Jean-Baptiste Hubert

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

ObjectiveTo 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. DesignA total of 330 patients with a known date of infection followed in the SEROCO cohort. MethodsHIV-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. ResultsIn 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/μl and the onset of a group B condition remained significant predictors of progression. ConclusionOur 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.

Impact of 5 years of maximally successful highly active antiretroviral therapy on CD4 cell count and HIV-1 DNA level.

Objectives: To evaluate the impact on CD4 cell count and HIV-1 DNA level in peripheral blood mononuclear cells (PBMC) of long-term highly active antiretroviral therapy (HAART) in the setting of maximal success, i.e., constant plasma HIV-1 RNA load suppression. Design: Retrospective analysis of patients selected for a constantly undetectable plasma HIV-1 RNA load since HAART initiation. Methods: HIV-1 DNA was measured in PBMC using a real-time polymerase chain reaction assay. Loess estimates and regression analysis were used for modelling the variations of the CD4 cell count and HIV DNA level over time. Results: The study included 41 patients chronically infected with HIV-1 who had been taking HAART for a median duration of 60.4 months and had an undetectable plasma HIV RNA load ever since the first 6 months of HAART; 25 were tested for HIV-1 DNA. The mean CD4 cell count increase was high during the first 18 months on therapy (168 × 106 cells/l per year), much lower afterwards (38 × 106 cells/l per year), independently of the baseline CD4 cell count. Most of the patients (73.2%) reached a CD4 cell count constantly ⩾ 400 × 106/l during follow-up. HIV-1 DNA showed a mean decrease of 0.48 log10 copies/106 PBMC during the first year, of 0.18 log10 copies/106 PBMC per year during the 2nd and 3rd years, but no significant decrease afterwards. Conclusions: These results question the benefit of very long-term maintenance of HAART in terms of CD4 gain and HIV-1 DNA reduction.

Early Levels of HIV-1 DNA in Peripheral Blood Mononuclear Cells Are Predictive of Disease Progression Independently of HIV-1 RNA Levels and CD4+ T Cell Counts

BACKGROUND The objective of this work was to assess the role of human immunodeficiency virus (HIV) reservoirs in the risk of disease progression, by studying the relationship between HIV DNA level in peripheral blood mononuclear cells (PBMCs) and progression toward acquired immunodeficiency syndrome (AIDS). METHODS HIV-1 DNA levels in PBMCs were determined by quantitative polymerase chain reaction for 383 patients enrolled in the SEROCO Cohort Study who had experienced seroconversion and had been followed up for >8 years. We compared the predictive values of HIV DNA level, HIV RNA level, and CD4+ cell count. RESULTS Between 6 and 24 months after seroconversion, HIV DNA level was a major predictor of progression to AIDS independently of HIV RNA level and CD4+ T cell count (adjusted relative risk [RR] for a 1-log(10) increase, 3.20 [95% confidence interval {CI}, 1.70-6.00]). HIV DNA level was also a major predictor of disease progression during the first 6 months after seroconversion (adjusted RR, 4.16 [95% CI, 1.70-10.21]), when HIV RNA level and CD4+ T cell count were less predictive. Thus, a combination of these 3 markers provides the best estimate of the risk of disease progression for each patient. CONCLUSIONS Our results suggest that HIV DNA level could be a useful additional marker in clinical practice and could aid in helping to define the best time to initiate treatment for each patient.

Early protective effect of CCR-5 Δ32 heterozygosity on HIV-1 disease progression : relationship with viral load

Objective:To determine the influence of heterozygosity for the Δ32 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 for 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.

Increase in at-risk sexual behaviour among Hiv-1-infected patients followed in the French Primo cohort

Objective: With the current increase in sexually transmitted infections in industrialized countries, we assessed the characteristics and plasma viral load of HIV-1-infected patients reporting sexual behaviour at risk for HIV transmission (SBR). Design: The study population consisted of 223 patients with primary HIV-1 infection who were enrolled in the French PRIMO cohort between 1996 and 2001 and who had at least 3 months of follow-up. Patients were interviewed on condom use at each visit according to the partner (gender, steady versus casual nature, and HIV serostatus). SBR was defined as unprotected sex with partners of unknown or negative HIV serostatus. Results: Sixty-one SBR were reported by 43 patients. SBR with casual partners increased from 5.1% in 1998 to 21.1% in 2001–2002, after a fall between 1997 and 1998. Reporting of SBR was more frequent among patients with casual partners, those with asymptomatic or briefly (⩽ 15 days) symptomatic primary infection, and those who had developed clinical lipodystrophy or signs of anxiety/depression. Eighty-six per cent of patients reporting SBR had previously initiated highly active antiretroviral therapy (HAART); plasma viral load was above the detection limit (200/500 copies/ml) in 41% of visits reporting an SBR. Viral load was similar in patients reporting SBR and other patients, suggesting that the patients knowledge of his/her response to HAART was not a major determinant of subsequent SBR. Conclusion: Our results confirm the recent increase in unsafe sex observed among HIV-infected individuals in industrialized countries. Levels of viral load of these individuals raise concern about the potential for re-emerging HIV epidemics.

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.

The HIV RNA setpoint theory revisited

BackgroundThe evolution of plasma viral load after HIV infection has been described as reaching a setpoint, only to start rising again shortly before AIDS diagnosis. In contrast, CD4 T-cell count is considered to show a stable decrease. However, characteristics of marker evolution over time depend on the scale that is used to visualize trends. In reconsidering the setpoint theory for HIV RNA, we analyzed the evolution of CD4 T-cell count and HIV-1 RNA level from HIV seroconversion to AIDS diagnosis. Follow-up data were used from two cohort studies among homosexual men (N = 400), restricting to the period before highly active antiretroviral therapy became widely available (1984 until 1996). Individual trajectories of both markers were fitted and averaged, both from seroconversion onwards and in the four years preceding AIDS diagnosis, using a bivariate random effects model. Both markers were evaluated on a scale that is directly related to AIDS risk.ResultsIndividuals with faster AIDS progression had higher HIV RNA level six months after seroconversion. For CD4 T-cell count, this ordering was less clearly present. However, HIV RNA level and CD4 T-cell count showed qualitatively similar evolution over time after seroconversion, also when stratified by rate of progression to AIDS. In the four years preceding AIDS diagnosis, a non-significant change in HIV RNA increase was seen, whereas a significant biphasic pattern was present for CD4 T-cell decline.ConclusionHIV RNA level has more setpoint behaviour than CD4 T-cell count as far as the level shortly after seroconversion is concerned. However, with respect to the, clinically more relevant, marker evolution over time after seroconversion, a setpoint theory holds as much for CD4 T-cell count as for HIV RNA level.

Cytomegalovirus seroconversion as a cofactor for progression to AIDS.

ObjectiveTo study the impact of cytomegalovirus (CMV) seroconversion on HIV-1 disease progression. DesignFollow-up of CMV-seronegative subjects enrolled in the French SEROCO/HEMOCO cohorts of HIV-infected subjects. MethodsA 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 × 106 cells/l and to clinical AIDS. ResultsOverall, 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 × 106 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]. ConclusionThis analysis of 61 CMV seroconversions, the largest study in the literature, confirms the impact of recent CMV infection on progression to AIDS.

CCR5 Δ32 Deletion and Reduced Risk of Toxoplasmosis in Persons Infected with Human Immunodeficiency Virus Type 1

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-Hodgkins lymphoma, Kaposis 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.

Causal Pathways of the Effects of Age and the ccr5 -δ32, ccr2-64i , and sdf-1 3′a Alleles on Aids Development

Objective:To investigate the causal pathways by which age and the CCR5-Δ32, CCR2-64I, and SDF-1 3′A alleles influence progression to AIDS. Design:Analysis of follow-up data from 2 cohort studies among homosexual men (n = 400), having >10 years of follow-up. Methods:The effects of the 4 cofactors on the CD4 and HIV-1 RNA trajectories after seroconversion were modeled in a random-effects model. A proportional hazards model was used to investigate their effect on the risk of AIDS after correction for CD4 cell count and RNA level. This approach allows investigation as to whether they influence AIDS progression by affecting CD4 count and RNA level or by other pathways. Results:Persons of younger age or having the CCR2-64I or SDF-1 3′A mutation have significantly higher CD4 levels. Persons with the CCR5-Δ32 deletion or CCR2-64I mutation have significantly lower RNA levels. After correction for both CD4 count and RNA level, only the SDF-1 3′A mutation significantly increases the AIDS risk. Conclusions:Age and the CCR5-Δ32 deletion and CCR2-64I mutation influence AIDS progression by affecting CD4 and HIV-1 RNA. The SDF-1 3′A allele increases the AIDS risk, but this effect is countered by its effect on CD4 and HIV-1 RNA level.