Anne Krivine

Increasing prevalence of transmitted drug resistance mutations and non-B subtype circulation in antiretroviral-naive chronically HIV-infected patients from 2001 to 2006/2007 in France

OBJECTIVES To estimate the prevalence of transmitted drug resistance mutations and non-B subtype circulation in antiretroviral-naive chronically HIV-1-infected patients in France. METHODS Resistance mutations were sought in samples from 530 newly diagnosed HIV-1-infected patients from October 2006 to March 2007. Protease and reverse transcriptase mutations were identified from the 2007 Stanford Resistance Surveillance list. RESULTS Reverse transcriptase and protease resistance mutations were determined in 466 patients with duration of seropositivity <5 years. 42% of patients were infected with non-B subtype strains (CRF02 18.3%). The overall prevalence of viruses with protease or reverse transcriptase mutations was 10.6% (95% confidence interval 6.7-16.3). The prevalence of protease inhibitor, nucleoside reverse transcriptase inhibitor and non-nucleoside reverse transcriptase inhibitor resistance-associated mutations was 4.7%, 5.8% and 2.8%, respectively. Frequency of resistance was not different in patients infected with B (9.5%) and non-B (CRF02 7.8% and other 11.2%) subtypes. Baseline characteristics such as gender, age, transmission group, country of transmission, disease stage, CD4 counts and viral load were not associated with the prevalence of transmitted drug resistance. CONCLUSIONS In France in 2006/2007, the prevalence of transmitted drug-resistant variants was 10.6%. Prevalence of transmitted drug resistance was comparable in B and non-B subtypes. Prevalence of non-B subtypes is still rising.

Evaluation of the One-Step Multiplex Real-Time Reverse Transcription-PCR ProFlu-1 Assay for Detection of Influenza A and Influenza B Viruses and Respiratory Syncytial Viruses in Children

ABSTRACT We evaluated the one-step multiplex real-time reverse transcription-PCR ProFlu-1 assay for the detection of influenza A and influenza B viruses and respiratory syncytial viruses from 353 pediatric nasopharyngeal aspirates. As assessed by comparison with the results of immunofluorescence testing and cell culture, the specificity and the sensitivity of the ProFlu-1 assay ranged from 97% to 100%. In addition, the ProFlu-1 assay amplified 9% of samples not detected by conventional methods.

Immunological efficacy of a three-dose schedule of hepatitis A vaccine in HIV-infected adults: HEPAVAC study.

Background:The immunogenicity of vaccines, including vaccine against hepatitis A virus (HAV), is impaired in patients with HIV infection, requiring revised immunization regimens. Methods:We evaluated the immunological efficacy and safety of a 3-dose schedule of hepatitis A vaccine in HIV-infected adults. HAV-seronegative HIV-infected adults were randomized to receive either 3 doses of 1440 UI of hepatitis A vaccine (HAVRIX; GlaxoSmithKline, Marly le Roi, France) at weeks 0, 4, and 24 (46 patients) or 2 doses 24 weeks apart (49 patients). Results:At week 28, seroconversion, defined as an anti-HAV antibody ≥20 mIU/mL, occurred in 82.6% and 69.4% of patients in the 3-dose and the 2-dose group, respectively (P = 0.13, intent-to-treat analysis, missing data = nonresponder), and in 88.4% and 72.3% of patients in the 3-dose and the 2-dose group, respectively (P = 0.06, observed analysis). Only 37.9% of patients experienced seroconversion after 1 vaccine dose (intent-to-treat analysis). Anti-HAV antibody geometric mean titers were 323 and 132 mIU/mL in the 3-dose group and 138 and 67 mIU/mL in the 2-dose group, respectively, 28 (P = 0.03) and 72 weeks (P = 0.05) after the first vaccine dose. There were no serious adverse events associated with the vaccine. Multivariate analysis showed no treatment group effect but indicated that absence of tobacco smoking (odds ratio = 2.92, 95% confidence interval: 1.07 to 7.97; P = 0.04) was an independent predictor of response to HAV vaccine. Conclusions:In HIV-infected adults, immunogenicity of hepatitis A vaccine is poor. Three doses of vaccine were safe and increased antibody titers.

Protective effect of A/H1N1 vaccination in immune-mediated disease—a prospectively controlled vaccination study

OBJECTIVES To assess the 2009 influenza vaccine A/H1N1 on antibody response, side effects and disease activity in patients with immune-mediated diseases. METHODS Patients with RA, SpA, vasculitis (VAS) or CTD (n = 149) and healthy individuals (n = 40) received a single dose of adjuvanted A/H1N1 influenza vaccine. Sera were obtained before vaccination, and 3 weeks, 6 weeks and 6 months thereafter. A/H1N1 antibody titres were measured by haemagglutination inhibition (HAI) assay. Seroprotection was defined as specific antibody titre ≥ 1 : 40, seroconversion as 4-fold increase in antibody titre. RESULTS Titres increased significantly in patients and controls with a maximum at Week 3, declining to levels below protection at Month 6 (P < 0.001). Seroprotection was more frequently reached in SpA and CTD than in RA and VAS (80 and 82% and 57 and 47%, respectively). There was a significantly negative impact by MTX (P < 0.001), rituximab (P = 0.0031) and abatacept (P = 0.045). Other DMARDs, glucocorticoids and TNF blockers did not significantly suppress response (P = 0.06, 0.11 and 0.81, respectively). A linear decline in response was noted in patients with increasing age (P < 0.001). Disease reactivation possibly related to vaccination was suspected in 8/149 patients. No prolonged side effects or A/H1N1 infections were noted. CONCLUSIONS The results show that vaccination response is a function of disease type, intensity and character of medication and age. A single injection of adjuvanted influenza vaccine is sufficient to protect a high percentage of patients. Therefore, differential vaccination recommendations might in the future reduce costs and increase vaccination acceptance.

Clinical and Serologic Baseline and Follow-Up Features of Syphilis According to HIV Status in the Post-HAART Era

There is a lack of large studies appraising the effect of the human immunodeficiency virus (HIV) on the course of syphilis since the advent of highly active antiretroviral therapy (HAART). We aimed to appraise the effect of HIV on clinical and serologic features of syphilis at baseline and during follow-up in the post-HAART era. We designed a retrospective cohort study of consecutive syphilis cases, diagnosed between 2000 and 2007, in an academic venereal disease center. Data were collected using standardized medical forms. Patients were treated according to the European guidelines. Serologic failure was defined as either a 4-fold rise in Venereal Disease Research Laboratory (VDRL) titers 30-400 days posttreatment or a lack of 4-fold drop in VDRL titers at 270-400 days posttreatment. Among 279 syphilis cases with informative baseline clinical and serologic data, HIV infection was significantly associated with men having sex with men, French origin, multiple partners, lesser usage of condom, history of sexually transmitted disease, early syphilis, anal primary chancre, and cutaneous eruption. Median baseline titer from the Treponema pallidum hemagglutination assay (TPHA) was higher in HIV-infected patients (p = 0.02). Among 144 informative syphilis cases, there was a nonsignificant trend for a lower rate of serologic response among HIV-positive patients (91.8% vs. 98.3%, p = 0.14). Serologic failure was significantly associated with a history of previous syphilis (p < 0.05). The median delay to serologic response was similar in HIV-positive (117 d) and in HIV-negative (123 d) patients (p = 0.44). We conclude that for patients under HAART treatment, the effect of HIV on serologic response to syphilis treatment is likely minimal or absent. Abbreviations: CSF = cerebrospinal fluid, FTA-abs = fluorescent treponemal antibody absorption test, HAART = highly active antiretroviral therapy, HIV = human immunodeficiency virus, HR = hazard ratio, MSM = men having sex with men, RPR = rapid plasma reagin, STD = sexually transmitted disease, TPHA = Treponema pallidum hemagglutination assay, VDRL = Venereal Disease Research Laboratory.

Factors influencing the efficacy of two injections of a pandemic 2009 influenza A (H1N1) nonadjuvanted vaccine in systemic lupus erythematosus

OBJECTIVE To assess the factors influencing the efficacy of 2 injections of a pandemic 2009 influenza A (H1N1) vaccine in patients with systemic lupus erythematosus (SLE). METHODS We conducted a single-center, observational prospective study of 111 patients who were vaccinated with a monovalent, inactivated, nonadjuvanted, split-virus vaccine during December 2009 and January 2010 and received a second dose of vaccine 3 weeks later. The antibody response was evaluated using the hemagglutination inhibition assay according to the guidelines recommended for the pandemic vaccine, consisting of 3 immunogenicity criteria (i.e., a seroprotection rate of 70%, a seroconversion rate of 40%, and a geometric mean ratio [GMR] of 2.5). RESULTS The 3 immunogenicity criteria were met on day 42 (seroprotection rate 80.0% [95% confidence interval (95% CI) 72.5-87.5%], seroconversion rate 71.8% [95% CI 63.4-80.2%], and GMR 10.3 [95% CI 2.9-14.2]), while only 2 criteria were met on day 21 (seroprotection rate 66.7% [95% CI 57.9-75.4%], seroconversion rate 60.4% [95% CI 51.3-69.5%], and GMR 8.5 [95% CI 3.2-12.0]). The vaccine was well tolerated. Disease activity, assessed by the Safety of Estrogens in Lupus Erythematosus National Assessment version of the SLE Disease Activity Index, the British Isles Lupus Assessment Group score, and the Systemic Lupus Activity Questionnaire, did not increase. In the multivariate analysis, vaccination failure was significantly associated with immunosuppressive treatment or a lymphocyte count of ≤ 1.0 × 10⁹/liter. The second injection significantly increased the immunogenicity in these subgroups, but not high enough to fulfill the seroprotection criterion in patients receiving immunosuppressive treatment. CONCLUSION Our findings indicate that the efficacy of the vaccine was impaired in patients who were receiving immunosuppressive drugs or who had lymphopenia. A second injection increased vaccine immunogenicity without reaching all efficacy criteria for a pandemic vaccine in patients receiving an immunosuppressive agent. These results open possibilities for improving anti-influenza vaccination in SLE.

Hiv-1 intermittent viraemia in patients treated by non-nucleoside reverse transcriptase inhibitor-based regimen

Background:It has been demonstrated that, in patients treated by protease-inhibitor-based regimen, intermittent viraemia occurred frequently and was associated with higher concentrations of residual replication but not with virological failure. Risk factors associated with intermittent viraemia and its impact in patients treated by non-nucleoside-reverse-transcriptase-inhibitor-based (NNRTI) regimen need to be evaluated. Methods:We analyzed the occurrence of blips (one HIV-1 RNA > 50 copies/ml with a subsequent value < 50 copies/ml), the level of these blips (between 3 and 50 copies/ml) and their effect on CD4 cell count and the occurrence of virological failure in 43 patients with stable suppression of HIV-1 plasma viraemia (< 50 copies/ml) under NNRTI-based therapy. Results:Eight out of 43 patients had one episode of blips during the follow-up (median = 350 copies/ml). Comparing patients with and without blips, the median level of HIV-1 RNA at baseline was 7.5 versus 3 copies/ml (P = 0.008), respectively. Patients with blips had a significantly lower CD4 cell count after 12 and 18 months than the others. Plasma concentrations of NNRTI before, during, and after the blips were adequate. In addition, the occurrence of blips was not associated with virological failure. Conclusion:These results suggest that blips may reflect ongoing viraemia of below 50 copies/ml and can impair the CD4 cell count recovery under an NNRTI regimen. The impairment of CD4 cell count recovery seems to be affected more by the occurrence of blips than by the level of viraemia (< 50 copies/ml) itself. Nevertheless, despite a tight genetic barrier for resistance with NNRTI drugs, no virologic failure occurred during the follow-up.

Low Rate of Pandemic A/H1N1 2009 Influenza Infection and Lack of Severe Complication of Vaccination in Pregnant Women: A Prospective Cohort Study

Background In 2009, pregnant women were specifically targeted by a national vaccination campaign against pandemic A/H1N1 influenza virus. The objectives of the COFLUPREG study, initially set up to assess the incidence of serious forms of A/H1N1 influenza, were to assess the consequences of maternal vaccination on pregnancy outcomes and maternal seroprotection at delivery. Methods Pregnant women, between 12 and 35 weeks of gestation, non vaccinated against A/H1N1 2009 influenza were randomly selected to be included in a prospective cohort study conducted in three maternity centers in Paris (France) during pandemic period. Blood samples were planned to assess hemagglutination inhibition (HI) antibody against A/H1N1 2009 influenza at inclusion and at delivery. Results Among the 877 pregnant women included in the study, 678 (77.3%) had serum samples both at inclusion and delivery, and 320 (36.5%) received pandemic A/H1N1 2009 influenza vaccine with a median interval between vaccination and delivery of 92 days (95% CI 48–134). At delivery, the proportion of women with seroprotection (HI antibodies titers against A/H1N1 2009 influenza of 1∶40 or greater) was 69.9% in vaccinated women. Of the 422 non-vaccinated women with serological data, 11 (2.6%; 95%CI: 1.3–4.6) had laboratory documented A/H1N1 2009 influenza (1 with positive PCR and 10 with serological seroconversion). None of the 877 study’s women was hospitalized for flu. No difference on pregnancy outcomes was evidenced between vaccinated women, non-vaccinated women without seroconversion and non-vaccinated women with flu. Conclusion Despite low vaccine coverage, incidence of pandemic flu was low in this cohort of pregnant women.No effect on pregnancy and delivery outcomes was evidenced after vaccination.

Twelve Months of Routine HIV Screening in 6 Emergency Departments in the Paris Area: Results from the ANRS URDEP Study

Objective In October 2009 the French National Authority for Health recommended that HIV testing be proposed at least once to all persons aged 15 to 70 years in all healthcare settings. We examined whether routine HIV screening with a rapid test in emergency departments (EDs) was feasible without dedicated staff, and whether newly diagnosed persons could be linked to care. Methods This one-year study started in December 2009 in 6 EDs in the Paris area, using the INSTI™ test. Eligible individuals were persons 18 to 70 years old who did not present for a vital emergency, for blood or sexual HIV exposure, or for HIV screening. Written informed consent was required. Results Among 183 957 eligible persons, 11 401 were offered HIV testing (6.2%), of whom 7936 accepted (69.6%) and 7215 (90.9%) were tested (overall screening rate 3.9%); 1857 non eligible persons were also tested. Fifty-five new diagnoses of HIV infection were confirmed by Western blot (0.61% (95% CI 0.46–0.79). There was one false-positive rapid test result. Among the newly diagnosed persons, 48 (87%) were linked to care, of whom 36 were not lost to follow-up at month 6 (75%); median CD4 cell count was 241/mm3 (IQR: 52–423/mm3). Conclusions Screening rates were similar to those reported in opt-in studies with no dedicated staff. The rate of new diagnoses was similar to that observed in free anonymous test centres in the Paris area, and well above the prevalence (0.1%) at which testing has been shown to be cost-effective.

Population analysis of the pregnancy-related modifications in lopinavir pharmacokinetics and their possible consequences for dose adjustment

OBJECTIVES To investigate the possible necessity of an increase in lopinavir dose during pregnancy in order to achieve the concentrations previously defined as predictive of virological efficacy. PATIENTS AND METHODS Lopinavir pharmacokinetics were investigated by a population approach performed on 145 HIV-infected women, including 74 pregnant women. The final model was used to determine the probability of achievement of the target trough concentrations by Monte Carlo simulations. RESULTS The typical population estimates (inter-individual variability %) of apparent clearance (CL/F) and volume of distribution were 4.38 L/h (24%) and 58.4 L (59%), respectively. Pregnancy associated with a gestational age >15 weeks and delivery were found to increase lopinavir CL/F by 39% and 58%, respectively. With the standard 400 mg twice-a-day regimen, the probability of reaching the 1 mg/L target trough concentration for protease inhibitor (PI)-naive patients was 99% and 96% for non-pregnant and pregnant women, respectively. An important decrease in the probability of achieving the 5.7 mg/L target trough concentration for salvage therapy was observed for non-pregnant women (55%), this decrease being even greater for pregnant women (21%). Raising the lopinavir dose to 600 mg twice daily increased these probabilities to 87% and 53% for non-pregnant and pregnant women, respectively. CONCLUSIONS Modification of the lopinavir dose is unlikely to be required for PI-naive pregnant women; however, in pregnant women who have previously received a PI, therapeutic drug monitoring and/or empirical increasing of the dose should be considered.