Phase II controlled trial of post-exposure immunization with recombinant gp160 versus antiretroviral therapy in asymptomatic HIV-1-infected adults. VaxSyn Protocol Team.

OBJECTIVE: To alter the natural course of HIV-1 infection by inducing or potentiating immune responses to HIV-1 envelope glycoprotein. DESIGN: Multicentre, double-blind, three-arm, placebo-controlled study. SETTING: Outpatients attending clinics in two University Hospitals. PATIENTS: Ninety-nine asymptomatic HIV-1-infected adults with CD4+ T-cell counts > 400 and < 600 x 10(6)/l and no previous antiretroviral therapy were included. INTERVENTIONS: Patients were randomly assigned to three groups treated with: (i) gp160 in alum over a 2-year period in combination with placebo for the full study duration (n = 32); (ii) gp160 in alum over a 2-year period in combination with zidovudine for the full study duration (n = 34); and (iii) alum over a 2-year period in combination with zidovudine for the full study duration (n = 33). RESULTS: Immunotherapy was well tolerated and no significant differences in disease progression were seen in the treatment groups. The majority of patients (85%) receiving gp160 showed persistent lymphoproliferative responses to the immunogen and to a different Env antigen preparation. CD4+ cell count changes in patients receiving zidovudine alone were significantly higher than those seen in patients receiving immunotherapy alone after 1 year of treatment. Zidovudine administration was associated with initial transient reduction of plasma viraemia. CONCLUSIONS: Prolonged immunization with a soluble HIV-1 subunit provided no benefit to asymptomatic HIV-1-infected patients and was inferior to zidovudine monotherapy. Furthermore, immunization with gp160 shortened the duration of the transient viral load reduction induced by zidovudine.

A randomized trial comparing the introduction of ritonavir or indinavir in 1251 nucleoside-experienced patients with advanced HIV infection.

ISS-IP1, a multicenter, randomized, 48-week open trial, was designed to compare the introduction of ritonavir or indinavir in patients with previous nucleoside experience and CD4+ cell counts below 50/mm3. Concomitant antiretroviral treatment with nucleoside analogs was allowed. Primary efficacy measures were survival and time to a new AIDS-defining event or death, analyzed through the whole period of observation by the intention-to-treat approach. Primary toxicity measures were time to treatment discontinuation and adverse events, grade at least 3/serious, analyzed by an on-treatment approach. Evaluation-of efficacy also included CD4+ cell and RNA response. The trial enrolled 1251 patients in 5 months. At baseline, mean CD4+ cell count was about 20 cells/mm3 and mean HIV RNA copy number was 4.9 log10/ml in both groups. Overall, 402 patients in the ritonavir group and 250 patients in the indinavir group permanently discontinued the assigned treatment (relative risk, 1.96; 95% CI, 1.68-2.30; p = 0.0001), with most of this difference dependent on a higher number of discontinuation for adverse events in the ritonavir group. After a mean follow-up of 307 days (ritonavir, 304; indinavir, 309), 124 deaths (ritonavir, 61; indinavir, 63; relative risk, 0.96; 95% CI, 0.67-1.36; p = 0.80) and 330 new AIDS-defining events (ritonavir, 170; indinavir, 160; relative risk, 1.05; 95% CI, 0.85-1.31; p = 0.60) were observed. CD4+ cell counts increased in both groups in patients still receiving treatment, with about 100 cells gained by week 24 and 150 cells gained by week 48. Body weight also increased over time in both groups. Analysis of RNA response showed a decrease of 1.5 log10 or higher in both treatment groups. Overall, 400 patients in the ritonavir group and 338 patients in the indinavir group developed at least one grade 3/serious new adverse event during follow-up (relative risk, 1.48; 95% CI, 1.28-1.72; p = 0.0001). Favorable CD4+ cell and RNA responses at 24 and 48 weeks were observed in both groups of patients remaining on treatment. Indinavir showed slightly better effects in sustaining RNA, CD4+ cell, and body weight responses. Ritonavir and indinavir results were comparable in terms of clinical outcome (survival and AIDS-defining events).

Alpha1 antichymotrypsin signal peptide polymorphism in sporadic Creutzfeldt-Jakob disease.

In Creutzfeldt-Jakob disease (CJD), a transmissible spongiform encephalopathy, the deposition of the pathological prion protein (PrP-res) in the brain of affected individuals is the key event that triggers the appearance of the disease. Since a polymorphism in the signal peptide of the serine-protease inhibitor alpha1 antichymotrypsin (ACT) is one of the factors that may enhance amyloid formation, we studied this polymorphism in 63 CJD patients and 103 control subjects. No difference in allele frequencies and genotype distribution was found between CJD cases and controls, nor any difference was found between the ACT genotype and the age at onset and disease duration. Interestingly, there was a significantly different (P = 0.04) ACT distribution between CJD patients and controls in apolipoprotein E (ApoE) E4, and the interaction between ACT and ApoE was almost significant (P = 0.053). Further studies on a larger number of patients will clarify whether this association can identify a possible risk factor for CJD.

Apolipoprotein E in sporadic and familial Creutzfeldt-Jakob disease.

We assessed the apolipoprotein E (ApoE) genotype in 49 sporadic and ten familial Creutzfeldt-Jakob disease (CJD) patients, in seven healthy siblings with a PRNP mutation and in 84 controls. In sporadic CJD, ApoE genotypes and allelic frequencies do not significantly differ from that of controls. No influence of ApoE genotypes on age at onset was found. In familial cases, the disease appeared in mutated subjects showing the same ApoE genotype as members who have not yet developed CJD. Our results provide further evidence that ApoE is not a risk factor for CJD.

AIDS dementia complex in the Italian National AIDS Registry: temporal trends (1987-93) and differential incidence according to mode of transmission of HIV-1 infection.

OBJECTIVES: To investigate the occurrence of AIDS dementia complex (ADC) in Italy and its incidence over time, examining possible correlations between this condition and some demographic and immunological variables. DESIGN: Inception cohort. Data collected from the case notification forms of the Italian National AIDS Registry. SUBJECTS: 16813 consecutive AIDS cases reported to the National AIDS Registry from August 1, 1987 through October 31, 1993 were included. STATISTICAL METHODS: All data refer to the time of AIDS diagnosis as reported on the case notification forms. Main analyses of the monthly proportion of ADC cases were by multiple logistic regression. RESULTS: 1364 subjects (8.1%) were reported with a diagnosis of ADC as the first AIDS defining disease, either as the only manifestation or associated with other AIDS defining conditions. At the time of AIDS diagnosis, the observed ADC/AIDS proportion was significantly higher among intravenous drug users (IVDU), 9.1%, compared to heterosexuals, 6.3%, and homo-bisexual men, 5.2%. Simple logistic regression analysis showed a significant (p < 0.0001) quadratic trend in the monthly ADC/AIDS proportion, peaking in March 1990 and decreasing thereafter. Multiple logistic regression, adjusting for month of diagnosis, showed that IVDUs have consistently the highest risk and homo-bisexual men the lowest, although differences tended to decrease with increasing age. Older age, in fact, was highly associated with an increased risk, especially within the homo-bisexual and heterosexual transmission categories. CD4 + cells counts proved to have no significant effect on the risk of progressing to AIDS with ADC rather than with any other AIDS indicative disease. CONCLUSIONS: ADC is a relatively frequent manifestation at diagnosis of AIDS among Italian patients, and particularly in IVDUs. Differences in its occurrence were found according to time of diagnosis, transmission category and age.

A randomized trial (ISS 902) of didanosine versus zidovudine in previously untreated patients with mildly symptomatic human immunodeficiency virus infection.

In this multicenter study (ISS 902), 554 previously untreated patients with <500 CD4 cells/mm3 and mildly symptomatic human immunodeficiency virus disease were randomized to receive zidovudine or didanosine (ddI). After a mean follow-up of 20 months, 80 patients (40 zidovudine, 40 ddI) had died and 146 had at least one AIDS-defining event (73 zidovudine, 73 ddI). Overall, no difference was found between treatments with respect to progression to AIDS or death. The analysis of relative risk (RR) of progression over time, however, showed an initially minor risk for zidovudine patients and an inversion in the zidovudine-ddI RR in the second and third years of follow-up. Didanosine showed a greater effect on CD4 cell count response. The two drugs confirmed the toxicity patterns already reported in other trials, with a low occurrence of pancreatitis (ddI 1.3%, zidovudine 0.4%). The overall results suggest that, in this population, zidovudine and ddI monotherapies have comparable long-term clinical efficacy and that more powerful regimens should be preferred.