We collected data on the outcome of partner notification (PN) for 356 index patients (iPs) newly diagnosed with HIV, all sexually infected, in six European countries, 1995-96. The PN period (the period during which exposed partners should be notified about their risk of being HIV infected) could be defined on the basis of last negative HIV test in 170/356 (48%), from other key dates for 12, and for 14 more on the sole basis of known HIV exposure (total 196/356, 55%). However, of the 170 iPs with a last negative HIV test date, PN period was not defined in 52 (31%), even though 28/52 were recent seroconverters (negative HIV test within 24 months of HIV diagnosis). Discrepancies in PN period evaluation were common: of the 85 iPs for whom PN period was reportedly defined as '3 months before last HIV-negative date', the period actually used was equal to this in only 12. A user-friendly worksheet would simplify the task of eliciting and using key dates to define the PN period. Forms on PN outcome were received for 166/200 (83%) reported current partners, but only 124/508 (24%) ex-partners. Fifty-two of 290 (18%) notified partners already knew they were HIV-positive, and 38/130 (29%) notified partners for whom pre-PN status was negative or unknown were HIV-positive on post-PN testing. Results of HIV tests (if any) after PN were unknown for 37/133 (28%) current partners not already known to be HIV-positive, and for 71/105 (68%) ex-partners-a doubling of the information loss rate. Notification of 133 current and 105 ex-partners not previously identified as HIV-positive thus produced 28 (21%) and 10 (10%) new HIV diagnoses, respectively. The total yield of HIV diagnoses was 38/100 (38%) partners of recent seroconverters (22 already known plus 16 PN-diagnosed), compared with 52/190 (27%) partners of other iPs (30 already known plus 22 PN-diagnosed). We propose prioritization for PN of partners of recent seroconverters, augmented surveillance for HIV diagnoses and recurrence in PN networks of at-risk, non-notified partners, and new measures that preserve anonymity to alert potential and past sexual contacts of HIV-diagnosed individuals who are unable or unwilling to assist in PN.

We describe the characterization of the B-cell epitopes of HIV-1 regulatory proteins Tat and Rev. The prevalence of antibodies to these proteins among human immunodeficiency virus (HIV)-1-infected individuals was examined by enzyme-linked immunosorbent assay (ELISA) and by Western blotting. The Tat and Rev antibody-positive sera were selected for epitope mapping performed with partially overlapping synthetic peptides bound to polyethylene pins. Eighteen and twelve percent of HIV-infected individuals had antibodies against Tat or Rev, respectively. In Tat, four epitopic regions were identified, situated within amino acids 6-10 (PRLEP), 21-37 (ACTNCYCKKCCFHCQVC), 39-58 (ITKALGISYGRKKRRQRRRA) and 74-82 (TSQSRGDPT). The most frequently recognized epitopic regions were located in the middle of the protein. In Rev, the two most frequently recognized epitopic regions were near the amino terminus of the protein within amino acids 12-20 (LIRTVRLIK) and 38-49 (RRNRRRRWRERQ). A third epitope was mapped around amino acids 55-62 (ISERILGT) and a fourth around amino acids 78-83 (LERLTU). To analyze the specificity of Tat and Rev epitopes, soluble synthetic peptides representing the identified epitopes were used in an ELISA assay, and the recognition of most epitopes was shown to be specific for HIV-1-infected individuals. In addition, many of the Tat and Rev epitopes were shown to overlap with regions having functional activity or with regions previously identified as T-cell epitopes.

OBJECTIVE: To study epidemiology and possible risk factors associated with the development of cryptosporidiosis among European patients with AIDS. METHODS: An inception cohort of 6548 patients with AIDS, consecutively diagnosed from 1979 to 1989, from 52 centres in 17 European countries was studied. Data on all AIDS defining events were collected retrospectively from patients' clinical records. Kaplan-Meier estimates, log rank tests and Cox proportional hazard models were used to examine for possible risk factors associated with cryptosporidiosis. RESULTS: Cryptosporidiosis was diagnosed in 432 (6.6%) patients, 216 at time of the AIDS diagnosis and 216 during follow-up. The probability of being diagnosed with cryptosporidiosis at AIDS diagnosis was significantly lower for intravenous drug users (1.3%) than for homosexual men (4.1%) and for patients belonging to other transmission categories (4.0%) (p < 0.001). The probability was also higher for patients from Central Europe compared with patients from South Europe (4.1% versus 2.5%, p = 0.005). The rate of developing cryptosporidiosis after the diagnosis of AIDS was 3 per 100 patient years of follow-up. The rate was significantly lower for intravenous drug users than for homosexual men (relative risk 0.34, 95% confidence limits 0.22-0.54) and for women compared with men (RR 0.43 (0.21-0.87)). The risk was higher in North Europe than in South and Central Europe. In a multivariate analysis only transmission category remained a significant predictor for the development of cryptosporidiosis. CONCLUSION: The development of cryptosporidiosis in AIDS patients may be associated with sexual risk behaviour.

This study examined the factors associated with the development of a first episode of Pneumocystis carinii pneumonia (PCP) in 5,025 patients with AIDS, including 1,976 patients with primary PCP at the time of AIDS diagnosis and 635 with primary PCP occurring subsequently. Compared with untreated patients, patients treated with zidovudine were at similar risk of developing PCP during the first year of therapy but were at greater risk after longer intervals of treatment. The following factors were associated with an increased risk of PCP (either at the time of AIDS diagnosis or thereafter): lack of primary PCP prophylaxis, male homosexuality/bisexuality, diagnosis of AIDS in northern Europe, and CD4 cell count below 200 x 10(6)/L at the time of AIDS diagnosis. Patients with severe weight loss had a 60% higher risk of developing PCP during follow-up than those without such weight loss. Thus, the occurrence of PCP depended on geographic location, mode of acquisition of human immunodeficiency virus and AIDS, degree of immunodeficiency, and use of various treatment regimens.

Objectives-To examine the pattern of survival and factors associated with the outcome of disease in patients with AIDS.Design-Inception cohort. Data collected retrospectively from patients' charts.Setting-52 clinical centres in 17 European countries.Subjects-6578 adults diagnosed with AIDS from 1 January 1979 to 31 December 1989.Main outcome measures-Survival after the time of diagnosis.Results-The median survival after diagnosis was 17 months, with an estimated survival at three years of 16% (95% confidence interval 15% to 17%). Patients diagnosed in southern Europe had a shorter survival, particularly immediately after the time of diagnosis, compared with patients diagnosed in central and northern Europe (survival at one year (95% confidence interval) 54% (52% to 56%) 66% (64% to 68%), 65% (63% to 66%), respectively. The three year survival, however, was similar for all regions. The regional differences in survival were less pronounced for patients diagnosed in 1989 compared with earlier years. Improved survival in recent years was observed for patients with a variety of manifestations used to define AIDS but was significant only for patients diagnosed with Pneumocystis carinii pneumonia. The three S ear survival, however, remains unchanged over time.Conclusions-Survival of AIDS patients seems to vary within Europe, being shorter in southern than central and northern Europe. The magnitude of these differences, however, has declined gradually over time. Short term survival has improved in recent years, but the long term prognosis has remained equally poor, reflecting the fact that the underlying infection with HIV and many of the complicating diseases remains essentially uncontrolled.

OBJECTIVE:To determine the association between elapsed time since starting zidovudine and survival in patients with acquired immunodeficiency syndrome (AIDS).DESIGN:Inception cohort and observational study of patients treated and not treated with zidovudine.SETTING:Fifty-one centers in 17 European countries.PATIENTS:A total of 4484 patients diagnosed as having AIDS from 1979 to 1989 who survived their initial AIDS-defining event and who had not started zidovudine before AIDS diagnosis.MAIN OUTCOME MEASURES:Use of zidovudine and mortality.RESULTS:Among patients who did not receive zidovudine, the death rate was approximately constant for the first 5 years after AIDS diagnosis. For patients treated with zidovudine, the death rate within the first year since starting zidovudine was markedly lower than for untreated patients who had developed AIDS at the same time (relative rate, 0.47; 95% confidence interval [CI], 0.42 to 0.51). For longer times since starting zidovudine, the association with reduced mortality rate was diminished, and for patients surviving more than 2 years since starting zidovudine, the death rate was greater than for untreated patients who had developed AIDS at the same time (relative rate, 1.35; 95% CI, 1.15 to 1.58). Adjustment for other prognostic factors failed to substantially affect this observation.CONCLUSIONS:When initiated after the time of AIDS diagnosis, zidovudine was associated with improved prognosis but for no more than 2 years after starting therapy.

We examined cognitive performance in 72 HIV-1 infected patients and 34 controls. None of the patients had opportunistic infections or unusual neoplasms of the central nervous system (CNS). Factors other than HIV-1 known to cause cognitive decline were excluded from both groups. Cognitive functioning analysed with special emphasis on the severity of HIV infection was related to neuroradiological and immunological findings. In patients with AIDS-related complex (CDC IVa) or AIDS (CDC IVc,d), a deterioration of memory as well as cognitive speed and flexibility was detected. Furthermore, memory deficits were associated with central cerebral and infratentorial atrophy in those patients, while no association was found between cognitive deficits and immunological abnormalities. Patients at CDC stages II or III showed slight association between altered cognitive speed and flexibility and elevated leukocyte count, suggesting a subclinical CNS disease already at early stages of HIV infection.

The regulatory proteins coded by the human immunodeficiency virus, (HIV)-1 genome are expressed by the infected cells before the initiation of the synthesis of structural proteins and thus immune response directed against these proteins could destroy infected cells before the release of infectious virions. The evaluation of T-lymphocyte responses toward Tat, one of the main HIV-1 regulatory proteins, is therefore of interest. We selected a group of HIV-infected patients with retained response to the recall antigen purified protein derivative and tested their CD4+ helper T-cell response toward recombinant Tat and toward 12 soluble synthetic partially overlapping 15-16-mer Tat peptides in a proliferation assay. Three peptides (amino acids 17-32, 33-48, and 65-80) were significantly recognized by the helper T-cells from infected individuals but not by the nine HIV-1-negative control persons. Nine of the 14 patients (64%) responded to at least one of these Tat peptides. Of the identified immunodominant peptides containing T-cell epitopes, one (aa 65-80) was recognized in association with human leukocyte antigens DR-2 allele, while the others appeared to be promiscuous and were equally recognized in association with several DR molecules. The identified immunogenic peptides were analyzed for the predicted presence of T-cell antigenic sites by several algorithms and positive correlation was detected for each peptide. Our results thus indicate that Tat protein can induce a cell-mediated immune response and identify three peptides containing T-cell epitopes that may be of importance in vaccine development.

One hundred and one persons infected with human immunodeficiency virus (HIV-1), in whom other central nervous system infections or diseases were excluded, underwent brain CT and/or MRI at various stages of HIV-1 infection: 29 were asymptomatic (ASX), 35 had lymphadenopathy syndrome (LAS), 17 had AIDS-related complex (ARC), and 20 had AIDS. A control group of 32 HIV-1-seronegative healthy persons underwent brain MRI. The most common finding was brain atrophy, found in 9% of controls, and 31% of ASX cases, 29% of LAS, 59% of ARC and 70% of AIDS. Even the difference between the ASX or LAS groups and controls was significant. The changes were bilateral and symmetrical, and they were more severe at later stages of infection. Infratentorial atrophy was seen in the early stages; supratentorial atrophy became more pronounced at ARC, and generalized atrophy was typical of AIDS. Non-specific small hyperintense foci were found on MRI in 13% of controls and 6-15% of the infected groups. Larger, diffuse, bilateral white matter infiltrates were detected in 4 demented patients with AIDS. Four patients with AIDS and 1 with LAS had focal hyperintense lesions in the internal capsules, lentiform nuclei or thalamus, often bilateral on MRI. One patient with AIDS, examined with CT only, had low density in the lentiform nucleus. Loss of brain parenchyma can occur at an early stage of HIV-1 infection, and the atrophic process becomes more intense at later stages (ARC and AIDS). Parenchymal infiltration, seen as hyperintense areas on MRI, is most often associated with severe clinical symptoms, in the later stages of the disease.

OBJECTIVE:To assess the frequency of mycoplasma infections in HIV-antibody-positive and -negative individuals by studying the serological responses against mycoplasmas, especially Mycoplasma fermentans and M. pirum. DESIGN:An enzyme-linked immunosorbent assay (ELISA) was used to measure immunoglobulin G (IgG) class antibody concentrations against six mycoplasma species in sera of HIV-positive and HIV-negative individuals. METHODS:Serum samples were obtained from 30 HIV-positive individuals (10 asymptomatics, 10 with lymphadenopathy syndrome and 10 with AIDS), 10 HIV-negative partners of HIV-positive individuals and 40 HIV-negative blood donors. Antibodies to M. fermentans strains incognitus and PG18, M. pirum, M. genitalium, M. pneumoniae and M. hominis were assessed by immunoblot or ELISA. Absorbance values were taken as a semiquantitative measurement for antibody concentration and an arbitrary cut-off value (0.8) was set to establish seroprevalence. RESULTS:There was no significant difference in the mean IgG concentrations of any of the six mycoplasmas between HIV-positive and HIV-negative groups. Antibody concentrations were also similar in different clinical phases of HIV infection. Antibody concentrations to different mycoplasma strains were compared with each other to reveal eventual cross-reactions caused by shared antigens; the strongest correlation (r = 0.836) was found between M. fermentans strains incognitus and M. pirum antibody concentrations. The correlation between M. fermentans strains incognitus and PG18 was also significant but weaker (r = 0.522). No shared antigens between M. fermentans strain incognitus and M. pirum were demonstrated by immunoblot. CONCLUSIONS:Antibodies against M. fermentans type strain PG18, strain incognitus and against M. pirum are detected infrequently and their presence does not correlate with HIV infection per se or with the clinical stage of HIV infection.

We analyzed the EEGs of 67 HIV-1-infected patients at various stages of the disease and of 35 HIV-1-seronegative controls. The most common EEG abnormality in HIV-1 infection was an increased amount of generalized episodic or persistent, predominantly anterior slow activity, associated with a low level of maximal amplitude. When compared to the controls, a lower maximal amplitude of dominant background activity (p less than 0.001), and more marked generalized (p less than 0.01) and anterior (p less than 0.001) disturbances were already seen in early stages of HIV-1 infection. EEG abnormalities were more severe in patients with advanced HIV-1 infection than in those at early infection (p less than 0.001 to p less than 0.05). The presence of a more marked, posteriorly (p less than 0.01) accentuated, generalized slow activity (p = 0.02) was found more often in patients with T-helper cell counts lower than 0.4 x 10(9) (p = 0.05) than in those with higher numbers of T-helper cells. No clear associations were found between the severity of EEG abnormalities and the duration of HIV-1 infection. Our results suggest that EEG is a sensitive method in detecting subclinical functional cerebral disturbances caused by HIV-1.

Paired serum and saliva samples were tested by enzyme-linked immunosorbent assay (ELISA) and Western blot (WB) for the presence of human immunodeficiency virus (HIV) antibodies. The study group included 36 individuals known to be HIV seropositive and 14 healthy, seronegative controls. HIV antibodies were detected in all but one of the saliva samples of the seropositive subjects. In this particular patient, seroconversion was documented 1 week earlier by sequential testings. A further saliva sample obtained 2 months later was ELISA positive for salivary HIV antibodies. Antibodies against HIV proteins gp120 and gp160 were detected by Western blot assay in all saliva specimens taken from HIV seropositive subjects (including the ELISA-negative patient who seroconverted. Antibodies against other viral proteins (p65, p55, p51, gp41, p35, p24 p18) were found in saliva haphazardly without any clear-cut correlation with the clinical stage of the disease. Pretreatment of the saliva with protease inhibitor was essential for the diagnostic use of saliva for the detection of HIV antibodies by Western blot assay. Calculation of the ratio of titres in serum to those in saliva showed the highest ratios in symptomless subjects (mean +/- SD; 1844 +/- 1412) and the lowest in patients with acquired immune deficiency syndrome (AIDS) (mean +/- SD; 811 +/- 445). The ratio of serum to saliva by ELISA showed a positive correlation with salivary flow rate, indicating a dilution of salivary HIV antibodies with increasing salivary flow rate. The gingival bleeding index was negatively correlated with the ratio, supporting the concept that salivary HIV antibodies transudate from blood to saliva via gingival fluid.

Department of Dermato-Venereology, University Central Hospital, Department of Public Health, Helsinki University, and Aurora Hospital, Helsinki, Finland.

Antibodies to the human immunodeficiency virus (HIV) regulatory gene nef (negative factor) product are claimed to be characteristic of early and latent HIV infection. We looked for anti-nef antibodies in individuals infected with HIV or at risk for HIV, in blood donors, and in patients with diverse dermatological disorders. In HIV-infected patients, antibodies to recombinant nef protein were seen by Western blot assay in 29 of 54 (54%) individuals at any time during a prospective follow-up. Except for a decline in the level prior to ARC and AIDS, the occurrence of antibodies did not significantly correlate with any pattern of disease progression in 22 patients followed for up to 4 years. Among the 141 HIV risk group members, negative in recombinant HIV ELISA tests, anti-nef antibodies were detected in 7 (5%) individuals. However, an anti-nef antibody response was also seen in 5 of 93 (5%) nonrisk dermatological patients and in 4 of 37 (11%) healthy blood donors. Solitary HIV gag protein antibody responses were most frequent (7%) in the group of individuals at risk for HIV but the majority of anti-nef positive sera did not react with HIV gag proteins. The relatively frequent occurrence of indistinguishable anti-nef antibody responses in nonrisk individuals suggests that immunological cross-reaction between nef and some cellular regulatory protein may occur.

Brain MRI and/or CT were performed on 72 HIV-infected patients at various stages of the disease, and on 34 controls. The neuroradiological findings were related to duration of the infection, neurological symptoms, and cognitive abnormalities as well as to immunological findings in the CSF and blood. All types of brain atrophy were more severe and more frequent in HIV-infected subjects than in controls. Patients with neurological symptoms, those with advanced HIV infection, and patients with a duration of HIV infection of more than 4 years showed the most severe and most frequent neuroradiological abnormalities, including central and cortical atrophy, brain stem atrophy, and cerebellar atrophy. Subjects with cognitive defects exhibited more severe central atrophy than cognitively intact patients. However, slight brain atrophy and/or parenchymal lesions were found in 57% of cognitively intact HIV-seropositive individuals. Patients with brain atrophy and those with radiologically normal brain, both showed increased intrathecal synthesis of total IgG, and intrathecal HIV-antibody synthesis. However, a declined general immune response and a lowered CSF leukocyte count were seen predominantly in patients with brain atrophy. The results suggest that subcortical, neurologically "silent" areas of brain white matter are an early target of HIV infection.

ABSTRACT— Elevated (< 2.2 mg/l) CSF β-2-microglobulin (β2m) level was found in 9 of 16 neurologically symptomatic patients but in only 4 of 21 who were neurologically symptom-free (P < 0.01). Serum β2m concentration was elevated (<2.5 mg/l) in 12 of 16 neurologically symptomatic patients but in only 8 of 21 symptom-free patients (P < 0.01). When the CSF and serum β2m levels were related to various stages of HIV infection, the highest mean values for both CSF and serum were found in patients with acquired immunodeficiency syndrome (AIDS), followed by lower values in AIDS-related complex (ARC), lymphadenopathy syndrome (LAS), and asymptomatic seropositive individuals (ASX), in decreasing order of preference. Our results suggest that elevated β2m in CSF and serum is related to the stage of general HIV infection and that elevated CSF β2m in the presence of intact BBB may be useful in evaluating CNS involvement in HIV-infected patients.