Blood Epstein-Barr virus DNA load and risk of progression to AIDS-related systemic B lymphoma.

BACKGROUND: AIDS-related lymphoma (ARL) remains the main cause of AIDS-related deaths in the combined antiretroviral therapy (cART) era. Although most ARLs are associated with the Epstein-Barr virus (EBV), whether patients with high EBV burden are more at risk of developing ARL is unknown. This study investigated the relationship between high blood EBV DNA loads and subsequent progression to ARL. METHODS: We identified 43 cases of ARL diagnosed between 1988 and 2007 within two cohorts (ANRS SEROCO/HEMOCO and PRIMO) and for which stored serum and peripheral blood mononuclear cell (PBMC) samples were available within 3 years before ARL diagnosis. For each case, two controls matched for the cohort and CD4 cell count in the year of ARL diagnosis were selected. EBV DNA was measured in PBMCs and serum samples with a commercial kit. RESULTS: High levels of EBV DNA in PBMCs collected a median of 10 months before diagnosis were associated with an increased risk of developing systemic B lymphoma (adjusted odds ratio 2.47; 95% confidence interval 1.15; 5.32 for each 1 log copies/10(6) PBMC increase in EBV load) but not with primary brain lymphoma. CONCLUSION: In this study, HIV-infected patients with undetectable EBV DNA in PBMCs did not develop ARL in the following 3 years, while high levels of EBV DNA in PBMCs predicted subsequent progression to systemic B lymphoma. Clinicians should be aware of the increased risk of developing systemic B lymphoma in HIV-infected patients with a high blood EBV DNA load.

Weak anti-HIV CD8(+) T-cell effector activity in HIV primary infection.

HIV-specific CD8(+) T cells play a major role in the control of virus during HIV primary infection (PI) but do not completely prevent viral replication. We used IFN-gamma enzyme-linked immunospot assay and intracellular staining to characterize the ex vivo CD8(+) T-cell responses to a large variety of HIV epitopic peptides in 24 subjects with early HIV PI. We observed HIV-specific responses in 71% of subjects. Gag and Nef peptides were more frequently recognized than Env and Pol peptides. The number of peptides recognized was low (median 2, range 0-6). In contrast, a much broader response was observed in 30 asymptomatic subjects with chronic infection: all were responders with a median of 5 peptides recognized (range 1-13). The frequency of HIV-specific CD8(+) T cells among PBMC for a given peptide was of the same order of magnitude in both groups. The proportion of HIV-specific CD8(+)CD28(-) terminally differentiated T cells was much lower in PI than at the chronic stage of infection. The weakness of the immune response during HIV PI could partially account for the failure to control HIV. These findings have potential importance for defining immunotherapeutic strategies and establishing the goals for effective vaccination.

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.

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.

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.

Pregnancy and contraception in a French cohort of HIV-infected women. SEROCO Study Group.

OBJECTIVE: To describe the impact of HIV diagnosis on contraception, incidence of pregnancy and live-births among HIV-infected women in France. DESIGN: Follow-up of women included in a French cohort of HIV-infected adults (SEROCO). METHODS: In 17 hospital-based units and one private practitioners' network in the Paris area and south-east region of France, 412 HIV-infected women (volunteers) were enrolled from 1988 to 1993, shortly after HIV diagnosis (median, 3 months), and followed for a median of 3 years. The main outcome measures were incidence and outcome of pregnancy, proportions of women sexually active and methods of contraception. RESULTS: The incidence of pregnancy decreased significantly from 20.4 per 100 person-years in the year preceding HIV diagnosis to 7.9 per 100 person-years after HIV diagnosis (P < 0.001), whereas the proportion of pregnancies voluntarily interrupted doubled (63 versus 29%). The proportion of women who were sexually inactive increased from 5% before HIV diagnosis to 20% thereafter. During followup, 80% of sexually active women were using contraceptive methods. CONCLUSIONS: The study supports an association between the discovery of HIV infection and a decrease in the proportion of women who are sexually active, a decrease in the incidence of pregnancy in general and live-births in particular, and an increase in the proportion of pregnancies voluntarily interrupted. Nevertheless, 24% of the women became pregnant and around 20% of sexually active women were not using any contraception. The high rate of voluntary abortion may indicate that many of these pregnancies were unplanned and could have been prevented.

Proviral HIV-1 DNA in subjects followed since primary HIV-1 infection who suppress plasma viral load after one year of highly active antiretroviral therapy.

OBJECTIVE: An assessment of the impact of one year potent antiretroviral treatment initiated during primary HIV infection on the cell-associated viral burden. DESIGN AND METHODS: Proviral HIV-1 DNA was quantified in serial peripheral blood mononuclear cell (PBMC) samples from 19 patients enrolled in the French prospective PRIMO Cohort for whom plasma HIV RNA was suppressed to undetectable levels after one year of triple therapy; that is, plasma HIV-1 RNA was maintained below 200 copies/ml. Results were compared with those observed in 19 patients with chronic HIV-1 infection presenting the same degree of virus suppression after 12 months of treatment. RESULTS: At study entry, PRIMO subjects presented heterogeneous levels of proviral HIV-1 DNA: 2-3.92 log10 copies/10(6) PBMC and plasma HIV RNA: 2.3-6.5 log10 copies/ml. One year of effective highly active antiretroviral therapy (HAART) resulted in a median diminution of proviral DNA of -0.78 log10/10(6) PBMC in PRIMO subjects. The median decline in chronic-phase patients was -0.32 for those who were pre-treated and -0.52 for those previously naive of treatment. CONCLUSION: The decline in cell-associated HIV DNA observed throughout one year treatment indicated that HAART reduces the proviral HIV-DNA load more effectively when initiated during the primary rather than the chronic phase of HIV infection. These findings therefore tend to lend support to the early initiation of treatment. Nevertheless, heterogeneous baseline values observed for CD4 cell count, plasma HIV RNA and proviral HIV DNA in PRIMO subjects, raise the question of whether treatment should be delayed in some to spare early adverse effects of HAART.

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.

Influence of age at infection on human immunodeficiency virus disease progression to different clinical endpoints: the SEROCO cohort (1988-1994). The Seroco Study Group.

METHOD: The influence of age at infection on progression of human immunodeficiency virus (HIV) disease to different clinical endpoints was studied among 393 HIV-seropositive adults selected from the French SEROCO cohort; follow-up lasted from January 1988 to November 1994. Selected patients had a known date of infection and were enrolled shortly after seroconversion. Age-associated risk ratios (RR) were estimated using the Cox model (age fitted as a continuous variable and RR expressed for each 10-year increment after adjustment for symptomatic primary infection and sexual preference). RESULTS: Age had a weak influence on progression from the date of infection to the first category B event (crude RR = 1.15; adjusted RR = 1.09; 95% confidence interval [CI]: 0.89-1.36) but a marked influence on progression from the first category B to the first category C event (crude RR = 1.95; adjusted RR = 1.97; 95% CI: 1.37-2.79). Similar results were obtained after adjustment for the CD4+ cell count at enrollment. A qualitative CD4+ cell defect could explain the influence of age, but this remains to be confirmed. CONCLUSION: Age at infection should be included in the definition of CD4+ cell count thresholds for clinical management and treatment initiation. Risk factors for progression should be assessed according to the different clinical endpoints.

Serum interleukin-10 in acquired immunodeficiency syndrome lymphoma patients. Seroco-Hemoco Study Group.

Interleukin-10 (IL-10) has multiple effects on lymphoid development, particularly as a stimulant of activated B-cell proliferation and differentiation. It is thought that IL-10 might play a role in the development of B lymphoid malignancies based on the observation that lymphomatous tissues from HIV+ patients contain numerous cells containing IL-10 mRNA as well as IL-10 protein. The aim of this study using an Elisa test was to analyze IL-10 in the serum of 18 HIV+ patients with non Hodgkin's B lymphoma (NHL) and compared the presence of this cytokine in the serum of 18 HIV+ patients without NHL. In this comparative study we also considered the different parameters such as the mode of contamination, sex, age and number of CD4 cells. 44% of the patients with HIV-related NHL had significant levels of IL-10 (> or = 12 pg/ml) in their serum, in comparison to the patients without NHL who did not show detectable serum IL-10.

[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.

[Multicenter French cohort of adults with HIV infection. Description and course after 4 years of follow-up. SEROCO]. / Cohorte francaise multicentrique d'adultes infectés par le VIH. Description et évolution après 4 ans de suivi. SEROCO.

OBJECTIVES: A prospective multicentric epidemiological study (SEROCO) of subjects with a diagnosis of human immunodeficiency virus (HIV) infection was started on January 1, 1988 in order to better understand the natural history of HIV infection and factors related to outcome. Observations after 4 years of follow-up are reported here. METHODS: After authorization by the French national ethics committee and the national commission for personal freedom, 18 French centres included non-haemophiliac volunteers who were asymptomatic, had had non anti-HIV treatment and whose HIV positivity had been known less than 1 year at inclusion. These last three criteria were not required for patients whose precise date of contamination was known within a range of +/- 3 months. RESULTS: On July 15, 1992, there were 1453 infected subjects in the cohort (1063 males, 417 females; age range at inclusion 18-75 years; mean age 31.3 +/- 9.4). Globally, 2.7% of the subjects were symptomatic at inclusion. Mean CD4 lymphocyte count at inclusion was 508/mm3. Clinically, 51.5% of the patients had a history of sexually transmitted disease at inclusion. After 4 years (on July 15, 1992) mean follow-up was 28 +/- 12.9 months for a total of 3428 patient-years. Disease progression to stage IV was observed in 439 patients including 202 who developed the acquired immuno-deficiency syndrome (AIDS). Among these 202 patients, 113 had died at the end-point of this report. The first manifestation of AIDS was Kaposi sarcoma in 44, pulmonary pneumocystosis in 38 and cerebral toxoplasmosis in 27. The probability of developing AIDS was calculated at 13.9% at 5 years, 27.7% at 7 years and 33.7% at 10 years. The probability of a CD4 count below 200/mm3 was 32.7, 55.6 and 67% at 5, 7 and 10 years respectively. For patients with a CD4 count below 200, the probability of developing AIDS was 18% at 1 year, 39% at 2 years and 51% at 3 years. CONCLUSIONS: SEROCO has been a most useful prospective epidemiological tool due to the diversity of the subjects included. The observed natural history of HIV infection will lead to specific research projects aimed at better understanding the disease process.

Prevalence of CXCR4-tropic viruses in clustered transmission chains at the time of primary HIV-1 infection.

During 2003-2010, 555 strains isolated from sexually-infected patients at the time of primary HIV-1 infection (PHI) were characterized. Tree topology revealed that 11.7% of PHIs segregated into transmission clusters. CXCR4-usage was identified in 27 strains (4.9%) and was significantly associated with subtype B (p 0.003) and low CD4 cell count (p 0.01). In clustered and unique PHIs, the prevalence of CXCR4-tropic strains was 1.5% and 5.3%, respectively (p 0.35). Our results are in line with the hypothesis of a mucosal bottleneck contributing to the high prevalence of CCR5 variants during PHI.

Impact of highly active antiretroviral therapy on the maturation of anti-HIV-1 antibodies during primary HIV-1 infection.

OBJECTIVES: To study the impact of highly active antiretroviral therapy (HAART) on isotype switching and avidity maturation of HIV-1-specific immunoglobulin G (IgG) in patients with primary HIV-1 infection (PHI). METHODS: We studied the emergence and the evolution of anti-HIV IgG antibodies by quantitative immunoblotting to analyse IgG subclasses and IgG avidity. Serum samples were obtained from 16 PHI patients from the French PRIMO Cohort Study at various points in the first year of infection: eight patients received no treatment (group I), and eight patients received efficient HAART (group II) during the study period. RESULTS: Early initiation of HAART in PHI patients partially prevented an increase in anti-HIV-1 IgG levels. Within IgG subclasses, the amount of anti-HIV-1 IgG1 gradually increased with time in both groups, although levels remained lower in treated patients. The anti-p24 IgG2 level was always lower in group II. We observed a decrease in anti-p24 IgG3 over time in both groups. Treatment did not affect the maturation of HIV-1 IgG avidity, which increased in both groups until month 3 and then remained high until the end of the 12-month follow-up period. CONCLUSIONS: HAART in PHI partially prevents the emergence of HIV-1 IgG antibodies, but does not affect the quality of these antibodies, as reflected in their isotype and avidity.

Increase in hepatitis C virus incidence in HIV-1-infected patients followed up since primary infection.

BACKGROUND: An increase in the incidence of sexually transmitted infections and hepatitis C virus (HCV) infections in HIV-infected men who have sex with men (MSM) has recently been reported. OBJECTIVE: To estimate HCV incidence and risk factors among HIV-1-infected patients followed up since primary HIV infection in the French PRIMO Cohort between 1996 and 2005. PATIENTS AND METHODS: All patients with at least 18 months of follow-up were studied. HCV antibody tests were performed on baseline plasma samples and repeated on the latest available sample when negative at baseline. RESULTS: In total, 402 patients with a median follow-up of 36 (range 18-104) months were eligible. HCV seroconversion was observed in 6 patients (4 men and 2 women), corresponding to an HCV incidence rate of 4.3 per 1000 person-years. Incidence rates in men and women were 3.5 and 7.8 per 1000 person-years, respectively. The incidence rate was 1.2 per 1000 person-years before January 2003 and 8.3 per 1000 person-years after January 2003 (p = 0.06). The classic risk factors for HCV infection were found in women (intravenous drug use, and body piercing), whereas the only identified risk factor for HCV acquisition was unsafe sex in the four men. CONCLUSIONS: Increase in the incidence of acute HCV infection in recently HIV-infected patients confirms the shift in sexual behaviour in the recent years, especially in HIV-infected MSM. Repeated testing for HCV antibodies should be carried out in HCV-negative HIV-infected patients and specific recommendations about protected sex should be clearly provided.

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.

HEMOCO: a French prospective study of hemophiliacs infected by human immunodeficiency virus type 1 (HIV-1).

HEMOCO is a multicenter prospective cohort set up in 1989 to monitor 407 French hemophiliacs infected by HIV-1 and recruited in 4 hemophilia treatment centers in the Paris region. As of 15 July 1995, 42% of the patients in the cohort had developed stage B HIV disease and 29% stage C disease (AIDS); 23.1% of the patients had died. The cumulative proportion of patients with AIDS was 4.5% at 5 years and 27.4% at 10 years, while the respective mortality rates were 3.8% and 19.5%. In our study, only age was predictive of AIDS, with an estimated relative risk of 1.2 per 10-year age increment; this factor was also predictive of death. After 10 years of follow-up, 6.1% of the study population had no clinical or laboratory signs of immunodepression. The follow-up protocol in the HEMOCO protocol is the same as that in the French SEROCO study, which includes men infected by HIV-1 through sexual contact. This will allow us to compare the progression of HIV infection between these two exposure groups.

Recent changes in the management of primary HIV-1 infection: results from the French PRIMO cohort.

OBJECTIVES: To describe the management of primary HIV infection (PHI), focusing on changes in the design of therapies and time to initiation of antiretroviral treatment, the clinical outcome, and the immuno-virological response over time to highly active antiretroviral therapy (HAART) and its tolerance. DESIGN AND METHODS: In the French PRIMO multicentre cohort, 291 patients presenting with PHI were enrolled between 1996 and 2001. Data were analysed to describe treatment prescription habits over a period of 5 years, and response to and tolerance of treatment. RESULTS: The proportion of patients who initiated treatment during PHI decreased from 92% in 1996 to 56% in 2001. At 6 months, whatever the initiated treatment, 74% of treated patients achieved a plasma viral load<400 HIV-1 RNA copies/mL and 53% achieved a viral load of<50 copies/mL. Prescription of protease inhibitor (PI)-sparing regimens has become more frequent since 1999. Despite a similar virological response, patients in the PI-containing group tended to experience a greater 1-year increase in CD4 cell count than those in the non-nucleoside reverse transcriptase (NNRTI)-containing group (218 cells/microL versus 157 cells/microL, respectively). An adverse event was recorded in 51% of treated patients. The most frequent events were gastrointestinal disorders (71%), lipodystrophy (27%) and mood disorders (19%). The main reason for modifying or stopping therapy was the occurrence of an adverse event. CONCLUSIONS: Limitations of therapy and poor tolerance to antiretroviral regimens have changed physician attitudes in PHI. This suggests the need for evaluation of better-tolerated regimens and new therapeutic strategies.