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Background Primary-HIV-1-infection in newborns that occurs under antiretroviral prophylaxis that is a high risk of drug-resistance acquisition. We examine the frequency and the mechanisms of resistance acquisition at the time of infection in newborns. Patients and Methods We studied HIV-1-infected infants born between 01 January 1997 and 31 December 2004 and enrolled in the ANRS-EPF cohort. HIV-1-RNA and HIV-1-DNA samples obtained perinatally from the newborn and mother were subjected to population-based and clonal analyses of drug resistance. If positive, serial samples were obtained from the child for resistance testing. Results Ninety-two HIV-1-infected infants were born during the study period. Samples were obtained from 32 mother-child pairs and from another 28 newborns. Drug resistance was detected in 12 newborns (20%): drug resistance to nucleoside reverse transcriptase inhibitors was seen in 10 cases, non-nucleoside reverse transcriptase inhibitors in two cases, and protease inhibitors in one case. For 9 children, the detection of the same resistance mutations in mothers' samples (6 among 10 available) and in newborn lymphocytes (6/8) suggests that the newborn was initially infected by a drug-resistant strain. Resistance variants were either transmitted from mother-to-child or selected during subsequent temporal exposure under suboptimal perinatal prophylaxis. Follow-up studies of the infants showed that the resistance pattern remained stable over time, regardless of antiretroviral therapy, suggesting the early cellular archiving of resistant viruses. The absence of resistance in the mother of the other three children (3/10) and neonatal lymphocytes (2/8) suggests that the newborns were infected by a wild-type strain without long-term persistence of resistance when suboptimal prophylaxis was stopped. Conclusion This study confirms the importance of early resistance genotyping of HIV-1-infected newborns. In most cases (75%), drug resistance was archived in the cellular reservoir and persisted during infancy, with or without antiretroviral treatment. This finding stresses the need for effective antiretroviral treatment of pregnant women.

We report two cases of sexually transmitted hepatitis C virus (HCV) superinfection in HIV/ HCV-co-infected patients with high-risk sexual behaviour. The two patients had chronic HCV and a history of sexually transmitted infections. HCV superinfection was confirmed by phylogenetic analysis. No risk factors for HCV were found except unprotected anal sex with multiple casual male partners. HCV serology and serum HCV RNA should be examined periodically in HIV-infected men who have sex with men engaging in high-risk sexual behaviours.

In the USA and West Europe, nearly 80% of HIV-1-infected adults, experiencing virologic failure, harbored virus strain resistant to at least one antiretroviral drug. Limited data are available on antiretroviral drug resistance in pediatric HIV infection. The aims of this study were to analyze prevalence of HIV-1 drug resistance and to identify risk factors associated with resistance in this population. Prevalence of genotypic resistance was estimated retrospectively in treated children who experienced virologic failure (with HIV-1-RNA > 500 copies/ml) followed in Necker hospital between 2001 and 2003. Among 119 children with resistance testing, prevalence of resistance to any drug was 82.4%. Resistance ranged from 76.5% to nucleoside reverse transcriptase inhibitor (NRTI), to 48.7% to non-nucleoside reverse transcriptase inhibitor (NNRTI) and 42.9% to protease inhibitor (PI). Resistance to at least one drug of two classes and three classes (triple resistance) was 31.9 and 26.9%, respectively. Resistance was not associated with geographic origin, HIV-1 subtype, and CDC status. In multivariate analysis, resistance to any drug remained associated independently with current low viral load and high lifetime number of past PI. Triple resistance was independently associated with the high lifetime number of past PI and with gender, particularly among children aged 11 years old or more with a prevalence seven times higher in boys than in girls. In conclusion, antiretroviral resistance is common among treated HIV-1-infected children and prevalence was similar with those observed in adult population in the same year period. However, adolescent boys seem to be at greater risk.

Multidrug resistant HIV-1 acquired at the time of primary infection in two patients persisted for at least 5 years with and without treatment. In each patient, only one back mutation to wild-type codon in the protease gene occurred, and that was concomitantly associated with a marked CD4 cell count decrease. In both cases, infection was caused by CCR5 viruses and no rapid clinical progression to AIDS after primary infection was observed.

In highly experienced HIV-1-infected patients, a ritonavir-boosted darunavir-containing regimen was associated with dramatic immunological and virological efficacy. Patients harbouring viruses with amprenavir-specific resistance profiles, such as I50V or V32I + I47V, failed on a darunavir/ritonavir-containing regimen. These key amprenavir mutations were also selected at the time of failure, suggesting their impact on darunavir efficacy.

Aims To develop a population pharmacokinetic model for stavudine in children and to investigate the consistency of the currently recommended dose based on adult target concentrations. Methods The pharmacokinetics of stavudine were investigated using a population approach. Individual estimates of CL/F were used to calculate the stavudine dose required to achieve the area under the concentration-time curve reported in adults given recommended doses. Results Stavudine pharmacokinetics were well described by a one-compartment model with zero-order absorption. Typical population estimates (% interindividual variability) of the apparent distribution volume (V/F) and plasma clearance (CL/F) were 40.9 l (32%) and 16.5 l h−1 (38%), respectively. Stavudine V/F and CL/F were similarly related to age. Mean calculated doses (0.61 mg kg−1 for children less than 2 weeks, 1.23 mg kg−1 for children more than 2 weeks with bodyweight less than 30 kg, and 31.5 mg for children with a bodyweight between 30 and 60 kg) were in agreement with the current paediatric doses (0.5 mg kg−1, 1 mg kg−1, and 30 mg, respectively). Conclusions Our findings support the current recommended paediatric dosage regimens for stavudine, as they result in the same exposure to the drug as in adults.

Background: Pediatric experience with atazanavir combined with antiretroviral drugs administered once daily is very limited. Objective: The objective of this prospective, single-center observation study was to evaluate efficacy and tolerance of once-a-day ritonavir-boosted atazanavir, including treatment. Results: Antiretroviral treatment of 23 children and adolescents with a median age of 16 years (range, 10-19 years) was changed to a single daily dose of a combination of ritonavir-boosted atazanavir and 2 other nucleoside or nonnucleoside analogs. The single daily dosing was expected to improve adherence to treatment. The mean follow-up period was 12 months (range, 6-17 months). At the time of the treatment switch, the previous treatment had been effective in 11 children (plasma viral load [pVL] 50 copies/mL). None of the viral genotypes had resistance to atazanavir. The susceptibility score for the drugs used in combination with atazanavir (GSS) was at least 1.5 in 12 of 20 children. The atazanavir dose was 300 mg per day for children weighing more than 50 kg and 200 mg per day for children weighing 30 to 50 kg, in all cases associated with 100 mg ritonavir. During follow up, the mean atazanavir plasma concentration at 12 to 15 hours was 2.18 ± 1.19 mg/L. Tolerance was good in most patients, but 4 children chose to stop treatment because of icterus (n = 2) or persistent nausea and vomiting (n = 2). In 6 of the 12 children in whom treatment was not virologically effective before the switch, pVL was below 50 copies/mL after 1 to 3 months of treatment. Poor compliance and virologic failure persisted in the other 6 children. Seven of the 11 children with good virologic control before the switch continued to have undetectable pVL but 4 experienced virologic failure after 1, 1, 3 or 12 months of treatment despite good compliance. Insufficient antiviral potency of associated drugs could have been the cause of 2 of these 4 unexpected virologic failures. Conclusion: In these children with extensive previous treatment, the change to a once-daily treatment, including ritonavir-boosted atazanavir, was associated with a significant risk of virologic failure.

Objectives To understand the virological mechanisms of 2-year persistence of multidrug-resistant virus without selective antiretroviral pressure in HIV-1-infected patients. Patients and Methods Two patients were contaminated recently by their HIV-1-infected partners, who had received, before the transmission, all available antiretroviral drugs and who exhibited a severe therapeutic failure. The resistance mutations analysis was performed by clonal sequencing of 1.2 kb of pol gene in plasma of index and sources patients. Sequencing of HIV-1 DNA was performed in PBMCs of index patients. Results Genotypic testing performed in index patients at time of seroconversion showed resistance mutations to three classes of drugs. All mutations were linked on the same viral genome and all quasispecies carried all mutations. No wild-type virus was detected. The same results were found in source patients and showed that all mutations were transmitted. In the index patients, all mutations persisted over 2 years without antiretroviral treatment. Moreover, the resistance mutations were all archived in the cellular reservoir. Viral load and CD4 count of index patients remained unchanged during 2 years of follow-up. Discussion Only multidrug-resistant viruses were detected in the source patients and could be transmitted in index patients. In the latter, an expansion of predominant multidrug-resistant quasispecies and the ‘archival’ of all mutations were observed. These results explain the persistence of mutations and suggest that it is highly difficult to return to a wild-type viral population, sensitive to an antiretroviral treatment. The treatment of index patients is limited and the major risk is the transmission of these multidrug-resistant viruses. This work was presented in part in the XII International HIV Drug Resistance Workshop, Los Cabos, Mexico, June 2003; and in the 2nd IAS Conference on HIV Pathogenesis & Treatment, Paris, France, July 2003.

Background: Both highly potent antiretroviral drug rescue therapy and treatment interruption have been suggested to be effective in patients with multiple treatment failure. Objective: To assess both the benefits and risks of an 8-week treatment interruption associated with a six to nine-drug rescue regimen in patients with multiple treatment failures. Design: A randomized comparative controlled trial in 19 university hospitals in France. Patients: Sixty-eight HIV-infected patients with multiple previous treatment failures and CD4 cell counts less than 200 x 10 6 cells/I and plasma HIV-1-RNA levels of 50 000 copies/ml or greater. Measurements: The primary efficacy outcome was the proportion of patients with at least a 1 log 10 decrease (copies/ml) in the plasma HIV-1-RNA level after 12 weeks of therapy. Results: Treatment interruption followed by multidrug salvage therapy led to a greater proportion of patients achieving virological success (i.e. 1 log 10 decrease) at 12 weeks compared with patients receiving multidrug therapy alone (62 versus 26%, intent-to-treat analysis; P = 0.007). The median decrease in the HIV-1-RNA level was -1.91 and -0.37 log 10 copies/ml (P= 0.008), respectively. Treatment interruption led to an increase in the number of sensitive drugs of the multidrug regimen (71 versus 35% of regimen with at least two sensitive drugs; P= 0.004). Factors associated with virological success were treatment interruption, the reversion of at least one mutation to wild type, adequate plasma drug concentration, and the use of lopinavir. Conclusion: Treatment interruption was beneficial for treatment-experienced HIV-infected patients with advanced HIV disease and multidrug-resistant virus.

The dynamics of mutations associated with resistance to antiretroviral drugs were analyzed after cessation of therapy. The results showed that the kinetics of the shift to wild-type amino acid residues were significantly faster for protease inhibitors, intermediate for nonnucleoside reverse transcriptase inhibitors, and slower for nucleoside reverse transcriptase inhibitors.

During ZDV or d4T exposure, mutations at codons 41, 67, 70, 210, 215, and 219 can be selected and were named thymidine analogue mutations (TAMs). Some previous results suggested that different TAMs patterns could exist and that the kind of TAMs pattern could influence the virological response to some nucleoside reverse transcriptase inhibitors (NRTIs). In order to get more data about the relative prevalence of these patterns, their associations with other NRTI resistance mutations and the identification of the different stages observed during the acquisition of TAMs under treatment by NRTIs, we collected 1,098 RT sequences harbouring at least one TAM from patients failing to antiretroviral regimen. Sequences were stored in a database designed specifically to allow the retrieval of sequences that met specific criteria such as the occurrence and frequency of a particular mutation, the nature and frequency of the amino acid substitution at a given codon, and/or the rate of association between resistance mutations. Two pathways of TAMs can be identified: profile #1 (T215Y mutation linked) and profile # 2 (T215F mutation linked). The frequency of selection of profile # 1 is two times higher than profile # 2. The E44D/A + V118I complex, 69 insertions, and L74V mutation are associated to profile #1, whereas the Q151M complex and M184V mutation are associated to both profiles. As some NRTI resistance mutations were associated preferentially with profile #1, further studies are needed to explore if, the weaker efficacy observed on viruses harbouring this profile using some NRTIs, could be explained by the TAMs profile itself or the other associated NRTI resistance mutations.

To assess the effect of interleukin (IL)-2 combined with highly active antiretroviral therapy (HAART) on HIV-1 pro-viral DNA quantification in HIV-1-infected patients with CD4200/mm3.Seventy patients with CD4200 cells/mm3 and CV1000 copies/ml were enrolled in a 6-month randomized controlled study to evaluate the subcutaneous injection of IL-2 in addition to HAART versus HAART alone. Then, in a non-comparative phase from week 28 to week 80, IL-2 was proposed to patients from both groups. The HIV-1 pro-viral DNA was quantified at baseline, week 24 and week 50 by a real-time polymerase chain reaction (PCR) assay in peripheral blood mononuclear cells (PBMC). Analysis of resistance mutations was performed at baseline and after 6-months of IL-2.HIV-1 DNA level in PBMC increased significantly in patients treated with 6 months of HAART combined to IL-2 (+0.24 log10, P=0.009) compared to a slight decrease in patients treated with HAART alone (-0.05 log10). Moreover, a DNA increase was observed in control group patients when receiving 6 months of IL-2 (+0.34 log10). No increase of HIV-1 DNA was seen when this measure was expressed per million CD4 cells; it was probably hidden by the intense increase of CD4 lymphocytes after 6 months of IL-2 administration. No evolution of resistance mutations in pro-viral DNA was observed during 6 months of IL-2, despite the increase of pro-viral DNA and the occurrence of transient increase of viraemia.Administration of IL-2 combined with HAART in HIV-1 infected-patients with advanced disease led to an increase of HIV-1 pro-viral DNA per million PBMC without virological failure or emergence of resistance.

A 2-month interruption of only nonnucleoside reverse transcriptase inhibitors (NNRTIs) for patients carrying mutations associated with resistance to NNRTIs was followed by no change in either viral load or CD4 cell counts. These data suggest that these compounds have lost all of their in vivo antiviral activity in such cases.

Forty-nine protease inhibitor (PI)-experienced but amprenavir (APV)-naïve patients experiencing virological failure were treated with ritonavir (RTV) (100 mg twice a day [b.i.d.]) plus APV (600 mg b.i.d.). Patients responded to therapy with a median viral load decrease of −1.32 log10by week 12. The addition of low-dose RTV enhanced the minimal APV concentration in plasma (APVCmin) up to 10-fold compared with that obtained with APV (1,200 mg b.i.d.) without RTV. Baseline PI resistance mutations (L10F/I/V, K20M/R, E35D, R41K, I54V, L63P, V82A/F/T/S, I84V) identified by univariate analysis and included in a genotypic score and APVCminat week 8 were predictive of the virological response at week 12. The response to APV plus RTV was significantly reduced in patients with six or more of the resistance mutations among the ones defined above. The genotypic inhibitory quotient, calculated as the ratio of the APVCminto the number of human immunodeficiency virus type 1 protease mutations, was a better predictor than the virological or pharmacological variables used alone. This genotypic inhibitory quotient could be used in therapeutic drug monitoring to define the concentrations in plasma needed to control replication of viruses with different levels of PI resistance, as measured by the number of PI resistance mutations.

HIV is known to have the ability to adapt rapidly its genome under drug pressure, resulting in clinical treatment failure. We present the case of an HIV-infected patient who developed mutations of resistance to nevirapine although he always had an undetectable viral load and without context of inobservance. The concepts of undetectability and virological success in HIV infection must be balanced by the possible appearance of resistance under a treatment considered as effective.

Antiretroviral treatment interruption in 20 extensively pre-treated HIV-1 patients with treatment failure led to genotype viral reversion of at least one class of drug-mutation resistance in half of the patients. The only predictive factor of reversion was found to be the duration of interruption. The outgrowth of residual wild-type virus seems not to be a true genetic reversion because drug mutations are detected rapidly at salvage therapy re-initiation.

The objectives were to determine the resistance profile and the rate of cross-resistance in HIV-1 infected patients failing an efavirenz or a nevirapine or a nevirapine then efavirenz containing regimens, and to investigate if zidovudine and more generally thymidine analog nucleosides lead to a particular genotypic pattern in nevirapine failing patients. A study was conducted in 104 patients with virological rebound to a non-nucleoside reverse transcriptase inhibitors (NNRTI) regimen (efavirenz n = 39, nevirapine n = 46 and nevirapine then efavirenz n = 19). Genotypic resistance testing was carried out of detectable plasma HIV-1 RNA (> 200 copies/ml). Among the 104 patients studied, only two patients failed to respond to the nevirapine regimen without selection of a NNRTI resistance mutation. All patients failing an efavirenz regimen harboured mutations conferring cross-resistance to nevirapine (K103N, Y188L, G190S). Among patients failing the nevirapine regimen and presenting with NNRTI mutations, 35 (80%) harboured mutations conferring cross-resistance to efavirenz (K101E, K103N, Y188L) and 9 (20%) harboured mutations conferring resistance to nevirapine alone (V106A and Y181C). In patients failing nevirapine then efavirenz therapy, all NNRTI resistance profile led to cross-resistance to all available NNRTIs. Among patients receiving nevirapine, the selection of mutations associated with a cross-resistance to efavirenz was more frequent statistically when a thymidine nucleoside analog (zidovudine or stavudine) was used in the regimen (P = 0.02). In conclusion, 100% of patients developed cross-resistance to nevirapine and efavirenz after treatment by efavirenz and 80% after treatment by nevirapine. The use of a thymidine analog concomitantly with nevirapine leads to the preferential selection of cross-resistance NNRTI mutations. J. Med. Virol. 65:445–448, 2001. © 2001 Wiley-Liss, Inc.

Entry into the cell cycle represents a fundamental step before generating an effector immune response. The relationship between the cell cycle and antigen-driven T cell response remains, however, poorly understood in virus infection, including HIV. We have identified a critical fraction of CD4+CD45RO+ memory T lymphocytes that express the Ki67 antigen in chronically HIV-infected patients. A high accumulation of Ki67 protein is detected in CD4+CD45RO+Ki67+ cells that are in the G1 phase of the cell cycle (92 ? 5 %) but not in S and G2 + M phases, in contrast to normal individuals. Of these cells, 20 - 60 % are spontaneously producing IL-2 and IFN-, unlike CD4+CD45RO+ that do not express Ki67. In addition, HIV-p24 antigen is detectable only in a small fraction CD4+Ki67+ cells. In conclusion, CD4+Ki67+ lymphocytes are circulating effector cells accumulated in the G1 phase of the cell cycle and may be involved in the immune surveillance during HIV infection.

Immune control of human immunodeficiency virus (HIV) is not restored by highly active antiretroviral therapies (HAART) during chronic infection. We examined the capacity of repeated structured therapeutic interruptions (STI) to restore HIV-specific CD4 and CD8 T-cell responses that controlled virus production. Eleven STI (median duration, 7 days; ranges, 4 to 24 days) were performed in three chronically HIV-infected patients with CD4 counts above 400/mm3and less than 200 HIV RNA copies/ml after 18 to 21 months of HAART; treatment resumed after 1 week or when virus became detectable. HIV-specific T-cell responses were analyzed by proliferation, gamma interferon (IFN-γ) production, and enzyme-linked immunospot assays. Seven virus rebounds were observed (median, 4,712 HIV-1 RNA copies/ml) with a median of 7 days during which CD4 and CD8 counts did not significantly change. After treatment resumed, the viral load returned below 200 copies/ml within 3 weeks. Significant CD4 T-cell proliferation and IFN-γ production against HIV p24 appeared simultaneously with or even before the virus rebounds in all patients. These CD4 responses lasted for less than 3 weeks and disappeared before therapeutic control of the virus had occurred. Increases in the numbers of HIV-specific CD8 T cells were delayed compared to changes in HIV-specific CD4 T-cell responses. No delay or increase in virus doubling time was observed after repeated STI. Iterative reexposure to HIV during short STI in chronically infected patients only transiently mobilized HIV-specific CD4 T1-helper cells, which might be rapidly altered by virus replication. Such kinetics might explain the failure at delaying subsequent virus rebounds and raises concerns about strategies based on STI to restore durable HIV-specific T-cell responses in chronic HIV infection.

Background Drug-resistance mutations (DRAM) are frequently selected in patients with virological failure defined as viral load (pVL) above 500 copies/ml (c/mL), but few resistance data are available at low-level viremia (LLV). Our objective was to determine the emergence and evolution of DRAM during LLV in HIV-1-infected patients while receiving antiretroviral therapy (ART). Methods Retrospective analysis of patients presenting a LLV episode defined as pVL between 40 and 500 c/mL on at least 3 occasions during a 6-month period or longer while on the same ART. Resistance genotypic testing was performed at the onset and at the end of LLV period. Emerging DRAM was defined during LLV if never detected on baseline genotype or before. Results 48 patients including 4 naive and 44 pretreated (median 9 years) presented a LLV episode with a median duration of 11 months. Current ART included 2NRTI (94%), ritonavir-boosted PI (94%), NNRTI (23%), and/or raltegravir (19%). Median pVL during LLV was 134 c/mL. Successful resistance testing at both onset and end of the LLV episode were obtained for 37 patients (77%), among who 11 (30%) acquired at least 1 DRAM during the LLV period: for NRTI in 6, for NNRTI in 1, for PI in 4, and for raltegravir in 2. During the LLV period, number of drugs with genotypic resistance increased from a median of 4.5 to 6 drugs. Duration and pVL level of LLV episode, duration of previous ART, current and nadir CD4 count, number of baseline DRAM and GSS were not identified as predictive factors of resistance acquisition during LLV, probably due to limited number of patients. Conclusion Persistent LLV episodes below 500 c/ml while receiving ART is associated with emerging DRAM for all drug classes and a decreasing in further therapeutic options, suggesting to earlier consider resistance monitoring and ART optimization in this setting.

Virological failure on a boosted-protease inhibitor (PI/r) first-line triple combination is usually not associated with the detection of resistance mutations in the protease gene. Thus, other resistance pathways are being investigated. First-line PI/r monotherapy is the best model to investigate in vivo if the presence of mutations in the cleavage sites (CS) of gag gene prior to any antiretroviral treatment might influence PI/r efficacy. 83 patients were assigned to initiate antiretroviral treatment with first-line lopinavir/r monotherapy in the randomised Monark trial. We compared baseline sequence of gag CS between patients harbouring B or non-B HIV-1 subtype, and between those who achieved viral suppression and those who experienced virological failure while on LPV/r monotherapy up to Week 96. Baseline sequence of gag CS was available for 82/83 isolates; 81/82 carried at least one substitution in gag CS compared to HXB2 sequence. At baseline, non-B subtype isolates were significantly more likely to harbour mutations in gag CS than B subtype isolates (p

BackgroundHealth authorities in several countries recently recommended the expansion of human immunodeficiency virus (HIV) antibody testing, including the use of rapid tests. Several HIV rapid tests are now licensed in Europe but their sensitivity on total blood and/or oral fluid in routine healthcare settings is not known.Methods and findings200 adults with documented HIV-1 (n=194) or HIV-2 infection (n=6) were prospectively screened with five HIV rapid tests using either oral fluid (OF) or finger-stick whole blood (FSB). The OraQuick Advance rapid HIV1/2 was first applied to OF and then to FSB, while the other tests were applied to FSB, in the following order: Vikia HIV 1/2, Determine HIV 1-2, Determine HIV-1/2 Ag/Ab Combo and INSTI HIV-1/HIV-2. Tests negative on FSB were repeated on paired serum samples. Twenty randomly selected HIV-seronegative subjects served as controls, and the results were read blindly. Most patients had HIV-1 subtype B infection (63.3%) and most were on antiretroviral therapy (68.5%). Sensitivity was 86.5%, 94.5%, 98.5%, 94.9%, 95.8% and 99% respectively, with OraQuick OF, OraQuick FSB, Vikia, Determine, Determine Ag/Ab Combo and INSTI (pConclusionWhen evaluated in a healthcare setting, rapid HIV tests were less sensitive on oral fluid than on finger-stick whole blood and less sensitive on finger-stick whole blood than on serum.

Introduction et objectifs L’efficacite des traitements antiretroviraux (ARV) avec inhibiteurs de protease est bien demontree. Afin d’eviter les effets secondaires du ritonavir, il est interessant d’evaluer des strategies utilisant des IP non booste comme l’ATV. Materiels et methodes Il s’agit d’une etude retrospective chez des patients (pts) ayant une charge virale (CV) VIH plasmatique 400 cp/ml, les facteurs de risques a l’initiation de l’ATV non booste identifies par un test de Gray et la probabilite d’echec par Kaplan Meier. Resultats L’analyse a porte sur 92 pts. A l’inclusion, l’âge median etait de 45 ans, 75 % etaient des hommes, 30 % stade C du CDC. La mediane de CD4 a l’inclusion et du nadir etait respectivement de 442/mm3 et 202/mm3. La duree mediane d’indetectabilite de la CV etait de 29 mois. Les raisons du switch etaient : simplification des ARV: 31 pts (34 %), effet secondaire des ARV : 54 pts (60 %). Le tenofovir etait utilise chez 37 pts (40 %). Apres un suivi median de 23 mois, 7 patients ont presente un echec virologique avec une probabilite d’echec a 3 ans estimee a 7,3 %, et a 15,5 % au seuil de 50 cp/ml. Seul un nadir de CD4 Conclusion Chez les patients bien controles sous ARV, un switch pour ATV non booste est associe a un faible risque d’echec virologique et peut etre propose aux patients avec un nadir de CD4 > 100/mm3 et sans antecedent d’echec aux ARV.

Introduction Chez des patients (pts) ayant ete en multi-echec, un traitement optimise comprenant l’ENF permet un bon controle virologique, mais il est difficile de prolonger ce traitement administre par voie sous-cutanee. Methodes 170 pts infectes par le VIH-1, avec un ARN VIH-1 Resultats Les pts etaient âges de 47,9 annees en mediane, 85 % etaient des hommes, 52 % au stade C du CDC, traites depuis 13.6 annees et par ENF depuis 2,3 annees en mediane ; la mediane des CD4 a l’inclusion et au nadir etait respectivement de 393/mm 3 et 50/mm 3 . En ITT, 1/85 (1,2 %) pts du bras MT et 1/84 (1,2 %) pts du bras SB ont presente un echec virologique entre S0 et S24 (difference 0,01 % ; IC95 % : − 6,7 ; + 6,8, p En analyse per protocole, 0/82 (0 %) pts du bras MT et 1/82 (1,2 %) pts du bras SB ont presente un echec virologique (difference 1,22 % ; CI95 % : − 5,6 ; + 8,1, p A S24, 88 % et 89 % des pts du bras MT et SB respectivement avaient une charge virale p = 0,31). La frequence des evenements biologiques de grade 3 et 4 etait de 7 % et 14 % dans le bras MT et SB respectivement ( p = 0,13). Conclusion Chez des pts ayant ete en multi-echec et controles par un traitement comprenant ENF, la substitution de l’ENF par le RAL est virologiquement non inferieure a la poursuite de l’ENF, avec une tolerance satisfaisante.

Introduction et objectifs Les associations d’inhibiteurs de protease (IP) peuvent representer une alternative therapeutique chez les patients (pts) en echec therapeutique. Les objectifs de cette etude etaient d’evaluer la tolerance et l’efficacite immunovirologique de differentes associations d’IP. Materiels et methodes Tous les patients suivis a l’hopital Cochin et Necker ayant recu un traitement antiretroviral (ARV) comportant une association d’IP entre 2002 et 2006 ont ete inclus dans cette etude retrospective. Resultats 73 pts ont ete inclus, traites en mediane depuis 9,2 ans (IQR : 6,8-10,8) ; ils avaient recu en mediane 9 retroviraux (IQR : 6-11). Le nombre de mutations totales aux IP etait en mediane de 7 (IQR : 3-10) et de 2 (IQR : 0-3) pour les mutations majeures. Les traitements comportaient lopinavir/ritonavir (r) + amprenavir ( n = 35), amprenavir + saquinavir/r ( n = 16), saquinavir + nelfinavir/r ( n = 5), ou autre association ( n = 11). L’enfuvirtide etait associe dans 4 cas. A l’instauration du traitement, les CD4 et la CV medians etaient respectivement a 207/mm 3 [IQR : 114-318] et 4,3 log10 copies/ml [IQR : 3,1-5,0]. Le suivi median etait de 18.2 mois (IQR : 9,6-26,4). Aucun evenement indesirable grave n’a ete observe. Dix points ont interrompu le traitement pour echec virologique ( n = 5) et toxicite ( n = 5). Les probabilites de survenue (methode de Kaplan Meier) d’une charge virale indetectable (CV 3 a 6 et 12 mois de 39,9 % (95 % CI = 29,5-52,4) et 53,8 % (95 % CI = 42,1-66,3). Conclusion Chez des pts lourdement pretraites, les associations d’IP ont une bonne efficacite immunovirologique et sont bien tolerees. Cette strategie reste une alternative interessante pour les pts vivant dans les pays ou les nouvelles classes d’ARV ne sont pas actuellement disponibles.

ContextIn the Trilege trial, following induction with a zidovudine, lamivudine, and indinavir regimen, human immunodeficiency virus (HIV) replication was less suppressed by 2-drug maintenance therapy than by triple-drug therapy.ObjectiveTo identify mechanisms of virologic failure in the 3 arms of the Trilege trial.DesignCase-control study conducted from February to October 1998.SettingThree urban hospitals in Paris, France.PatientsFifty-eight case patients with virologic failure (HIV RNA rebound to >500 copies/mL in 2 consecutive samples) randomized to 3 therapy groups: triple drug (zidovudine, lamivudine, and indinavir), 8; zidovudine-lamivudine, 29; and zidovudine-indinavir, 21; the case patients were randomly matched with 58 control patients with sustained viral suppression.Main Outcome MeasuresAt virologic failure (S1 sample) and 6 weeks later (S2 sample), assessment of protease and reverse transcriptase gene mutations, plasma indinavir level, and degree of viral load rebound; pill count during induction and maintenance periods.ResultsOnly 1 primary resistance mutation, M184V, was detected in S1 plasma samples from 4 of 6 patients in the triple-drug and in all 22 in the zidovudine-lamivudine therapy groups and in S2 plasma samples from 3 of 6 in the triple-drug and 20 of 21 in the zidovudine-lamivudine groups. Of controls, M184V was detected in 11 of 13 S1 plasma samples and in 10 of 11 S2 plasma samples. Indinavir levels were undetectable in all S1 samples but 2 in 7 triple-drug cases tested and in the expected range in 11 of 18 S1 and 5 of 12 S2 zidovudine-indinavir case plasma samples tested. Maintenance adherence rates were lower for cases vs controls for zidovudine (P = .05) and indinavir (P = .05). Low indinavir levels, lower adherence rates for zidovudine (P = .04) and lamivudine (P = .03), and rebound to near-baseline values suggested adherence as cause of early failure for 4 of 8 triple-drug cases. In the zidovudine-lamivudine arm, for which case and control adherence rates did not differ significantly (P = .96), most failures occurred late with low rebound, suggesting suboptimal drug potency. In the zidovudine-indinavir arm, virologic failures may be related to both mechanisms.ConclusionsDuring the maintenance phase early and late virologic failures appeared to be related more to problems of adherence and antiretroviral treatment potency, respectively, than to selection of resistant mutant viruses.

Summary Background Data for on-demand pre-exposure prophylaxis (PrEP) are scarce. We implemented a cohort study to assess its efficacy, safety, and effect on sexual behaviour. Methods We invited men and transgender women who have sex with men, previously enrolled in the randomised placebo-controlled ANRS IPERGAY trial at seven sites (six in France and one in Canada), to participate in an open-label extension with on-demand tenofovir disoproxil fumarate (300 mg) and emtricitabine (200 mg) to be taken before and after sexual intercourse. We assessed the incidence of HIV and other sexually transmitted infections (STIs), PrEP adherence, safety, and sexual behaviour. Statistical analyses included comparisons of proportions and incidence between the randomised phase of the ANRS IPERGAY trial and the open-label phase, and all participants were included in safety analyses. ANRS IPERGAY is registered with ClinicalTrials.gov, number NCT01473472. Findings Between Nov 4, 2014, and Jan 27, 2015, we enrolled 361 participants. Median follow-up was 18·4 months (IQR 17·7–19·1). One participant who discontinued PrEP acquired HIV infection. HIV incidence was 0·19 per 100 person-years (95% CI 0·01–1·08), compared with 6·60 per 100 person-years (3·60–11·05) in the placebo group of the randomised study, indicating a relative reduction of 97% (95% CI 81–100) in the incidence of HIV with on-demand PrEP. Participants used a median of 18 pills of study drugs per month (IQR 11–25), and at the 6 month visit 240 (71%) of 336 participants had tenofovir detected in plasma. Drug-related gastrointestinal events were reported in 49 participants (14%) but were self-limited. Only four participants (1%) discontinued PrEP, three because of an increase in plasma creatinine. The proportion of participants reporting condomless sex at their last receptive anal intercourse significantly increased from 77% (136 of 176 participants) at baseline to 86% (66 of 77 participants) at 18 months' follow-up (p for trend=0·0004). The incidence of a first bacterial STI during this open-label phase did not change significantly compared with the randomised phase (59·0 vs 49·1 per 100 person-years, respectively; p=0·11). Interpretation On-demand oral PrEP is highly effective at preventing HIV infection among high-risk men who have sex with men and therefore represents an alternative to daily PrEP, expanding choices for HIV prevention. High rates of STIs resulting from low condom use did not undermine PrEP efficacy, but warrant frequent testing. Funding ANRS (France Recherche Nord and Sud Sida-HIV Hepatites), the Canadian HIV Trials Network, Fonds Pierre Berge—Sidaction, Gilead Sciences, and the Bill & Melinda Gates Foundation.

ObjectivesMutations usually associated with zidovudine exposure have been observed in zidovudine-naive patients treated by stavudine in combination. These mutations were named thymidine analogue mutations (TAMs). This fact, combined with phenotypical and biochemical findings provided additional evidence for cross-resistance between zidovudine and stavudine. A recent genotypic study in naive patients receiving stavudine/didanosine combination showed emergence of TAMs and a multidrug-resistance mutation (MDR), Q151M, in 36 and 10% of cases, respectively. Stavudine plus lamivudine is one of the most used binucleoside associations in the antiretroviral combinations. The objective of this study was to assess the genotypic changes in the HIV-1 reverse transcriptase (RT) gene in antiretroviral-naive patients treated by stavudine plus lamivudine.MethodsWe analysed the RT gene of 44 HIV-1 patients, naive of antiretroviral therapy, who were treated for 24 or 48 weeks with stavudine/lamivudine. Results: At the end of the follow-up, all patients acquired the lamivudine-associated mutation M184V. Only two subjects (4.5%) developed a TAM (T215Y; M41L), one subject developed a V75T/A mutation and one subject developed the particular MDR pattern F116Y, Q151M.ConclusionsOur study clearly demonstrated that naive subjects treated with stavudine/lamivudine for 24–48 weeks selected a low rate of TAMs and MDR Q151M. One hypothesis explaining these results could be the development of the M184V mutation.

Background The aim of this study was to characterize the mutations selected upon failure on etravirine (ETR)-containing regimen in non-nucleoside reverse transcriptase inhibitors (NNRTIs)-experienced HIV-infected patients and the associated factors. Methods Forty-two patients displaying virological failure after a 6 months ETR-containing regimen were studied. For each patient the reverse transcriptase (RT) sequence at failure was compared with all the RT sequences available before introduction of ETR. The effect of baseline and failure HIV-1 RNA, HIV-1 subtype, baseline number of NNRTI resistance mutations, protease inhibitor and nucleoside RT inhibitor genotypic sensitivity scores, number of new drugs used in the treatment, and previous use of efavirenz or nevirapine on the selection of NNRTI resistance mutations were investigated. Results At failure, 12/42 (29%) patients showed development of at least 1 new NNRTI mutation (7 patients selected 1 mutation and 5 patients 2 mutations). NNRTI mutations selected were V179I (5 patients), V179L (1), V179F (2), L100I (1), K103N (2), Y181C (3), K101E (1), K101R (1) and H221Y (1). Univariate analysis showed that HIV-1 RNA level at failure ( P=0.033) and past exposure to efavirenz ( PConclusion In this study, 29% of viruses from patients experiencing ETR failure selected new NNRTI resistance mutations (at position V179 in 2/3 of cases) in a context of multiple NNRTI resistance mutations.

ObjectiveStavudine-based antiretroviral combinations are less effective in zidovudine-experienced patients than in naive subjects and recently, mutations have been described to be associated to the use of both stavudine and zidovudine. In the ALTIS 2 trial, it was shown that a combination of stavudine and lamivudine is less effective in zidovudine-experienced patients than in naive patients. We conducted a retrospective genotypic and phenotypic resistance study (expressed as stavudine phenotypic index, calculated by dividing the inhibitory concentrations 50% [IC50] by the mean value of the sensitive viruses) to evaluate the factors associated with decrease in plasma HIV-1 RNA.DesignAssociations with continuous variables were studied using non-parametric Spearman correlation coefficients. Associations with categorical variables were studied using non-parametric Mann–Whitney tests. Multivariate stepwise regression analyses were used to determine independent prognostic factors of the virological response.ResultsAt baseline, most of the subjects harboured zidovudine-associated mutations in plasma and peripheral blood mononuclear cells. Zidovudine and stavudine IC50and IC90were strongly associated with response. It appears that a cut-off of stavudine phenotypic index of 1.8-fold of IC50, much lower than the usually used value, could be clinically significant for response to stavudine. In the multivariate analysis, the stepwise model with the higher multiple correlation coefficient ( R2=0.742) included the presence of a 215 Y/F mutation, the number of previously used nucleoside analogues and a resistant stavudine phenotype.ConclusionThese results argue for a phenotypic and genotypic cross resistance between stavudine and zidovudine. Modest increases of IC50and IC90for stavudine had an important impact on the virological response during the trial and plead for a new definition of the threshold value for stavudine phenotypic index.

Background: Surveillance of HIV-1 drug resistance in antiretro-viral-treated patients is important from the public health perspective of the spread of resistance and to evaluate the proportion of patients for whom new drugs are needed. Methods: Patients were consecutively included in 28 centers in France and 1 center in Switzerland if they had a viral load measurement performed in June 2004, with a result ≥ 1000 copies/mL. Reverse transcriptase, protease, and gp41 genes were sequenced, and resistance mutations were reported as listed on the Web site (www.iasusa.org). The genotypic resistance results were interpreted by the Agence Nationale de Recherches sur le SIDA et les Hepatites Virales (ANRS) and Stanford algorithms. Results: The 498 patients included had been exposed to 9 (interquartile ratio [IQR]: 6 to 12) antiretroviral drugs. Patients' viruses harbored 4 nucleoside reverse transcriptase inhibitor (IQR: 1 to 6) and 4 protease inhibitor (PI; IQR: 2 to 8) resistance mutations, whereas 44% had at least 1 nonnucleoside reverse transcriptase inhibitor resistance mutation. The frequency of resistance to at least 1 drug was 88% with the ANRS algorithm and 83% with the Stanford algorithm. The frequencies of complete resistance to 1, 2, and 3 classes of drugs were 37%, 15%, and 4%, respectively, with the ANRS algorithm and 27%, 23%, and 24%, respectively, with the Stanford algorithm. The most important differences between algorithms were for PIs. Using the ANRS algorithm and extrapolation on the whole French database, 19% of all treated patients could contribute to the spread of resistance and 4% had complete resistance to 2 classes of antiretroviral drugs. Conclusions: The observed patterns of resistance are linked to a long-lasting history of antiretroviral therapy. The frequency of multiresistance can vary according to the interpretation systems.

Objective To assess the effect of interleukin (IL)-2 combined with highly active antiretroviral therapy (HAART) on HIV-1 pro-viral DNA quantification in HIV-1-infected patients with CD43. Patients and methods Seventy patients with CD43 and CVResults HIV-1 DNA level in PBMC increased significantly in patients treated with 6 months of HAART combined to IL-2 (+0.24 log10, P=0.009) compared to a slight decrease in patients treated with HAART alone (–0.05 log10). Moreover, a DNA increase was observed in control group patients when receiving 6 months of IL-2 (+0.34 log10). No increase of HIV-1 DNA was seen when this measure was expressed per million CD4 cells; it was probably hidden by the intense increase of CD4 lymphocytes after 6 months of IL-2 administration. No evolution of resistance mutations in pro-viral DNA was observed during 6 months of IL-2, despite the increase of pro-viral DNA and the occurrence of transient increase of viraemia. Conclusion Administration of IL-2 combined with HAART in HIV-1 infected-patients with advanced disease led to an increase of HIV-1 pro-viral DNA per million PBMC without virological failure or emergence of resistance.

Introduction Tandis que le pic epidemique du COVID-19 semble passe dans la majorite des pays europeens, le nouveau challenge est d’evaluer l’immunite de la population a grande echelle. De nombreux tests serologiques aux performances tres variables sont proposes. Il est necessaire et urgent d’en realiser la validation qualitative afin de ne pas mesestimer la seroprevalence COVID-19. Nous proposons l’evaluation des performances du test de diagnostic rapide (TDR) Orient Gene (OG) COVID-19 IgG/IgM en comparaison au test ELISA-Abbott SARS-CoV-2 IgG immunoassay (ASIA). Materiels et methodes Il s’agit d’un test immuno-chromatographique a flux lateral permettant l’obtention d’un resultat en 10 minutes. Un total de 102 serums provenant de patients ayant eu une RT-PCR SARS-CoV-2 positive ont ete teste. Ces patients etaient asymptomatiques (n = 2), presentaient des symptomes legers (n = 37), des symptomes severes necessitant l’hospitalisation (n = 35) ou ont du etre admis en reanimation (n = 28). La specificite a ete evaluee a partir de 42 serums provenant de patients presentant diverses pathologies virales (dont des coronavirus endemique), parasitaires ou avec un taux de facteur rhumatoide eleve et preleve en periode pre-pandemique. Resultats La sensibilite de l’OG etait de 95,8 % (IC95 %: 89,6–98,8) pour les echantillons collectes ≥ 10 jours apres le debut des symptomes ce qui etait equivalent a la sensibilite 90,5 % (IC95 %: 82,8–95,6) de l’ASIA. L’OG a permis de detecter 6 serums negatifs en ASIA parmi lesquels 2 presentaient uniquement des IgM sur l’OG. Parmi les 7 serums negatifs en l’OG, 3 avaient ete preleves moins de 10 jours avant le debut des symptomes et les 4 autres serums provenaient de patients presentant des deficits immunitaires acquis pouvant expliquer la negativite du test malgre une PCR positive anterieure. La specificite etait de 100 % (IC95 %: 93,4–100) avec les deux tests. Conclusion Les caracteristiques de l’OG indique que ce TDR est approprie a une utilisation en routine au laboratoire avec une sensibilite equivalente a un test ELISA classique. Ce test s’adapte egalement a une utilisation ambulatoire en raison de sa facilite d’utilisation. L’evaluation de ce test sur un plus grand nombre de personnes asymptomatiques peut etre necessaire afin de confirmer nos resultats dans cette population.

International audience; Following US Food and Drugs Administration approval in July 2012 of daily oral tenofovir and emtricitabine for pre-exposure prophylaxis (PrEP) to prevent HIV infection in high-risk individuals in the USA, there has been much controversy about the implementation of this PrEP regimen in other countries throughout the world, and in Europe in particular. In this review, we focus on the challenges and opportunities of a daily oral PrEP regimen to curb the rising incidence of HIV infection in high-risk groups, and particularly in men who have sex with men. A number of issues would need to be addressed before PrEP could be implemented, including assessing the real effectiveness and cost-effectiveness of daily PrEP, the sustainability of daily adherence, the risk of selecting resistance, the long-term safety, and the risk of change in sexual behavior that might offset the benefit of PrEP. Alternatives to a daily oral PrEP regimen are being explored.

Background Guidelines for the use of antiretroviral agents for HIV-1 infection recommend combining at least three agents. The toxicity, cost, and complexity of such regimens warrant the search for other options. Methods MONARK is a prospective, open-label, randomized, 96-week trial comparing the safety and efficacy of lopinavir/ritonavir monotherapy with a standard lopinavir/ritonavir plus zidovudine and lamivudine regimen as an initial treatment regimen in HIV-infected patients with HIV-RNA levels less than 100,000 copies/ml. The primary endpoint was the proportion of patients with HIV-1-RNA levels below 400 copies/ml at week 24 and below 50 copies/ml at week 48. Results Eight-three and 53 patients were randomly assigned and exposed in the monotherapy and triple-drug groups, respectively. At week 48, by an intent-to-treat analysis, 53 of 83 patients (64%) in the monotherapy group and 40 of 53 patients (75%) in the triple-drug group achieved the primary endpoint (P = 0.19). The on-treatment analysis indicates that 80 and 95% of patients reached the primary endpoint in the monotherapy and triple-drug groups, respectively (P = 0.02). In the monotherapy arm, protease inhibitor-associated resistance mutations were seen in three of the 21 patients qualifying for genotypic resistance testing, with a modest impact on lopinavir susceptibility. None of the serious reported adverse events were considered to be related to study treatment. Conclusion Our results suggest that lopinavir/ritonavir monotherapy demonstrates lower rates of virological suppression when compared with lopinavir/ritonavir triple therapy and therefore should not be considered as a preferred treatment option for widespread use in antiretroviral-naive patients.

BackgroundThe systemic antibody responses to SARS-CoV-2 in COVID-19 patients has been extensively studied. However, much less is known about the mucosal responses in the upper airways at the site of initial SARS-CoV-2 replication. Local antibody responses in the nasopharyngeal epithelium, that are likely to determine the course of infection, have not been analysed so far nor their correlation with antibody responses in serum.MethodsThe IgG and IgA antibody responses were analysed in the plasma as well as in nasopharyngeal swabs (NPS) from the first four COVID-19 patients confirmed by RT-qPCR in France. Two were pauci-symptomatic while two developed severe disease. Taking advantage of a comprehensive series of plasma and nasopharyngeal samples, we characterized their antibody profiles from the second week post symptoms onset, by using an in-house ELISA to detect anti-SARS-CoV-2 Nucleoprotein (N) IgG and IgA.ResultsAnti-N IgG and IgA antibodies were detected in the NPS of severe patients. Overall, the levels of IgA and IgG antibodies in plasma and NPS appeared specific to each patient.ConclusionsAnti-N IgG and IgA antibodies are detected in NPS, and their levels are related to antibody levels in plasma. The two patients with severe disease exhibited different antibody profiles that may reflect different disease outcome. For the pauci-symptomatic patients, one showed a low anti-N IgG and IgA response in the plasma only, while the other one did not exhibit overt serological response.