Awareness, Knowledge and Perceptions of Biosimilars among Specialty Physicians

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Description and UDS results for virologic failure samples.

<p><b>a:</b> Virologic failure samples for UDS. UDS: Ultra Deep Sequencing; VF: Virologic Failure. 78 subjects had virologic failure at week 48 and/or 96. *21 samples were either exhausted or could not be located. 57 patients with virologic failure without PI resistance had samples for UDS. 21 patients failed with HIV RNA<1,000 copies and UDS could not be performed. 36 unique patients had UDS data. <b>b:</b> UDS results for 36 Virologic Failures. VF: Virologic Failure; PR: Protease; RT: Reverse Transcriptase. UDS: Ultra Deep Sequencing; DRMs: Drug Resistance Mutations. 36 patients without PI resistance mutations at VF by standard genotype were evaluated by UDS. 36 patients with VF had PR evaluated by UDS. 24/36 samples had HIV VL>10,000 c/ml. 9/24 had PI DRMs at low levels. 12/36 samples had HIV VL<10,000 c/ml. 4/12 had PI DRMs at low levels. Only 3/36 patients with VF had PI mutations with HIVdb weight >12 for ATV or LPV. 24/36 patients with HIV VL>10,000 c/ml had RT evaluated by UDS. 18/24 samples had NRTI DRMs.</p

Virologic outcome at Week 48 and specific TDR at Baseline known to affect NRTI Backbone.

<p>Thymidine Analog Mutations (TAMs); Virologic Success at week 48 (VS), Virologic Failure at week 48 (VF). Transmitted Drug Resistance Mutations (TDRs); 9 subjects with M184V/I +/− TAMs and/or +/− K65R at baseline. 16 subjects with >1 TAMs at baseline. 2 subjects with K65R at baseline.</p

Prevalence of transmitted drug resistance (TDR) mutations by Ultra-deep Sequencing (UDS) and by standard genotyping (SG).

<p>N(<b>t</b>)RTI – nucleoside(tide) reverse transcriptase inhibitor; NNRTI – non-nucleoside reverse transcriptase inhibitor, PI – protease inhibitor. 141 subjects with UDS data; 147 subjects with standard genotypic data.</p

Specific TDR patterns and levels for subjects with a M184V/I and/or K65R +/− TAMs.

<p>VF: Virologic Failure VS: Virologic Success NRTI: Nucleoside Reverse Transcriptase Inhibitor NNRTI: Non-Nucleoside Reverse Transcriptase Inhibitor PI: Protease Inhibitor. TAMs: Thymidine Analogue Mutations. HIV VL: HIV Viral Load. TDRs: Transmitted Drug Resistance Mutations. 6-LPV^# has both a M184V and a K65R TDR. <b>Bold: M184V, TAMs, Major PI mutations according to HIV Stanford Database.</b></p

Prevalence of low and high abundance Transmitted Drug Resistance Mutations (TDRs) by antiretroviral drug class.

<p>N(<b>t</b>)RTI(s)- nucleoside(tide) reverse transcriptase inhibitor; NNRTI – non-nucleoside reverse transcriptase inhibitor, PI – protease inhibitor. Samples with multiple TDRs present with at least one TDR representing ≥20% of the viral populations were scored as having ≥20% of the viral population (e.g. M184V at 5% and a T215Y at >20% are in the ≥20% column). Only samples where all TDRs were at <20% levels are represented in the <20% column; 21 subjects had at least 1 TDR at high level ≥20%: 6 VFs and 15 VSs. There was no difference between VFs (6/51) and VSs (15/90) regarding the rate of high level (≥20%) TDRs. P-value = 0.47 Fisher's exact test.</p>1<p>Only TDRs occurring at <20% of the viral population.</p>2<p>At least 1 TDR occurring at ≥20% of the viral population.</p

Transmitted Drug Resistance by ARV Class and Virologic Outcome.

<p>Transmitted Drug Resistance by ARV Class and Virologic Outcome: Note: TDRs are not mutually exclusive (i.e. a subject could have a TDR from more than one ARV class). VS: Virologic Success, VF: Virologic Failure N(t)RTI(s)- nucleoside(tide) reverse transcriptase inhibitor; NNRTI – non-nucleoside reverse transcriptase inhibitor, PI – protease inhibitor. Any: Any transmitted drug resistance mutations. Any TDR: p-value = 0.35, NRTI: p-value = 1, NNRTI: p-value = 1, PI: p-value = 0.02.</p

Primary and secondary time-to-event outcomes for the comparison of atazanavir plus didanosine-EC and emtricitabine to efavirenz plus lamivudine-zidovudine using data collected through 22 May 2008.

a<p>Also known as relative risk. Estimated from Cox regression model stratified by both country and RNA stratum and including randomized treatment group as sole covariate.</p>b<p><i>p</i>-Value calculated from stratified log-rank test between arms.</p>c<p>The five most common causes of death were infection (six deaths), liver disease (three deaths), malignancy (two deaths), suicide (two deaths), and unknown cause (two deaths).</p>d<p>Disease progression diagnoses are in <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1001290#pmed.1001290.s007" target="_blank">Table S2</a>; grade 3 and 4 laboratory events in <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1001290#pmed.1001290.s008" target="_blank">Table S3</a>; and signs and symptoms in <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1001290#pmed.1001290.s009" target="_blank">Table S4</a>.</p>e<p>All events meeting these criteria are reported; some participants met criteria for multiple endpoints.</p>f<p>Confirmed plasma HIV RNA≥1,000 copies/ml at study week 16 or later.</p>g<p>Elevated bilirubin concentration not included.</p>h<p>Change in any component of initial randomized antiretroviral regimen.</p>i<p>The following antiretroviral substitutions were prespecified and were not included in this endpoint: TDF for DDI, stavudine or TDF for ZDV, or nevirapine for EFV.</p>j<p>CD4+ lymphocytes <100/µl at week 48 or later.</p

Primary and secondary time-to-event outcomes for comparison of efavirenz plus emtricitabine-tenofovir-DF to efavirenz plus lamivudine-zidovudine using data collected through 31-May-2010.

a<p>Also known as relative risk. Estimated from Cox regression model stratified by both country and RNA stratum and including randomized treatment group as sole covariate.</p>b<p><i>p</i>-Value calculated from stratified log-rank test between arms. Not applicable (NA) because no formal hypothesis testing was performed based on DSMB recommendations.</p>c<p>The five most common causes of death were infection (17 deaths) and unknown cause (five deaths) followed by suicide, trauma, and stroke (three deaths each).</p>d<p>Disease progression diagnoses are in <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1001290#pmed.1001290.s012" target="_blank">Table S7</a>; grade 3 and 4 laboratory adverse events in <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1001290#pmed.1001290.s013" target="_blank">Table S8</a>; and signs and symptoms in <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1001290#pmed.1001290.s014" target="_blank">Table S9</a>.</p>e<p>All events meeting these criteria are reported; some participants met criteria for multiple endpoints.</p>f<p>Confirmed plasma HIV RNA≥1,000 copies/ml at study week 16 or later.</p>g<p>Change in any component of initial randomized antiretroviral regimen.</p>h<p>The following antiretroviral substitutions were prespecified and were not included in this endpoint: stavudine or TDF for ZDV, nevirapine for EFV, or didansoine for TDF.</p>i<p>CD4+ lymphocytes <100/µl at week 48 or later.</p

Subgroup analysis for primary efficacy and safety endpoints by randomly assigned antiretroviral treatment.

<p>Subgroup analyses were conducted for the baseline covariates self-reported sex and race/ethnicity and the countries in which the participating research sites were located. The relative risk and 95% CIs are provided for all participants (overall) and for each subgroup. <i>p</i>-Value represents interaction test between baseline covariate and randomized treatment group. Comparisons between ATV plus DDI and FTC and EFV plus 3TC-ZDV are in red. Comparisons between EFV plus FTC-TDF and EFV plus 3TC-ZDV are in green. (A) Treatment failure (efficacy) composite endpoint. (B) Safety events composite endpoint.</p