Usefulness of therapeutic drug monitoring of rilpivirine and its relationship with virologic response and resistance in a cohort of naive and pretreated HIV-infected patients.

AIMS: The purpose of this study was to assess the antiviral activity of the rilpivirine/emtricitabine/tenofovir disoproxil fumarate combination and to describe the pharmacokinetics of rilpivirine and its association with resistance in clinical routine. METHODS: A retrospective multicentre cohort study was performed in both naive and pretreated HIV patients receiving the once-daily rilpivirine/emtricitabine/tenofovir disoproxil fumarate regimen. Immuno-virologic and resistance data, and rilpivirine plasma trough concentrations were collected over the follow-up. Statistical analyses were performed to evaluate the relationship between rilpivirine pharmacokinetics and virological response. Receiver operating characteristic (ROC) curve analysis was performed to determine the best target rilpivirine trough concentration. RESULTS: Overall, 379 patients were included. After a median follow-up of 28 months, 26% of patients discontinued mainly due to toxicity and the virological success rate was 65.7%. Virological failure occurred in 5% of patients. A significant proportion of patients with HIV-RNA > 40 copies/mL displayed rilpivirine plasma trough concentrations below the currently used 50 ng/mL efficacy threshold at both M6 (28%) and M12 (31%), in agreement with a significant lower median rilpivirine plasma trough concentration compared with patients virologically suppressed. Half of the patients with virologic failure who acquired rilpivirine resistance mutations had at least one suboptimal rilpivirine trough concentration. The optimal target for rilpivirine trough concentration was 70 ng/mL (sensitivity 75.4%; specificity 61.5%). CONCLUSIONS: This study shows the impact of rilpivirine plasma trough concentration on both virological response and the emergence of rilpivirine mutations. Moreover, our results suggest that a higher target of rilpivirine trough concentration could be proposed in clinical practice.

Concentration-response model of rilpivirine in a cohort of HIV-1-infected naive and pre-treated patients.

BACKGROUND: Rilpivirine is widely prescribed in people living with HIV. Although trough plasma concentrations have been associated with virological response, the drug pharmacodynamics remain incompletely characterized. OBJECTIVES: To develop the first pharmacodynamic model of rilpivirine in order to establish the rilpivirine concentration-response relationship for future treatment optimization. METHODS: A retrospective observational study was conducted in patients receiving the once-daily rilpivirine/tenofovir disoproxil fumarate/emtricitabine regimen. Individual rilpivirine trough plasma concentrations over time were predicted using a previous pharmacokinetic model. An established susceptible, infected, recovered model was used to describe HIV dynamics without assuming disease steady-state. Population analysis was performed with MONOLIX 2018 software. Simulations of the viral load evolution as a function of time and rilpivirine trough plasma concentration were performed. RESULTS: Overall, 60 naive and 39 pre-treated patients were included with a follow-up ranging from 2 to 37 months. The final model adequately described the data and the pharmacodynamic parameters were estimated with a good precision. The population typical value of rilpivirine EC50 was estimated at 65 ng/mL. A higher infection rate constant of CD4 cells for HIV-1 was obtained in pre-treated patients. Consequently, the time to obtain virological suppression was longer in pre-treated than in naive patients. CONCLUSIONS: The concentration-response relationship of rilpivirine was satisfactorily described for the first time using an original population pharmacodynamic model. Simulations performed using the final model showed that the currently used 50 ng/mL rilpivirine trough plasma concentration efficacy target might need revision upwards, particularly in pre-treated patients.

Incidence, Persistence, Clearance, and Correlates of Genital Human Papillomavirus Infection and Anogenital Warts in a Cohort of Men Living With Human Immunodeficiency Virus in South Africa.

OBJECTIVE: To estimate the incidence; persistence and correlates of human papillomavirus (HPV) infection and anogenital warts (AGW) among men living with human immunodeficiency virus (MLHIV). METHODS: Overall, 304 MLHIV 18 years or older were enrolled and attended follow-up visits at 6, 12, and 18 months. Clinicians examined for AGW, collected blood, and penile swabs for HPV testing (Roche Linear Array) at each visit. Time to AGW incidence or clearance was estimated by Kaplan-Meier method. Factors associated with persistent HPV infection and AGW clearance were evaluated with generalized estimating equations and Cox regression, respectively. RESULTS: Mean age of participants was 38 years (standard deviation, 8 years); 25% reported more than 1 sexual partner in the past 3 months. Most (65%) participants were on antiretroviral treatment (ART) with a median CD4 count of 445 cells/µL (interquartile range, 328-567). Prevalence of HPV infection and AGW at enrolment were 79% (224 of 283) and 12% (36 of 304), respectively. Two hundred fifty-nine men were followed up for a median (interquartile range) 1.4 years (0.5-1.7 years). Incidence of any-genital HPV infection was 2.9 (95% confidence interval, 1.5-5.5) per 100 person-years. Persistence of any-genital HPV infection was 35% (68 of 192) and was higher among MLHIV with low CD4 count (adjusted odds ratio, 3.54; 95% confidence interval, 2.07-6.05). Incidence of AGW was 1.4 per 100 person-years. Men living with human immunodeficiency virus with high CD4 count were more likely to clear AGW than those with low CD4 count (adjusted hazard ratio, 3.69; 95% confidence interval, 1.44-9.47). No associations were observed between persistent genital HPV infection, AGW clearance with enrolment ART status or duration. CONCLUSIONS: Human immunodeficiency virus-positive men have a high burden of genital HPV infection and AGW. The ART and HPV vaccine could reduce this burden.

Human papillomavirus type 7-associated anal condyloma after renal transplantation in a child.

The prevalence, clinical significance, and spectrum of many HPV genotypes are currently largely untapped. We report a case of anal condyloma associated with a rare HPV genotype in a 11-year-old kidney transplant recipient. Eleven months post-graft, rectal bleeding revealed a 5-cm-large anal condyloma for which immuno-histopathology revealed typical papillomatosis. HPV genotyping performed on anal biopsy identified a HPV type 7, for which a single sequence was found in the GenBank sequence database. HPV7 is classically found in hand cutaneous warts, but HPV7-associated condyloma was only described in two patients. Total resection of the anal lesion was performed by electrocoagulation with no recurrence after 6 years. Post-transplant immunosuppression may promote anal condyloma with uncommon HPV types. HPV genotyping in such lesions is useful to get a better understanding of the epidemiology and clinical significance of such unusual HPV types as HPV7.

Emergence of uncommon HIV-1 non-B subtypes and circulating recombinant forms and trends in transmission of antiretroviral drug resistance in patients with primary infection during the 2013-2015 period in Marseille, Southeastern France.

Primary HIV-1 infections (PHI) with non-B subtypes are increasing in developed countries while transmission of HIV-1 harboring antiretroviral resistance-associated mutations (RAMs) remains a concern. This study assessed non-B HIV-1 subtypes and RAMs prevalence among patients with PHI in university hospitals of Marseille, Southeastern France, in 2005-2015 (11 years). HIV-1 sequences were obtained by in-house protocols from 115 patients with PHI, including 38 for the 2013-2015 period. On the basis of the phylogenetic analysis of the reverse transcriptase region, non-B subtypes were identified in 31% of these patients. They included 3 different subtypes (3A, 1C, 4F), 23 circulating recombinant forms (CRFs) (CRF02_AG, best BLAST hits being CRF 36_cpx and CRF30 in 7 and 1 cases, respectively), and 5 unclassified sequences (U). Non-B subtypes proportion increased significantly, particularly in 2011-2013 vs in 2005-2010 (P = .03). CRF02_AG viruses largely predominated in 2005-2013 whereas atypical strains more difficult to classify and undetermined recombinants emerged recently (2014-2015). The prevalence of protease, nucleos(t)ide reverse transcriptase, and first-generation nonnucleoside reverse transcriptase inhibitors-associated RAMs were 1.7% (World Health Organization [WHO] list, 2009/2.6% International AIDS Society [IAS] list, 2017), 5.2%/4.3%, and 5.2%/5.2%, respectively. Etravirine/rilpivirine-associated RAM (IAS) prevalence was 4.3%. Men who have sex with men (MSM) were more frequently infected with drug-resistant viruses than other patients (26% vs 7%; P = .011). The recent increase of these rare HIV-1 strains and the spread of drug-resistant HIV-1 among MSM in Southeastern France might be considered when implementing prevention strategies and starting therapies.

Ledipasvir and tenofovir drug interaction in human immunodeficiency virus-hepatitis C virus coinfected patients: Impact on tenofovir trough concentrations and renal safety.

We evaluate the impact of ledipasvir on both tenofovir plasma trough concentration and estimated glomerular renal function in human immunodeficiency virus-hepatitis C virus coinfected patients receiving a tenofovir-based antiretroviral regimen and treated with ledipasvir/sofosbuvir. Twenty-six patients [81% male, median age: 51 years; hepatitis C virus genotype 1(75%)/4(15%)] were included. Tenofovir trough concentration (interquartile range) increased from 78 ng ml-1 (53-110) at baseline to 141 ng ml-1 (72-176) at 1 month (P = 0.003). No significant difference on estimated glomerular renal function using both Cockroft-Gault and Modification of Diet in Renal Disease formulae, respectively, [median (interquartile range)] was observed between baseline [101.3 ml min-1 (91.1-114.1); 95.6 ml min-1 (86.5-111.2)], 1 month [102.4 ml min-1 (89.8-112.9), P = 0.26; 92.5 ml min-1 (88.1-114.3), P = 0.27], end-of-treatment [96.5 ml min-1 (82.4-115.4), P = 0.39; 95.4 ml min-1 (84.2-105.4), P = 0.16] and 12 weeks after the end of treatment [100.5 ml min-1 (83.3-111.9), P = 0.24; 93.4 ml min-1 (82.2-103.5), P = 0.16]. Three patients progressed from chronic kidney disease stage 1 to stage 2 at 12 weeks post-treatment. A significant increase in tenofovir exposure through P-glycoprotein inhibition by ledipasvir was confirmed without significant impact on glomerular renal function in our population with normal renal function or mild renal impairment.

Population pharmacokinetics of Rilpivirine in HIV-1-infected patients treated with the single-tablet regimen rilpivirine/tenofovir/emtricitabine.

PURPOSE: Rilpivirine, prescribed for the treatment of HIV infection, presents an important inter-individual pharmacokinetic variability. We aimed to determine population pharmacokinetic parameters of rilpivirine in adult HIV-infected patients and quantify their inter-individual variability. METHODS: We conducted a multicenter, retrospective, and observational study in patients treated with the once-daily rilpivirine/tenofovir disoproxil fumarate/emtricitabine regimen. As part of routine therapeutic drug monitoring, rilpivirine concentrations were measured by UPLC-MS/MS. Population pharmacokinetic analysis was performed using NONMEM software. Once the compartmental and random effects models were selected, covariates were tested to explain the inter-individual variability in pharmacokinetic parameters. The final model qualification was performed by both statistical and graphical methods. RESULTS: We included 379 patients, resulting in the analysis of 779 rilpivirine plasma concentrations. Of the observed trough individual plasma concentrations, 24.4% were below the 50 ng/ml minimal effective concentration. A one-compartment model with first-order absorption best described the data. The estimated fixed effect for plasma apparent clearance and distribution volume were 9 L/h and 321 L, respectively, resulting in a half-life of 25.2 h. The common inter-individual variability for both parameters was 34.1% at both the first and the second occasions. The inter-individual variability of clearance was 30.3%. CONCLUSIONS: Our results showed a terminal half-life lower than reported and a high proportion of patients with suboptimal rilpivirine concentrations, which highlights the interest of using therapeutic drug monitoring in clinical practice. The population analysis performed with data from "real-life" conditions resulted in reliable post hoc estimates of pharmacokinetic parameters, suitable for individualization of dosing regimen.

Epidemiological, clinical, virological features of hepatitis B newly diagnosed in 2011 in Marseille University hospitals, southeastern France.

Hepatitis B virus (HBV) infection is a public health problem. In France, 0.68% of adults are chronically infected. We aimed to describe the epidemiological, virological and clinical characteristics of HBV infections newly diagnosed in 2011 in University hospitals of Marseille, the second largest French city. HBV serology was performed for 18,130 sera from 15,744 patients. A total of 167 patients were newly-diagnosed with HBV based upon the detection of hepatitis B surface antigen and anti-hepatitis B core antibodies. Clinico-epidemiological features were analyzed for 78 patients. Patients included a majority of men (59%), women being significantly younger with a mean age of 36 ± 17 versus 43.5 ± 16.2 years (P = 0.009). Country of birth was available for 52 patients and 35% of them originated from sub-Saharan Africa. Levels of the liver biological parameters were significantly lower in women compared to men, in whom mean alanine aminotransferase and gammaglutamyl transferase levels were 24 ± 39 versus 37 ± 36 IU/l (P = 0.0001) and 20 ± 20 versus 51 ± 53 IU/l (P = 0.0001), respectively. Co-infections with hepatitis C and human immunodeficiency viruses were found in 5% and 6% of the patients, respectively. HBV DNA was detectable in 90% of the HBeAg-negative patients. In addition, there was a positive correlation between the HBsAg titer and the HBV DNA level (P = 0.001). Genotype D was the most common HBV genotype and was found in 53% of the patients tested, followed by genotype E (21%). HBV remains a major concern with a slightly greater number of new diagnoses than in 2004. HBV genetic diversity was substantial in the present cohort.

Feasibility and Acceptability of Anal Self-Sampling for Human Papillomavirus Screening in HIV-Infected Patients.

OBJECTIVES: Anal cancer incidence is increasing among HIV-positive patients. No consensus currently exists for the screening of anal dysplasia. This study aimed at evaluating the feasibility and acceptability of anal self-sampling and assessing the prevalence of human papillomavirus (HPV) types among HIV-positive patients from Marseille University Hospitals. METHODS: Between October 2013 and March 2014, during their regular visits for the monitoring of their HIV infection in an HIV outpatient clinical unit of Marseille University Hospitals, patients were asked to self-sample anal swabs for HPV detection. A specimen self-collection kit was provided. HPV detection and genotyping were performed using in-house protocols. The quality of self-sampling was assessed by concurrent cellular quantification in collected samples. RESULTS: The acceptability rate of anal self-sampling was 91%, and 91% of the self-sampled specimens were appropriate for HPV screening. In addition, 76% of the samples were positive for HPV, including 54% of HPV types with oncogenic potential. CONCLUSIONS: This study indicates that HPV detection and typing through anal self-sampling is a valuable strategy to screen patients at high risk for anal cancer development. This could allow earlier management of anal lesions and related cancer in patients at high risk for HPV.

Relationship between HPV 16, 18, 31, 33, 45 DNA detection and quantitation and E6/E7 mRNA detection among a series of cervical specimens with various degrees of histological lesions.

Better understanding of the correlation between high-risk HPV DNA testing, viral load quantitation, and E6/E7 mRNA detection is required. The aim of this study was to assess the relationship between these markers and the severity of cervical lesions. One-hundred and fifty one directed cervical specimens were analysed (normal, cervical intraepithelial neoplasia, and cancer). HPV types 16, 18, 31, 33, and 45 DNA detection and quantititation and E6/E7 mRNA detection were performed. DNA was detected in 87 (57.6%) samples and increased from 0% (normal) to 93.9% (cancer). E6/E7 mRNA was detected in 65 (43%) samples and increased with the severity of the lesions from 0% (normal) to 78.8% (26/33) (cancers) (P < 0.001). HPV DNA and E6/E7 mRNA detection were compared in the 141 samples harbouring HPV16, 18, 31, 33, or 45 infection: 45.4% (64/141) of specimens were DNA-/mRNA-, 46% (65/141) were DNA + /mRNA+ and 8.5% (12/141) were DNA + /mRNA-. The proportion of DNA + /mRNA+ specimens increased with the severity of the lesions (P < 0.001). All normal cervix specimens were DNA-/mRNA-. Among grade 2 cervical intraepithelial neoplasia, prevalence of DNA was higher than that of mRNA: 41.6% (5/12) versus 25% (3/12), whereas it was 79.3% (46/58) versus 62% (36/58) among grade 3 cervical intraepithelial neoplasia. Full concordance was observed in cancers as all the 26 DNA+ specimens were mRNA +. Median overall HPV load was higher in DNA + /mRNA+ than in DNA + /mRNA- specimens (1.41 × 10(6) vs. 9.1 × 10(2) copies per million cells, P < 0.001). Both E6/E7 mRNA detection and concordant DNA + /mRNA+ detection increases with the severity of the lesions and with the HPV DNA load.

Emergence of clusters of CRF02_AG and B human immunodeficiency viral strains among men having sex with men exhibiting HIV primary infection in southeastern France.

The number of new HIV diagnoses is increasing in the western world and transmission clusters have been recently identified among men having sex with men despite Highly Active Antiretroviral Therapy efficacy. The objective of this study was to assess temporal trends, epidemiological, clinical and virological characteristics of primary HIV infections. A retrospective analysis of 79 patients presenting primary HIV infections from 2005 to 2012 was performed in Marseille University Hospitals, southeastern France. Clinical, epidemiological and immunovirological data including phylogeny based on the polymerase gene were collected. 65 males and 14 females were enrolled. The main transmission route was homosexual contact (60.8%). Patients were mostly infected with subtype B (73.4%) and CRF02_AG (21.5%) HIV-1 strains. An increase in the annual number of HIV seroconversions among new HIV diagnoses from 5% in 2005 to 11.2% in 2012 (P = 0.06) and of the proportion of CRF02_AG HIV strains among primary HIV infections in 2011-2012 as compared to 2005-2010 (P = 0.055) was observed. Phylogenetic analysis revealed four transmission clusters including three transmission clusters among men having sex with men: two large clusters of nine CRF02_AG, six B HIV strains; and one small cluster of three B HIV strains. Clusters involved more frequently men (P = 0.01) belonging to caucasian ethicity (P = 0.05), with a higher HIV RNA load at inclusion (P = 0.03). These data highlight the importance of improving epidemiological surveillance and of implementing suitable prevention strategies to control the spread of HIV transmission among men having sex with men.

Diversity of 1,213 hepatitis C virus NS3 protease sequences from a clinical virology laboratory database in Marseille university hospitals, southeastern France.

Infection with hepatitis C virus (HCV) represents a major public health concern worldwide. Recent therapeutic advances have been considerable, HCV genotype continuing to guide therapeutic management. Since 2008, HCV genotyping in our clinical microbiology laboratory at university hospitals of Marseille, Southeastern France, has been based on NS3 protease gene population sequencing, to allow concurrent HCV genotype and protease inhibitor (PI) genotypic resistance determinations. We aimed, first, to analyze the genetic diversity of HCV NS3 protease obtained from blood samples collected between 2003 and 2013 from patients monitored at university hospitals of Marseille and detect possible atypical sequences; and, second, to identify NS3 protease amino acid patterns associated with decreased susceptibility to HCV PIs. A total of 1,213 HCV NS3 protease sequences were available in our laboratory sequence database. We implemented a strategy based on bioinformatic tools to determine whether HCV sequences are representative of our local HCV genetic diversity, or divergent. In our 2003-2012 HCV NS3 protease sequence database, we delineated 32 clusters representative of the majority HCV genetic diversity, and 61 divergent sequences. Five of these divergent sequences showed less than 85% nucleotide identity with their top GenBank hit. In addition, among the 294 sequences obtained in 2013, three were divergent relative to these 32 previously delineated clusters. Finally, we detected both natural and on-treatment genotypic resistance to HCV NS3 PIs, including a substantial prevalence of Q80K substitutions associated with decreased susceptibility to simeprevir, a second generation PI.

Hepatitis C virus of subtype 2l in Marseille, southeastern France.

The rate of eradication of chronic hepatitis C considerably increases with direct-acting antiviral agents, particularly hepatitis C virus (HCV) polymerase inhibitors. While implementing full-length HCV NS5B polymerase sequencing in our clinical microbiology laboratory, we identified atypical HCV sequences, classified as subtype 2l, from 2 patients. HCV-2l NS5B polymerase sequences were detected from 5 and 14 additional patients by screening our laboratory hepatitis virus sequence database and the NCBI GenBank sequence database. Phylogenetic analyses show unambiguously that all HCV-2l sequences are clustered apart from HCV 2 non-l sequences, which compose a second cluster. Mean (±SD) nucleotide identity between near full-length NS5B fragments of subtype 2l was 93.4 ± 0.8% (range: 92.4-95.1). Of note, all HCV-2l sequences obtained in our laboratory and in other centers were from serum samples collected in France. Analysis of the HCV-2l NS5B polymerase amino acid sequences at 30 positions critical for interaction with or resistance to HCV polymerase inhibitors showed specific patterns.

Distribution of human papillomavirus genotypes, assessment of HPV 16 and 18 viral load and anal related lesions in HIV positive patients: a cross-sectional analysis.

Natural history of anal intraepithelial neoplasia and anal cancer is not fully understood. Factors associated with cytological abnormalities and predictors of progression to high-grade anal intraepithelial neoplasia still deserve investigation. The aim of this cross-sectional study was to assess the prevalence of HPV types, the relationship between HPV genotypes, HPV 16/18 viral load and cytological abnormalities in male and female HIV-infected patients. One hundred and twenty-two (72.6%) patients were infected with HPV, 75 (61%) had multiple HPV infection, and 94 (77%) had high-risk HPV infection. The most frequently identified HPV types were HPV 16 (64%), HPV 6 (39%), HPV 18 (31%), HPV 53 (14.7%), HPV 33 (10.6%), HPV 11 (8.2%), HPV 70 (5.7%), and HPV 61 (4.9%). The HPV types which were most frequently found in combination were HPV 6 + 16 (9.8%), 6 + 16 + 18 (8.2%), 16 + 18 (6.6%), 6 + 18 (4.9%), 16 + 33 (3.3%), 16 + 53 (3.3%). Median HPV16 and 18 viral loads were 6.1 log10 copies/10(6) cells [IQR 5.0-7.3] and 6.1 log10 copies/10(6) cells [IQR 5.7-6.0], respectively. Male gender (P = 0.03, OR: 1.2 [1.0-1.4]) and homo/bisexual transmission routes (P = 0.044, OR: 1.4 [1.0-1.9]) were associated with HPV 16 infection. An HPV 16 viral load cut-off ≥5.3 log10 copies/10(6) cells and a CD4+ cell count ≤200/µl were independent factors associated with abnormal cytology. In the absence of national consensus guidelines, a strict regular follow-up at shorter intervals is recommended for HIV-infected patients with abnormal cytology, especially low grade squamous intraepithelial lesions, an HPV 16 viral load ≥5.3 log/10(6) cells and a CD4+ cell count ≤200/µl.

Hepatitis C virus NS3 protease genotyping and drug concentration determination during triple therapy with telaprevir or boceprevir for chronic infection with genotype 1 viruses, southeastern France.

Telaprevir and boceprevir, the two first hepatitis C virus (HCV) NS3 protease inhibitors (PIs), considerably increase rates of sustained virologic response in association with pegylated interferon and ribavirin in chronic HCV genotype 1 infections. The 30 first patients treated by telaprevir or boceprevir including anti-HCV therapies since 2011 in Marseille University hospitals, France, were monitored. HCV loads and plasmatic concentrations of telaprevir and boceprevir were determined on sequential blood samples. HCV NS3 protease gene population sequencing was performed at baseline of treatment and in case of treatment failure. Fifteen patients (including 7 co-infected with HIV) received telaprevir and the other 15 patients (including 4 co-infected with HIV) received boceprevir. At baseline, HCV NS3 protease from six patients harbored amino acid substitutions associated with PI-resistance. Treatment failure occurred at week 12 for 7 patients. Amino acid substitutions associated with PI-resistance were observed in six of these cases. HCV NS3 R155K and T54A/S mutants, all of genotype 1a, were found from four patients. Median (interquartile range) plasma concentrations were 3,092 ng/ml (2,320-3,525) for telaprevir and 486 ng/ml (265-619) for boceprevir. For HIV-HCV co-infected patients, median concentrations were 3,162 ng/ml (2,270-4,232) for telaprevir and 374 ng/ml (229-519) for boceprevir. Plasma drug concentration monitoring revealed undetectable concentrations for two patients at week 4, and probable non-adherence to therapy for another patient. These findings indicate that routine HCV NS3 protease sequencing and plasma PI concentration monitoring might be helpful to characterize cases of therapy failure, at a cost dramatically low compared to that of anti-HCV therapy.

Failure of combined antiretroviral therapy intensification with maraviroc and raltegravir in chronically HIV-1 infected patients to reduce the viral reservoir: the IntensHIV randomized trial.

BACKGROUND: Ongoing HIV-1 replication in lymphoid cells is one explanation of the persistence of HIV-1 reservoirs despite highly active antiretroviral therapy (cART). We tested the potential of cART intensification by Maraviroc plus Raltegravir to decrease proviral HIV-1 DNA levels in lymphoid cells during a randomized trial. PATIENTS AND METHODS: We randomly assigned for 48 weeks 22 patients to continue their current first line regimen of Truvada® plus Kaletra® or intensify it with Maraviroc and Raltegravir. The primary objective was to obtain a 50% decrease in proviral HIV-1 DNA levels in lymphoid cells with intensification. Blood samples were drawn at W-2, W0, W2, W4, W12, W24 and W48. Plasma viremia, cellular proviral DNA and cellular RNA, 2-LTR circles and lymphocytes subsets were assayed using validated methods. Patients in the intensified group underwent a gut biopsy at baseline and W48 to measure proviral DNA levels. Statistical analysis used parametric and non-parametric tests. RESULTS: Ten patients in each arm completed the trial. The 2 populations were comparable at baseline. No change in the reservoir size was observed in the intensified arm compared to the control arm measured in peripheral blood mononuclear cells (PBMCs). No change in the reservoir size was observed in gut proviral DNA in the intensified arm. In this group, no increase in 2-LTR circles was observed as early as 2 weeks after intensification and no change was found in residual plasma RNA levels measured by the single copy assay. However, a decrease in CD8(+) T cells activation was observed at 24 and 48 weeks, as well as in PBMCs HIV-1 RNA levels. CONCLUSION: We conclude that the intensification of a Protease Inhibitor regimen with Maraviroc and Raltegravir does not impact the blood proviral DNA reservoir of HIV but can decrease the cell-associated HIV RNA, the CD8 activation and has a possible impact on rectal proviral HIV DNA in some patients. TRIAL REGISTRATION: ClinicalTrials.gov identifier number NCT00935480.

Hepatitis B and E co-primary infections in an HIV-1-infected patient.

We report an autochthonous hepatitis E virus (HEV)-hepatitis B virus co-primary infection in a 41-year-old man having sex with men and infected with human immunodeficiency virus (HIV). This case prompts testing for HEV in HIV-infected patients with acute hepatitis even if primary infection with another hepatitis virus is diagnosed.

National sentinel surveillance of transmitted drug resistance in antiretroviral-naive chronically HIV-infected patients in France over a decade: 2001-2011.

OBJECTIVES: As recommended by the French ANRS programme for the surveillance of HIV-1 resistance, we estimated the prevalence of transmitted drug resistance-associated mutations (RAMs) in antiretroviral-naive, chronically HIV-1-infected patients. METHODS: RAMs were sought in samples from 661 newly diagnosed HIV-1-infected patients in 2010/11 at 36 HIV clinical care centres. Weighted analyses were used to derive representative estimates of the percentage of patients with RAMs. RESULTS: At patient inclusion, the prevalence of virus with protease (PR) or reverse transcriptase (RT) RAMs was 9.0% (95% CI 6.8%-11.2%). No integrase RAMs were observed. The prevalences of protease inhibitor, nucleoside RT inhibitor and non-nucleoside RT inhibitor RAMs were 1.8%, 6.2% and 2.4%, respectively. Resistance to one, two and three classes of antiretroviral agent was observed in 7.9%, 0.9% and 0.2% of patients, respectively. The frequency of RAMs was higher in patients infected with B compared with non-B subtype virus (11.9% versus 5.1%, P = 0.003). Baseline characteristics (gender, age, country of transmission, CD4 cell count and viral load) were not associated with the prevalence of transmitted RAMs. However, men having sex with men (MSM) were more frequently infected with resistant virus than were other transmission groups (12.5% versus 5.8%, P = 0.003). Compared with the 2006/07 survey, the overall prevalence of resistance remained stable. However, a significant decrease in the frequency of virus with PR RAMs was observed in 2010/11 compared with the 2006/07 survey (1.8% versus 5.0%, P = 0.003). CONCLUSIONS: In France in 2010/11, the global prevalence of transmitted drug-resistant variants was 9.0%, and the prevalence was stable compared with the 2006/07 survey. MSM and B subtype-infected patients are the groups with a higher prevalence of drug resistance.

Significance of HPV 16 and 18 viral load quantitation in women referred for colposcopy.

The clinical utility of HPV 16 and 18 viral loads remains debated. The aim of this study was to assess the clinical significance of HPV 16 and 18 viral load and to determine a cut-off for optimal prediction of grade 2 or higher cervical intraepithelial neoplasia among patients referred to colposcopy. A total of 186 cervico-vaginal specimens harboring HPV 16 and/or 18 obtained at the time of colposcopy from patients without previous cervical neoplasia were tested for HPV 16 and 18 detection and quantitation using quantitative duplex real-time PCR method. Grade 2 or higher cervical intraepithelial neoplasia was diagnosed in 87 (46.8%) cases. Only HPV 16 median viral load increased significantly with the lesion grade: 9.1 × 10(4) in normal cervix or grade 1 cervical intraepithelial lesion versus 4.0 × 10(6) copies per million cells in grade 2 or higher cervical intraepithelial lesion (P < 0.001). The highest predictive value for grade 2 or higher cervical intraepithelial lesion was observed with a HPV 16 viral load cut-off of 3.0 × 10(6) copies per million cells (91% specificity, 58.2% sensitivity). Using this cut-off, the highest predictive value of HPV 16 viral load was observed among those referred for previous low-grade abnormal cervical cytology (96.4% specificity, 88% sensitivity). HPV 18 quantitation showed very poor predictive value. Specific attention should be given when performing colposcopic examination of women with an HPV 16 viral load higher than 3.0 × 10(6) copies per million cells, especially among those referred after a low-grade abnormal cytology.