Detecting spins by their fluorescence with a microwave photon counter.

Quantum emitters respond to resonant illumination by radiating part of the absorbed energy. A component of this radiation field is phase coherent with the driving tone, whereas another component is incoherent and consists of spontaneously emitted photons, forming the fluorescence signal1. Atoms, molecules and colour centres are routinely detected by their fluorescence at optical frequencies, with important applications in quantum technology2,3 and microscopy4-7. By contrast, electron spins are usually detected by the phase-coherent echoes that they emit in response to microwave driving pulses8. The incoherent part of their radiation-a stream of microwave photons spontaneously emitted upon individual spin relaxation events-has not been observed so far because of the low spin radiative decay rate and of the lack of single microwave photon detectors (SMPDs). Here using superconducting quantum devices, we demonstrate the detection of a small ensemble of donor spins in silicon by their fluorescence at microwave frequencies and millikelvin temperatures. We enhance their radiative decay rate by coupling them to a high-quality-factor and small-mode-volume superconducting resonator9, and we connect the device output to a newly developed SMPD10 based on a superconducting qubit. In addition, we show that the SMPD can be used to detect spin echoes and that standard spin characterization measurements (Rabi nutation and spectroscopy) can be achieved with both echo and fluorescence detection. We discuss the potential of SMPD detection as a method for magnetic resonance spectroscopy of small numbers of spins.

Sport and self-esteem in people living with HIV: a cross-sectional study.

BACKGROUND: In the general population, sport activity is associated with better health and better self-esteem. Among people living with HIV (PLHIV), sport activity could also be associated with better self-esteem. The main objective of our study was to assess the association between sport activity and self-esteem among people living with HIV. The secondary objectives were to evaluate the associations between sport activity with fatigue as well as with pain. METHODS: We performed a cross-sectional observational study among PLHIV in our region (Pays de la Loire in France). Each adult seen in routine HIV care was invited to participate in the study. Participants were invited to fill out self-questionnaires about sport activity, self-esteem, fatigue, and pain. The 2 groups of participants with and without sport activity were compared with a T Student test for self-esteem, fatigue, and pain scales. RESULTS: Among the 1160 people included in the study, 47% performed sport activity. The self-esteem score was better in the "sporting group" compared with the "non sporting group" (Rosenberg mean scale 32.7 ± 5.1/40 vs 31.9 ± 5 p = 0.01). The Functional Assessment of Chronic Illness Therapy Fatigue scale showed a lower fatigue in the sporting group than in the non-sporting group (mean total score 125 ± 22 vs 118 ± 24 p < 0.0001). The sporting group had a lower mean pain score (1.1 ± 1.8) than the non sporting group (1.4 ± 1.9 p = 0.004). CONCLUSIONS: Among PLHIV in our region, sport activity was associated with better self-esteem, lower fatigue and lower pain. Sport activity should be included in patient care for people living with HIV.

Risk of severe clinical events after sustained virological response following direct-acting antiviral therapy in HIV and hepatitis C virus coinfected participants.

OBJECTIVES: Sustained virological response (SVR) decreases the risk of hepatitis C virus (HCV)-related events. Nevertheless, a substantial risk of events persists. We estimated incidences and identified factors associated with severe clinical events after SVR following treatment with a direct-acting antiviral (DAA) in HIV/HCV-coinfected patients. METHODS: Participants from the ANRS CO13 HEPAVIH were included if they reached SVR. Incidence rates of overall mortality, liver-related events, AIDS-defining events, ischaemic events and non-liver non-AIDS-defining cancers (NLNA) were estimated. Factors associated with the risk of those events were identified using Poisson models adjusted on age at SVR and sex. RESULTS: In all, 775 participants were included. Incidence rates (95% confidence interval) of liver-related events, overall mortality, AIDS-defining events, ischaemic events and NLNA cancers per 1000 person-years were 5.9 (3.3-10.3), 22.2 (16.8-29.5), 0.6 (0.1-4.5), 7.3 (4.4-12.2) and 13.7 (9.4-20.0), respectively. For all events, incidence rates were higher in cirrhotic than in non-cirrhotic participants. Cirrhosis, liver stiffness and CD4 count were associated with liver-related events. Factors associated with overall mortality were age, cirrhosis, liver stiffness and gamma-glutamyl transferase (GGT). For ischaemic events and NLNA cancers, associated factors were total cholesterol and CD4 count, respectively. CONCLUSIONS: After SVR following a DAA treatment, liver-related and AIDS-defining events were observed less frequently than NLNA cancers. Severity of liver disease was associated with the risk of liver-related events and of overall mortality but not with ischaemic events and NLNA cancers. Factors reflecting HIV infection were associated with NLNA cancers and liver-related events.

Assessment of drug-drug interaction in an elderly human immunodeficiency virus population: Comparison of 3 expert databases.

AIMS: Polypharmacy increase the risk of drug-drug interactions (DDIs) in the elderly population living with human immunodeficiency virus (HIV). Several expert databases can be used to evaluate DDIs. The aim of the study was to describe actual DDIs between antiretroviral drugs and comedications in an elderly population and to compare grading of the DDIs in 3 databases. METHODS: All treatments of HIV-infected subjects aged 65 years and older were collected in 6 French HIV centres. Summary of Product Characteristic (SPC), French DDI Thesaurus (THES), and Liverpool HIV DDI website (LIV) were used to define each DDI and specific grade. DDIs were classified in yellow flag interaction (undefined grade in SPC and THES or potential weak interaction in LIV), amber flag interaction (to be considered/precaution of use in SPC and THES and potential interaction in LIV) and red flag interaction (not recommended/contraindication in SPC and THES and do not administer/contraindication in LIV). RESULTS: Among 239 subjects included, 60 (25.1%) had at least 1 DDI for a total of 126 DDIs: 23/126 red flag DDIs were identified in 17 patients. All these 23 DDIs were identified in LIV. THES and SPC missed 6 and 1 red flag DDIs, respectively. Seven of 23 red flag DDIs were identified in the 3 databases concomitantly. CONCLUSION: Polypharmacy is frequent in this elderly HIV population leading to DDI in a quarter of the subjects. The discrepancies between databases can be explained by differences in analysis methods. A consensus between databases would be helpful for clinicians.

Dispensation des antirétroviraux pour une durée de plus d'un mois : retour sur une recherche exploratoire qualitative.

This article presents the results of a qualitative research on practices of dispensing antiretroviral medication concerning requests for greater than one month, for departure abroad. In spite of a strict regulation, a cartography shows a heterogeneity of its application leading to a great diversity of dispensing practices. This qualitative research with 22 pharmacies across the territory reveals relational and regulatory logics that contribute to this non-uniformity of practices. The concepts of embarrassment, professional commitment, regulatory concerns and personal relationships with patients largely explain the accommodations and crafts observed in this type of ARV dispensing request.

Dolutegravir Monotherapy Versus Dolutegravir/Abacavir/Lamivudine for Virologically Suppressed People Living With Chronic Human Immunodeficiency Virus Infection: The Randomized Noninferiority MONotherapy of TiviCAY Trial.

BACKGROUND: We investigated whether dolutegravir (DTG) monotherapy could be used to maintain virological suppression in people living with human immunodeficiency virus (HIV) on a successful dolutegravir-based triple therapy. METHODS: MONCAY (MONotherapy of TiviCAY) was a 48-week, multicentric, randomized, open-label, 12% noninferiority margin trial. Patients with CD4 nadir >100/µL, plasma HIV-1 RNA <50 copies/mL for ≥12 months, and stable regimen with DTG/abacavir (ABC)/lamivudine (3TC) were 1:1 randomized to continue their regimen or to DTG monotherapy. The primary endpoint was the proportion of patients with HIV RNA <50 copies/mL at week 24 in intention-to-treat snapshot analysis. Virologic failure (VF) was defined as 2 consecutive HIV RNA >50 copies/mL within 2 weeks apart. RESULTS: Seventy-eight patients were assigned to DTG monotherapy and 80 to continue DTG/ABC/3TC. By week 24, 2 patients in the DTG group experienced VF without resistance to the integrase strand transfer inhibitor (INSTI) class; 1 patient discontinued DTG/ABC/3TC due to an adverse event. The success rate at week 24 was 73/78 (93.6%) in the DTG arm and 77/80 (96.3%) in the DTG/ABC/3TC arm (difference, 2.7%; 95% confidence interval [CI], -5.0 to 10.8). During subsequent follow-up, 5 additional VFs occurred in the DTG arm (2 of which harbored emerging resistance mutation to INSTI). The cumulative incidence of VF at week 48 was 9.7% (95% CI, 2.8 to 16.6) in the DTG arm compared with 0% in the DTG/ABC/3TC arm (P = .005 by the log-rank test). The Data Safety Monitoring Board recommended to reintensify the DTG arm with standardized triple therapy. CONCLUSIONS: Because the risk of VF with resistance increases over time, we recommend avoiding DTG monotherapy as a maintenance strategy among people living with chronic HIV infection. CLINICAL TRIALS REGISTRATION: NCT02596334 and EudraCT 2015-002853-36.

Tenofovir DF/emtricitabine/rilpivirine as HIV post-exposure prophylaxis: results from a multicentre prospective study.

OBJECTIVES: Since 2016, French guidelines have recommended the single-tablet regimen of tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC)/rilpivirine (RPV) as HIV post-exposure prophylaxis (PEP), but few data support this usage. We evaluated the tolerability, treatment completion and occurrence of HIV seroconversion associated with this combination in occupational and non-occupational PEP. PATIENTS AND METHODS: We conducted an observational, prospective, multicentre, open-label, non-randomized study in five French HIV centres. Adults requiring PEP according to national French guidelines were prescribed TDF/FTC/RPV one pill once a day for 28 days. Clinical and biological tolerability was assessed at week 4; occurrence of HIV seroconversion was evaluated after week 16. RESULTS: From March 2016 to March 2017, 163 courses of PEP were prescribed for 150 sexual exposures (44% heterosexual and 56% MSM) and 13 non-sexual exposures. Five participants stopped PEP after a few days because the source person was HIV uninfected. Of the remaining 158 individuals, 15 (9.5%) were lost to follow-up at week 4, 7 (4.4%) prematurely discontinued PEP [patient's decision/non-adherence (n = 3) or adverse events (gastrointestinal intolerance n = 3, fatigue n = 1)] and 136 (86.1%) completed the 28 day treatment. Overall, 69.6% of participants declared at least one adverse event, mostly of mild to moderate intensity and no serious adverse events or hepatic or renal toxicity occurred. No HIV seroconversion occurred at week 16. CONCLUSIONS: The low rate of premature treatment interruption, the good tolerability and the absence of documented HIV seroconversion support the current French guidelines of a 28 day course of TDF/FTC/RPV for sexual and non-sexual PEP.

Efficacy and safety of direct-acting antiviral regimens in HIV/HCV-co-infected patients - French ANRS CO13 HEPAVIH cohort.

BACKGROUND & AIMS: There is little data available on the use of new oral direct-acting antiviral (DAA) regimens to treat human immunodeficiency virus and hepatitis C virus (HIV/HCV) co-infected patients in real-life settings. Here, the efficacy and safety of all-oral DAA-based regimens in HIV/HCV-co-infected patients enrolled in the French nationwide ANRS CO13 HEPAVIH observational cohort are reported. METHODS: HIV/HCV-co-infected patients enrolled in the ANRS CO13 HEPAVIH observational cohort were included if they began an all-oral DAA-based regimen before 1st May 2015 (12-week regimens) or 1st February 2015 (24-week regimens). Treatment success (SVR12) was defined by undetectable HCV-RNA 12weeks after treatment cessation. Exact logistic regression analysis was used to identify factors associated with SVR12. RESULTS: A total of 323 patients (74% men) with a median age of 53years were included, 99% of whom were on combination antiretroviral therapy (cART). HIV RNA load was <50 copies/ml in 88% of patients; median CD4 cell count was 540/mm3; 60% of patients were cirrhotic; 68% had previously received unsuccessful anti-HCV treatment. cART was protease inhibitor (PI)-based in 23%, non-nucleoside reverse transcriptase inhibitor (NNRTI)-based in 15%, and integrase inhibitor (II)-based in 38%, while 24% of patients received other regimens. The SVR12 rate was 93.5% overall (95% confidence interval [CI]: 90.2-95.9), 93.3% (88.8-96.4) in patients with cirrhosis and 93.8% (88.1-97.3) in patients without cirrhosis. The SVR12 rates were 93.1% (84.5-97.7), 91.8% (80.4-97.7) and 95.8% (90.5-98.6) respectively, in patients receiving PI-based, NNRTI-based and II-based cART. In adjusted analysis, SVR12 was not associated with HIV RNA load, the cART regimen, cirrhosis, prior anti-HCV treatment, the duration of anti-HCV therapy, or ribavirin use. The most common adverse effects were fatigue and digestive disorders. CONCLUSIONS: New all-oral DAA regimens were well-tolerated and yielded high SVR12 rates in HIV/HCV-co-infected patients. LAY SUMMARY: We evaluated efficacy and safety of all-oral DAA regimens in a large French nationwide observational cohort study of HIV/HCV co-infected patients. Sustained virological response 12weeks after treatment cessation was 93.5% overall. The all-oral DAA regimens were well-tolerated and most common adverse effects were fatigue and digestive disorders.

Safety and efficacy of daclatasvir-sofosbuvir in HCV genotype 1-mono-infected patients.

BACKGROUND & AIMS: We report the first real-life results of the sofosbuvir+daclatasvir combination in hepatitis C virus (HCV) genotype 1 infected patients. METHODS: The France REcherche Nord&Sud Sida-hiv Hépatites (ANRS) CO22 HEPATHER "Therapeutic options for hepatitis B and C: A French cohort" is a multicentre observational cohort which aims to include 15,000 HCV- and 10,000 HBV-infected patients. We selected all participants (n=768) with a HCV genotype 1 who initiated sofosbuvir (400mg/day) and daclatasvir (60mg/day) before October 1st 2014, with or without ribavirin (1-1.2g/day) for a duration of 12weeks or 24weeks. The main endpoint criterion was sustained virological response at 12weeks (SVR12), defined by the absence of detectable HCV-RNA 12weeks after the last treatment intake. Missing SVR12 measurements were imputed using SVR24 measurements (n=45), otherwise considered as virological failure (n=18). RESULTS: A SVR12 was obtained in 729/768 (95%) patients, ranging from 92% (12-week sofosbuvir+daclatasvir) to 99% (24-week sofosbuvir+daclatasvir+ribavirin). The SVR12 rates did not significantly differ between the 24-week (550/574 (96%)) and the 12-week (179/194 (92%); p=0.0688) durations or between regimens with (165/169 (98%)) or without ribavirin (564/599 (94%); p=0.0850). The SVR12 rate was greater than 97% in non-cirrhotic patients irrespective of the treatment duration or the addition of ribavirin. Among cirrhotic patients, the SVR12 rate was higher with 24 than 12-week regimen (423/444 (95%) vs. 105/119 (88%); p=0.0054). CONCLUSION: The sofosbuvir+daclatasvir combination is associated with a high rate of SVR12 in patients infected by genotype 1, with an optimal duration of 12weeks in non-cirrhotic and 24weeks in cirrhotic patients. The number of patients receiving ribavirin was too low to adequately assess its impact. LAY SUMMARY: The sofosbuvir+daclatasvir combination of antiviral drugs is associated with a high rate (95%) of viral eradication in patients infected by HCV genotype 1. The best duration of a ribavirin-free sofosbuvir+daclatasvir combination seems to be 12weeks in non-cirrhotic patients and 24weeks for those with cirrhosis. Clinical trial number: NCT01953458.

Modeling HIV-HCV coinfection epidemiology in the direct-acting antiviral era: the road to elimination.

BACKGROUND: HCV treatment uptake has drastically increased in HIV-HCV coinfected patients in France since direct-acting antiviral (DAA) treatment approval, resulting in HCV cure in 63% of all HIV-HCV patients by the end of 2015. We investigated the impact of scaling-up DAA on HCV prevalence in the whole HIV population and in various risk groups over the next 10 years in France using a transmission dynamic compartmental model. METHODS: The model was based on epidemiological data from the French Dat'AIDS cohort. Eight risk groups were considered, including high-risk (HR) and low-risk (LR) men who have sex with men (MSM) and male/female heterosexuals, intra-venous drug users, or patients from other risk groups. The model was calibrated on prevalence and incidence data observed in the cohort between 2012 and 2015. RESULTS: On January 1, 2016, 156,811 patients were registered as infected with HIV in France (24,900 undiagnosed patients) of whom 7938 (5.1%) had detectable HCV-RNA (722 undiagnosed patients). Assuming a treatment coverage (TC) rate of 30%/year (i.e., the observed rate in 2015), model projections showed that HCV prevalence among HIV patients is expected to drop to 0.81% in 2026. Sub-analyses showed a similar decrease of HIV-HCV prevalence in most risk groups, including LR MSM. Due to higher infection and reinfection rates, predicted prevalence in HR MSM remained stable from 6.96% in 2016 to 6.34% in 2026. Increasing annual TC rate in HR MSM to 50/70% would decrease HCV prevalence in this group to 2.35/1.25% in 2026. With a 30% TC rate, undiagnosed patients would account for 34% of HCV infections in 2026. CONCLUSIONS: Our model suggests that DAA could nearly eliminate coinfection in France within 10 years for most risk groups, including LR MSM. Elimination in HR MSM will require increased TC.

Failure to achieve immunological recovery in HIV-infected patients with clinical and virological success after 10 years of combined ART: role of treatment course.

OBJECTIVES: We assessed factors, including treatment course, associated with failure to obtain a 10 year immunological response after starting first-generation PI-containing combined ART (cART). PATIENTS AND METHODS: In the prospective COPILOTE cohort of HIV-infected patients started on a first-generation PI-containing regimen in 1997-99, the impact of cART history on the failure to achieve immunological response measured at 10 years was assessed by multivariate logistic regression models in the 399 patients with clinical and virological success of cART. RESULTS: Failure of CD4 response (CD4 >500/mm3) was associated with age ≥40 years at baseline (P < 0.001), CD4 cell counts ≤500/mm3 at month 4 (P = 0.016) or month 12 (P < 0.001) and ≥3 months of cART interruption (P = 0.016). Factors associated with failure to achieve complete immunological response (CD4 >500/mm3 and CD4:CD8 ratio >1) were CD4:CD8 ratio ≤0.8 at month 8 (P < 0.001) or month 12 (P < 0.001), ≥3 months of cumulative cART interruption (P = 0.011), ≥3 antiretroviral regimens (P = 0.009) and ≤4 treatment lines (P = 0.015). Baseline CD4 and CD4:CD8 ratio were not predictors of the 10 year immunological outcomes. CONCLUSIONS: In this therapeutic cohort of patients starting first-generation PI-containing cART in 1997-99, poor initial immunological response had a negative impact on 10 year CD4 and CD4 plus CD4:CD8 ratio response, despite prolonged virological success. Lack of treatment interruption may improve long-term immunological outcome in HIV infection.

All-oral Direct-acting Antiviral Regimens in HIV/Hepatitis C Virus-coinfected Patients With Cirrhosis Are Efficient and Safe: Real-life Results From the Prospective ANRS CO13-HEPAVIH Cohort.

BACKGROUND: Human immunodeficiency virus (HIV)/hepatitis C virus (HCV)-coinfected patients with cirrhosis have long been considered to be difficult to treat, and real-life efficacy and tolerance data with all-oral direct-acting antiviral (DAA) combinations in these patients are scarce. METHODS: Cirrhotic HIV/HCV-coinfected patients enrolled in the French National Agency for Research on AIDS and Viral Hepatitis (ANRS) CO13 HEPAVIH cohort initiating an all-oral DAA regimen were consecutively included. A negative HCV RNA result at 12 weeks of follow-up or thereafter was assumed as a sustained virologic response (SVR12). Adjusted exact logistic regression was used to study factors associated with treatment outcome. RESULTS: We included 189 patients who initiated an all-oral DAA regimen with the following characteristics: median age 53.2 years; 74.6% male; Centers for Disease Control and Prevention classification A/B/C: 37%/31%/32%; Child-Pugh class A/B/C: 91%/8%/1%; 87% with HIV RNA <50 copies/mL; 99% on antiretrovirals; median CD4 count: 489 cells/µL; HCV treatment naive 29%; HCV genotype 1/2/3/4: 58%/4%/17%/21%. Sofosbuvir (SOF) + daclatasvir ± ribavirin (RBV) was used in 123 patients, SOF + RBV in 30, SOF + simeprevir in 11, and SOF + ledipasvir in 23. An SVR12 was reported in 93.1% of the patients (95% confidence interval, 88.5%-96.3%). In adjusted analyses, no difference was found between 12 or 24 weeks of treatment, in patients receiving RBV or not, and in treatment-naive vs experienced patients. Premature stop of DAA was reported for 8 patients. One patient died during treatment (unknown cause), and 12 other patients developed liver-related events. CONCLUSIONS: In this prospective real-life cohort, all-oral DAA regimens were well tolerated and associated with a high virologic efficacy in cirrhotic HIV/HCV-coinfected patients. This should not alleviate the surveillance for liver-related events in these patients.

Hepatitis C treatment initiation in HIV-HCV coinfected patients.

BACKGROUND: There are few data regarding HCV treatment initiation among HIV/HCV coinfected patients. The objective of this study was to analyze the changing patterns of HCV coinfection and HCV treatment initiation over time in a large French cohort of HIV/HCV coinfected patients at the beginning of DAA's era and to analyze factors associated with treatment initiation. METHODS: All HIV/HCV coinfected patients enrolled during 2000-2012 were analyzed. HCV status was defined per calendar year as naïve, spontaneous cure, sustained virological response (SVR), failure or reinfection. HCV treatment initiation rate was determined per year. Trends over time were analyzed using Chi-2 test for trend and linear regression analysis. The effect of covariates on treatment initiation over time was analyzed using generalized estimating equations. RESULTS: Among 34,308 HIV-infected patients enrolled between 2000 and 2012, 5,562 were HCV coinfected. HCV prevalence declined from 38.4 to 15.1 %. HCV treatment initiation rate fluctuated from 5.6 to 7.4 %/year from 2000 to 2007, dropped to 5.6 % in 2011 and increased to 8.5 % in 2012 due to the use of first-generation DAAs (29.1 % of initiations in 2012). Cumulative HCV treatment initiation rate increased from 14.8 % in 2000 to 54.7 % in 2012. HCV cure rate increased from 12.4 to 45.2 %. Older age, male gender, male homosexuality, high CD4, undetectable HIV-RNA, CDC stage A-B, and severe fibrosis/cirrhosis were associated with a higher treatment initiation rate. The role of HCV genotype 1, CDC stage, fibrosis and recent HCV infection on treatment initiation rate changed over time. CONCLUSION: A high rate of HCV treatment initiation was observed at the beginning of DAAs era in HIV/HCV coinfected patients. Given the very high efficacy of new DAA-based regimens and if treatment initiation keeps increasing, HCV prevalence among HIV patients will drastically decrease during the forthcoming years.

A multifaceted intervention designed to improve medical management of moderate to advanced chronic kidney disease in HIV-infected patients: a cluster randomized trial.

BACKGROUND: Chronic kidney disease (CKD) is frequent in individuals infected with human immunodeficiency virus (HIV). Progression to end-stage renal disease can be slowed by appropriate medical management. METHODS: To assess whether active promotion of guidelines improves CKD management, we conducted a cluster randomized controlled trial within the French Hospital Database on HIV (FHDH-ANRS CO4). We randomized 46 centers participating in the FHDH to either simple information on guideline availability or active promotion with a multifaceted and repeated intervention comprising reminders and audit feedback and targeting of local opinion leaders carried out between April 2009 and April 2010. Outcome measure was CKD management adequacy assessed before and 2 years after the beginning of the intervention in HIV-infected patients with moderate to severe CKD. CKD management was considered adequate in case of referral to a nephrologist or if proteinuria, blood pressure, low-density lipoprotein cholesterol level, and glycemia had been measured during the previous year and medications had been prescribed when necessary. RESULTS: Three hundred six patients were enrolled, of whom 238 (78%) completed the 2 years of follow-up. During the study period, the percentage of patients receiving adequate CKD management improved from 64.1% to 70.4% (+6.3%) in the active arm and from 68.3% to 75.6% (+7.3%) in the control arm (adjusted mean difference, -0.7 percentage points [95% confidence interval: -9.2 to 7.9]; P = .95). The biggest impact of active promotion was on the management of proteinuria and blood pressure. CONCLUSIONS: Adequate compliance with CKD management guidelines improved slightly between 2009 and 2011, with no difference between the simple information and active promotion arms. CLINICAL TRIALS REGISTRATION: CCTIRS 10.150 and CNIL DR-2010-379.

High Cure Rate With 24 Weeks of Daclatasvir-Based Quadruple Therapy in Treatment-Experienced, Null-Responder Patients With HIV/Hepatitis C Virus Genotype 1/4 Coinfection: The ANRS HC30 QUADRIH Study.

BACKGROUND: Few direct anti-hepatitis C virus (HCV) agents have been studied in difficult-to-treat null responder and cirrhotic human immunodeficiency virus (HIV)-coinfected patients. Daclatasvir and asunaprevir combined with pegylated interferon/ribavirin (peg-IFN/RBV) have shown promising results in HCV-monoinfected patients. METHODS: An open-label, single-arm, phase 2 study was conducted in HIV/HCV genotype 1/4-coinfected patients who were null responders to prior peg-IFN/RBV standard therapy and on a raltegravir-based regimen with HIV RNA <400 copies/mL. They received a 4-week lead-in phase with peg-IFN/RBV, followed by 24 weeks of asunaprevir (100 mg twice daily), daclatasvir (60 mg once daily), and peg-IFN/RBV. The primary endpoint was sustained virologic response 12 weeks after the end of treatment (SVR12) using intent-to-treat analysis. RESULTS: Seventy-five patients were included, of whom 27 (36%) had cirrhosis. The median baseline CD4 count was 748 (interquartile range, 481-930) cells/µL. The global SVR12 rate was 96.0% (95% confidence interval [CI], 88.8%-99.2%; n = 72/75), 92.6% (95% CI, 75.7%-99.1%; n = 25/27) in cirrhotic patients, 94.6% (95% CI, 81.8%-99.3%; n = 35/37) in genotype 1 patients, and 97.4% (95% CI, 86.2%-99.9%; n = 37/38) in genotype 4 patients. Six patients (8%) stopped HCV therapy prematurely: 2 due to HCV breakthrough, 4 to adverse events (1 lung cancer, 3 infections). One patient with cirrhosis (with baseline platelet count <150 000 platelets/µL and albuminemia <35 g/L) died from multiorgan failure. Overall, 36 serious adverse events occurred in 21 (28%) patients. No HIV breakthrough was observed. CONCLUSIONS: In HIV/HCV genotype 1/4-coinfected null responders, a 24-week regimen combining daclatasvir, asunaprevir, and peg-IFN/RBV was associated with a very high cure rate. The safety profile was acceptable, even though cirrhotic patients with low albuminemia and platelets should be monitored closely. This combination is a new option in this difficult-to-treat population. CLINICAL TRIALS REGISTRATION: NCT01725542.

Influence of nevirapine administration on the pharmacokinetics of dolutegravir in patients infected with HIV-1.

OBJECTIVES: The metabolic pathways of dolutegravir and nevirapine suggest a potential pharmacokinetic interaction between these drugs. The objective of this study was to investigate the influence of nevirapine administration on the pharmacokinetics of dolutegravir in patients infected with HIV-1. PATIENTS AND METHODS: This study was an investigator-initiated trial registered at ClinicalTrials.gov under identifier NCT02067767. Dolutegravir (50 mg once daily) was added to the antiretroviral regimen (400 mg of nevirapine once daily + 600/300 mg of abacavir/lamivudine once daily) in 10 adult patients for 5 days. After discontinuation of nevirapine, the combination of dolutegravir + abacavir/lamivudine was continued. Full pharmacokinetic profiles were assessed on the day of nevirapine discontinuation and 2 weeks after discontinuation of nevirapine. The pharmacokinetic parameters of dolutegravir were calculated by non-compartmental analysis. The log-transformed values of these parameters were compared between periods with and without nevirapine co-administration. RESULTS: The co-administration of nevirapine led to a significant decrease (P < 0.05) in the area under the plasma concentration-time curve for dolutegravir from the time the dose was administered until the end of the dosing interval (-19%, P = 0.011), as well as decreases in trough plasma concentration (-34%, P = 0.018) and terminal half-life (-15%, P = 0.039), and a significant increase (P < 0.05) in apparent oral clearance for dolutegravir (+23%, P = 0.011). CONCLUSIONS: The decrease in dolutegravir exposure in combination with nevirapine suggests that the metabolism of dolutegravir is induced by nevirapine. According to therapeutic drug monitoring for dolutegravir, some patients may need a higher dose than 50 mg of dolutegravir once daily to maintain the therapeutic plasma concentration throughout the dosing interval.

Residual viremia in patients on antiretroviral therapy incorporating nevirapine is not associated with the gag-specific cellular immune response.

To determine whether residual plasma viremia in HIV(+) patients on nevirapine-including antiretroviral therapy (ART) is related to anti-HIV cellular immune responses, a case-control study was conducted comparing residual viremia in patients with detectable and undetectable Gag-specific T-cell responses. Gag-specific responses were measured by IFN-γ ELISpot. Residual viremia was determined at two consecutive hospital visits by an ultra-sensitive technique with a detection limit of 2 copies/ml. Median residual viremia was not different in patients with a positive Gag-specific ELISpot (n = 25) compared to those with a negative Gag-specific ELISpot (n = 30, P = 0.91). Ten of 25 (40%) patients with consistent detectable residual viremia and 4 of 12 (33%) patients with consistently undetectable residual viremia had a positive Gag-specific ELISpot. Undetectable residual viremia was associated with the duration of ART including nevirapine (P < 0.05), but not with the Gag-specific ELISpot response. Gag-specific CTL in patients on ART therefore appear to have no impact on the virus-producing cells that are responsible for residual viremia during ART.

Evaluation of residual viremia and quantitation of soluble CD14 in a large cohort of HIV-infected adults on a long-term non-nucleoside reverse transcriptase inhibitor-based regimen.

Beyond virological suppression and immunologic recovery, the objective of long-term antiretroviral therapy is to suppress maximally viremia and to control for persistent immune activation. Non-nucleoside reverse transcriptase inhibitor (NNRTI)-containing regimens are associated with lower residual viremia. The objective of the study was to evaluate the impact of long term NNRTI-containing treatment on residual viremia and on monocyte activation in a cohort of patients infected with HIV-1. To identify factors associated with residual viremia, adult patients infected with HIV on nevirapine or efavirenz-based therapy with viral load <50 copies/ml for >6 months were included. Residual plasma viremia was quantified using an adapted Cobas/Taqman HIV-1 assay. Viral loads with no detected signal were considered as <1 copy/ml. Monocyte activation was evaluated by quantitation of plasma sCD14 by ELISA assay at the time of residual viremia measurement. Logistic regression was used to determine factors associated with residual viremia <1 copy/ml. In this cohort of 421 patients on long-term NNRTI regimen, three quarters had a residual viremia <1 copy/ml. In multivariate analysis, duration of plasma viral load below 50 copies/ml was the only factor associated with residual viremia <1 copy/ml. Soluble CD14 was in the normal range although treatment with nevirapine was associated with a significant lower level of sCD14 compared to efavirenz. Residual viremia <1 copy/ml was frequent in this cohort of patients with long term virological control and confirmed the results of previous studies. Apart from its antiviral effect, nevirapine as well as efavirenz could decrease monocyte activation.

[Assessing the implementation of the 2010-2014 National Plan against HIV in the Regional Coordination Centers for the Fight against HIV (COREVIHs)]. / Déclinaison du plan national de lutte contre le VIH 2010/2014 au sein des COREVIH.

INTRODUCTION: In France, 50,000 people are unaware of their HIV status because they have not been screened. Every year, there are nearly 7,000 new HIVinfections. To address this issue, the French Ministry of Health and Sport published the 2010-2014 National Plan against HIV/AIDS and other sexually transmitted diseases. A national survey was conducted among the Regional Coordination Centers for the Fight against HIV (COREVIHs) to assess their views of the National Plan and their current funding levels. METHOD: A questionnaire was sent to the presidents and coordinators of the 28 COREVIHs. RESULTS: After two reminders, 19 of the 28 COREVIHs responded. The National Plan was the original impetus for an assessmentofcurrent practices, accompanied by the implementation ofnew measures and new working groups. There is evidence that the COREVIHs are committed to developing incentive measures to promote screening and that they are also working to coordinate regional training programs in the area of screening and testing. The assessment also found that 11 COREVIHs were considering a reorganization of the CDAG/CIDDIST centers (CDAG: Free Anonymous Testing Center/ CIDDIST: STI Information, Testing and Diagnosis Center). Some COREVIHs have been involved in coordinating therapeutic education at a regional level. Most COREVIHs are also actively involved in the fight against discrimination. However, a number of obstacles to the implementation of the plan were identified. DISCUSSION: The purpose of this study was to examine the involvement of the COREVIHs in the implementation of the 2010-2014 National Plan against HIV The results indicate that implementing a system involving a specific form ofregionalcoordination of a public health problem is possible and should provide a basis for the decentralized implementation of public health plans.

Recombination of hepatitis B virus DNA in patients with HIV.

INTRODUCTION: Hepatitis B is a major cause of death in patients with HIV who usually receive drugs active against hepatitis B virus (HBV). The variability of HBV DNA over time has been little studied. Recombination between different HBV genotypes has been described in many cross-sectional studies, but the frequency of intergenotypic and intragenotypic recombinations in individual patients is unknown. METHODS: 32 HIV-positive and 11 HIV-negative patients who remained HBV viraemic despite antiviral therapy for at least 1 year were studied. Genotyping was based on line probe assays and genotype-specific PCR. The variability of HBV DNA over time was examined with restriction length and single-strand conformational polymorphism (RFLP-SSCP). HBV DNA sequences obtained by cloning a 2800 bp PCR fragment were analysed for phylogenetic parameters (diversity and selection pressure) and recombination was detected with RDP3 software. RESULTS: Large fragments of HBV DNA could be amplified at two different time points in 33 patients. Marked quasi-species modifications occurred in 14 patients. In seven of these patients and in one patient with no change detectable by RFLP-SSCP, the 2800 bp fragment was cloned at two time points at least. In four (57%) of these seven patients, various intergenotypic or intragenotypic recombination events were detected between subvariants present in the initial quasi-species. Recombinant fragments mostly harboured antiviral resistance determinants and reflected a large increase in diversity and in positive selection pressure on the entire HBV quasi-species. CONCLUSIONS: In coinfected patients, HBV DNA recombination events are frequent during antiviral therapy, corresponding to increased positive selection pressure on the HBV quasi-species and to conservation of antiviral resistance mutations. In this population and at the individual level, recombination is a significant source of HBV genetic variability.