Pre-treatment and post-treatment assessment of the C(6) test in patients with persistent symptoms and a history of Lyme borreliosis.

It was recently reported that antibody to C(6), a peptide that reproduces an invariable region of the VlsE lipoprotein of Borrelia burgdorferi, declined in titer by a factor of four or more in a significant proportion of patients after successful antibiotic treatment of acute localized or disseminated Lyme borreliosis. The present study evaluated the C(6) test as a predictor of therapy outcome in a population of patients with post-treatment Lyme disease syndrome. The serum specimens tested were from patients with well-documented, previously treated Lyme borreliosis who had persistent musculoskeletal or neurocognitive symptoms. All of the patients had participated in a recent double-blind, placebo-controlled antibiotic trial in which serum samples were collected at baseline and 6 months thereafter, i.show $132#e. 3 months following treatment termination. In this patient population no correlation was found between a decline of C(6) antibody titer of any magnitude and treatment or clinical outcome. Antibodies to C(6) persisted in these patients with post-treatment Lyme disease syndrome following treatment, albeit at a markedly lower prevalence and titer than in untreated patients with acute disseminated Lyme disease. The results indicate that C(6) antibody cannot be used to assess treatment outcome or the presence of active infection in this population.

The Advanced Glaucoma Intervention Study (AGIS): 10. Variability among academic glaucoma subspecialists in assessing optic disc notching.

PURPOSE: An analysis of data from the Advanced Glaucoma Intervention Study (AGIS) has found eyes reported to have partial optic disc rim notching (not to the edge) at baseline to have less risk of subsequent visual field loss than eyes with no notching. Because this is counterintuitive and because classification of notching had not been defined in the AGIS protocol, we have assessed AGIS ophthalmologists interobserver and intraobserver agreement on notching. METHODS: Fourteen glaucoma subspecialists classified notching in 26 pairs of stereoscopic disc photographs of eyes with mild to severe glaucomatous optic neuropathy. They classified images as showing either no notching, notching not to the edge, or notching to the edge. Several hours later, 10 of them classified the same images a second time. RESULTS: In an analysis of interobserver agreement, of 26 stereoscopic images, a plurality of ophthalmologists classified notching as absent in 9 (35%), as present but not to the edge in 7 (27%), and as present and not to the edge in 10 (38%). All 14 ophthalmologists (100%) agreed on the classification of 7 (27%) of the images, and 13 of the 14 ophthalmologists (93%) agreed on the classification of 4 additional images (15%). Of these 11 images with at least 93% agreement, notching was reported as absent in 3 (27%) and to the edge in 8 (73%). In the remaining 15 images, there was substantial disagreement about whether notching was present and, if so, whether it was to the edge. In an analysis of intraobserver agreement, none of the 10 ophthalmologists who completed the viewing a second time classified all eyes exactly the same as the first time, though 5 ophthalmologists made 4 or fewer reclassifications. Overall, 80% of the original classifications were reproduced on second reading. Of the initial classifications that were not reproduced, slightly more than half were first classified as having notching not to the edge. CONCLUSION: Without definitions or examples of optic disc rim notching, the glaucoma subspecialists had relatively high intraobserver agreement but were likely to disagree with each other in characterizing the degree of disc rim notching. We recommend development of a standard photographic classification of disc rim notching. The classification should be tested for inter- and intra-observer agreement.

Early immune reconstitution after potent antiretroviral therapy in HIV-infected children correlates with the increase in thymus volume.

DESIGN: Despite significant rises in total CD4 T cells, the process of immune reconstitution in adults with HIV infection treated with potent antiretroviral treatment results in a rather slow increase in phenotypically naive lymphocytes. In children more than in adults, thymic function may be at least partly restored when disease-induced immunosuppression is attenuated by pharmacological means. METHODS: Twenty-five vertically infected and antiretroviral-experienced [zidovudine (ZDV)/ZDV plus didanosine (ddl)] children were prospectively followed during 12 months of treatment with lamivudine (3TC), stavudine (d4T) and indinavir (IDV). The plasma HIV viral load and phenotypic and functional cellular immunity-defining parameters were examined. The relationship between the degree of immune reconstitution and thymus volume assessed by nuclear magnetic resonance was also examined. RESULTS: An early and steep increase in CD45RA+62L+ T cells was observed in parallel with a sustained decrease in plasma HIV RNA levels and a significant rise in total CD4 T cells. This increase was significantly greater than that observed in CD4+CD45RO+ T cells. Analysis of the CD4 T cell receptor (TCR) beta repertoire and T helper function showed the ability to reconstitute families almost completely absent at baseline, and a substantial improvement of antigen-specific responses by peripheral blood lymphocytes. The rise in CD4 cells and in CD4+CD45RA+62L+ T cells was statistically associated with changes in thymus size observed over time. CONCLUSION: These data suggest a relevant contribution of the thymus to reconstitution of the peripheral pool of T cells in vertically HIV-infected children treated with potent antiretroviral regimens.

Regional survival differences across Europe in HIV-positive people: the EuroSIDA study.

OBJECTIVES: To analyse the survival differences between macro-regions of Europe (northern, central and southern Europe) between 1994 and early 1999, and their possible association with antiretroviral treatment differences. DESIGN: From September 1994 the EuroSIDA study has prospectively followed non-selected HIV-infected people from 50 clinical sites in 18 European countries (n = 7331). METHODS: Cox proportional hazards models were used to compare death rates between regions and to investigate the relationship between treatment usage and regional mortality rates. Kaplan-Meier curves were used to compare survival from the first CD4 lymphocyte count of < 200 x 10(6)/l or < 50 x 10(6)/l. RESULTS: At the time of analysis, the median follow-up was 21 months and there was a total of 1544 deaths. In people with a CD4+ cell count that fell below 200 or 50 x 10(6)/l those from central Europe had a better prognosis compared with those from the two other regions (P < 0.05). Patients from central Europe were more frequently exposed to reverse transcriptase inhibitors and protease inhibitors compared with patients from other regions (P < 0.001). There was a significant difference in risk of death between regions after adjustment for baseline differences in demography, presence of AIDS and level of immunodeficiency (risk of death in central Europe was 37% lower than that in southern Europe (P < 0.0001) and 33% lower than in northern Europe (P < 0.0001)). After adjustment for use of individual antiretroviral agents, intensity of treatment regimen, CD4 lymphocyte count, weight, haemoglobin and development of AIDS as time-dependent covariates, the differences became much smaller (risk in central Europe 13% lower than that in southern Europe (P = 0.071) and 15% lower than in northern Europe (P = 0.054). CONCLUSION: Antiretroviral therapy has been used more aggressively in Europe in recent years, resulting in improved prognosis. In this study we observed that the HIV mortality rate in central Europe was significantly lower than those in northern and southern Europe in the period 1994 to early 1999. This finding appears to be due to the effect on survival of different treatment policies and drug availability in the three regions of Europe during this time period, with central European countries, on average, having introduced more aggressive treatment strategies earlier.

Cancer prevalence in Italian regions with local cancer registries.

OBJECTIVE: To provide estimates and projections of cancer incidence and prevalence for those Italian regions whose population is partially covered by a cancer registry (CR) and to determine to what extent local CRs can be considered representative of the region, thus improving the potential of the information provided by CRs. METHODS: A statistical method, MIAMOD (mortality-incidence analysis model), was used to estimate regional cancer incidence and prevalence from regional cancer mortality data and patient survival data recorded by the cancer registries. Estimates of the cancer incidence and prevalence in the various regions have thus been obtained for a number of major cancer sitas. A first and important step in validating the regional estimates has been the comparison of the MIAMOD estimates in the areas covered by the cancer registries with empirical incidence and prevalence observed by CRs, in order to assess the consistency in data, methods and assumptions. Empirical prevalence has been calculated by counting patients with a diagnosis of cancer who were alive on the reference date by PREVAL method. A correction factor has been applied to include patients diagnosed before the period of activity of the registry. RESULTS: General consistency was found between empirical and estimated (by MIAMOD) incidence and prevalence in the registry areas, which is indicative of the quality and the completeness of all data involved as well as the appropriateness of model choices. The prevalence of all cancers combined for Italian regions with CRs was estimated and projected to the year 2000 as ranging between 1,240 per 100,000 in Sicilia and 2,781 in Emilia-Romagna for men, while for women these figures were 1,765 in Sicilia and 4,019 in Liguria. Comparison of cancer prevalence in CR areas with regional estimates shows quite good consistency for Piemonte, Liguria and Lombardia, which means that the local CRs (of Torino, Genova and Varese, respectively) are representative of their respective regions. Prevalence in Emilia-Romagna appears to be rather well represented by only one, the Parma CR, of the three local CRs. The southern Italian registries of Latina and Ragusa recorded a lower cancer prevalence than was actually estimated in their respective regions. DISCUSSION: Cancer registries with a longer period of activity showed better agreement between empirical and estimated figures due to the more precise information provided, particularly regarding survival and incidence trends. In conclusion, this work shows the potential of the cancer registries not only to represent their population with respect to cancer morbidity but also as an invaluable tool to extrapolate this information to the larger areas they represent.

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 901) of switching to didanosine versus continued zidovudine after the diagnosis of AIDS.

Although the efficacy of switching from zidovudine (AZT) to didanosine (ddI) has already been evaluated in controlled studies, prior investigations were not specifically designed to evaluate this issue in patients with acquired immune deficiency syndrome (AIDS). This open, randomized, multicenter study (ISS 901) was designed to evaluate the clinical benefit in patients with AIDS of switching to ddI after 6-18 months of AZT and no major intolerance. Patients were randomized to continue AZT, maintaining the current dosage at randomization (n = 79), or to receive ddI (n = 80) at the dosage of 375 mg and 250 mg b.i.d. for body weight > 60 and < or = 60 kg, respectively. Primary efficacy measures were survival and time to new AIDS-defining events, analyzed by the intent-to-treat approach. The two groups were comparable for baseline characteristics, follow-up (15 months), and time spent on allocated treatment. At the end of the study, 104 patients (48 AZT, 56 ddI) had died and 90 had at least one new AIDS-defining event (44 AZT, 46 ddI). Kaplan-Meier estimates of survival and of time to first new AIDS-defining event showed no differences between the treatment groups. No differences were detected in other efficacy measurements (p24 antigenemia, CD4+ count, Karnofsky score, and body weight), occurrence of severe toxicities, and treatment modifications. Pancreatitis occurred only in ddI-treated patients (6%). In our population of patients with advanced disease, switching from AZT to ddI did not produce apparent benefits, suggesting that application of this strategy earlier in the course of human immunodeficiency virus disease should be considered.

Epidemiology of AIDS dementia complex in Europe. AIDS in Europe Study Group.

The aim of the study was to describe the epidemiology of AIDS dementia complex (ADC) in Europe and to assess the possible role of zidovudine therapy in preventing or delaying its occurrence. We used an inception cohort, with data collected retrospectively from patients' clinical records from 52 clinical centers in 17 countries across Europe. The subjects were 6,548 adult people with AIDS consecutively diagnosed from 1979 to 1989. The main outcome measures were codiagnosis of ADC at the time of AIDS diagnosis and ADC-free time after AIDS diagnosis. ADC was reported in 295 patients (4.5%) at the time of AIDS diagnosis and during follow-up in a further 402 of the 5,160 patients (7.8%) who were diagnosed with AIDS based on diseases other than ADC. Whether at the time of AIDS diagnosis or later, the occurrence of ADC was significantly associated with age, transmission category, and CD4+ cell counts. The risk was greater in older patients (14 and 19% greater, at AIDS diagnosis and after, respectively, for a 5-year difference in age), in i.v. drug users than in homosexual and bisexual men (89 and 60% greater, at AIDS diagnosis and after, respectively), and for people with lower CD4+ cell counts (14 and 30% greater for a reduction of 1 on the natural log scale). Risk was almost double for women than for men. A significant reduction, of approximately 40%, was found in the risk of developing ADC after AIDS diagnosis for patients receiving zidovudine therapy, but this effect was present only during the first 18 months of treatment, irrespective of whether treatment began before or after AIDS diagnosis. In conclusion, an increase in the risk of developing ADC either at the time of AIDS diagnosis or thereafter is associated with increasing age, i.v. drug use, and decreased CD4+ cell count. Women tend to have a higher risk of ADC at the time of AIDS diagnosis. Zidovudine therapy appears to have a definite, but time-limited, effect of protecting patients against ADC development after AIDS diagnosis.

Differential survival of patients with AIDS according to the 1987 and 1993 CDC case definitions.

OBJECTIVE: To evaluate the impact of the 1993 Centers for Disease Control and Prevention (CDC) revised classification system for human immunodeficiency virus and expanded surveillance case definition for acquired immunodeficiency syndrome (AIDS) on the number of cases and on survival of patients with AIDS. DESIGN: Retrospective analysis of data from a prospective cohort study of patients treated with zidovudine. PATIENTS: A total of 3515 patients enrolled in the Italian National Registry of Zidovudine-Treated Patients between July 1987 and December 1991 were analyzed. MAIN OUTCOME MEASURES: Numbers and survival probability estimates (using the Kaplan-Meier method) for patients satisfying the 1993 CDC case definition compared with patients fulfilling the 1987 CDC classification. Multiple regression analysis was also used to analyze the combined effect of independent variables on survival. RESULTS: According to the new classification system, the number of AIDS cases in the study population would increase by 188%. While the median survival of patients meeting the 1987 definition was 24 months, at the end of 57 months 53% of patients meeting the 1993 definition were still alive. Among the patients meeting the laboratory criteria for AIDS diagnosis using the new definition (CD4+ lymphocyte count < 0.20 x 10(9)/L [200/microL]), the presence of an AIDS-defining illness was a strong independent predictor of death. CONCLUSIONS: The application of the new definition results in a considerable increase in the number of cases. Survival for patients classified according to the 1993 definition is much longer than for those classified with the 1987 definition. Clinical status plays a major role in predicting survival outcome among patients whose CD4+ lymphocyte counts meet the new case definition.

Long-term follow-up of zidovudine therapy in asymptomatic HIV infection: results of a multicenter cohort study. The Italian Zidovudine Evaluation Group.

In 1990 the results of a placebo-controlled study conducted within the AIDS Clinical Trials Group (ACTG 019) showed that in the short term, zidovudine was effective in slowing progression to advanced disease in HIV-infected asymptomatic patients with low CD4 cell counts. More recently, the preliminary results of the Concorde Trial suggested that while the data at 1 year agreed with those of ACTG 019, no sustained clinical benefit was detectable at 3 years for early versus deferred therapy. Therefore, the length of the clinical usefulness of zidovudine in this population is still to be determined. We evaluated the 2-year outcome of zidovudine therapy in asymptomatic patients through the prospective follow-up of a cohort of 936 subjects with low CD4+ (< 500/mm3) counts who strictly satisfied, at enrollment, the inclusion and exclusion criteria of the ACTG 019 trial. The clinical end point of the analysis was the development of AIDS. The majority (72.2%) of the individuals in the cohort acquired HIV infection through intravenous drug use; 26.6% were women. The median baseline CD4 cell count was 308/mm3. At 55 weeks of mean follow-up, the progression rate to AIDS (3.2 events per hundred person-years) appears to be comparable to that already reported at the same mean follow-up time for the ACTG 019 zidovudine-treated asymptomatic patients. After 124 weeks of mean follow-up, the overall rate of progression to AIDS was 5.2 per hundred person-years.(ABSTRACT TRUNCATED AT 250 WORDS)

[Decrease in notifications of AIDS dementia complex in 1989-1990 in Italy: possible role of the early treatment with zidovudine]. / Diminuzione delle notifiche di AIDS Dementia Complex nel periodo 1989-1990 in Italia: possibile ruolo del trattamento precoce con zidovudina.

We evaluated the incidence of AIDS dementia complex (ADC) in groups of patients who acquired infection through different risk behaviours, and attempted to evaluate the possible role of zidovudine (AZT) treatment in preventing or delaying the onset of ADC. The Italian National AIDS Registry was used to study patients with AIDS for whom ADC was reported as an index disease. Relative risk of presenting ADC between different patient categories has been determined. Logistic regression was used to analyse temporal trends in the proportion of AIDS cases presenting with ADC. Of the 6466 cases reported between August '87 and August '90, ADC was seen in 640 (9.9%). I. V. drug addicts had twice the risk (estimated odds ratio: 1.9; 95% confidence interval: 1.5-2.6, p less than 0.001), compared to homo/bisexuals, of presenting with ADC. There is significant evidence (p less than 0.0001) that after a progressive increase in the period '87-'89, it began a definite decrease in the monthly proportion of ADC cases, starting August '89. AZT was introduced in Italy in July 1987 for patients with AIDS or advanced ARC. The incidence of AIDS dementia complex at the moment of AIDS diagnosis in our population of patients, began to decline 24 months after the introduction of systematic AZT treatment in Italy. This could have been due to inhibition of HIV replication in the Central Nervous System among patients who initiated AZT-treatment before developing full-blown AIDS.