catheterization (OR, 7.6; CI95, 1.8 to 32.3), skin colonization at the insertion site (OR, 56.5; CI95, 10.8 to 296), and hub colonization (OR, 17.9; CI95, 2.4 to 132). The risk associated with skin colonization varied with use of jugular access or simultaneous colonization of the hub. When only symptomatic CRI was considered, the risk associated with hub colonization was consistently higher (OR, 36.6; CI95, 7 to 190) than that associated with skin colonization (OR, 3.2; CI95, 0.7 to 14). Age, transparent dressing, jugular insertion, male gender, duration of catheterization, and hub colonization were independent risk factors for skin colonization. The effect of age varied by type of dressing and vice versa; the effect of jugular access varied by sex; and the effect of transparent dressing varied by length of catheterization and vice versa. Total parenteral nutrition and skin colonization were independently associated with an increased risk of hub colonization. CONCLUSIONS Skin and hub colonization are the two major determinants for endemic CRIs; colonization of the hub, however, is more frequently associated with more severe infections. In order to reduce CRIs, more efforts should be focused on understanding which factors increase the risk of colonization both of the skin and of the hub.

Production of β-Chemokines in Human Immunodeficiency Virus (HIV) Infection: Evidence that High Levels of Macrophage Inflammatory Protein-1β Are Associated with a Decreased Risk of HIV Disease Progression

Macrophage inflammatory protein (MIP)-1alpha, MIP-1beta, and RANTES production were measured by ELISA in whole blood that had been stimulated for 4.5 h with phytohemagglutinin. The blood was from 90 healthy human immunodeficiency virus (HIV)-negative controls and from 245 HIV-infected subjects who were followed for < or = 4.5 years. HIV-infected persons without AIDS had increased levels of MIP-1alpha, MIP-1beta, and RANTES (P < .01) compared with levels in controls. Subjects with AIDS, compared with controls, had decreased production levels of MIP-1beta (P < .0001) and similar levels of MIP-1alpha and RANTES. A high level of MIP-1beta production was associated with a decreased risk of progressing to AIDS or death, as determined by univariate analysis (P < .01) and adjusted for CD4 cell count and age (P = .07, P = .06, respectively). The findings suggest that the production level of beta-chemokine changes during HIV infection and that a high level of beta-chemokine production in peripheral blood lymphocytes may be associated with less rapid disease progression in HIV infection.

When to start highly active antiretroviral therapy in chronically HIV-infected patients: evidence from the ICONA study.

ObjectivesTo compare the response to highly active antiretroviral therapy (HAART) in individuals starting HAART at different CD4 cell counts. DesignThe 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. ResultsAfter 96 weeks of therapy, the mean rise in CD4 cell count was 280, 281 and 186 × 106 cells/l in patients starting HAART with a CD4 cell count < 200, 201–350 and > 350 × 106 cells/l, respectively. Patients starting HAART with a CD4 cell count < 200 × 106 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 with > 350 × 106 cells/l. There was no difference in risk between the 201–350 and the > 350 × 106 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 count < 50 was 0.03/person-year (95% CI, 0.10–0.33) during the time in which the patients CD4 cell count had been raised to > 200 × 106 cells/l. ConclusionsThere was no clear immunological or virological advantage in starting HAART at a CD4 cell count > 350 rather than at 200–350 × 106 cells/l. The increase in CD4 cells restored by HAART is meaningful in that they are associated with reduced risk of disease/death.

Category of exposure to HIV and age in the progression to AIDS: Longitudinal study of 1199 people with known dates of seroconversion

Abstract Objectives: To determine whether rate of development of AIDS is affected by category of exposure to HIV and whether the more rapid development found in older subjects persists for each exposure category. Design: Longitudinal study of people with known date of seroconversion to HIV. Setting: 16 HIV treatment centres throughout Italy. Subjects: 1199 people infected with HIV through use of injected drugs, homosexual sex, or heterosexual sex. Main outcome measures: AIDS as defined by 1987 definition of Centers for Disease Control (including and excluding neoplasms) and by 1993 European definition. Results: 225 subjects (18.8%) progressed to AIDS (Centers for Disease Control 1987 definition) during median follow up of 5.8 years. Univariate analyses showed more rapid progression to AIDS for older subjects compared with younger subjects and for homosexual men compared with other exposure categories. The age effect was of similar size in each exposure category and in men and women. In a bivariate model with age and exposure categories simultaneously included as covariates, differences by exposure category disappeared for use of injected drugs and heterosexual sex compared with homosexual sex (relative hazards 1.02 (95% confidence interval 0.71 to 1.45) and 1.07 (0.70 to 1.64) respectively), while the age effect remained (relative hazard 1.55 (1.32 to 1.83) for 10 year increase in age). Analyses using the other definitions for AIDS did not appreciably change these results. Conclusions: There was no evidence of differences in rate of development of AIDS by exposure category, while there was a strong tendency for more rapid development in older subjects for all three groups. This supports the view that external cofactors do not play major role in AIDS pathogenesis but that age is of fundamental importance. Key messages Many studies have found an age effect on progression to AIDS, but it is not clear if this is due to specific AIDS defining diseases such as neoplasms and if it differs by exposure groups or by sex Our study of 1199 subjects with known date of seroconversion to HIV showed that older subjects progressed to AIDS more rapidly in all exposure groups considered, for both men and women, and for different definitions of AIDS After adjustment for age at seroconversion, there was no evidence of different rates of progression among subjects belonging to different exposure categories Behavioural cofactors do not seem to play a major role in AIDS pathogenesis but age is of fundamental importance in disease progression

The relative prognostic value of plasma HIV RNA levels and CD4 lymphocyte counts in advanced HIV infection

Objective:It has been suggested that the plasma HIV RNA level is a better predictor of AIDS and death than the CD4 lymphocyte count. We assessed whether the prognostic value of plasma virus levels was different according to the CD4 count. Design:Prospective cohort study of HIV-infected patients followed for a median of 2.91 years (range, 0.02–4.54). Setting:Department of Infectious Diseases at Rigshospitalet, Copenhagen, Denmark. Participants:A group of 255 HIV-infected individuals with an initial measurement of CD4 lymphocyte count and plasma HIV RNA. Main outcome measure:Survival time. Results:The plasma HIV RNA (median 101 410 copies/ml; range (range 200–7 200 000) and the CD4 lymphocyte count (median 250 cells × 106/l; range 1–1247) were negatively correlated (Pearson r = −0.53; P < 0.00001). Of the 255 patients, 110 died during follow-up. Overall, a higher HIV RNA level was associated with increased risk of death, but the association was smaller in patients with lower CD4 lymphocyte counts (test for interaction P < 0.0001). In patients with CD4 count below 50 cells × 106/l the association between HIV RNA and risk of death was not statistically significant (relative hazard per 10-fold higher HIV RNA level was 1.53; P = 0.11; adjusted for age and CD4 count) while that between the CD4 count and risk of death was highly significant (relative hazard per 50% lower CD4 count 1.38; P = 0.005; adjusted for age and HIV RNA level). Conclusions:Patients were relatively lightly treated with antiretroviral drugs both before and during this study. In this situation, it appears that the HIV RNA level has a relatively weak association with risk of death in patients with advanced HIV infection and that the CD4 lymphocyte count is probably more useful in assessing prognosis.

Durability of HIV-1 viral suppression over 3.3 years with multi-drug antiretroviral therapy in previously drug-naive individuals

BackgroundRelatively little is known about the long-term durability of viral suppression in individuals initially achieving a viral load of less than 50 copies/ml within 24 weeks of starting antiretroviral therapy, nor the extent to which therapy interruption accounts for the loss of suppression. MethodsWe intensely followed all 336 antiretroviral-naive patients attending the Goethe Universitat Clinic who began multi-drug combination regimens and in whom a viral load of less than 50 copies/ml was achieved within 24 weeks, in order to assess the risk of viral load rebound. Inspection of case notes allowed the distinction of viral rebound according to whether there was an associated complete interruption of therapy. ResultsA total of 61 patients experienced viral rebound during 543.1 person-years of follow-up, giving a 25.3% risk of rebound by 3.3 years from first achieving viral suppression. However, for 47 of the patients with viral rebound there was an associated documented complete interruption of antiretroviral therapy, mostly as a result of co-morbidities, leaving 14 who appear to represent a failure of the virological efficacy of therapy (viral breakthrough; 5.2% risk by 3.3 years). The risk of viral breakthrough declined with the increased duration of suppression (P = 0.01). ConclusionThe intrinsic virological effectiveness of multi-drug antiretroviral therapy in previously drug-naive individuals appears to be such that viral suppression, once achieved, can be maintained for several years in patients not interrupting therapy. The major challenge is to develop regimens that can be taken consistently and safely for such long periods of time.

The virological response to highly active antiretroviral therapy over the first 24 weeks of therapy according to the pre-therapy viral load and the weeks 4-8 viral load

ObjectivesTo describe the viral response to HAART by weeks 4 and 8 in previously antiretroviral-naive patients. To assess whether the weeks 4 or 8 viral loads are useful predictors of viral suppression by week 24. DesignA large clinical database including 453 antiretroviral-naive patients whose plasma viral load was monitored every 4 weeks. MethodsObserved probabilities of achieving a viral load ⩽ 500 copies/ml by week 24 (days 84–168) from starting highly active antiretroviral therapy (HAART) were calculated according to viral loads at weeks 4 and 8. ResultsA total of 42.4% of patients (153/361) reached ⩽ 500 copies/ml viral load by week 4 and 70.4% (245/348) by week 8. Viral suppression below 500 copies/ml by 4–8 weeks was similar irrespective of the pre-HAART viral load. In patients with viral loads above 10 000 copies/ml at week 4, 60.6% (20/33) achieved ⩽ 500 copies/ml by week 24. In patients with viral loads still above 10 000 copies/ml at week 8, only 42.3% (11/26) achieved ⩽ 500 copies/ml by week 24, and only 33.3% (3/9) maintained viral suppression below 500 copies/ml to week 48. ConclusionViral loads at weeks 4 and 8 should be monitored to detect early signs of low subsequent viral suppression. For previously antiretroviral-naive patients whose viral loads after 8 weeks of HAART are still above 10 000, there is an urgent need to assess adherence to therapy, drug levels and resistance, so management can be modified accordingly to reduce the rate of week 24 virological failure.

Increased losses of CD4+CD45RA+ cells in late stages of HIV infection is related to increased risk of death : evidence from a cohort of 347 HIV-infected individuals

Objective:To examine changes in the distribution of CD4+CD45RA+ (naive) and CD4+CD45RO+ (memory) lymphocytes in various stages of HIV infection and the effect of these changes on disease progression. Design and methods:Expression of CD45RA+ and CD45RO+ on CD4+ lymphocytes was analysed by flow cytometry in a prospectively followed cohort of 300 HIV-infected individuals (median follow-up time, 2.90 years; range, 0.02–4.54 years) and in a group of 102 age- and sex-matched uninfected controls. Survival analysis was performed considering AIDS development and death as endpoints. Results:The median CD4+ CD45RA+/CD45RO+ ratio was 1.3 (25–75% quartiles, 0.9–2.4) in controls; it was increased to 1.8 (1.1–2.5) in 40 HIV-infected individuals with CD4+ cell counts > 500 × 106/l (P < 0.05); it was similar at 1.4 (0.8–2.0) in 106 HIV-infected individuals with CD4+ cell counts of 200–500 × 106/l; and it was decreased to 0.9 (0.5–1.4) in 154 HIV-infected individuals with CD4+ cell counts < 200 × 106/l (P<10−6). When fitted in a Cox model adjusting for the total number of CD4+ cells and age a lower concentration of CD4+CD45RA+ cells was associated with an increased risk of dying. The concentration of CD4+CD45RO+ cells was not significantly associated with AIDS or death in age- and CD4+ cell count-adjusted Cox models. Conclusions:This study confirms a selective loss of memory CD4+ cells early in HIV infection followed by increased loss of naive CD4+ cells in later stages of the infection. The loss of naive CD4+ cells seems to be important in the pathogenesis of terminal HIV infection.