Switch to dolutegravir and unboosted atazanavir in HIV-1 infected patients with undetectable viral load and long exposure to antiretroviral therapy.

: We evaluated the efficacy and safety of a two-drug regimen including dolutegravir (DTG) and unboosted atazanavir (uATV) in 151 HIV-1 infected patients with HIV-RNA of more than 50 copies/ml. During a median follow-up of 62 (42-97) weeks, two virological failures (1%) and 13 treatment discontinuations (9%) occurred; the 48-week probability of virological failure was 0.8% (95% confidence interval 0.2-5.6%). Switch to DTG + uATV may represent a boosting and transcriptase reverse inhibitors sparing otion in individuals with long exposure to antiretroviral therapy and risk of cardiovascular disease.

Characterisation of AIDS presenters and their response to antiretroviral therapy at legnano general hospital (Italy) during the period 2000-2008.

The aim of this study was to characterise the AIDS presenters diagnosed between 2000 and 2008 in Legnano (Italy), and describe their initial response to highly active antiretroviral therapy (HAART) and trends over time. Seventy-six (48.7%) of 156 patients diagnosed as having AIDS in the period 2000-2008 were AIDS presenters. The proportion of AIDS presenters increased from 23.8% in 2000 to 70.6% in 2008 (p = 0.009). The major risk factors were heterosexual transmission and a foreign place of birth, and did not significantly change over time. The median CD4+ cell count at diagnosis was 30 cells/microl and the median level of HIV RNA was 5.38 log copies/ml, with no differences between the transmission risk groups. Fifteen AIDS presenters died of AIDS-defining diseases; the others started HAART (72% with 2 NRTIs + boosted PI), and 40% after a drug resistance test. The median duration of the initial HAART was 107 days. After three months, 34% of the patients had undetectable HIV-RNA levels and the median CD4+ cell count was 140 cells/microl; the corresponding figures after 12, 24 and 48 months were respectively 84%, 82.3% and 94.1%, and 310, 370 and 380 cells/microl. In conclusion, the AIDS presenters were mainly heterosexual men and immigrants. Their proportion increased significantly over time, and a substantial proportion maintained an immunovirological response to HAART.

A comparison between abacavir and efavirenz as the third drug used in combination with a background therapy regimen of 2 nucleoside reverse-transcriptase inhibitors in patients with initially suppressed viral loads.

BACKGROUND: Our objective was to compare the rate of viral rebound and therapy failure in patients receiving abacavir or efavirenz as the third drug (in addition to 2 non-abacavir nucleosides) in combination antiretroviral therapy (cART) and to compare the rate of metabolic alteration associated with these regimens. METHODS: We conducted a multicohort prospective observational study of human immunodeficiency virus-infected patients who had attained viral loads < or = 80 copies/mL while receiving cART, without having previously received antiretrovirals. The rates of virological rebound, therapy failure, and lipid-level alteration during follow-up were calculated as the number of events divided by person-years of follow-up (PYFU). A multivariable analysis was performed using a Poisson regression model. RESULTS: We studied a total of 744 patients; the median age was 37 years, 27% of the patients were female, and 41% were heterosexual. There was a total of 854 PYFU spent receiving efavirenz and 285 spent receiving abacavir. The nucleoside reverse-transcriptase inhibitor pairs most frequently used were zidovudine/lamivudine (66% of PYFU), stavudine/lamivudine (17.6%), and stavudine/didanosine (5.4%). The adjusted relative rates of virological failure and therapy failure for abacavir, compared with those for efavirenz, were 2.17 (95% confidence interval [CI], 1.12-4.18; P = .02) and 1.41 (95% CI, 1.01-2.01; P = .05), respectively. CONCLUSIONS: Patients with virological suppression while receiving regimens containing abacavir appear more likely to experience virological and therapy failure than those receiving efavirenz as their third drug. Although this is a selected group of adherent patients, bias cannot be ruled out, because this is a nonrandomized comparison.

Prognostic significance of JC virus DNA levels in cerebrospinal fluid of patients with HIV-associated progressive multifocal leukoencephalopathy.

BACKGROUND: Progressive multifocal leukoencephalopathy (PML) remains a frequent and life-threatening complication of human immunodeficiency virus (HIV) infection in the era of highly active antiretroviral therapy (HAART). Although one-half of patients with this disease will survive, the outcome is unpredictable at diagnosis, and prognostic markers are needed. METHODS: JC virus (JCV) DNA levels were measured in cerebrospinal fluid (CSF) samples obtained from 61 HIV-infected patients with PML, including 38 patients who were treated with HAART and 23 patients who did not receive HAART, with use of real-time polymerase chain reaction. The diagnostic reliability of the assay was evaluated by comparing CSF findings with histopathological findings in patients with PML or other HIV-related diseases of the central nervous system. The prognostic value was assessed by comparing JCV DNA levels with survival and other patient variables. RESULTS: The assay had a diagnostic sensitivity of 76% and specificity of 100%. In the first CSF sample obtained after onset of PML symptoms, JCV DNA values ranged from undetectable to 7.71 log copies/mL (median, 3.64 log copies/mL). JCV DNA levels >3.64 log copies/mL correlated significantly with shorter survival and lower CD4+ cell counts in patients not receiving HAART. However, neither relationship was found in patients who were treated with HAART. The analysis of sequential CSF samples obtained from 24 patients demonstrated a marked decrease in JCV DNA levels over time in HAART-treated patients showing PML stabilization, but not in untreated or HAART-treated patients with progressively fatal disease. CONCLUSIONS: Measurement of JCV DNA levels in CSF samples may be a useful virological marker for management of PML in patients receiving HAART.

Sequence analysis of the JC virus transcriptional control region detected in urine from HIV-positive patients.

OBJECTIVE: To investigate the correlation between transcriptional control region (TCR) types and virus replication and the role of decreased host immunity in inducing TCR changes. STUDY DESIGN: In a previous study, urine specimens from 78 unselected HIV-positive patients were independently evaluated by cytology, immunohistochemistry and nested polymerase chain reaction (n-PCR) to detect the presence of polyomaviruses. The JC virus (JCV) large T region was positive in 44/78 (56%) urine specimens by n-PCR. In the current study, these cases further underwent to n-PCR to detect TCR, and the amplified products were sequenced. The JCV types identified were compared using: (1) morphologic evidence of replication (decoy cells and/or immunohistochemical staining of cells detected using anti-SV 40 antiserum), and (2) patients' immune status (CD4+ cell counts). RESULTS: TCR was successfully amplified in 30/44 cases (68%). TCR sequence analysis disclosed 6/30 archetype (20%) and 24/30 archetypelike sequences, the latter distributed as follows: 4 G2 (4/30, 13%) with G-->A substitutions in the C sequence (nt 9), and 20 CY (20/30, 67%) with A-->G substitutions in the F sequence (nt 19). There were no correlations with morphologic evidence of viral replication or immune status. CONCLUSION: The present study indicated that TCR in urine samples from PML-free HIV-positive subjects are archetypes or archetypelike. Immune suppression does not seem to influence minor changes in the TCR genome, and single by mutations do not change JCV replication activity.

Impact of highly active antiretroviral therapy on the presenting features and outcome of patients with acquired immunodeficiency syndrome-related Kaposi sarcoma.

BACKGROUND: The objective of the current study was to evaluate the impact of highly active antiretroviral therapy (HAART) on clinical characteristics of presentation and the natural history of Kaposi sarcoma (KS) in patients already receiving HAART at the time of KS diagnosis. METHODS: The authors conducted a retrospective cohort study comparing epidemiologic, clinical, and outcome data for 160 patients who were naive to HAART at the time of KS diagnosis (KS-naive) with the corresponding data for 51 patients already receiving HAART at the time of KS diagnosis (KS-HAART). The analysis included all patients with a diagnosis of KS since January 1996 within two Italian cohorts of patients with human immunodeficiency virus. RESULTS: Immunologic and virologic status at the time of KS diagnosis were significantly more favorable in the KS-HAART group than in the KS-naive group. The frequency of cutaneous involvement was similar in both groups, but cutaneous disease was more indolent among KS-HAART patients, with 1 anatomic site of involvement in 9 patients (21%) and less than 10 lesions in 26 patients (60%), compared with 16 patients (12%; P = 0.06) and 47 patients (34%; P = 0.01), respectively, in the KS-naive group. A smaller proportion of KS-HAART patients presented with visceral disease (24% vs. 39%; P = 0.06); in particular, gastrointestinal tract involvement was significantly less frequent among KS-HAART patients (14%) compared with KS-naive patients (28%; P = 0.05). Median survival was not reached in either group, and the 3-year survival rates of KS-HAART patients (64%) and KS-naive patients (78%) were not significantly different. CONCLUSIONS: The data from the current study indicate that KS exhibits a less aggressive presentation in patients already receiving HAART compared with patients who are naive to HAART at KS diagnosis. Natural history and outcome do not appear to be influenced by the initiation of HAART before development of KS.

AIDS-related Kaposi's Sarcoma: evaluation of potential new prognostic factors and assessment of the AIDS Clinical Trial Group Staging System in the Haart Era--the Italian Cooperative Group on AIDS and Tumors and the Italian Cohort of Patients Naive From Antiretrovirals.

PURPOSE: To assess potential new prognostic factors and to validate the AIDS Clinical Trials Group (ACTG) for AIDS-related Kaposi's sarcoma (AIDS-KS) staging system in the highly active antiretroviral therapy (HAART) era. PATIENTS AND METHODS: We collected epidemiologic, clinical, staging, and survival data from 211 patients with AIDS-KS enrolled in two prospective Italian human immunodeficiency virus (HIV) cohort studies. We included in the analysis all patients with the diagnosis of KS made from January 1996, the time at which HAART became available in Italy. RESULTS: In the univariate analysis, survival was not influenced by sex, age, level of HIV viremia at KS diagnosis, HAART at KS diagnosis (HAART-naïve v HAART-experienced), or type of HAART combination. Regarding ACTG classification, the 3-year survival rate was 85% for T0 patients and 69% for T1 patients (P =.007), 83% for S0 patients and 63% for S1 patients (P =.003), and 83% for I0 patients and 71% for I1 patients (P =.06). In the multivariate analysis, only the combination of poor tumor stage (T1) and poor systemic disease (S1) risk identified patients with unfavorable prognosis. The 3-year survival rate of patients with T1S1 was 53%, which was significantly lower compared with the 3-year survival rates of patients with T0S0, T1S0, and T0S1, which were 88%, 80%, and 81%, respectively (P =.0001). CONCLUSION: In the era of HAART, a refinement of the original ACTG staging system is needed. CD4 level does not seem to provide prognostic information. Two different risk categories are identified: a good risk (T0S0, T1S0, T0S1) and a poor risk (T1S1).

Clinical epidemiology and survival of progressive multifocal leukoencephalopathy in the era of highly active antiretroviral therapy: data from the Italian Registry Investigative Neuro AIDS (IRINA).

Human immunodeficiency virus (HIV)-associated progressive multifocal leukoencephalopathy (PML) remains a relevant clinical problem even in the era of highly active antiretroviral therapy (HAART). Aims of the study were to analyze clinical and treatment-related features and the survival probability of PML patients observed within the Italian Registry Investigative Neuro AIDS (IRINA) during a 29-month period of HAART. Intravenous drug use, the presence of focal signs, and the involvement of white matter at neuroradiology increased the risk of having PML. A reduced probability of PML was observed when meningeal signs were reported. Patients starting HAART at PML diagnosis and previously naïve for antiretrovirals showed significantly higher 1-year probability of survival (.58), compared to those continuing HAART (.24), or never receiving HAART (.00). Higher CD4 cell count were associated with a higher survival probability (.45). At multivariate analysis, a younger age, higher CD4, starting HAART at PML diagnosis, the absence of previous acquired immunodeficiency syndrome (AIDS)-defining events, and the absence of a severe neurologic impairment were all associated with a reduced hazard of death. The use of cidofovir showed a trend towards a reduced risk of death.

The effect of highly active antiretroviral therapy-induced immune reconstitution on development and outcome of progressive multifocal leukoencephalopathy: study of 43 cases with review of the literature.

The authors investigated the effect of highly active antiretroviral therapy (HAART) on the onset and outcome of progressive multifocal leukoencephalopathy (PML) in a group of 43 patients with histological or clinicovirological diagnosis of PML. In eight of these cases (19%), PML symptoms presented 21 to 55 days after the start of HAART, concomitantly with a CD4 cell-count increase and plasma human immunodeficiency virus type 1 (HIV-1) RNA load (VL) decrease. Four of these patients died of PML. Apart from baseline VL, we did not identify any other variable that could distinguish these forms of immune reconstitution PML from those occurring in patients either untreated or failing to respond to therapy. To compare the viroimmunological response to HAART with PML outcome, we evaluated a subgroup of 23 patients untreated at the time of PML onset. No different pattern of response to HAART was observed between patients who died or survived to PML. However, start of HAART was delayed of > or =3 months after onset of PML in half of the latter patients. In conclusion, HAART-associated immune reconstitution seems to play a role on development of a substantial number of PML cases. Although the authors could not demonstrate a directly deleterious effect of HAART on PML progression, prompt initiation of HAART after diagnosis of PML and subsequent successful response were often associated with bad PML outcome.

Stanford V regimen and concomitant HAART in 59 patients with Hodgkin disease and HIV infection.

A phase 2 prospective study was performed to evaluate the feasibility and activity of a short, dose-intensive chemotherapy regimen and radiotherapy (the Stanford V regimen) plus highly active antiretroviral therapy (HAART) and granulocyte colony-stimulating factor (G-CSF) support in patients with Hodgkin disease and HIV infection. Fifty-nine patients were enrolled. Stanford V was well tolerated and 69% of the patients completed treatment with no dose reduction or delayed chemotherapy administration. The most important dose-limiting side effects were bone marrow toxicity and neurotoxicity. Complete remission was achieved by 81% of the patients, and after a median follow-up of 17 months 33 patients (56%) were alive and disease-free. The estimated 3-year overall survival (OS), disease-free survival (DFS), and freedom from progression (FFP) were 51%, 68%, and 60%, respectively. Probability of FFP was significantly (P =.02) higher among patients with an International Prognostic Score (IPS) of 2 or lower than in those with an IPS higher than 2, and the percentages of FFP at 2 years in these groups were 83% and 41%, respectively. Similarly, the probability of OS was significantly (P =.0004) different in the 2 groups, and the percentages of OS at 3 years were 76% and 33%, respectively. Our data confirm that the Stanford V regimen with concomitant HAART is feasible and active in an HIV setting. However, a more intensive approach should be considered in patients with high IPSs.