Improved virological response to highly active antiretroviral therapy in HIV-1-infected patients carrying the CCR5 Delta32 deletion.

BACKGROUND: Patients heterozygous for the C-C chemokine receptor 5 (CCR5) Delta32 deletion spontaneously progress less rapidly to AIDS and death than do wild-type patients. We investigated whether the CCR5 Delta32 deletion has an impact on immunological, virological and clinical responses to highly active antiretroviral therapy (HAART) in HIV-1-infected patients. PATIENTS AND METHODS: We included in the study 565 HIV-1-infected patients from the French HIV-1 infected cohort with documented date of seroconversion (SEROCO)/haemophiliacs HIV-1 infected (HEMOCO) cohorts, who started HAART after 1996. We investigated virological responses to HAART at 6 months (defined as a plasma HIV-1 RNA measurement below the threshold of detection or a 2 log HIV-1 RNA decrease) and at 12 months (defined as a plasma HIV-1 RNA measurement below the threshold of detection) and clinical response to HAART by Kaplan-Meier survival curves, with AIDS and death as outcomes. RESULTS: The Delta32 heterozygous patients (n=83; 15%) had a better virological response to HAART than wild-type patients (73 vs 53% at 6 months, P=0.01; and 60 vs 44% at 12 months, P=0.01). This better virological response was still observed after adjustment for antiretroviral status (whether or not patients were naïve to antiretroviral therapy), year of HAART initiation, number of new antiretroviral drugs and baseline viral load. There was no statistical difference between heterozygous patients and wild-type patients in terms of survival and AIDS-free survival. CONCLUSIONS: CCR5 Delta32 heterozygous patients were more likely to have a virological response to HAART than wild-type patients at 6 and 12 months. However, this virological response did not produce better immunological and clinical responses. The long-term impact of the Delta32 deletion on survival in HIV-1-infected treated patients should be investigated in a meta-analysis.

[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.

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.

Sexual behavior changes and protease inhibitor therapy. SEROCO Study Group.

OBJECTIVE: To examine changes in sexual activity and unprotected sexual intercourse among HIV-infected patients before and after the initiation of protease inhibitor therapy. DESIGN: An analysis of data from the SEROCO Study, a French prospective cohort. METHODS: All 191 patients who initiated protease inhibitor therapy after 1 January 1996, who were interviewed within one year before the initiation of therapy (Time 1), and who had at least 6 months of follow-up after therapy initiation (Time 2) were included. Patients provided information about sex partner characteristics and unprotected sexual intercourse. RESULTS: Eighty-one (42%) were gay or bisexual men, 46 (24%) were heterosexual men, and 64 (34%) were women. No significant increases were found in either the number of patients reporting anal or vaginal sex or the number reporting unprotected sexual intercourse after protease inhibitor initiation. However, in matched pair analysis, gay or bisexual men were three times more likely to report having had unprotected sexual intercourse with partners who were of HIV-negative or unknown serostatus after protease inhibitor initiation [relative risk (RR) = 3.0, 95% confidence interval (CI) = 1.2-7.6]. Non-significant decreases in unprotected sexual intercourse among both heterosexual men and women were also observed. No relationship between plasma viral load after protease inhibitor initiation and unprotected sexual intercourse was found in these data. CONCLUSIONS: A relapse in sex risk practices among some HIV-infected gay or bisexual men cannot be ruled out and requires both continued monitoring and immediate secondary preventative intervention.

HIV-1-related encephalopathy in infants compared with children and adults. French Pediatric HIV Infection Study and the SEROCO Group.

OBJECTIVE: To characterize the specificities of HIV-1-related encephalopathy in children. METHODS: Comparison of patients from the French Perinatal Cohort of children born to HIV-1-infected mothers and followed from birth with the French SEROCO Cohort of adults with a known date of infection. Our study examines 1) the characteristics of encephalopathy with onset before 1 year, after 1 year, and in adults, and 2) the maternal and birth characteristics of infants who developed AIDS before 1 year and went on to develop either encephalopathy or opportunistic infection. RESULTS: The incidence of encephalopathy was higher in children than in adults during the first year (9.9% versus 0.3%) and intermediate during the second year (4.2% versus 0%) after infection but was similar thereafter (less than 1% per year in each group). The resulting cumulative incidence at 7 years postinfection reached 16% in children and 5% in adults. Encephalopathy that developed before 1 year 1) was more frequently an isolated symptom of AIDS, 2) was associated with a reduction of intrauterine brain growth, 3) was associated with a very low level of HIV-1 RNA in CSF, 4) occurred at a higher level of immunocompetence after taking into account the decrease in CD4 lymphocytes with age, and 5) was not prevented by zidovudine treatment during gestation. CONCLUSIONS: Early encephalopathy in infants has a different pathophysiologic mechanism than that occurring in children, which in turn shows similarities with that observed in adults. Early encephalopathy is probably related to the occurrence of pathologic events during late fetal life.

Late coronary angioplasty and ventricular late potentials.

To assess the effect of successful late coronary angioplasty of an occluded infarct-related artery on the prevalence of ventricular late potentials, signal-averaged electrocardiograms were recorded in 123 consecutive patients surviving a first acute myocardial infarction (58 with and 65 without mechanical reperfusion of the occluded coronary artery). Multivariate analysis showed that successful reperfusion by late angioplasty of the infarct artery contributes to a decrease in the prevalence of late potentials.

Relation between successful late coronary angioplasty of an occluded, infarction-related artery and lower prevalence of ventricular late potentials.

BACKGROUND: The effect of mechanical reperfusion of the infarction-related artery on ventricular late potentials (VLP) continues to be debated. OBJECTIVE: To assess the influence of successful late coronary angioplasty on the prevalence of VLP after acute myocardial infarction (AMI). METHODS: We studied 113 consecutive patients (97 men, 16 women, mean age 57 +/- 10.8 years) in whom the infarction-related artery was occluded (thrombolysis in myocardial infarction score 0 or 1) at the time of the initial coronary arteriography 10.9 +/- 6.4 days after a first AMI. Successful late angioplasty of the infarcted artery was performed in 55 patients a mean of 11.5 +/- 7.2 days after AMI. The remaining 58 patients received a conservative treatment. Signal-averaged electrocardiograms (SAECGs) were recorded 25 +/- 10.2 days after AMI. Multivariate analysis was undertaken to assess the influence of late coronary angioplasty with respect to age, sex, infarction site, angiographic ejection fraction, extent of diseased coronary arteries, thrombolysis and time of recording the SAECG. RESULTS: The overall prevalence of VLP was 27%. It was greater in patients without than in those with angioplasty (40% compared with 15%, P = 0.017). Multivariate analysis demonstrated that successful angioplasty (odds ratio 3.2; P = 0.019) and ejection fraction >0.4 (odds ratio 5.1; P = 0.0051) were the strongest independent predictors of an absence of VLP. 'Non-inferior' myocardial infarction was also correlated with the absence of VLP (odds ratio 2.6), but with borderline significance (P = 0.053). CONCLUSION: When performed in an occluded, infarction-related artery, successful late coronary angioplasty contributes to a significant decrease in the prevalence of VLP.

[Risk reduction and intravenous drug use abstinence in patients with HIV infection. The SEROCO group]. / Réduction des risques et arrêt de la prise de drogues intraveineuses chez des sujets infectés par le VIH. Groupe SEROCO.

BACKGROUND: Little is known about the complex stepwise process of giving up intravenous (i.v.) drugs. However, HIV risk reduction programs directed towards i.v. drug users have been accused by some opponents to encourage users to continue. In order to better assess the relationships between risk reduction and abstinence, we studied factors associated with abstinence in HIV-infected patients using i.v. drugs at enrollment in the SEROCO cohort (1988-1994). METHODS: 63 HIV-infected patients injecting i.v. drugs at enrollment were followed-up every 6 months with a clinical examination and a questionnaire concerning sexual and drugs practices since last consultation. Abstinence was defined as non injecting for at least 6 months. The 30 patients who became abstinent during a follow-up period of 3 years were compared to the 33 remaining. RESULTS: Abstinence during follow-up was not related to age at inclusion, duration of i.v. drug use, gender or marital status. However, patients who became abstinent were more likely to have a professional activity at inclusion than the remaining (70% vs 42%, p = 0.03). Before knowledge of HIV infection, frequency of injections, needle sharing and use of condoms did not differ between the 2 groups. During follow-up, behavioural changes occurred in the two groups, but were more marked in those who lately became abstinent. These latter were more likely to always inject with new needles/syringes (57% vs 18%, p = 0.003), and to use condoms with HIV-negative partners or of unknown status (73% vs 39%, p = 0.06). Professional activity and systematic use of new needles/syringes remained independently associated with abstinence in multivariate analysis. CONCLUSION: In this cohort, abstinence appeared as a stepwise process in which risk reduction preceded abstinence. This confirms that risk reduction programs do not work against those messages aimed at stopping i.v. drug use. Since this analysis selected particular subjects, enrolled in a cohort of HIV-infected patients, results should be confirmed in other samples of i.v. drugs users.

PIP: Few prospective studies have described the stepwise process of giving up intravenous drug (IV) use. In an effort to deepen the understanding of the relationship between risk reduction related to IV drug use and giving up such drug use, the authors studied factors associated with IV drug abstinence among HIV-infected patients using IV drugs at their enrollment in the multicenter French cohort SEROCO between 1988 and 1994. 63 HIV-infected patients injecting IV drugs at enrollment were followed clinically every 6 months and with a questionnaire on their sexual practices and drug use since their most recent consultations. The termination of drug use was defined as not using drugs for a period of at least 6 months. The 30 subjects who gave up IV drug use over the 3-year follow-up were compared to the 33 subjects who continued using IV drugs. Those who gave up IV drugs were more likely to be professionally active at enrollment than those who kept injecting, they more often used during the follow-up period new injection materials for each injection, and more often used condoms with HIV-negative partners and those of unknown serostatus. The abandonment of IV drug use in this study followed a stepwise process in which the reduction of risks preceded the eventual cessation of drug use.

[Factors determining the improvement of effort capacity in aged patients with coronary disease during the 1st month following coronary surgery]. / Facteurs déterminant l'amélioration de la capacité à l'effort des coronariens âgés dans le premier mois suivant la chirurgie coronaire.

UNLABELLED: In order to determine the predictive factors of improvement of the physical capacity of elderly coronary patients following coronary surgery, we retrospectively analysed the data of 204 consecutive patients over the age of 65 years (181 men, 23 women, mean age: 70 +/- 4.4 years), admitted for a phase II active training programme. METHODS: The patients were divided into two groups as a function of the rate of improvement of the duration of the stress test: group A (improvement greater than or equal to 25%; n = 108) and group B (less than 25%; n = 96). Comparison of these 2 groups by multivariate analysis identified predictive factors of improvement among seven variables: age, sex, excess weight, haemoglobin, number of training sessions, duration of baseline stress test, interval between bypass graft and start of training. RESULTS: After training, the duration of the stress test and the maximal power were improved by 26.5% and 24%, respectively: 7.1 +/- 1.7 vs 8.9 +/- 2.3 minutes (p = 0.0001); 79 +/- 18.4 vs 97.8 +/- 23.7 watts (p = 0.0001). 34 (1.4%) of the 2,396 training sessions were temporarily interrupted, because of muscle fatigue in 47% of cases. Patients who had readapted before the 15th postoperative day presented fewer incidents: 4.3% vs 13.1%; NS. Only three variables appeared to be predictive of improvement of physical capacity: a duration less than 6 minutes on the baseline stress test (p = 0.0003), more than 12 training sessions (p = 0.0029) and age less than or equal to 70 years (p = 0.014). CONCLUSION: In elderly subjects undergoing coronary surgery, the improvement of physical capacity is greater the lower the baseline effort, the lower the age-group and the greater the number of training sessions. In the absence of contraindication, it appears justified to include elderly coronary patients in training programmes, even when their baseline effort level appears to be low. This training can be started by the 15th postoperative day.

The use of auxiliary events to improve the analysis of survival for HIV-infected patients: application to the French Prospective Multicenter Cohort (SEROCO).

SUMMARY: A multicenter prospective cohort study, including 512 patients for whom date of HIV infection was known, showed that the use of an appropriate auxiliary event can improve the analysis of survival data and lead to an earlier detection of risk factors for HIV patients. Age at seroconversion and primary symptomatic infection were used as risk factors. Two age groups were defined as age at seroconversion >30 years (n = 203) and < or = 30 years (n = 309). Patients with primary symptomatic infection PSI (n = 215) were compared with patients without any clinical manifestation during primary infection (n = 297). Death was considered as the endpoint of primary interest and occurred in 76 patients in the study. Classical non-parametric methods (Kaplan-Meier estimate and long-rank test) and parametric regression model (Weibull model) were used for a standard analysis of survival data. A parametric approach using auxiliary information was used to estimate the survival function and to test the effect of age at seroconversion and PSI. We also applied a recently proposed distribution-free method to produce a non-parametric estimate of the survival function and to test age at seroconversion and PSI with respect to survival estimates. Both methods are compared for two distinct auxiliary events (Karnofsky score below 75 and a first drop of CD4 lymphocyte counts below 200 cells/MM3). The use of CD4 lymphocyte counts below 200 cells/MM3 as an auxiliary event improved the analysis of survival data available in December 1994. For both methods incorporating CD4 counts below 200 cells/mm3 in addition to survival data, the effect of age at seroconversion on survival was significant in April 1992 whereas it was not significant with standard methods. For PSI exposure group, results shown in this work do not indicate any improvement in using auxiliary information. Conditions for using an appropriate auxiliary event as well as advantages and shortcomings of both methods are discussed. Methods used in this work, with appropriate auxiliary information, are promising either through a reduction in the time to follow-up to detect risk factors for cohort studies or the time needed for drug development in clinical trials.

High risk of HIV disease progression after infection through a sexual partner with AIDS.

OBJECTIVE: To investigate whether HIV-1 infection acquired through a severely immunodepressed sexual partner increases the risk of disease progression. DESIGN: A prospective cohort of patients infected through sexual contact at a known date and enrolled a few months (median, 2 months) after their first HIV-positive test. At enrolment, 12 subjects stated having had unprotected intercourse (anal or vaginal penetration) with a partner with AIDS within the 6 months prior to their first HIV-positive test. For the same period, 60 subjects stated having had unprotected intercourse with a partner, known to be HIV-positive, but who had not developed AIDS. METHOD: The endpoint was the first occurrence of an HIV-related illness (group IV or AIDS, 1987 Centers for Disease Control and Prevention revised classification). Event-free survival curves since infection were constructed using the Kaplan-Meier method and compared by the log-rank test. The Cox model was used for multivariate analysis. RESULTS: Disease progression was more rapid among the 12 subjects who stated having sex with a person with AIDS at a time close to infection, than among the other subjects (P = 0.03). Homosexuality and age at infection were also related to HIV disease progression. The adjusted relative risk of developing an HIV-related illness among those 12 subjects was 3.9 (95% confidence interval, 1.5-9.9). CONCLUSION: Our results confirm the influence of virus-related factors on the onset of immunodepression in subjects infected through sexual contact.

Influence of neurologic manifestations of primary human immunodeficiency virus infection on disease progression. SEROCO Study Group.

To determine the influence of neurologic manifestations of primary human immunodeficiency virus (HIV) infection on disease progression, 277 nonhemophiliac adults enrolled < 1 year after HIV infection were studied. Patients with neurologic manifestations during symptomatic primary HIV infection (PSI) (group N+; n = 23), with nonneurologic manifestations (group N-; n = 112) during PSI, and without any clinical manifestation during primary infection (group NPI; n = 142) were compared for disease progression. Age at infection, sex, mode of infection and CD4+ cell count at first visit did not differ between groups. In a Cox model, the relative risk (RR) of developing AIDS was 6.11 (95% confidence interval [CI], 1.94-19.28) in group N+ and 2.32 (95% CI, 0.93-5.83) in group N- compared with group NPI. The RR of AIDS onset after adjustment for treatment and age at infection was, respectively, 4.65 (95% CI, 1.43-15.03) and 2.03 (95% CI, 0.80-5.19) in groups N+ and N-. Neurologic manifestations of primary HIV infection are associated with an accelerated progression of disease.

Effect of age and exposure group on the onset of AIDS in heterosexual and homosexual HIV-infected patients. SEROCO Study Group.

OBJECTIVE: To analyse the influence of age at seroconversion and sexual exposure group on the progression of HIV disease. DESIGN: This multicentre prospective cohort study involved 443 subjects whose date of HIV infection was known to within +/- 1 year. Individuals whose sexual behaviour was exclusively heterosexual after HIV infection constituted the heterosexual group (n = 131). AIDS-free survival was compared with that of men (n = 312) infected through homosexual sex and who continued homosexual activity after HIV infection. They constituted the homosexual group. METHODS: The end-point was the onset of an AIDS-defining illness listed in the 1987 revised Centers for Disease Control and Prevention (CDC) criteria. Using the Kaplan-Meier method, AIDS-free survival curves were plotted for three age categories (< 20, 20-39, > or = 40 years). A Cox model was used to quantify the effect of age and to assess the influence of exposure group on AIDS onset after adjustment for age. Because of the high incidence of Kaposi's sarcoma (KS) among homosexual men, a disease that can be an early AIDS-defining illness, multivariate analysis was performed with and without consideration of the occurrence of KS. RESULTS: Patients aged > or = 40 years at seroconversion progressed more rapidly to AIDS than younger patients (P < 0.006). When age was fitted as a continuous variable and adjusted for exposure group, the relative risk of developing AIDS by any time after seroconversion was 1.34 for a 10-year increase difference [P = 0.03; 95% confidence interval (CI), 1.03-1.77]. After adjustment for age, the relative risk of developing AIDS (CDC criteria) was 2.42 (P = 0.008; 95% CI, 1.18-4.97) among the homosexual men (AIDS cases, n = 56). All cases of KS (n = 19) involved the homosexual group. Excluding KS as a first manifestation of AIDS, homosexual or bisexual subjects had a risk of AIDS of 1.92 (P = 0.07; 95% CI, 0.92-4.03) compared with heterosexual subjects. CONCLUSIONS: The risk of AIDS increases with age at seroconversion. The more rapid progression towards AIDS in the homosexual group than in the heterosexual group persisted after adjustment for age. Further studies are required to determine the possible role of repeated exposure to HIV or other pathogens acquired sexually.

The 'corpuscle' stereological problem--re-evaluation using slab fragment volumes and application to the correction of DNA histograms from sections of spherical nuclei.

A new category of stereological size distribution unfolding models is introduced. It is based on the use of the volumes of particle slab fragments, in addition to their profile dimensions. When spheres are cut by a slab of known (constant) thickness, as estimation of discrete sphere sizes from section data is then possible, as only one parent sphere solution exists for any slab fragment, given the latter's projection size and volume. The unfolding algorithm consists in sequentially testing a set of equations: only one of the solutions satisfies various constraints on bounds. A precise determination of the section thickness is required. Truncation parameters, instead of being troublesome inputs as in classical unfolding models, become valuable outputs. This model offers the first stereologically valid solution to the important problem of correcting DNA-amount histograms obtained from sectioned spherical nuclei. Under the (biologically reasonable) assumption that the nuclear volume is proportional to the DNA amount, it is possible to estimate the DNA concentration and, subsequently, compute discrete slab fragment volumes from corresponding DNA values. An application to Feulgen-stained rat liver sections is shown. Measurements of hepatocytic nuclear-profile areas and integrated optical densities are obtained by automated image analysis (IBAS), and the model is used to unfold the section-obtained DNA histogram. A maximum likelihood fitting of the final distribution with chi functions allows a parametric estimation of ploidy frequencies. This model can only be used for acceptably spherically shaped particles.