Efficacy and safety of three antiretroviral therapy regimens for treatment-naive African adults living with HIV-2 (FIT-2): a pilot, phase 2, non-comparative, open-label, randomised controlled trial.

BACKGROUND: Due to the low number of individuals with HIV-2, no randomised trials of HIV-2 treatment have ever been done. We hypothesised that a non-comparative study describing the outcomes of several antiretroviral therapy (ART) regimens in parallel groups would improve understanding of how differences between HIV-1 and HIV-2 might lead to different therapeutic approaches. METHODS: This pilot, phase 2, non-comparative, open-label, randomised controlled trial was done in Burkina Faso, Côte d'Ivoire, Senegal, and Togo. Adults with HIV-2 who were ART naive with CD4 counts of 200 cells per µL or greater were randomly assigned 1:1:1 to one of three treatment groups. A computer-generated sequentially numbered block randomisation list stratified by country was used for online allocation to the next available treatment group. In all groups, tenofovir disoproxil fumarate (henceforth tenofovir) was dosed at 245 mg once daily with either emtricitabine at 200 mg once daily or lamivudine at 300 mg once daily. The triple nucleoside reverse transcriptase inhibitor (NRTI) group received zidovudine at 250 mg twice daily. The ritonavir-boosted lopinavir group received lopinavir at 400 mg twice daily boosted with ritonavir at 100 mg twice daily. The raltegravir group received raltegravir at 400 mg twice daily. The primary outcome was the rate of treatment success at week 96, defined as an absence of serious morbidity event during follow-up, plasma HIV-2 RNA less than 50 copies per mL at week 96, and a substantial increase in CD4 cells between baseline and week 96. This trial is registered at ClinicalTrials.gov, NCT02150993, and is closed to new participants. FINDINGS: Between Jan 26, 2016, and June 29, 2017, 210 participants were randomly assigned to treatment groups. Five participants died during the 96 weeks of follow-up (triple NRTI group, n=2; ritonavir-boosted lopinavir group, n=2; and raltegravir group, n=1), eight had a serious morbidity event (triple NRTI group, n=4; ritonavir-boosted lopinavir group, n=3; and raltegravir group, n=1), 17 had plasma HIV-2 RNA of 50 copies per mL or greater at least once (triple NRTI group, n=11; ritonavir-boosted lopinavir group, n=4; and raltegravir group, n=2), 32 (all in the triple NRTI group) switched to another ART regimen, and 18 permanently discontinued ART (triple NRTI group, n=5; ritonavir-boosted lopinavir group, n=7; and raltegravir group, n=6). The Data Safety Monitoring Board recommended premature termination of the triple NRTI regimen for safety reasons. The overall treatment success rate was 57% (95% CI 47-66) in the ritonavir-boosted lopinavir group and 59% (49-68) in the raltegravir group. INTERPRETATION: The raltegravir and ritonavir-boosted lopinavir regimens were efficient and safe in adults with HIV-2. Both regimens could be compared in future phase 3 trials. The results of this pilot study suggest a trend towards better virological and immunological efficacy in the raltegravir-based regimen. FUNDING: ANRS MIE.

Feasibility, safety, efficacy and potential scaling-up of sofosbuvir-based HCV treatment in Central and West Africa: (TAC ANRS 12311 trial).

Access to Hepatis C treatment in Sub-Saharan Africa is a clinical, public health and ethical concern. The multi-country open-label trial TAC ANRS 12311 allowed assessing the feasibility, safety, efficacy of a specific care model of HCV treatment and retreatment in patients with hepatitis C in Sub Saharan Africa. Between November 2015 and March 2017, with follow-up until mid 2019, treatment-naïve patients with HCV without decompensated cirrhosis or liver cancer were recruited to receive 12 week-treatment with either sofosbuvir + ribavirin (HCV genotype 2) or sofosbuvir + ledipasvir (genotype 1 or 4) and retreatment with sofosbuvir + velpatasvir + voxilaprevir in case of virological failure. The primary outcome was sustained virological response at 12 weeks after end of treatment (SVR12). Secondary outcomes included treatment adherence, safety and SVR12 in patients who were retreated due to non-response to first-line treatment. The model of care relied on both viral load assessment and educational sessions to increase patient awareness, adherence and health literacy. The study recruited 120 participants, 36 HIV-co-infected, and 14 cirrhotic. Only one patient discontinued treatment because of return to home country. Neither death nor severe adverse event occurred. SVR12 was reached in 107 patients (89%): (90%) in genotype 1 or 2, and 88% in GT-4. All retreated patients (n = 13) reached SVR12. HCV treatment is highly acceptable, safe and effective under this model of care. Implementation research is now needed to scale up point-of-care HCV testing and SVR assessment, along with community involvement in patient education, to achieve HCV elimination in Sub-Saharan Africa.

Incidence and Predictors of Tuberculosis-associated IRIS in People With HIV Treated for Tuberculosis: Findings From Reflate TB2 Randomized Trial.

Background: After antiretroviral therapy (ART) initiation, people with HIV (PWH) treated for tuberculosis (TB) may develop TB-associated immune reconstitution inflammatory syndrome (TB-IRIS). Integrase inhibitors, by providing a faster HIV-RNA decline than efavirenz, might increase the risk for this complication. We sought to assess incidence and determinants of TB-IRIS in PWH with TB on raltegravir- or efavirenz-based ART. Methods: We conducted a secondary analysis of the Reflate TB 2 trial, which randomized ART-naive PWH on standard TB treatment, to receive raltegravir- or efavirenz-based ART. The primary objective was to evaluate the incidence of TB-IRIS. Incidence rate ratio comparing TB-IRIS incidence in each arm was calculated. Kaplan-Meier curves were used to compare TB-IRIS-free survival probabilities by ART arm. Cox regression models were fitted to analyze baseline characteristics associated with TB-IRIS. Results: Of 460 trial participants, 453 from Brazil, Côte d'Ivoire, Mozambique, and Vietnam were included in this analysis. Baseline characteristics were median age 35 years (interquartile range [IQR], 29-43), 40% female, 69% pulmonary TB only, median CD4, 102 (IQR, 38-239) cells/mm³, and median HIV RNA, 5.5 (IQR, 5.0-5.8) log copies/mL. Forty-eight participants developed TB-IRIS (incidence rate, 24.7/100 PY), 19 cases in the raltegravir arm and 29 in the efavirenz arm (incidence rate ratio 0.62, 95% confidence interval .35-1.10). Factors associated with TB-IRIS were: CD4 ≤ 100 cells/µL, HIV RNA ≥500 000 copies/mL, and extrapulmonary/disseminated TB. Conclusions: We did not demonstrate that raltegravir-based ART increased the incidence of TB-IRIS compared with efavirenz-based ART. Low CD4 counts, high HIV RNA, and extrapulmonary/disseminated TB at ART initiation were associated with TB-IRIS.

Virologic response to antiretroviral therapy in people with HIV and tuberculosis in high tuberculosis burden countries.

OBJECTIVE: We sought to compare virologic outcomes on antiretroviral therapy (ART) between people with HIV (PWH) also treated for tuberculosis in the different countries who participated to two randomized trials. DESIGN: Pooled analysis of two randomized clinical trials. METHODS: In the phase II Reflate TB and phase III Reflate TB2 trials conducted in Brazil, Côte d'Ivoire, Mozambique and Vietnam, ART-naïve PWH treated for tuberculosis were randomized to receive raltegravir or efavirenz. We assessed country differences in baseline characteristic using Wilcoxon tests and chi-square, or Fisher's exact test. We used logistic regression to analyze determinants of virologic success, defined as week-48 plasma HIV-1 RNA <50 copies/ml. RESULTS: Of 550 participants (140 from Brazil, 170 from Côte d'Ivoire, 129 from Mozambique and 111 from Vietnam) with median baseline HIV-1 RNA of 5.4 log 10  copies/ml, 362 (65.8%) achieved virologic success at week 48. Virologic success rates were: 105/140 (75.0%) in Brazil, 99/170 (58.2%) in Côte d'Ivoire, 84/129 (65.1%) in Mozambique and 74/111 (66.7%) in Vietnam ( P  = 0.0233). Baseline HIV-1 RNA, but not the country, was independently associated with virologic success: baseline HIV-1 RNA ≥500 000 copies/ml (reference), HIV RNA <100 000 copies/ml odds ratio 3.12 [95% confidence interval (CI) 1.94; 5.01] and HIV-1 RNA 100 000-499 999 copies/ml odds ratio: 1.80 (95% CI 1.19; 2.73). Overall, 177/277 (63.9%) patients treated with raltegravir and 185/273 (67.9%) patients treated with efavirenz had a plasma HIV-1 RNA <50 copies/ml at week 48. CONCLUSIONS: Virologic response to antiretroviral therapy in PWH with TB varied across countries but was mainly driven by levels of pretreatment HIV-1 RNA.

Determinants of Antiretroviral Treatment Success and Adherence in People With Human Immunodeficiency Virus Treated for Tuberculosis.

Background: In people with human immunodeficiency virus [HIV] presenting with advanced disease, rates of virologic success may be lower than expected. The Reflate TB2 trial did not show non-inferiority of raltegravir versus efavirenz in people with HIV (PWH) treated for tuberculosis. We aimed to identify factors associated with virologic success and higher adherence in the trial. Methods: In this analysis, we included participants enrolled in the Reflate TB2 trial with adherence data available. The primary outcome was virologic success (HIV-1 ribonucleic acid [RNA] <50 copies/mL) at week 48, and the secondary outcome was adherence as assessed by the pill count adherence ratio. We used logistic regression to study determinants of virologic success and optimal adherence in 2 separate analyses. Results: Four hundred forty-four participants were included in the present analysis. Over the 48-week follow-up period, 290 of 444 (65%) participants had a pill count adherence ratio ≥95%. At week 48, 288 of 444 (65%) participants were in virologic success. In the multivariate analysis, female sex (adjusted odds ratio [aOR], 1.77; 95% confidence interval [CI], 1.16-2.72; P = .0084), lower baseline HIV-1 RNA levels (<100 000; aOR, 2.29; 95% CI, 1.33-3.96; P = .0087), and pill count adherence ratio ≥95% (aOR, 2.38; 95% CI, 1.56-3.62; P < .0001) were independently associated with virologic success. Antiretroviral pill burden was the only factor associated with pill count adherence ratio ≥95% (OR, 0.81; 95% CI, .71-.92; P = .0018). Conclusions: In PWH with tuberculosis receiving raltegravir or efavirenz-based regimens, female sex, optimal adherence, and baseline HIV-1 RNA <100 000 copies/mL were associated with virologic success, and the number of antiretroviral tablets taken daily was a strong predictor of adherence.

Intensified tuberculosis treatment to reduce the mortality of HIV-infected and uninfected patients with tuberculosis meningitis (INTENSE-TBM): study protocol for a phase III randomized controlled trial.

BACKGROUND: Tuberculous meningitis (TBM) is the most lethal and disabling form of tuberculosis (TB), particularly in sub-Saharan Africa. Current anti-TB treatment is poorly effective since TBM mortality reaches 40% in HIV-negative patients and up to 70% in HIV-co-infected patients. To reduce TBM-induced morbidity and mortality, the INTENSE-TBM trial evaluates two interventions in both HIV-infected and uninfected patients: an anti-TB treatment intensification using oral high-dose rifampicin (35 mg/kg daily) and linezolid (1200 mg daily and then 600 mg daily) during the first 8 weeks of the anti-TB treatment and the use of adjunctive aspirin (200 mg daily). METHODS: This is a randomized controlled, phase III, multicenter, 2 × 2 factorial plan superiority trial. The trial has four arms, combining the two experimental treatments (intensified TBM regimen and aspirin) with the two reference treatments (WHO standard TB treatment and placebo), and is open-label for anti-TB treatment and double-blind placebo-controlled for aspirin treatment. This trial is conducted in adults or adolescents of age ≥15 years with TBM defined as "definite," "probable," or "possible" using Tuberculosis Meningitis International Research Consortium criteria, in four African countries: Ivory Coast, Madagascar, Uganda, and South Africa. The primary outcome is all-cause death between inclusion and week 40. DISCUSSION: The INTENSE-TBM trial represents a key opportunity to enhance TBM treatment with widely available existing drugs notably in high-incidence settings of both TB and HIV. The trial design is pragmatic and the results will permit early and effective applications in TBM patient care, in both HIV and TB high-incidence countries. TRIAL REGISTRATION: ClinicalTrials.gov NCT04145258. Registered on October 30, 2019.

Standard dose raltegravir or efavirenz-based antiretroviral treatment for patients co-infected with HIV and tuberculosis (ANRS 12 300 Reflate TB 2): an open-label, non-inferiority, randomised, phase 3 trial.

BACKGROUND: In patients co-infected with HIV and tuberculosis, antiretroviral therapy options are limited due to drug-drug interactions with rifampicin. A previous phase 2 trial indicated that raltegravir 400 mg twice a day or efavirenz 600 mg once a day might have similar virological efficacy in patients given rifampicin. In this phase 3 trial, we assessed the non-inferiority of raltegravir to efavirenz. METHODS: We did a multicentre, open-label, non-inferiority, randomised, phase 3 trial at six sites in Côte d'Ivoire, Brazil, France, Mozambique, and Vietnam. We included antiretroviral therapy (ART)-naive adults (aged ≥18 years) with confirmed HIV-1 infection and bacteriologically confirmed or clinically diagnosed tuberculosis who had initiated rifampicin-containing tuberculosis treatment within the past 8 weeks. Using computerised random numbers, we randomly assigned participants (1:1; stratified by country) to receive raltegravir 400 mg twice daily or efavirenz 600 mg once daily, both in combination with tenofovir and lamivudine. The primary outcome was the proportion of patients with virological suppression at week 48 (defined as plasma HIV RNA concentration <50 copies per mL). The prespecified non-inferiority margin was 12%. The primary outcome was assessed in the intention-to-treat population, which included all randomly assigned patients (excluding two patients with HIV-2 infection and one patient with HIV-1 RNA concentration of <50 copies per mL at inclusion), and the on-treatment population, which included all patients in the intention-to-treat population who initiated treatment and were continuing allocated treatment at week 48, and patients who had discontinued allocated treatment due to death or virological failure. Safety was assessed in all patients who received at least one dose of the assigned treatment regimen. This study is registered with ClinicalTrials.gov, NCT02273765. FINDINGS: Between Sept 28, 2015, and Jan 5, 2018, 460 participants were randomly assigned to raltegravir (n=230) or efavirenz (n=230), of whom 457 patients (230 patients in the raltegravir group; 227 patients in the efavirenz group) were included in the intention-to-treat analysis and 410 (206 patients in the raltegravir group; 204 patients in the efavirenz group) in the on-treatment analysis. At baseline, the median CD4 count was 103 cells per µL and median plasma HIV RNA concentration was 5·5 log10 copies per mL (IQR 5·0-5·8). 310 (68%) of 457 participants had bacteriologically-confirmed tuberculosis. In the intention-to-treat population, at week 48, 140 (61%) of 230 participants in the raltegravir group and 150 (66%) of 227 patients in the efavirenz had achieved virological suppression (between-group difference -5·2% [95% CI -14·0 to 3·6]), thus raltegravir did not meet the predefined criterion for non-inferiority. The most frequent adverse events were HIV-associated non-AIDS illnesses (eight [3%] of 229 patients in the raltegravir group; 21 [9%] of 230 patients in the efavirenz group) and AIDS-defining illnesses (ten [4%] patients in the raltegravir group; 13 [6%] patients in the efavirenz group). 58 (25%) of 229 patients in raltegravir group and 66 (29%) of 230 patients in the efavirenz group had grade 3 or 4 adverse events. 26 (6%) of 457 patients died during follow-up: 14 in the efavirenz group and 12 in the raltegravir group. INTERPRETATION: In patients with HIV given tuberculosis treatment, non-inferiority of raltegravir compared with efavirenz was not shown. Raltegravir was well tolerated and could be considered as an option, but only in selected patients. FUNDING: National French Agency for AIDS Research, Ministry of Health in Brazil, Merck. TRANSLATIONS: For the Portuguese and French translations of the abstract see Supplementary Materials section.

Meropenem vs standard of care for treatment of neonatal late onset sepsis (NeoMero1): A randomised controlled trial.

BACKGROUND: The early use of broad-spectrum antibiotics remains the cornerstone for the treatment of neonatal late onset sepsis (LOS). However, which antibiotics should be used is still debatable, as relevant studies were conducted more than 20 years ago, recruited in single centres or countries, evaluated antibiotics not in clinical use anymore and had variable inclusion/exclusion criteria and outcome measures. Moreover, antibiotic-resistant bacteria have become a major problem in many countries worldwide. We hypothesized that efficacy of meropenem as a broad-spectrum antibiotic is superior to standard of care regimens (SOC) in empiric treatment of LOS and aimed to compare meropenem to SOC in infants aged <90 days with LOS. METHODS AND FINDINGS: NeoMero-1 was a randomized, open-label, phase III superiority trial conducted in 18 neonatal units in 6 countries. Infants with post-menstrual age (PMA) of ≤44 weeks with positive blood culture and one, or those with negative culture and at least with two predefined clinical and laboratory signs suggestive of LOS, or those with PMA >44 weeks meeting the Goldstein criteria of sepsis, were randomized in a 1:1 ratio to receive meropenem or one of the two SOC regimens (ampicillin+gentamicin or cefotaxime+gentamicin) chosen by each site prior to the start of the study for 8-14 days. The primary outcome was treatment success (survival, no modification of allocated therapy, resolution/improvement of clinical and laboratory markers, no need of additional antibiotics and presumed/confirmed eradication of pathogens) at test-of-cure visit (TOC) in full analysis set. Stool samples were tested at baseline and Day 28 for meropenem-resistant Gram-negative organisms (CRGNO). The primary analysis was performed in all randomised patients and in patients with culture confirmed LOS. Proportions of participants with successful outcome were compared by using a logistic regression model adjusted for the stratification factors. From September 3, 2012 to November 30th 2014, total of 136 patients (instead of planned 275) in each arm were randomized; 140 (52%) were culture positive. Successful outcome at TOC was achieved in 44/136 (32%) in the meropenem arm vs. 31/135 (23%) in the SOC arm (p = 0.087). The respective numbers in patients with positive cultures were 17/63 (27%) vs. 10/77 (13%) (p = 0.022). The main reason of failure was modification of allocated therapy. Treatment emergent adverse events occurred in 72% and serious adverse events in 17% of patients, the Day 28 mortality was 6%. Cumulative acquisition of CRGNO by Day 28 occurred in 4% of patients in the meropenem and 12% in the SOC arm (p = 0.052). CONCLUSIONS: Within this study population, we found no evidence that meropenem was superior to SOC in terms of success at TOC, short term hearing disturbances, safety or mortality were similar in both treatment arms but the study was underpowered to detect the planned effect. Meropenem treatment did not select for colonization with CRGNOs. We suggest that meropenem as broad-spectrum antibiotic should be reserved for neonates who are more likely to have Gram-negative LOS, especially in NICUs where microorganisms producing extended spectrum- and AmpC type beta-lactamases are circulating.

Plasma and CSF pharmacokinetics of meropenem in neonates and young infants: results from the NeoMero studies.

Background: Sepsis and bacterial meningitis are major causes of mortality and morbidity in neonates and infants. Meropenem, a broad-spectrum antibiotic, is not licensed for use in neonates and infants below 3 months of age and sufficient information on its plasma and CSF disposition and dosing in neonates and infants is lacking. Objectives: To determine plasma and CSF pharmacokinetics of meropenem in neonates and young infants and the link between pharmacokinetics and clinical outcomes in babies with late-onset sepsis (LOS). Methods: Data were collected in two recently conducted studies, i.e. NeoMero-1 (neonatal LOS) and NeoMero-2 (neonatal meningitis). Optimally timed plasma samples (n = 401) from 167 patients and opportunistic CSF samples (n = 78) from 56 patients were analysed. Results: A one-compartment model with allometric scaling and fixed maturation gave adequate fit to both plasma and CSF data; the CL and volume (standardized to 70 kg) were 16.7 (95% CI 14.7, 18.9) L/h and 38.6 (95% CI 34.9, 43.4) L, respectively. CSF penetration was low (8%), but rose with increasing CSF protein, with 40% penetration predicted at a protein concentration of 6 g/L. Increased infusion time improved plasma target attainment, but lowered CSF concentrations. For 24 patients with culture-proven Gram-negative LOS, pharmacodynamic target attainment was similar regardless of the test-of-cure visit outcome. Conclusions: Simulations showed that longer infusions increase plasma PTA but decrease CSF PTA. CSF penetration is worsened with long infusions so increasing dose frequency to achieve therapeutic targets should be considered.

Current management of late onset neonatal bacterial sepsis in five European countries.

UNLABELLED: Late onset neonatal sepsis (LOS) has a high mortality and the optimal management is poorly defined. We aimed to evaluate new expert panel-derived criteria to define LOS and characterize the current management and antibiotic susceptibility of LOS-causing organisms in Europe. A prospective observational study enrolled infants aged 4 to 90 days in five European countries. Clinical and laboratory findings as well as empiric treatment were recorded and patients were followed until the end of antibiotic therapy. Failure was defined as a change of primary antibiotic, no resolution of clinical signs, appearance of new signs/pathogens or death. Antibiotic therapy was considered appropriate if the organism was susceptible to at least one empiric antibiotic. 113 infants (median age 14 days, 62 % ≤1500 g) were recruited; 61 % were culture proven cases (28 CoNS, 24 Enterobacteriaceae, 11 other Gram-positives and 6 Gram-negative non-fermentative organisms). The predictive value of the expert-panel criteria to identify patients with a culture proven LOS was 61 % (95 % CI 52 % to 70 %). Around one third of Enterobacteriaceae were resistant to ampicillin + or cefotaxime + gentamicin but only 10 % to meropenem. Empiric treatment contained a total of 43 different antibiotic regimens. All-cause mortality was 8 % with an additional 45 % classified as failure of empiric therapy, mainly due to change of primary antibiotics (42/60). CONCLUSIONS: The expert panel-derived diagnostic criteria performed well identifying a high rate of culture proven sepsis. Current management of LOS in Europe is extremely variable suggesting an urgent need of evidence-based guidelines.

Maternal immune response and neonatal seroprotection from a single dose of a monovalent nonadjuvanted 2009 influenza A(H1N1) vaccine: a single-group trial.

BACKGROUND: Pregnant women and infants who get influenza are at increased risk for severe illness. OBJECTIVE: To evaluate the immunogenicity and transplacental antibody transfer of 2009 pandemic influenza A(H1N1) vaccine administered during pregnancy. DESIGN: Prospective, multicenter, single-group clinical trial. (ClinicalTrials.gov registration number: NCT01024400) SETTING: Five level-3 perinatal centers in France. PATIENTS: 107 pregnant women between 22(0/7) and 32(0/7) weeks of gestation. INTERVENTION: An intramuscular dose of a nonadjuvanted H1N1 vaccine that contained 15 mcg of hemagglutinin. MEASUREMENTS: Proportion of women with an influenza antibody titer of 1:40 or greater at days 21 and 42 after vaccination, delivery, and 3 months after delivery. Seroconversion rate, fold increase in the geometric mean titer 21 days after vaccination, and proportion of neonates with an antibody titer of 1:40 or greater at birth were also assessed. RESULTS: At baseline, 19% of the women had an antibody titer of 1:40 or greater. At day 21, 98% of the women had an antibody titer of 1:40 or greater, the seroconversion rate was 93%, and the fold increase in geometric mean titer was 67.4. At day 42, delivery, and 3 months after delivery, 98%, 92%, and 90% of the women, respectively, had an antibody titer of 1:40 or greater. Ninety-five percent of the cord serum samples obtained from 88 neonates showed an antibody titer of 1:40 or greater. The median neonate-mother antibody titer ratio was 1.4. LIMITATIONS: Only healthy pregnant women were selected. Data on hemagglutination inhibition antibody titers of infants were reported only at birth. CONCLUSION: A single dose of a nonadjuvanted influenza A(H1N1) vaccine with 15 mcg of hemagglutinin triggered a strong immune response in pregnant women and a high rate of neonatal seroprotection. PRIMARY FUNDING SOURCE: French National Institute of Health and Medical Research.

Dynamics of gag-pol minority viral populations in naive HIV-1-infected patients failing protease inhibitor regimen.

OBJECTIVE: Recently, we have reported the role of baseline gag cleavage site mutations on the virological outcome of a dual-boosted protease inhibitor regimen in antiretroviral-naive patients (2IP-ANRS 127 trial). The objective of this substudy was to characterize, in patients experiencing virological failure, from the 2IP-ANRS 127 trial, the viral quasispecies present at baseline and at virological failure in gag cleavage site, in gag-pol frameshift and in protease-coding region. METHODS: In four patients, we analysed by clonal analysis the viral population in gag cleavage site (p17/p24, p24/p2, p2/p7, p7/p1, p1/p6(gag)), in p6(gag), in gag-pol frameshift [p1/transframe protein (TFP)/p6(pol)] and in protease-coding region. RESULTS: Clonal analysis of protease-coding region failed to detect major as well as minor protease inhibitor resistance-associated mutations in all four patients. In one patient, a I15V-mutated variant increased from 13 to 100% between baseline and week 24. Clonal analysis of gag and gag-pol cleavage site showed an increase in specific viral populations in p2/p7 cleavage site between baseline and virological failure in three patients. Among them, we described in one patient, that the predominant population at virological failure harboured in p2/p7 and TFP/p6(pol)-specific genotypic profiles associated with duplication of the P(T)APP motif in p6(gag) and the I15V protease mutation on the same individual molecular clones. CONCLUSION: We highlighted the emergence of minority viral populations in the p2/p7 cleavage site between baseline and virological failure. In addition, we showed the association of a specific protease mutation with gag and gag-pol cleavage site substitutions, suggesting their possible role in virological outcome.

Efficacy and safety of ritonavir-boosted dual protease inhibitor therapy in antiretroviral-naive HIV-1-infected patients: the 2IP ANRS 127 study.

OBJECTIVES: We evaluate the efficacy and tolerability of ritonavir-boosted dual protease inhibitor as a nucleoside reverse transcriptase inhibitor-sparing regimen in a prospective open-label randomized pilot trial in antiretroviral-naive patients. METHODS: Thirty patients received fosamprenavir/atazanavir/ritonavir (Group 1) and 31 patients received saquinavir/atazanavir/ritonavir (Group 2). The primary endpoint for efficacy was the rate of early virological success, defined as plasma viral load <50 copies/mL at week 16. The study is registered with ClinicalTrials.gov (NCT00122603). RESULTS: At baseline, median (range) viral load was 4.8 log(10) copies/mL (4.0-5.7) and the median CD4 cell count was 271/mm(3) (197-740). Viral load was <50 copies/mL in 12/30 patients [40%, 95% confidence interval (CI) 23%-58%] and 13/31 patients (42%, 95% CI 25%-59%) at week 16 in Groups 1 and 2, respectively. Patients with failing regimens (viral load >or=400 copies/mL at week 16 or >or=50 copies/mL at week 24) were switched to a standard antiretroviral regimen. At week 48, by an intention-to-treat analysis, 23/30 patients (77%) and 26/31 patients (84%) had plasma HIV-1 RNA <50 copies/mL in Groups 1 and 2, respectively. Four patients discontinued treatment for adverse events, all before week 4. No major changes in the protease gene were detected at treatment failure relative to baseline. Baseline viral load <50 000 copies/mL was the only predictor of virological success at week 16. CONCLUSIONS: Ritonavir-boosted dual protease inhibitor regimens targeting only one step of viral replication were insufficient to rapidly suppress plasma HIV RNA to <50 copies/mL in antiretroviral-naive patients with high viral load at baseline.

Resistance and virological response analyses in a three initial treatment strategy trial: a substudy of the INITIO trial.

PURPOSE: To study the impact of baseline resistance mutations and HIV-1 subtypes on virological response to first-line antiretroviral therapy and to analyse the concordance of the results of two antiretroviral resistance interpretation tools in the INITIO trial. METHOD: Genotype and virco TYPE resistance analyses were studied at baseline, Year 2, Year 3, and at first therapeutic failure on plasma specimens stored at -80 degrees C. Relations between resistance mutations at baseline, subtype, initial virological response, and virological outcome after Week 24 were studied. RESULTS: 781 participants had genotypic results available at baseline. Therapeutic failure occurred for 112 participants. Initial virological response as well as virological outcome after Week 24 were not associated with HIV subtype. Before Week 24, the proportion of participants remaining under strict initial regimen was lower in patients with resistance mutations at baseline than in those without any resistance mutations. Presenceof resistance mutations at baseline also impacted negatively long-term virological outcome. Few discrepancies were observed between genotypic and virco TYPE for resistance interpretation. CONCLUSION: These data showed that presence of resistance mutations at baseline was associated with a poorer long-term virological outcome in the INITIO trial.

Renal function in antiretroviral-experienced patients treated with tenofovir disoproxil fumarate associated with atazanavir/ritonavir.

OBJECTIVE: To determine the evolution of renal function in highly treatment-experienced patients with normal renal function at baseline receiving tenofovir disoproxil fumarate (TDF) as part of a fixed combined antiretroviral regimen and to identify prognostic factors of change in renal function, including tenofovir concentrations. METHODS: A prospective 48-week open-label trial was carried out, evaluating the safety of TDF, associated with atazanavir/ritonavir, and optimized nucleoside reverse transcriptase inhibitors, in patients with documented failure in previous treatments. Statistical analysis was performed on an intent-to-treat basis. RESULTS: Fifty-three patients were included, with a median CD4+ T-cell count of 206 x 10(6)/l and a median HIV RNA level of 5 log10 copies/ml. All patients had normal serum creatinine levels and creatinine clearances (CL(Cr)) at baseline, which were stable within the 2 months preceding inclusion. Two patients discontinued TDF as a result of severe renal impairment. Two patients never started TDF. A total of 49 patients without clinical nephrotoxicity were analysed. The median creatinine level increased significantly from baseline to week 48 (+0.04 mg/dl [+5.8%]; P = 0.008), and the median CL(Cr) decreased significantly (-7.8 ml/min [-7.6%]; P = 0.005). Trough tenofovir concentration was not associated with change in CL(Cr), (P = 0.79). No risk factors, including tenofovir plasma trough levels, were significantly associated with change in CL(Cr) at week 24. CONCLUSIONS: This study confirms that TDF-related severe nephrotoxicity is an uncommon event. In patients without clinical nephrotoxicity, the use of TDF during a 1-year period was associated with a slight but significant alteration of renal function, which was not associated with increased trough concentration.

Salvage therapy with atazanavir/ritonavir combined to tenofovir in HIV-infected patients with multiple treatment failures: randomized ANRS 107 trial.

BACKGROUND: Ritonavir (RTV)-boosted atazanavir (ATV) and tenofovir disoproxil fumarate (TDF-DF) are promising in highly experienced patients because of their pharmacokinetic profile, activity, safety and resistance properties. METHODS: A 26-week study of the safety and efficacy of RTV-boosted ATV plus TDF-DF was conducted in 53 HIV-infected patients who were failing their current highly active antiretroviral therapy (HAART) regimen. Patients with history of failure to at least two protease inhibitors (PIs) and one non-nucleoside reverse transcriptase inhibitor (NNRTI) were randomized to either continue their current regimen (group 1) or replace the PI by ATV (300 mg once daily) boosted by RTV (100 mg; group 2) for 2 weeks. Then, all patients received the same combination of ATV, RTV and TDF-DF (300 mg) plus optimized NRTIs regimen. RESULTS: At baseline, median CD4+ T-cell count was 206/mm3, median viral load (VL) 5.0 log10/ml and median numbers of NRTI, NNRTI and PI resistance mutations were 7, 1 and 8, respectively. At week 2, median VL remained unchanged from baseline in group 2 as compared with group 1 (-0.1 vs -0.1 log10/ml). At week 26, a mild decrease in median VL from baseline of 0.2 log10/ml was observed, with 16 (31%) and 9 (17%) patients exhibiting a decrease in viral load of at least 0.5 and 1.0 log10/ml, respectively. Baseline phenotypic and genotypic resistance to ATV were the most predictive independent factors of virological response. The regimen was well tolerated. CONCLUSION: In these very advanced patients failing highly HAART, the combination of boosted ATV plus TDF-DF yielded low antiretroviral activity.

Virological and immunological impact of non-nucleoside reverse transcriptase inhibitor withdrawal in HIV-infected patients with multiple treatment failures.

No significant changes in viral load and CD4 cell count were observed 2-4 weeks after the withdrawal of non-nucleoside reverse transcriptase inhibitors (NNRTI) from the current therapy of patients exhibiting resistance mutations to this class of drugs. The data suggest that in the presence of specific resistance mutations NNRTIexert no residual antiretroviral activity and could be withdrawn without viral rebound.

Interactions between atazanavir-ritonavir and tenofovir in heavily pretreated human immunodeficiency virus-infected patients.

The aim of the present study was to assess the pharmacokinetic behavior of atazanavir-ritonavir when it is coadministered with tenofovir disoproxil fumarate (DF) in human immunodeficiency virus (HIV)-infected patients. Eleven patients enrolled in Agence Nationale de Recherche sur le SIDA (National Agency for AIDS Research, Paris, France) trial 107 were included in this pharmacokinetic study. They received atazanavir at 300 mg and ritonavir at 100 mg once a day (QD) from day 1 to the end of study. For the first 2 weeks, their nucleoside analog reverse transcriptase inhibitor (NRTI) treatments remained unchanged. Tenofovir DF was administered QD from day 15 to the end of the study. Ongoing NRTIs were selected according to the reverse transcriptase genotype of the HIV isolates from each patient. The values of the pharmacokinetic parameters for atazanavir and ritonavir were measured before (day 14 [week 2]) and after (day 42 [week 6]) initiation of tenofovir DF and are reported for the 10 patients who completed the study. There was a significant decrease in the area under the concentration-time curve from 0 to 24 h (AUC(0-24)) for atazanavir with the addition of tenofovir DF (AUC(0-24) ratio, 0.75; 90% confidence interval, 0.58 to 0.97; P = 0.05). There was a trend for a decrease in the minimum concentrations of atazanavir and ritonavir in plasma when they were combined with tenofovir, but none of the differences reached statistical significance. The median decreases in the HIV RNA loads at week 2 and week 6 were 0.1 and 0.2 log copies/ml, respectively. In summary, our data are consistent with the existence of a significant interaction between atazanavir and tenofovir DF.

Successful implementation of a low-cost method for enumerating CD4+ T lymphocytes in resource-limited settings: the ANRS 12-26 study.

OBJECTIVE: To evaluate the feasibility and the relevance of the implementation of an alternative technique to flow cytometry (FC) for enumerating CD4 T cells (Dynabeads; Dynal Biotech, Oslo, Norway), based on quantifying CD4 T cells by epifluorescent microscopy following their isolation using anti-CD4 monoclonal antibody-coated magnetic beads. DESIGN: International multi-center study. Five consecutive runs of dual CD4 T-lymphocyte enumeration by both techniques in six sites in five countries of West Africa. METHODS: A total of 657 pairs of values of CD4 cell counts were generated by 43 technicians by both FC (TruCount; Becton Dickinson Immunocytometry Systems, San Jose, California, USA) and Dynabeads from blood samples obtained from 301 HIV-infected patients, seen in one (n = 112), two (n = 61), three (n = 75), four (n = 40) or five (n = 13) occasions. RESULTS: The correlation coefficient between the results of the two techniques was 0.89. The overall systematic difference between Dynabeads and FC was -16 x 10(6) cells/l (P < 10(-4)). The median difference was insignificant (+7.5 cells) for CD4 cell counts below 200 x 10(6) cells/l and increased with CD4 levels. Patients were consistently classified at the threshold of 200 x 106 cells/l by both methods in 88.7% of cases. Among the 74 discrepant pairs of values, only 31 (4.7%) exhibited a difference of more than 100 x 10(6) cells/l. CONCLUSIONS: Results from Dynabeads and FC were highly correlated. The ability of the alternative method to consistently classify results in agreement with FC, at thresholds of CD4 cell counts relevant for clinical care, was high. The implementation of this low-cost method was easy and successful in the West African context.