Pub Date : 2016-03-01Epub Date: 2016-02-11DOI: 10.1080/15284336.2015.1135553
Isabelle Poizot-Martin, Eric Bellissant, Rodolphe Garraffo, Philippe Colson, Lionel Piroth, Caroline Solas, Alain Renault, Marc Bourlière, Philippe Halfon, Jade Ghosn, Laurent Alric, Alissa Naqvi, Patrizia Carrieri, Jean-Michel Molina
Background: Scarce data exist on the efficacy and safety of the PEGylated-interferon/ribavirin/boceprevir regimen in HIV/HCV-coinfected patients who failed to respond to PEGylated-interferon/ribavirin treatment.
Objectives: To evaluate the efficacy and safety of this drug regimen and the impact of the addition of boceprevir(BOC) on atazanavir (ATV) or raltegravir (RAL) pharmacokinetic parameters in a subgroup of patients.
Methods: In this single-arm phase 2 trial, HIV-1/HCV-genotype-1-coinfected patients received PEGylated-interferonα2b (1.5 μg/kg/week)+ ribavirin (800-1400 mg/day) alone until W4 and with BOC(800 mgTID) until W48. Based on virologic response at W8, the three drugs were stopped or PEGylated-interferon/ribavirin was continued alone until W72. The primary endpoint was SVR at W24 off-therapy (SVR24).
Results: 64 patients were included. SVR24 was achieved in 53% of patients (CI90%: 43-63%) and in 90% of previous relapsers. In univariate analysis, SVR24 was associated with response to previous HCV treatment, HCV-1b subtype, HCV-RNA decline, ribavirin-Ctrough at W4, and HCV-RNA at W8 but not to fibrosis score, IL28B genotype, or boceprevir-Ctrough at W8. In multivariate analysis, SVR24 remained associated with response to previous HCV treatment [non-responders versus null responders: OR=5.0(1.3-20.0); relapsers vs. null responders: OR=28.8(4.9-169.5)]. HCV treatment was discontinued for adverse events in 17% of patients. A 51% decrease in ATV/r-AUC0-8 h (p<0.01) and a 57% increase in RAL-AUC0-8 h (p<0.01) were observed, although atazanavir/r or raltegravir did not affect BOC-AUC0-8 h significantly. The ATV mean Cthrough fell from 763.8 ng/mL (CI 95%: 230.3-1297.3) without BOC to 507.7 ng/mL (CI 95%: 164-851.4) with BOC.
Conclusions: Boceprevir-based regimen demonstrated a high SVR24 rate in treatment-experienced HIV-HCV genotype-1-coinfected relapsers.
{"title":"Addition of boceprevir to PEG-interferon/ribavirin in HIV-HCV-Genotype-1-coinfected, treatment-experienced patients: efficacy, safety, and pharmacokinetics data from the ANRS HC27 study.","authors":"Isabelle Poizot-Martin, Eric Bellissant, Rodolphe Garraffo, Philippe Colson, Lionel Piroth, Caroline Solas, Alain Renault, Marc Bourlière, Philippe Halfon, Jade Ghosn, Laurent Alric, Alissa Naqvi, Patrizia Carrieri, Jean-Michel Molina","doi":"10.1080/15284336.2015.1135553","DOIUrl":"https://doi.org/10.1080/15284336.2015.1135553","url":null,"abstract":"<p><strong>Background: </strong>Scarce data exist on the efficacy and safety of the PEGylated-interferon/ribavirin/boceprevir regimen in HIV/HCV-coinfected patients who failed to respond to PEGylated-interferon/ribavirin treatment.</p><p><strong>Objectives: </strong>To evaluate the efficacy and safety of this drug regimen and the impact of the addition of boceprevir(BOC) on atazanavir (ATV) or raltegravir (RAL) pharmacokinetic parameters in a subgroup of patients.</p><p><strong>Methods: </strong>In this single-arm phase 2 trial, HIV-1/HCV-genotype-1-coinfected patients received PEGylated-interferonα2b (1.5 μg/kg/week)+ ribavirin (800-1400 mg/day) alone until W4 and with BOC(800 mgTID) until W48. Based on virologic response at W8, the three drugs were stopped or PEGylated-interferon/ribavirin was continued alone until W72. The primary endpoint was SVR at W24 off-therapy (SVR24).</p><p><strong>Results: </strong>64 patients were included. SVR24 was achieved in 53% of patients (CI90%: 43-63%) and in 90% of previous relapsers. In univariate analysis, SVR24 was associated with response to previous HCV treatment, HCV-1b subtype, HCV-RNA decline, ribavirin-Ctrough at W4, and HCV-RNA at W8 but not to fibrosis score, IL28B genotype, or boceprevir-Ctrough at W8. In multivariate analysis, SVR24 remained associated with response to previous HCV treatment [non-responders versus null responders: OR=5.0(1.3-20.0); relapsers vs. null responders: OR=28.8(4.9-169.5)]. HCV treatment was discontinued for adverse events in 17% of patients. A 51% decrease in ATV/r-AUC0-8 h (p<0.01) and a 57% increase in RAL-AUC0-8 h (p<0.01) were observed, although atazanavir/r or raltegravir did not affect BOC-AUC0-8 h significantly. The ATV mean Cthrough fell from 763.8 ng/mL (CI 95%: 230.3-1297.3) without BOC to 507.7 ng/mL (CI 95%: 164-851.4) with BOC.</p><p><strong>Conclusions: </strong>Boceprevir-based regimen demonstrated a high SVR24 rate in treatment-experienced HIV-HCV genotype-1-coinfected relapsers.</p>","PeriodicalId":13216,"journal":{"name":"HIV Clinical Trials","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2016-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/15284336.2015.1135553","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34750828","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2016-01-07DOI: 10.1080/15284336.2015.1125077
Z. Michelini, S. Baroncelli, A. Fantauzzi, Chiara Pasquale, C. Galluzzo, M. Sanchez, M. Gatto, R. Amici, Marina Franco, G. d’Ettorre, C. Fimiani, I. Mezzaroma, V. Vullo, M. Merli, L. Palmisano
Background: Microbial translocation (MT) is a shared feature of HIV infection and inflammatory bowel disease (IBD). Aims: This study was conducted to assess the impact of IBD (and particularly ulcerative colitis, UC) on plasma markers of MT and immune activation in HIV+ subjects. Methods: A cross-sectional study was conducted in 3 groups of patients: HIV+/UC+(group HIV/UC); HIV+/UC- (group HIV); HIV-/UC+(group UC). Plasma levels of soluble CD14 (sCD14), intestinal fatty acid-binding protein (I-FABP), and endotoxin core antibodies (endoCAB) were measured as plasma markers of MT. Inflammation and immune activation were evaluated by measuring plasma levels of IL-6, IL-21, TNF-alpha, and high-sensitivity C-reactive protein (hs-CRP). T- and B-cells subpopulations were characterized by FACS analysis. Results: Seven patients were enrolled in group HIV/UC, 9 in HIV, and 10 in UC. All HIV-positive patients had plasma values of HIV-1 RNA < 37 copies/mL for at least 12 months and good immunological recovery. All patients with UC were treated with oral mesalazine. Markers of MT, immune activation, and inflammation were not increased in subjects with HIV/UC. In fact, they had lower levels of I-FABP (p = 0.001) and sCD14 (p = 0.007) when compared to other patients groups. Positive correlations were found between I-FABP and sCD14 (r = .355, p = 0.076). Frequency of T- and B-cell subsets did not differ among groups. Conclusions: Our results suggest that UC does not worsen MT, inflammation, or immune activation in HIV-infected subjects. The anti-inflammatory activity of chronic mesalazine administration on intestinal mucosa may contribute to this finding.
{"title":"Reduced Plasma Levels of sCD14 and I-FABP in HIV-infected Patients with Mesalazine-treated Ulcerative Colitis","authors":"Z. Michelini, S. Baroncelli, A. Fantauzzi, Chiara Pasquale, C. Galluzzo, M. Sanchez, M. Gatto, R. Amici, Marina Franco, G. d’Ettorre, C. Fimiani, I. Mezzaroma, V. Vullo, M. Merli, L. Palmisano","doi":"10.1080/15284336.2015.1125077","DOIUrl":"https://doi.org/10.1080/15284336.2015.1125077","url":null,"abstract":"Background: Microbial translocation (MT) is a shared feature of HIV infection and inflammatory bowel disease (IBD). Aims: This study was conducted to assess the impact of IBD (and particularly ulcerative colitis, UC) on plasma markers of MT and immune activation in HIV+ subjects. Methods: A cross-sectional study was conducted in 3 groups of patients: HIV+/UC+(group HIV/UC); HIV+/UC- (group HIV); HIV-/UC+(group UC). Plasma levels of soluble CD14 (sCD14), intestinal fatty acid-binding protein (I-FABP), and endotoxin core antibodies (endoCAB) were measured as plasma markers of MT. Inflammation and immune activation were evaluated by measuring plasma levels of IL-6, IL-21, TNF-alpha, and high-sensitivity C-reactive protein (hs-CRP). T- and B-cells subpopulations were characterized by FACS analysis. Results: Seven patients were enrolled in group HIV/UC, 9 in HIV, and 10 in UC. All HIV-positive patients had plasma values of HIV-1 RNA < 37 copies/mL for at least 12 months and good immunological recovery. All patients with UC were treated with oral mesalazine. Markers of MT, immune activation, and inflammation were not increased in subjects with HIV/UC. In fact, they had lower levels of I-FABP (p = 0.001) and sCD14 (p = 0.007) when compared to other patients groups. Positive correlations were found between I-FABP and sCD14 (r = .355, p = 0.076). Frequency of T- and B-cell subsets did not differ among groups. Conclusions: Our results suggest that UC does not worsen MT, inflammation, or immune activation in HIV-infected subjects. The anti-inflammatory activity of chronic mesalazine administration on intestinal mucosa may contribute to this finding.","PeriodicalId":13216,"journal":{"name":"HIV Clinical Trials","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2016-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/15284336.2015.1125077","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"59913366","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2016-01-02DOI: 10.1080/15284336.2015.1112494
E. Teófilo, N. Rocha-Pereira, B. Kuhlmann, A. Antela, H. Knechten, Jesús Santos, M. Jiménez-Expósito
Background: Boosted protease inhibitors (PIs), including ritonavir-boosted atazanavir (ATV/r), are a recommended option for the initial treatment of HIV-1 infection based upon clinical trial data; however, long-term real-life clinical data are limited. Objective: We evaluated the long-term use of ATV/r as a component of antiretroviral combination therapy in the real-life setting in the REMAIN study. Methods: This was an observational cohort study conducted at sites across Germany, Portugal, and Spain. Retrospective historical and prospective longitudinal follow-up data were extracted every six months from medical records of HIV-infected treatment-naïve patients aged ≥ 18 years initiating a first-line ATV/r-containing regimen. Results: Eligible patients (n = 517) were followed up for a median of 3.4 years. The proportion remaining on ATV/r at 5 years was 51.5% with an estimated Kaplan-Meier median time to treatment discontinuation of 4.9 years. Principal reasons for discontinuation were adverse events (15.9%; 8.9% due to hyperbilirubinemia) and virologic failure (6.8%). The Kaplan-Meier probability of not having virologic failure (HIV-1 RNA < 50 copies/mL) was 0.79 (95% CI: 0.75, 0.83) at five years. No treatment-emergent major PI resistance occurred. ATV/r was generally well tolerated during long-term treatment with no significant changes in estimated glomerular filtration rate over five years. Conclusions: In a real-life clinical setting over five years, treatment-naïve patients with HIV-1 infection initiating an ATV/r-based regimen showed sustained virologic suppression, an overall treatment persistence rate of 51.5%, an absence of treatment-emergent major PI resistance mutations at virologic failure, a long-term safety profile consistent with that observed in clinical trials, and no significant decline in renal function.
{"title":"Long-Term Efficacy, Tolerability, and Renal Safety of Atazanavir/Ritonavir-based Antiretroviral Therapy in a Cohort of Treatment-Naïve Patients with HIV-1 Infection: the REMAIN Study","authors":"E. Teófilo, N. Rocha-Pereira, B. Kuhlmann, A. Antela, H. Knechten, Jesús Santos, M. Jiménez-Expósito","doi":"10.1080/15284336.2015.1112494","DOIUrl":"https://doi.org/10.1080/15284336.2015.1112494","url":null,"abstract":"Background: Boosted protease inhibitors (PIs), including ritonavir-boosted atazanavir (ATV/r), are a recommended option for the initial treatment of HIV-1 infection based upon clinical trial data; however, long-term real-life clinical data are limited. Objective: We evaluated the long-term use of ATV/r as a component of antiretroviral combination therapy in the real-life setting in the REMAIN study. Methods: This was an observational cohort study conducted at sites across Germany, Portugal, and Spain. Retrospective historical and prospective longitudinal follow-up data were extracted every six months from medical records of HIV-infected treatment-naïve patients aged ≥ 18 years initiating a first-line ATV/r-containing regimen. Results: Eligible patients (n = 517) were followed up for a median of 3.4 years. The proportion remaining on ATV/r at 5 years was 51.5% with an estimated Kaplan-Meier median time to treatment discontinuation of 4.9 years. Principal reasons for discontinuation were adverse events (15.9%; 8.9% due to hyperbilirubinemia) and virologic failure (6.8%). The Kaplan-Meier probability of not having virologic failure (HIV-1 RNA < 50 copies/mL) was 0.79 (95% CI: 0.75, 0.83) at five years. No treatment-emergent major PI resistance occurred. ATV/r was generally well tolerated during long-term treatment with no significant changes in estimated glomerular filtration rate over five years. Conclusions: In a real-life clinical setting over five years, treatment-naïve patients with HIV-1 infection initiating an ATV/r-based regimen showed sustained virologic suppression, an overall treatment persistence rate of 51.5%, an absence of treatment-emergent major PI resistance mutations at virologic failure, a long-term safety profile consistent with that observed in clinical trials, and no significant decline in renal function.","PeriodicalId":13216,"journal":{"name":"HIV Clinical Trials","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2016-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/15284336.2015.1112494","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"59912720","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2016-01-02DOI: 10.1080/15284336.2015.1112480
Pornpimol Thamrongwonglert, P. Chetchotisakd, S. Anunnatsiri, P. Mootsikapun
Rilpivirine (RPV) is a non-nucleoside reverse transcriptase inhibitor, which has better lipid profiles than efavirenz (EFV) in treatment naïve patients. However, the data on treatment experience are limited especially in dyslipidemic HIV patients; thus, we aimed to assess the change of lipid profiles after switching from EFV to RPV in these patients. In this prospective, open-label, cohort study, we enrolled HIV-1 infected adults who had received at least 6 months of EFV-based regimen, with HIV RNA <50 copies/mL for ≥6 months prior to switching. The objectives of this study were to analyze lipid changes and to evaluate the efficacy, safety, tolerability at 24 weeks after switching therapy. Fifty-three patients were enrolled and completed the study. At week 24, a significant decrease in the mean (95% confident interval, CI) total cholesterol (−28.06 mg/dL, 95%CI −35.20 to −20.91, p < 0.0001), LDL-cholesterol (−20.96 mg/dL, 95%CI −28.12 to −13.80, p < 0.0001), high-density lipoprotein (HDL)-cholesterol (−5.11 mg/dL, 95%CI −7.79 to −2.44, p < 0.0001), and triglyceride (−29.79 mg/dL. 95%CI −52.39 to −7.19, p = 0.011) levels were observed. One patient had virologic rebound with HIV RNA of 114 copies/mL at week 24. Three (5.7%) patients had grade 2 elevations of liver enzymes. None of the patients discontinued RPV during the study. Switching from EFV-based therapy to RPV-based regimen improved lipid profiles in fully suppressed HIV patients with dyslipidemia. This treatment should be considered in these patients.
{"title":"Improvement of lipid profiles when switching from efavirenz to rilpivirine in HIV-infected patients with dyslipidemia","authors":"Pornpimol Thamrongwonglert, P. Chetchotisakd, S. Anunnatsiri, P. Mootsikapun","doi":"10.1080/15284336.2015.1112480","DOIUrl":"https://doi.org/10.1080/15284336.2015.1112480","url":null,"abstract":"Rilpivirine (RPV) is a non-nucleoside reverse transcriptase inhibitor, which has better lipid profiles than efavirenz (EFV) in treatment naïve patients. However, the data on treatment experience are limited especially in dyslipidemic HIV patients; thus, we aimed to assess the change of lipid profiles after switching from EFV to RPV in these patients. In this prospective, open-label, cohort study, we enrolled HIV-1 infected adults who had received at least 6 months of EFV-based regimen, with HIV RNA <50 copies/mL for ≥6 months prior to switching. The objectives of this study were to analyze lipid changes and to evaluate the efficacy, safety, tolerability at 24 weeks after switching therapy. Fifty-three patients were enrolled and completed the study. At week 24, a significant decrease in the mean (95% confident interval, CI) total cholesterol (−28.06 mg/dL, 95%CI −35.20 to −20.91, p < 0.0001), LDL-cholesterol (−20.96 mg/dL, 95%CI −28.12 to −13.80, p < 0.0001), high-density lipoprotein (HDL)-cholesterol (−5.11 mg/dL, 95%CI −7.79 to −2.44, p < 0.0001), and triglyceride (−29.79 mg/dL. 95%CI −52.39 to −7.19, p = 0.011) levels were observed. One patient had virologic rebound with HIV RNA of 114 copies/mL at week 24. Three (5.7%) patients had grade 2 elevations of liver enzymes. None of the patients discontinued RPV during the study. Switching from EFV-based therapy to RPV-based regimen improved lipid profiles in fully suppressed HIV patients with dyslipidemia. This treatment should be considered in these patients.","PeriodicalId":13216,"journal":{"name":"HIV Clinical Trials","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2016-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/15284336.2015.1112480","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"59912667","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2016-01-02DOI: 10.1080/15284336.2015.1122874
L. Calza, I. Danese, E. Magistrelli, V. Colangeli, R. Manfredi, I. Bon, M. Re, Matteo Conti, P. Viale
Background: Nucleoside reverse transcriptase inhibitor (NRTI)-sparing antiretroviral therapies may be useful in HIV-infected patients with resistance or intolerance to this class. Methods: We performed an observational study of patients on suppressive antiretroviral therapy containing two NRTIs plus one ritonavir-boosted protease inhibitor who switched to a dual regimen containing raltegravir (400 mg twice daily) and darunavir/ritonavir (800/100 mg once daily) and were followed-up for 48 weeks. Results: As a whole, 82 patients were enrolled. Mean duration of current regimen was 4.6 years and mean duration of plasma HIV RNA < 50 copies/mL before the switch was 46.2 months. Reason for simplification was toxicity in 76 patients and resistance to NRTIs in 13. After switching, the percentage of patients with HIV RNA < 50 copies/mL at week 48 was 92.7% in the intent-to-treat-exposed analysis and 97.6% in the per-protocol analysis. The switch led to a significant reduction in the mean triglyceride value (−85.2 mg/dL), in the prevalence of tubular proteinuria (−56%) and in the mean level of interleukin-6 (−0.94 pg/mL), with a significant increase in the mean phosphoremia (+0.58 mg/dL). Mean trough concentrations of both raltegravir and darunavir were within the therapeutic range. Two patients (2.4%) had virological failure due to suboptimal adherence and 4 subjects (4.9%) discontinued treatment due to adverse events, but no patients experienced Grade 3 or 4 adverse events. Conclusion: In our study, simplification to a dual therapy containing raltegravir plus darunavir/ritonavir after 48 weeks maintained viral suppression in more than 90% of patients and showed a good tolerability with a favourable effect on proteinuria, ipophosphoremia, and lipid metabolism.
{"title":"Dual Raltegravir–Darunavir/Ritonavir Combination in Virologically Suppressed HIV-1-Infected Patients on Antiretroviral Therapy Including a Ritonavir-Boosted Protease Inhibitor Plus Two Nucleoside/Nucleotide Reverse Transcriptase Inhibitors","authors":"L. Calza, I. Danese, E. Magistrelli, V. Colangeli, R. Manfredi, I. Bon, M. Re, Matteo Conti, P. Viale","doi":"10.1080/15284336.2015.1122874","DOIUrl":"https://doi.org/10.1080/15284336.2015.1122874","url":null,"abstract":"Background: Nucleoside reverse transcriptase inhibitor (NRTI)-sparing antiretroviral therapies may be useful in HIV-infected patients with resistance or intolerance to this class. Methods: We performed an observational study of patients on suppressive antiretroviral therapy containing two NRTIs plus one ritonavir-boosted protease inhibitor who switched to a dual regimen containing raltegravir (400 mg twice daily) and darunavir/ritonavir (800/100 mg once daily) and were followed-up for 48 weeks. Results: As a whole, 82 patients were enrolled. Mean duration of current regimen was 4.6 years and mean duration of plasma HIV RNA < 50 copies/mL before the switch was 46.2 months. Reason for simplification was toxicity in 76 patients and resistance to NRTIs in 13. After switching, the percentage of patients with HIV RNA < 50 copies/mL at week 48 was 92.7% in the intent-to-treat-exposed analysis and 97.6% in the per-protocol analysis. The switch led to a significant reduction in the mean triglyceride value (−85.2 mg/dL), in the prevalence of tubular proteinuria (−56%) and in the mean level of interleukin-6 (−0.94 pg/mL), with a significant increase in the mean phosphoremia (+0.58 mg/dL). Mean trough concentrations of both raltegravir and darunavir were within the therapeutic range. Two patients (2.4%) had virological failure due to suboptimal adherence and 4 subjects (4.9%) discontinued treatment due to adverse events, but no patients experienced Grade 3 or 4 adverse events. Conclusion: In our study, simplification to a dual therapy containing raltegravir plus darunavir/ritonavir after 48 weeks maintained viral suppression in more than 90% of patients and showed a good tolerability with a favourable effect on proteinuria, ipophosphoremia, and lipid metabolism.","PeriodicalId":13216,"journal":{"name":"HIV Clinical Trials","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2016-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/15284336.2015.1122874","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"59912792","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2016-01-02DOI: 10.1080/15284336.2015.1115585
D. Porter, J. Toma, Yuping Tan, Owen D Solberg, Suqin Cai, R. Kulkarni, K. Andreatta, Y. Lie, S. Chuck, F. Palella, Michael D. Miller, K. White
Objectives: Antiretroviral regimen switching may be considered for HIV-1-infected, virologically-suppressed patients to enable treatment simplification or improve tolerability, but should be guided by knowledge of pre-existing drug resistance. The current study examined the impact of pre-existing drug resistance mutations on virologic outcomes among virologically-suppressed patients switching to Rilpivirine (RPV)/emtricitabine (FTC)/tenofovir disoproxil fumarate (TDF). Methods: SPIRIT was a phase 3b study evaluating the safety and efficacy of switching to RPV/FTC/TDF in virologically-suppressed HIV-1-infected patients. Pre-existing drug resistance at baseline was determined by proviral DNA genotyping for 51 RPV/FTC/TDF-treated patients with known mutations by historical RNA genotype and matched controls and compared with clinical outcome at Week 48. Results: Drug resistance mutations in protease or reverse transcriptase were detected in 62.7% of patients by historical RNA genotype and in 68.6% by proviral DNA genotyping at baseline. Proviral DNA sequencing detected 89% of occurrences of NRTI and NNRTI resistance-associated mutations reported by historical genotype. Mutations potentially affecting RPV activity, including E138A/G/K/Q, Y181C, and H221Y, were detected in isolates from 11 patients by one or both assays. None of the patients with single mutants had virologic failure through Week 48. One patient with pre-existing Y181Y/C and M184I by proviral DNA genotyping experienced virologic failure. Nineteen patients with K103N present by historical genotype were confirmed by proviral DNA sequencing and 18/19 remained virologically-suppressed. Discussion: Virologic success rates were high among virologically-suppressed patients with pre-existing NRTI and NNRTI resistance-associated mutations who switched to RPV/FTC/TDF in the SPIRIT study. While plasma RNA genotyping remains preferred, proviral DNA genotyping may provide additional value in virologically-suppressed patients for whom historical resistance data are unavailable.
{"title":"Clinical Outcomes of Virologically-Suppressed Patients with Pre-existing HIV-1 Drug Resistance Mutations Switching to Rilpivirine/Emtricitabine/Tenofovir Disoproxil Fumarate in the SPIRIT Study*","authors":"D. Porter, J. Toma, Yuping Tan, Owen D Solberg, Suqin Cai, R. Kulkarni, K. Andreatta, Y. Lie, S. Chuck, F. Palella, Michael D. Miller, K. White","doi":"10.1080/15284336.2015.1115585","DOIUrl":"https://doi.org/10.1080/15284336.2015.1115585","url":null,"abstract":"Objectives: Antiretroviral regimen switching may be considered for HIV-1-infected, virologically-suppressed patients to enable treatment simplification or improve tolerability, but should be guided by knowledge of pre-existing drug resistance. The current study examined the impact of pre-existing drug resistance mutations on virologic outcomes among virologically-suppressed patients switching to Rilpivirine (RPV)/emtricitabine (FTC)/tenofovir disoproxil fumarate (TDF). Methods: SPIRIT was a phase 3b study evaluating the safety and efficacy of switching to RPV/FTC/TDF in virologically-suppressed HIV-1-infected patients. Pre-existing drug resistance at baseline was determined by proviral DNA genotyping for 51 RPV/FTC/TDF-treated patients with known mutations by historical RNA genotype and matched controls and compared with clinical outcome at Week 48. Results: Drug resistance mutations in protease or reverse transcriptase were detected in 62.7% of patients by historical RNA genotype and in 68.6% by proviral DNA genotyping at baseline. Proviral DNA sequencing detected 89% of occurrences of NRTI and NNRTI resistance-associated mutations reported by historical genotype. Mutations potentially affecting RPV activity, including E138A/G/K/Q, Y181C, and H221Y, were detected in isolates from 11 patients by one or both assays. None of the patients with single mutants had virologic failure through Week 48. One patient with pre-existing Y181Y/C and M184I by proviral DNA genotyping experienced virologic failure. Nineteen patients with K103N present by historical genotype were confirmed by proviral DNA sequencing and 18/19 remained virologically-suppressed. Discussion: Virologic success rates were high among virologically-suppressed patients with pre-existing NRTI and NNRTI resistance-associated mutations who switched to RPV/FTC/TDF in the SPIRIT study. While plasma RNA genotyping remains preferred, proviral DNA genotyping may provide additional value in virologically-suppressed patients for whom historical resistance data are unavailable.","PeriodicalId":13216,"journal":{"name":"HIV Clinical Trials","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2016-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/15284336.2015.1115585","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"59912780","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2016-01-02DOI: 10.1080/15284336.2015.1111555
F. Crouzat, Anita C. Benoit, C. Kovacs, Graham H R Smith, N. Taback, I. Sandler, Megan Acsai, W. Barrie, J. Brunetta, B. Chang, D. Fletcher, David C. Knox, B. Merkley, Malika Sharma, D. Tilley, M. Loutfy
Background: The resistance profiles for patients on first-line antiretroviral therapy (ART) regimens after viremia have not been well studied in community clinic settings in the modern treatment era. Objective: To determine time to viremia and the ART resistance profiles of viremic patients. Methods: HIV-positive patients aged ≥16 years initiating a three-drug regimen were retrospectively identified from 01/01/06 to 12/31/12. The regimens were a backbone of two nucleoside reverse transcriptase inhibitors (NRTIs) and a third agent: a protease inhibitor (PI), non-nucleoside reverse transcriptase inhibitor (NNRTI), or an integrase inhibitor (II). Time to viremia was compared using a proportional hazards model, adjusting for demographic and clinical factors. Resistance profiles were described in those with baseline and follow-up genotypes. Results: For 653 patients, distribution of third-agent use and viremia was: 244 (37%) on PIs with 80 viremia, 364 (56%) on NNRTIs with 84 viremia, and 45 (7%) on II with 11 viremia. Only for NNRTIs, time to viremia was longer than PIs (p = 0.04) for patients with a CD4 count ≥200 cells/mm3. Of the 175 with viremia, 143 (82%) had baseline and 37 (21%) had follow-up genotype. Upon viremia, emerging ART resistance was rare. One new NNRTI (Y181C) mutation was identified and three patients taking PI-based regimens developed NRTI mutations (M184 V, M184I, and T215Y). Conclusions: Time to viremia for NNRTIs was longer than PIs. With viremia, ART resistance rarely developed without PI or II mutations, but with a few NRTI mutations in those taking PI-based regimens, and NNRTI mutations in those taking NNRTI-based regimens.
{"title":"Time to Viremia for Patients Taking their First Antiretroviral Regimen and the Subsequent Resistance Profiles","authors":"F. Crouzat, Anita C. Benoit, C. Kovacs, Graham H R Smith, N. Taback, I. Sandler, Megan Acsai, W. Barrie, J. Brunetta, B. Chang, D. Fletcher, David C. Knox, B. Merkley, Malika Sharma, D. Tilley, M. Loutfy","doi":"10.1080/15284336.2015.1111555","DOIUrl":"https://doi.org/10.1080/15284336.2015.1111555","url":null,"abstract":"Background: The resistance profiles for patients on first-line antiretroviral therapy (ART) regimens after viremia have not been well studied in community clinic settings in the modern treatment era. Objective: To determine time to viremia and the ART resistance profiles of viremic patients. Methods: HIV-positive patients aged ≥16 years initiating a three-drug regimen were retrospectively identified from 01/01/06 to 12/31/12. The regimens were a backbone of two nucleoside reverse transcriptase inhibitors (NRTIs) and a third agent: a protease inhibitor (PI), non-nucleoside reverse transcriptase inhibitor (NNRTI), or an integrase inhibitor (II). Time to viremia was compared using a proportional hazards model, adjusting for demographic and clinical factors. Resistance profiles were described in those with baseline and follow-up genotypes. Results: For 653 patients, distribution of third-agent use and viremia was: 244 (37%) on PIs with 80 viremia, 364 (56%) on NNRTIs with 84 viremia, and 45 (7%) on II with 11 viremia. Only for NNRTIs, time to viremia was longer than PIs (p = 0.04) for patients with a CD4 count ≥200 cells/mm3. Of the 175 with viremia, 143 (82%) had baseline and 37 (21%) had follow-up genotype. Upon viremia, emerging ART resistance was rare. One new NNRTI (Y181C) mutation was identified and three patients taking PI-based regimens developed NRTI mutations (M184 V, M184I, and T215Y). Conclusions: Time to viremia for NNRTIs was longer than PIs. With viremia, ART resistance rarely developed without PI or II mutations, but with a few NRTI mutations in those taking PI-based regimens, and NNRTI mutations in those taking NNRTI-based regimens.","PeriodicalId":13216,"journal":{"name":"HIV Clinical Trials","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2016-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/15284336.2015.1111555","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"59912616","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2016-01-01Epub Date: 2016-07-29DOI: 10.1080/15284336.2016.1201300
Isaac Singini, Thomas B Campbell, Laura M Smeaton, Nagalingeswaran Kumarasamy, Alberto La Rosa, Sineenart Taejareonkul, Steven A Safren, Timothy P Flanigan, James G Hakim, Michael D Hughes
Background: Practical issues, including cost, hinder implementing virologic monitoring of patients on antiretroviral therapy (ART) in resource-limited settings. We evaluated factors that might guide monitoring frequency and efforts to prevent treatment failure after initial virologic suppression.
Methods: Participants were the 911 HIV-infected antiretroviral-naïve adults with CD4 count <300 cells/μL who started efavirenz-based ART in the international A5175/PEARLS trial and achieved HIV-1 RNA <1000 copies/mL at 24 weeks. Participant report of ART adherence was evaluated using a structured questionnaire in monthly interviews. Adherence and readily available clinical and laboratory measures were evaluated as predictors of late virologic failure (late VF: confirmed HIV-1 RNA ≥1000 copies/mL after 24 weeks).
Results: During median follow-up of 3.5 years, 82/911 participants (9%) experienced late VF. Of 516 participants reporting missed doses during the first 24 weeks of ART, 55 (11%) experienced late VF, compared with 27 (7%) of 395 participants reporting no missed doses (hazard ratio: 1.73; 95% CI: 1.08, 2.73). This difference persisted in multivariable analysis, in which lower pre-ART hemoglobin and absence of Grade ≥3 laboratory results prior to week 24 were also associated with higher risk of late VF.
Discussion: In this clinical trial, the late VF rate after successful suppression was very low. If achievable in routine clinical practice, virologic monitoring involving infrequent (e.g. annual) measurements might be considered; the implications of this for development of resistance need evaluating. Patients reporting missed doses early after ART initiation, despite achieving initial suppression, might require more frequent measurement and/or strategies for promoting adherence.
{"title":"Predictors of late virologic failure after initial successful suppression of HIV replication on efavirenz-based antiretroviral therapy.","authors":"Isaac Singini, Thomas B Campbell, Laura M Smeaton, Nagalingeswaran Kumarasamy, Alberto La Rosa, Sineenart Taejareonkul, Steven A Safren, Timothy P Flanigan, James G Hakim, Michael D Hughes","doi":"10.1080/15284336.2016.1201300","DOIUrl":"https://doi.org/10.1080/15284336.2016.1201300","url":null,"abstract":"<p><strong>Background: </strong>Practical issues, including cost, hinder implementing virologic monitoring of patients on antiretroviral therapy (ART) in resource-limited settings. We evaluated factors that might guide monitoring frequency and efforts to prevent treatment failure after initial virologic suppression.</p><p><strong>Methods: </strong>Participants were the 911 HIV-infected antiretroviral-naïve adults with CD4 count <300 cells/μL who started efavirenz-based ART in the international A5175/PEARLS trial and achieved HIV-1 RNA <1000 copies/mL at 24 weeks. Participant report of ART adherence was evaluated using a structured questionnaire in monthly interviews. Adherence and readily available clinical and laboratory measures were evaluated as predictors of late virologic failure (late VF: confirmed HIV-1 RNA ≥1000 copies/mL after 24 weeks).</p><p><strong>Results: </strong>During median follow-up of 3.5 years, 82/911 participants (9%) experienced late VF. Of 516 participants reporting missed doses during the first 24 weeks of ART, 55 (11%) experienced late VF, compared with 27 (7%) of 395 participants reporting no missed doses (hazard ratio: 1.73; 95% CI: 1.08, 2.73). This difference persisted in multivariable analysis, in which lower pre-ART hemoglobin and absence of Grade ≥3 laboratory results prior to week 24 were also associated with higher risk of late VF.</p><p><strong>Discussion: </strong>In this clinical trial, the late VF rate after successful suppression was very low. If achievable in routine clinical practice, virologic monitoring involving infrequent (e.g. annual) measurements might be considered; the implications of this for development of resistance need evaluating. Patients reporting missed doses early after ART initiation, despite achieving initial suppression, might require more frequent measurement and/or strategies for promoting adherence.</p>","PeriodicalId":13216,"journal":{"name":"HIV Clinical Trials","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2016-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/15284336.2016.1201300","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34714294","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2016-01-01Epub Date: 2016-07-04DOI: 10.1080/15284336.2016.1201321
Kaveh Manavi, James Hodson
Background: Tuberculosis (TB) remains a main cause of morbidity and mortality among individuals infected with HIV. We investigated the incidence of TB among a cohort of HIV infected patients attending a setting with low TB burden where screening for latent TB infection is not routinely carried out.
Methods: an observational cohort study on HIV-infected adults attending the HIV clinic at Queen Elizabeth Hospital Birmingham, UK between 1 January 2011 and 30 September 2015. Patients with culture-proven TB after HIV diagnosis, or those treated for clinical diagnosis of the infection, were classified as having "active TB".
Results: 1824 patients were included in the study (5347 patient years of follow up), of whom 21 patients developed TB (16 microbiology confirmed). Of the 666 new HIV diagnoses, six patients developed TB within one month, giving a TB prevalence at the time of HIV diagnosis of 0.9%. The total TB incidence for the remaining 1818 patients was 2.81 cases per 1000 patient years (95% CI: 1.63-4.53). TB incidence was significantly more common among patients with CD4 ≤ 200 cells/mm3 compared to those with CD4 > 500 cells/mm3 (28.2 vs. 1.22 per 1000 patient years, p < 0.001), and in patients with VL ≥ 40 copies/mL compared to <40 copies/mL (8.30 vs. 1.42, p < 0.001).
Conclusion: In settings with low TB prevalence, early start of combined antiretroviral therapy and intensified TB case finding protocols may significantly reduce the incidence of TB.
背景:结核病(TB)仍然是艾滋病毒感染者发病和死亡的主要原因。我们调查了一组HIV感染患者的结核病发病率，这些患者在结核病负担较低的环境中没有常规进行潜伏性结核病感染筛查。方法:对2011年1月1日至2015年9月30日在英国伯明翰伊丽莎白女王医院HIV门诊就诊的HIV感染成人进行观察性队列研究。经艾滋病毒诊断后经培养证实患有结核病的患者，或经临床诊断为感染的患者，被归类为“活动性结核病”。结果:共纳入1824例患者(随访5347例患者年)，其中21例患者发展为TB(16例确诊为微生物学)。在666例新诊断的艾滋病毒病例中，有6例患者在1个月内出现结核病，因此艾滋病毒诊断时的结核病患病率为0.9%。其余1818例患者的结核总发病率为每1000例患者年2.81例(95% CI: 1.63-4.53)。与CD4细胞/mm3 > 500细胞/mm3的患者相比，CD4细胞≤200细胞/mm3的患者的结核病发病率明显更高(28.2 vs. 1.22 / 1000患者年)。结论:在结核病患病率较低的环境中，早期开始联合抗逆转录病毒治疗和强化结核病病例发现方案可能显著降低结核病发病率。
{"title":"An observational study on the incidence of tuberculosis among a cohort of HIV infected adults in a setting with low prevalence of tuberculosis.","authors":"Kaveh Manavi, James Hodson","doi":"10.1080/15284336.2016.1201321","DOIUrl":"https://doi.org/10.1080/15284336.2016.1201321","url":null,"abstract":"<p><strong>Background: </strong>Tuberculosis (TB) remains a main cause of morbidity and mortality among individuals infected with HIV. We investigated the incidence of TB among a cohort of HIV infected patients attending a setting with low TB burden where screening for latent TB infection is not routinely carried out.</p><p><strong>Methods: </strong>an observational cohort study on HIV-infected adults attending the HIV clinic at Queen Elizabeth Hospital Birmingham, UK between 1 January 2011 and 30 September 2015. Patients with culture-proven TB after HIV diagnosis, or those treated for clinical diagnosis of the infection, were classified as having \"active TB\".</p><p><strong>Results: </strong>1824 patients were included in the study (5347 patient years of follow up), of whom 21 patients developed TB (16 microbiology confirmed). Of the 666 new HIV diagnoses, six patients developed TB within one month, giving a TB prevalence at the time of HIV diagnosis of 0.9%. The total TB incidence for the remaining 1818 patients was 2.81 cases per 1000 patient years (95% CI: 1.63-4.53). TB incidence was significantly more common among patients with CD4 ≤ 200 cells/mm<sup>3</sup> compared to those with CD4 > 500 cells/mm<sup>3</sup> (28.2 vs. 1.22 per 1000 patient years, p < 0.001), and in patients with VL ≥ 40 copies/mL compared to <40 copies/mL (8.30 vs. 1.42, p < 0.001).</p><p><strong>Conclusion: </strong>In settings with low TB prevalence, early start of combined antiretroviral therapy and intensified TB case finding protocols may significantly reduce the incidence of TB.</p>","PeriodicalId":13216,"journal":{"name":"HIV Clinical Trials","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2016-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/15284336.2016.1201321","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34637780","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2015-11-02DOI: 10.1080/15284336.2015.1123944
Felicia P. Hardnett, C. Rose
Objective:In recent HIV intervention trials, intervention efficacies appear to decline over time. Researchers have attributed this to “waning,” or a loss of intervention efficacy. Another possible reason is heterogeneity in infection risk or “frailty.” We propose an approach to assessing the impact of frailty and waning on measures of intervention efficacy and statistical power in randomized-controlled trials. Methods:Using multiplicative risk reduction, we developed a mathematical formulation for computing disease incidence and the incidence rate ratio (IRR) as a function of frailty and waning. We designed study scenarios, which held study-related factors constant, varied waning and frailty parameters and measured the change in disease incidence, IRR, and statistical power. Results:We found that frailty alone can impact disease incidence over time. However, frailty has minimal impact on the IRR. The factor that has the greatest influence on the IRR is intervention efficacy and the degree to which it is projected to wane. We also found that even moderate waning can cause an unacceptable decrease in statistical power while the impact of frailty on statistical power is minimal. Discussion:We conclude that frailty has minimal impact on trial results relative to intervention efficacy. Study resources would, therefore, be better spent on efforts to keep the intervention efficacy constant throughout the trial (e.g., enhancing the vaccine schedule or promoting treatment adherence).
{"title":"Measuring the potential role of frailty in apparent declining efficacy of HIV interventions","authors":"Felicia P. Hardnett, C. Rose","doi":"10.1080/15284336.2015.1123944","DOIUrl":"https://doi.org/10.1080/15284336.2015.1123944","url":null,"abstract":"Objective:In recent HIV intervention trials, intervention efficacies appear to decline over time. Researchers have attributed this to “waning,” or a loss of intervention efficacy. Another possible reason is heterogeneity in infection risk or “frailty.” We propose an approach to assessing the impact of frailty and waning on measures of intervention efficacy and statistical power in randomized-controlled trials. Methods:Using multiplicative risk reduction, we developed a mathematical formulation for computing disease incidence and the incidence rate ratio (IRR) as a function of frailty and waning. We designed study scenarios, which held study-related factors constant, varied waning and frailty parameters and measured the change in disease incidence, IRR, and statistical power. Results:We found that frailty alone can impact disease incidence over time. However, frailty has minimal impact on the IRR. The factor that has the greatest influence on the IRR is intervention efficacy and the degree to which it is projected to wane. We also found that even moderate waning can cause an unacceptable decrease in statistical power while the impact of frailty on statistical power is minimal. Discussion:We conclude that frailty has minimal impact on trial results relative to intervention efficacy. Study resources would, therefore, be better spent on efforts to keep the intervention efficacy constant throughout the trial (e.g., enhancing the vaccine schedule or promoting treatment adherence).","PeriodicalId":13216,"journal":{"name":"HIV Clinical Trials","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2015-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/15284336.2015.1123944","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"59913238","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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