Agence Nationale De Recherche Research Articles

Undetectable Viremia without Antiretroviral Therapy in Patients with HIV Seroconversion: An Uncommon Phenomenon?

The objective of this study was to identify the frequency and characteristics of patients with human immunodeficiency virus (HIV) infection who had spontaneously achieved viremia below the detection limit of either 400 or 500 copies/mL (depending on the test used) and to describe the duration of undetectable viremia without antiretroviral therapy (ART). In the French Agence Nationale de Recherches sur le SIDA SEROCO cohort, 426 patients with HIV seroconversion (i.e., seroconverters) enrolled between 1988 and 1995 had serial measurement of HIV RNA levels during follow-up (with a cutoff date of 31 December 2002). Factors that distinguished those patients who had spontaneously achieved undetectable viremia (> or =2 consecutive viral loads <400 or <500 copies/mL while not receiving ART) were identified by logistic regression. A Cox model was used to estimate the predictive value of factors related to the duration of undetectable viremia. Undetectable viremia had been spontaneously achieved in 36 of 426 seroconverters. Women (adjusted odds ratio [aOR], 2.44; 95% confidence interval [CI], 1.03-5.80) and subjects with baseline HIV RNA level < or =3.76 log10 copies/mL (aOR, 0.31; 95% CI, 0.11-0.82), baseline HIV DNA level < or =2.61 log10 copies/mL (aOR, 0.14; 95% CI, 0.04-0.44), and high baseline CD4+ cell count (aOR, 1.18 for each 100 cells/mm3; 95% CI, 1.03-1.35]) were more likely to have achieved undetectable viremia. The sustainability of this phenomenon (median duration, 11.9 months; range, 4.6-62.8 months) was associated with low baseline HIV DNA and RNA levels. Achieving undetectable viremia without ART was not rare, because 6.7% of seroconverters still had a viral load of <400 or <500 copies/mL 5 years after seroconversion. These data should be considered when assessing virologic outcome for patients who interrupt highly active ART initiated during primary infection.

Reply to Bruno et al.

We would like to thank Bruno and colleagues for their interest in the updated recommendations from the HIV–HCV International Panel published in the journal earlier this year [1]. The authors mentioned that there are some incorrect figures in two of the studies recorded in the table, in which the results of trials using pegylated interferon (peg-IFN) plus ribavirin are summarized. However, the two trials were ongoing at the time the manuscript was submitted for publication. Two of the main investigators of those trials were members of the panel and they updated their results at the time the manuscript was written, which explains the apparent discordances found by Bruno et al. looking at abstracts presented at older conferences. The final results of one of those studies, the French RIBAVIC trial, were recently presented at the 11th Conference on Retroviruses and Opportunistic Infections [2]. Moreover, more updated results from the other study were presented at the Digestive Disease Week, 2003, which took place in Orlando in May 2003. In that Italian trial, 69 patients were randomly assigned to receive peg-IFN plus ribavirin; the virological response at 24 weeks had been reached by 19 of the 34 co-infected patients (56%) treated until that moment [3]. The authors ended their comments highlighting the results of the APRICOT trial, another study presented at the latest Retrovirus Conference, in which peg-IFN plus ribavirin was used for treating hepatitis C virus (HCV) in HIV-co-infected patients [4]. Although the results from that trial are the best obtained so far, Bruno et al. should not ignore the fact that the response rates are much lower than in HCV-monoinfected patients. Moreover, other studies in co-infected individuals have provided even lower response rates using similar treatment regimens, including another two trials presented at the 11th Conference on Retroviruses and Opportunistic Infections (see Table 1). We would like to take the opportunity in this letter to update and discuss briefly the most recent data on this matter.Table 1: Main features and results of the three trials presented at the 11th Conference on Retroviruses and Opportunistic Infections using pegylated interferon plus ribavirin for the treatment of hepatitis C in HIV-positive patients.The ACTG 5071 included 66 co-infected patients from several US centres, who were treated with a fixed dose of 180 μg/week of peg-IFN alpha-2a (Pegasys) plus ribavirin [5]. All subjects began ribavirin at doses of 600 mg per day and increased up to 1000 mg at week 12 if the tolerance was acceptable. In this trial, 77% of patients carried HCV genotype 1, which tended to respond less well to HCV therapy. End-of treatment response was reached by 41% of patients, but sustained virological response was only maintained by 27% (14% in patients with HCV genotype 1 and 73% in patents with other genotypes). The previously mentioned RIBAVIC trial was a multicentre French study conducted by the Agence Nationale de Recherche sur le SIDA, in which 205 co-infected patients were treated with a weight-adjusted dose (1.5 μg/kg per week) of peg-IFN alpha-2b (PegIntron) plus a fixed dose of 800 mg ribavirin [2]. Overall, 27% of patients reached a sustained virological response (15% for HCV genotypes 1 or 4, and 43% for genotypes 2 or 3). The APRICOT is the largest trial conducted so far in co-infected patients assessing the response to current HCV therapy. A total of 289 patients received at least one dose of peg-IFN alpha-2a (Pegasys) 180 μg/week plus a fixed dose of 800 mg ribavirin per day [4]. In contrast with the previous two trials, that study was conducted by the industry (Roche) and included patients from several countries and continents. This was reflected in a lower proportion of patients with HCV genotype 1 (60%) in that trial with respect to the others. The overall rate of sustained virological response was 40%, but dropped to 29% among patients with HCV genotype 1. A close monitoring of patients and strict inclusion criteria provided a relatively low discontinuation rate in that trial (25%), whereas in the French RIBAVIC study up to 36% of patients did not complete therapyapy [2]. The reasons for the poorest response in HCV/HIV-co-infected patients with respect to HCV-monoinfected individuals are many, and have already been discussed in more detail in the HIV–HCV consensus guidelines [1]. Clearly, new treatment schedules and hopefully new drugs should be investigated to improve the response rates in co-infected patients.

Field evaluation of a rapid human immunodeficiency virus (HIV) serial serologic testing algorithm for diagnosis and differentiation of HIV type 1 (HIV-1), HIV-2, and dual HIV-1-HIV-2 infections in West African pregnant women.

We evaluated a two-rapid-test serial algorithm using the Determine and Genie II rapid assays, performed on-site in four peripheral laboratories during the French Agence Nationale de Recherches sur le SIDA (ANRS) 1201/1202 Ditrame Plus cohort developed for prevention of mother-to-child transmission of human immunodeficiency virus (HIV) infection in Côte d'Ivoire. A total of 1,039 specimens were retested by two commercial enzyme-linked immunosorbent assays (ELISAs). The following specimens were tested: 315 specimens found on-site to be infected with HIV type 1 (HIV-1), 8 specimens found on-site to be infected with HIV-2, 71 specimens found on-site to be infected with both HIV-1 and HIV-2, 40 specimens found on-site to have indeterminate results for HIV infection, and 605 specimens taken during a quality assurance program. For HIV discrimination, 99 positive serum samples (20 with HIV-1, 8 with HIV-2, and 71 with HIV-1 and HIV-2 on the basis of our rapid test algorithm) were retested by the Peptilav test, Western blot (WB) assays, and homemade monospecific ELISAs. Real-time DNA PCRs for the detection of HIV-1 and HIV-2 were performed with peripheral blood mononuclear cells from 35 women diagnosed on-site with HIV-1 and HIV-2 infections. Compared to the results of the ELISAs, the sensitivities of the Determine and Genie II assays were 100% (95% lower limit [95% LL], 99.1%) and 99.5% (95% confidence interval [95% CI], 98.2 to 99.9%), respectively. The specificities were 98.4% (95% CI, 96.9 to 99.3%) and 100% (95% LL, 99.3%), respectively. All serological assays gave concordant results for infections with single types. By contrast, for samples found to be infected with dual HIV types by the Genie II assay, dual reactivity was detected for only 37 samples (52.1%) by WB assays, 34 samples (47.9%) by the Peptilav assay, and 23 samples (32.4%) by the monospecific ELISAs. For specimens with dual reactivity by the Genie II assay, the rates of concordance between the real-time PCR assays and the serological assays were 25.7% for the Genie II assay, 82.9% for the Peptilav assay, 74.3% for WB assays, and 80% for the homemade ELISAs. Our algorithm provided high degrees of sensitivity and specificity comparable to those of ELISAs. Even if they are rare, women identified by the Genie II assay as being infected with HIV-1 and HIV-2 mostly appeared to be infected only with HIV-2.

Baseline Resistance and Virological Outcome in Patients with Virological Failure who Start a Regimen Containing Abacavir: Eurosida Study

To investigate the ability of several HIV-1 drug-resistance interpretation systems, as well as the number of pre-specified combinations of abacavir-related mutations, to predict virological response to abacavir-containing regimens in antiretroviral therapy-experienced, abacavir-naive patients starting an abacavir-containing regimen in the EuroSIDA cohort. A total of 100 HIV-infected patients with viral load (VL) >500 copies/ml who had a plasma sample available at the time of starting abacavir (baseline) were included. Resistance to abacavir was interpreted by using eight different commonly used systems that consisted of rules-based algorithms or tables of mutations. Correlation between baseline abacavir-resistance mutations and month 6 virological response was performed on this population using a multivariable linear regression model accounting for censored data. The baseline VL was 4.36 log10 RNA copies/ml [interquartile range (IQR): 3.65-4.99 log10 RNA copies/ml] and the median CD4 cell count was 210 cells/microl (IQR: 67-305 cells/microl). Our patients were pre-exposed to a median of seven antiretrovirals (2-12) before starting abacavir therapy. The median (range) number of abacavir mutations (according to the International AIDS Society-USA) detected at baseline was 3.5 (0-8). Overall, the Kaplan-Meier estimate of the median month 6 VL decline was 0.86 log10 RNA copies/ml [95% confidence intervals (95% CI): 0.45-1.24]. The VL in those patients (n=31) who intensified treatment by adding only abacavir decreased by a median 0.20 log10 RNA copies/ml (95% CI: -0.18; +0.94). The proportion of patients who harboured viruses fully resistant to abacavir among the eight genotypic resistance interpretation algorithms ranged from 12% [Agence Nationale de Recherches sur le SIDA (ANRS)] to 79% [Stanford HIV RT and PR Sequence Database (HIVdb)]. Some interpretation systems showed statistically significant associations between the predicted resistance status and the virological response while others showed no consistent association. The number of active drugs in the regimen was associated with greater virological suppression (additional month 6 VL reduction per additional sensitive drug=0.51, 95% CI: 0.15-0.88, P=0.006); baseline VL was also weakly associated (additional month 6 VL reduction per log10 higher=0.30, 95% CI: -0.02; +0.62, P=0.06). In contrast, the number of drugs previously received was associated with diminished viral reduction (additional month 6 VL reduction per additional drug=-0.14, 95% CI: -0.28; 0.00, P=0.05). Our results revealed a high degree of variability among several genotypic resistance interpretation algorithms currently in use for abacavir. Therefore, the interpretation of genotypic resistance for predicting response to regimens containing abacavir remains a major challenge.

How was the UNAIDS drug access initiative implemented in Chile?

In 1997, UNAIDS decided to implement Drug Access Initiatives (DAI) in four different pilot-countries. We studied the implementation of the DAI in Chile as part of the evaluation program conducted by the ‘Agence Nationale de Recherche sur le SIDA’ (ANRS/France). The objective was to understand how the politico-organizational dynamic influenced the implementation process of the DAI. Approximately 50 semi-directed interviews and observation activities were conducted with the actors who participated in the implementation of the DAI or who played a role in the HIV/AIDS context. The program theory models were established and their evolution analyzed. This article offers an original analysis of an international HIV/AIDS drug access program that was put in place at a time when such programs were seen as a priority by international and governmental institutions. It also offers some insights for the creation of international projects that will be locally implemented.

Psychosexual Development among HIV-Positive Adolescents in Abidjan, Côte d'Ivoire

Some 84,000 children with HIV/AIDS live in the Côte d'Ivoire, where very little therapeutic or psychological help is available to them. The Yopougon Child Programme of the “Agence Nationale de Recherche sur le Sida” was launched in Abidjan in October 2000. It provides services for HIV-infected children and psychological consultations for children and their parents. This paper is about the psychosexual development of the HIV-positive adolescents in the Programme, 11 girls and 8 boys aged 13–17, their problems with HIV-related physiological and psychosexual changes, and relationships with their parents. The information was gathered in individual therapy sessions, group discussions and family support sessions. Bodily development was of major importance to these adolescents, particularly among those who had not yet developed secondary sexual characteristics and were shorter and weighed less than their peers. Those who had not achieved puberty were unable to participate in traditional rituals and worried whether they could ever marry or have children. In most cases, adolescents with HIV have been infected by a sexually transmitted virus without having had sexual relations themselves. They need support dealing with their sexual development and sexual feelings, along with medical care, in a context in which HIV infection is a secret, impossible to talk about with their peers.

Construction, Training and Clinical Validation of An Interpretation System for Genotypic HIV-1 Drug Resistance Based on Fuzzy Rules Revised by Virological Outcomes

To evaluate whether fuzzy operators can be usefully applied to the interpretation of genotypic HIV-1 drug resistance by experts, and to improve the prediction of salvage therapy outcome by adapting interpretation rules of genotypic resistance on the basis of their association with virological response data. We used a clinical dataset of 231 patients failing highly active antiretroviral therapy (HAART) and starting salvage therapy with baseline resistance genotyping and virological outcomes after 3 and 6 months. A set of rules predicting genotypic resistance was initially derived from an expert (ADL). Rules were implemented using a fuzzy logic approach and the virological outcomes dataset used for the training phase. The resulting algorithm was validated using a separate set of 184 selected patients by correlating the resulting predicted activity with observed virological response at 3 months. For comparison, the expert systems from the drug resistance group of the Agence Nationale de Recherches sur le SIDA (ANRS-AC11) and the algorithm from the Stanford's HIV drug resistance database (Stanford HIVdb) were evaluated on the same set. The starting algorithm had a correlation with virological outcomes of R2=0.06 (P=0.0001). After the training phase the correlation with virological outcomes increased to R2=0.19 (P<0.000001). In the validation set of patients, the activity of the salvage regimen predicted by the fuzzy algorithm was the only variable independently predictive of the 3-month viral load change even after adjusting by the activity predicted by the two expert systems and baseline viral load (for each 10% salvage regimen's activity increase, mean HIV RNA change from baseline: -0.27 log10 copies/ml; 95% CI -0.39, -0.15). Using fuzzy operators in a virological outcomes training database to implement a rules-based algorithm for genotypic resistance interpretation, significant improvements of outcomes prediction were obtained. The resulting algorithm showed an independent predictive capability of virological outcomes over that of two rules-based interpretation algorithms made by experts. Although the system was trained and validated on a limited number of cases, the approach deserves further evaluation.

Factors related to lipodystrophy and metabolic alterations in patients with human immunodeficiency virus infection receiving highly active antiretroviral therapy.

Morphologic and metabolic changes associated with protease inhibitor (PI) therapy have been reported since the introduction of PIs for treatment of human immunodeficiency virus infection. These changes were measured 12-20 months after initiation of PI therapy in a cross-sectional study involving 614 patients from the Antiprotéases Cohorte (APROCO) Study (Agence Nationale de Recherches sur le Sida-EP11). The prevalence was 21% for isolated peripheral atrophy, 17% for isolated fat accumulation, 24% for mixed syndrome, 23% for glucose metabolism alterations, 28% for hypertriglyceridemia (triglyceride level, > or =2.2 mM), and 57% for hypercholesterolemia (cholesterol level, > or =5.5 mM). Age was significantly associated with different phenotypes of lipodystrophy and metabolic alterations, but body-mass index, CD4(+) cell count, and type of nucleoside reverse-transcriptase inhibitor or PI received were not constantly associated with these changes. Furthermore, in all models tested, exposure to stavudine was associated with lipoatrophy and exposure of ritonavir was associated with hypertriglyceridemia. Detection and management of these disorders should be implemented to prevent further complications.

HIV/host interactions: new lessons from the Red Queen's country.

HIV/host interactions: new lessons from the Red Queen's country.

PH-Sensitive Liposomes and Antisense Oligonucleotide Delivery

AbstractJ. R. Philippot and B. Lebleu acknowledge the Agence Nationale de Recherche sur le SIDA and the Association de Recherche contre le Cancer for support. The authors thank A. Bienveniie from URA-CNRS 1856 (University Montpellier II) for many fruitful discussions during the course of this study. We thank M.-T. Cabanis from the Laboratory of Analytical Chemistry (Faculty of Pharmacy, Montpellier) for titrating calcium. J. P. Bongartz was the recipient of a postdoctoral fellowship from ANRS.The degradation of a drug, its toxicity, the unsuitable target binding or intracellular routing may be circumvented by an efficient drug delivery system. The efficacy of pH-sensitive liposomes is well documented for these purposes: These liposomes have a lipidic composition that makes escape from the endosome and delivery into the cytoplasm possible. The efficacy of pH-sensitive liposomes, comprising dioleoyl phosphatidyl ethanolamine, oleic acid, and cholesterol (DOPE/OA/Chol), loaded with polyrI:polyrC (polyIC), ha...

Zidovudine could cut transmission of HIV by mothers

Zidovudine reduces the risk of mothers who are HIV positive transmitting the virus to their fetuses by two thirds, according to preliminary results of a multicentre clinical trial. The trial was sponsored by the US National Institutes of Health and the French Agence Nationale de Recherches sur le SIDA. The study, in which 59 centres participated, was stopped early when analysis of data showed a transmission rate of 8.3% when both mothers and their babies received zidovudine compared with a rate …