Cytomegalovirus seroconversion as a cofactor for progression to AIDS.

OBJECTIVE: To study the impact of cytomegalovirus (CMV) seroconversion on HIV-1 disease progression. DESIGN: Follow-up of CMV-seronegative subjects enrolled in the French SEROCO/HEMOCO cohorts of HIV-infected subjects. METHODS: A total of 290 subjects were CMV-seronegative at enrolment in the cohort. Serological testing for CMV infection was done at enrolment and then every 6 months in CMV-seronegative subjects. The person-years method was used to calculate the incidence of CMV seroconversion. After adjustment for age, the CD4+ cell count at enrolment and the HIV exposure group in a Cox model, we studied CMV seroconversion as a time-dependent variable in progression to a CD4+ cell count below 200 x 10(6) cells/l and to clinical AIDS. RESULTS: Overall, 61 CMV seroconversions were observed. The overall incidence rate was 4.4 per 100 person-years [95% confidence interval (CI), 3.3-5.5]. The risk of progression to a CD4+ cell count below 200 x 10(6) cells/l was not increased in CMV seroconverters. However, the risk of progression to AIDS was increased two-fold in CMV seroconverters compared with subjects who remained CMV-seronegative [relative risk (RR) = 2.09; 95% CI, 1.16-3.74; P = 0.01]. CONCLUSION: This analysis of 61 CMV seroconversions, the largest study in the literature, confirms the impact of recent CMV infection on progression to AIDS.

Determinants of delayed diagnosis of HIV infection in France, 1993-1995.

OBJECTIVE: To describe the circumstances of the first HIV-positive test and to study the determinants of a delayed diagnosis of HIV infection. METHODS: In a retrospective study among adult AIDS patients diagnosed between July 1993 and May 1995 in two French districts, data on socioeconomic characteristics, circumstances of first HIV-positive test and attitudes and behaviours regarding medical care were collected in a confidential interview and analysed for potential association with a late test, defined as a first HIV-positive test within 6 months of AIDS diagnosis. RESULTS: Of the 359 AIDS patients studied, 69 (19.2%) had a late test. Late testers were more likely than other patients to have had an HIV-positive test because of clinical symptoms (89.7 versus 38.9%, P < 0.001) and not to perceive themselves as being at risk of infection with HIV (53.6 versus 39.3%, P < 0.05). The proportion of late testers was 34.6% among heterosexually infected patients, 12.7% among homo-/ bisexual men and 9.6% among injecting drug users. Factors independently associated with a late test were male gender [adjusted odds ratio (aOR), 5.6; 95% confidence interval (CI), 1.7-18.9] and absence of earned income (aOR, 5.2; 95% CI, 1.4-19) among heterosexually infected patients; high education (aOR, 3.1; 95% CI, 1.0-9.6) and having consulted a person practising alternative medicine (aOR, 3.4; 95% CI, 1.2-10) in homo-/bisexual men. CONCLUSIONS: Despite incentives to be tested for HIV, many individuals in France are still tested too late, even if they are in known high-risk groups. Efforts to test HIV-infected people as early as possible should be made by increasing the perception of HIV risk and decreasing the level of missed opportunities for testing. Current case management approaches make this recommendation critically important from both public health and an individual perspective.

Early protective effect of CCR-5 delta 32 heterozygosity on HIV-1 disease progression: relationship with viral load. The SEROCO Study Group.

OBJECTIVE: To determine the influence of heterozygosity for the delta 32 mutant CCR-5 allele on HIV-1 disease progression. DESIGN: HIV-1 disease progression and serum viral load were analysed according to the C-C chemokine receptor (CCR)-5 genotype in 412 Caucasian patients (319 men and 93 women) with a known date of seroconversion, who were enrolled in the SEROCO cohort (median follow-up, 74 months). RESULTS: The frequency of heterozygosity for the mutant allele was 17% and did not differ according to sex or risk factor of HIV infection. Heterozygotes were significantly less likely than patients with two functional alleles to have symptomatic primary infection. Their serum viral load was lower during the 6- to 24-month plateau phase after seroconversion. This difference persisted afterwards, although the rate of decline in CD4+ cells was similar. Kaplan-Meier survival curves showed slower progression to clinical AIDS in heterozygotes during the first 7 years following infection (P < 0.02), the two curves tending to join thereafter (overall log-rank test, P = 0.17). However, the interaction term with time did not reach significance in a Cox model. The overall relative risk of progression was 0.67 (95% confidence interval, 0.38-1.18) and was not influenced by adjustment for age at seroconversion or symptomatic primary infection. After adjustment for early viral load the relative risk was 0.83. Pneumocystis carinii pneumonia and toxoplasmosis were less likely to be the first AIDS-defining illness in heterozygotes than in the other patients (0 versus 24.7% of AIDS cases, P = 0.04), despite similar management. CONCLUSION: Deletion of one CCR-5 gene allele appears to protect against HIV-1 disease progression, mainly during the early years of the infection. Heterozygosity for the deletion leads to persistently lower viral load, and also seems to protect against some opportunistic infections.

Natural history of serum HIV-1 RNA levels in 330 patients with a known date of infection. The SEROCO Study Group.

OBJECTIVE: To describe the spontaneous course, before the introduction of highly active antiretroviral therapy (HAART), of HIV-1 RNA during the AIDS-free period of the disease. To assess the predictive value of changes in HIV-1 RNA levels. DESIGN: A total of 330 patients with a known date of infection followed in the SEROCO cohort. METHODS: HIV-1 RNA levels (threshold, 200 copies/ml) were evaluated from 2243 frozen sera obtained from enrolment until the onset of AIDS or until February 1996. Lowess curves were used to describe the variations of viraemia during follow-up. A Cox regression model was used to assess the predictive value of early and updated CD4 cell count and viral load. RESULTS: In addition to a lower early viral load, patients who remained AIDS-free had, on average, a longer period of viral load decrease after infection (36 versus 18 months), followed by a slower viral load increase compared with those who progressed to AIDS. A true plateau-phase after the seroconversion period, lasting approximately 4 years, was identified only in patients who remained AIDS-free for at least 90 months. In multivariate analysis, both early viral load and later changes were significant predictors of progression to AIDS. A decrease in the CD4 cell count to less than 200 cells/microl and the onset of a group B condition remained significant predictors of progression. CONCLUSION: Our study extends to the early post-seroconversion phase the prognostic value of extracellular HIV-1 RNA levels. Moreover, our data suggest that, in most HIV-infected individuals, a progressive loss of control of viral replication arises during the early years of HIV-1 infection.

Predictive value of viral load and other markers for progression to clinical AIDS after CD4+ cell count falls below 200/microL. SEROCO & HEMOCO Study Group.

BACKGROUND: To assess the predictive value of biological and clinical events for progression to AIDS (1993 European classification) when the CD4+ cell count falls below 200/microL (CD4 threshold) in different exposure groups. To investigate whether such markers remain predictive independently of the serum HIV-1 RNA level at the CD4 threshold. METHODS: The predictive value of biological and clinical events occurring during the 24 months prior to the occurrence of CD4 threshold (n = 333) was quantified in a Cox model. Another Cox model was carried out in a subset of 77 patients in whom viral load from stored sera was available. Furthermore, changes in viral load during the 24 months preceding the CD4 threshold were assessed in a mixed model according to subsequent development of AIDS. RESULTS: Among the 333 patients, the slope of the CD4+ cell counts, the emergence of p24 antigen, persistent thrush, and age at the CD4 threshold were independent predictors of progression to clinical AIDS (44.7%). Among the subset of 77 patients, the HIV-1 RNA level at the CD4 threshold, persistent thrush and age remained independent predictors of progression to AIDS (45.5%). The increase of the HIV-1 RNA level was moderate, both in non-progressors (24.0% per year) and in those who subsequently developed AIDS (27.1% per year), (P = 0.93). Viral load was consistently higher in the latter group (P = 0.002). CONCLUSION: At a late stage of infection, age and persistent thrush remain predictive of progression to AIDS, independently of viral load.

Bioconversion of a L-carnitin precursor in a one- or two-phase system.

The ability of the yeast Saccharomyces cerevisiae to bioconvert stereo-selectively octyl-4-chloroacetoacetate (OCA) into the corresponding chiral alcohol, precursor of L-carnitin, an important physiological agent, was investigated. In a monophasic system with free cells, more than 90% of OCA (0.018 M) bioconversion have been reached after 6 h (enantiomeric excess for the R form, eeR:97%). Immobilized cells in alginate beads were less efficient in conversion of OCA than free cells. In a two-phase system with free cells, the level of reduction of OCA (0.018 M) reached 85% after 48 h. With a medium containing a higher OCA concentration (0.270 M), 41% of this product were bioconverted after the same period. On the other hand, immobilized cells did not show any significant bioconversion of OCA in two-phase reactors. The limiting factor of these reactors in the regeneration of the cofactors involved in the OCA reduction.

[Management of the bank of biological material in the hospital-based SEROCO and HEMOCO cohorts of HIV-infected patients]. / Utilisation de la biothèque dans les cohortes hospitalières SEROCO et HEMOCO de patients infectés par le VIH.

The French SEROCO and HEMOCO hospital-based cohorts have enrolled and followed HIV-infected patients, before and after the highly active antiretroviral therapy era. Among the objectives in 1988, was explicitly mentioned the constitution of a centralised bank of biological material (serums at enrollment and every 6 months, PBMC at enrollment and every 18 months). This paper details the organisation of the bank and the numerous studies performed from this bank, and presents a few simple decision rules which have been developed with the growing acquired experience.

Migraine and risk of ischaemic stroke: a case-control study.

OBJECTIVES: To determine whether migraine is a risk factor for ischaemic stroke. DESIGN: A case-control study. SETTING: Two hospitals in Paris. SUBJECTS: 212 patients with stroke (137 men and 75 women) and 212 controls matched for sex, age (to within five years), and history of hypertension. MAIN OUTCOME MEASURES: Ischaemic stroke, confirmed by brain computed tomography or magnetic resonance imaging, and history of headache, recorded with structured questionnaire during interview. RESULTS: Prevalence of migraine did not differ between patients with stroke and controls: 18/137 v 17/137 for men (odds ratio 1.1 (95% confidence interval 0.5 to 2.2), p = 0.86); 23/75 v 17/75 for women (odds ratio 1.6 (0.7 to 3.5), p = 0.24); and 41/212 v 34/212 for both sexes (odds ratio 1.3 (0.8 to 2.3), p = 0.33). When subjects were split into two age groups, however, prevalence of migraine was significantly higher among younger women (aged < 45) with stroke compared with their controls (13/20 v 6/20, odds ratio 4.3 (1.2 to 16.3), p = 0.03). Furthermore, the risk of ischaemic stroke was higher among younger women who smoked (7/20 v 1/20, odds ratio 10.2 (1.1 to 93.3)). CONCLUSIONS: Prevalence of migraine was not different between patients with stroke and matched controls except among women aged < 45, when migraine and stroke were significantly associated.

[Effect of primary prevention of Pneumocystis carinii pneumonia on the inaugural clinical and biological presentation of AIDS: 624 cases (Aquitaine Cohort, 1985-1994)]. / Effet de la prophylaxie primaire de la pneumocystose pulmonaire sur la présentation clinique et biologique inaugurale du SIDA: 624 observations (cohorte Aquitaine, 1985-1994). d'épidémiologie clinique du SIDA en Aquitaine (GECSA).

In a cohort of HIV-infected patients, this study compares the clinical and immunological features at the time of AIDS diagnosis of patients who either received primary Pneumocystis carinii prophylaxis (P+; n = 335) or who did not (P-; n = 289). Frequency of P carinii pneumonia was lower in P+ than in P- patients (14.9% vs 26.0%; p < 0.001). Conversely, toxoplasmic encephalitis, esophageal candidiasis, cytomegalovirus disease and M avium complex disease were more frequent in P+ patients. CD4+ count (median/mm3) at the time of AIDS diagnosis was lower in P+ than in P- patients: 22 vs 97 (p < 0.001); this suggests that early intervention delays the onset of AIDS for about one year. While searching for new prevention strategies against other opportunistic infections, efforts should be expanded to improve prophylaxis of P carinii pneumonia which remains in France the most frequent first AIDS-related illness.

Is cytomegalovirus infection a co-factor in HIV-1 disease progression?

The influence of cytomegalovirus (CMV) infection as a co-factor in HIV-1 disease progression has mainly been studied in haemophiliacs and remains controversial. Based on the files of 1683 HIV-1-infected patients in the Seropositive Cohort (SEROCO) and Haemophiliacs Cohort (HEMOCO) cohorts, we studied the role of CMV infection in progression to CD4+ cell counts of less than 200 microl, AIDS onset and death, in various HIV exposure groups. Adjusted relative risk (aRR) of progression to AIDS and to death was respectively 1.30 (P = 0.05) and 1.58 (P = 0.007). In the sexual exposure group the influence of CMV infection on the risk of progression to AIDS was of borderline significance (aRR = 1.50; P = 0.07) and was more marked on the risk of death (aRR = 2.00; P = 0.03). No such influence of CMV infection was observed in the transfusion and intravenous drug use exposure groups. When we studied the influence of CMV infection according to the stage of HIV disease, the main effect was on progression from AIDS to death, probably because CMV disease is a late event. Sexual CMV transmission and frequent re-exposure to CMV may explain why CMV infection emerged as an important co-factor for HIV progression only in the sexual exposure group.

CCR5 delta32 deletion and reduced risk of toxoplasmosis in persons infected with human immunodeficiency virus type 1. The SEROCO-HEMOCO-SEROGEST Study Groups.

This study attempted to determine whether the CCR5 Delta32 deletion affected progression to certain first AIDS-defining illnesses in human immunodeficiency virus type 1-infected patients enrolled in the French SEROCO/HEMOCO/SEROGEST cohorts. Toxoplasmosis onset as a first AIDS-defining illness was significantly delayed in 253 heterozygous patients, compared with 1404 wild type patients. The relative risk of toxoplasmosis associated with heterozygosity was 0. 39 (95% confidence interval, 0.16-0.96) after adjustment for age, CD4 cell count, and primary specific prophylaxis. A nonsignificant protective trend was observed with regard to the onset of mycobacterial, cytomegalovirus, and herpesvirus diseases, but these events were less frequent than toxoplasmosis. Progression to other conditions (e.g., wasting, non-Hodgkin's lymphoma, Kaposi's sarcoma) was similar in the 2 groups as was the frequency of toxoplasmosis as a subsequent AIDS-defining illness. As chemokines are involved in numerous infectious processes, the Delta32 deletion could delay progression to certain opportunistic infections such as toxoplasmosis.