First-line Failure Research Articles

Treatment for Metastatic Penile Cancer After First-line Chemotherapy Failure: Analysis of Response and Survival Outcomes

To retrospectively estimate the efficacy of various treatments used in men with metastatic penile cancer that progresses after first-line chemotherapy. Patients were from a 30-patient cohort with stage TxN2-3M0 penile squamous cell carcinoma treated with neoadjuvant paclitaxel, ifosfamide, and cisplatin chemotherapy before planned lymphadenectomy. Nineteen patients (63.3%) had tumor progression or recurrence, and we evaluated the response to subsequent treatment and survival. Seventeen had received ≥ 1 salvage therapies; their median survival from first treatment failure was 5.7 months (range, 1.4-30.3 months). Four patients underwent salvage surgery, all of whom experienced further disease progression within 2 months. Four patients received chemoradiotherapy, 1 with stable disease for 13.5 months and 3 with no apparent benefit. Two of 5 evaluable patients (40%) who had received bleomycin, methotrexate, and cisplatin had objective responses (1 complete, 1 partial) but 1 developed fatal pneumonitis. There were no other documented responses to systemic therapy. Median overall survival was 5.6 months for patients who had received a second cisplatin-based treatment at any time and 4.3 months for those who had not (P = .4). Patients whose metastatic penile carcinoma progresses through or recurs after front-line cisplatin-based chemotherapy experience poor responses to the described salvage treatments, with a median overall survival time of <6 months. Emphasis should be placed on clinical trials for development of effective therapy in this setting.

Metronomic capecitabine as second-line treatment in hepatocellular carcinoma after sorafenib failure

BackgroundNo standard second-line treatments are available for hepatocellular carcinoma patients who fail sorafenib therapy. We assessed the safety and efficacy of metronomic capecitabine after first-line sorafenib failure. MethodsRetrospective analysis of consecutive hepatocellular carcinoma patients receiving metronomic capecitabine between January 2012 and November 2014. The primary end-point was safety, secondary end-point was efficacy, including time-to-progression and overall survival. ResultsTwenty-six patients (80% Child–Pugh A, 80% Barcelona Clinic Liver Cancer stage C) received metronomic capecitabine (500mg/bid). Median treatment duration was 3.2 months (range 0.6–31). Fourteen (53%) patients experienced at least one adverse event. The most frequent drug-related adverse events were bilirubin elevation (23%), fatigue (15%), anaemia (11%), lymphoedema (11%), and hand–foot syndrome (7.6%). Treatment was interrupted in 19 (73%) for disease progression, in 4 (15%) for liver deterioration, and in 1 (3.8%) for adverse event. Disease control was achieved in 6 (23%) patients. Median time-to-progression was 4 months (95% confidence interval 3.2–4.7). Median overall survival was 8 months (95% confidence interval 3.7–12.3). ConclusionsMetronomic capecitabine was well tolerated in hepatocellular carcinoma patients who had been treated with sorafenib. Preliminary data show potential anti-tumour activity with long-lasting disease control in a subgroup of patients that warrants further evaluation in a phase III study.

Retrospective study on the treatment effect of second-line antiretroviral therapy for acquired immunodeficiency syndrome patients in Henan Province from 2009 to 2013

Objective To evaluate the efficacy and tolerance of antiretroviral therapy (ART) regimen containing lopinavir/ritonavir (LPV/r) as a second-line regimen. Methods Data of acquired immunodeficiency syndrome (AIDS) patients who have received the first-line therapy for over a year and changed to the second-line antiviral therapy regimen containing LPV/r for more than one year were collected retrospectively from the database of free antiviral therapy in Henan Province from January 1, 2009 to December 31, 2013. Based on the viral load inhibition status after the alteration of the regimen, the patients were assigned to virology failure with first-line therapy group, and successful viral inhibition but poor immunological reconstruction with first-line therapy group. The variation trend of CD4+ T lymphocyte counts of the two groups in 6, 12, 24 months after changed to the second-line regimen of LPV/r, the virology inhibition rates between 6 and 12 months, 12 and 24 months, and occurrence of adverse events were analyzed. Quantitative data were analyzed by rank sum test, and qualitative data were analyzed by chi-square test. Results A total of 4 113 patients were divided into two groups, including the first-line therapy failure group (n=3 802) and poor immunological reconstruction group (n=311). At 6, 12 and 24 months after the alteration of the regimen, the CD4+ T lymphocyte counts increased gradually (all P<0.01). Between 6 and 12 months after the first-line therapy failure group changed to the second-line regimen, viral inhibition rate was 61.65%(1 408/2 284), while that 12 and 24 months was 68.91%(2 044/2 966). The incidences of adverse reaction of the two groups were 21.88%(832/3 802) and 22.19%(69/311), respectively, which were not significantly different (χ2=0.015, P=0.901). Conclusion The ART regimen containing LPV/r still has good viral inhibition effect and immunological reconstruction effect for AIDS patients who failed the initial therapy with poor immunological reconstruction. Key words: Acquired immunodeficiency syndrome; Lopinavir; Ritonavir; Viral inhibition; Immunological reconstruction

Characterization of HIV drug resistance mutations among patients failing first-line antiretroviral therapy from a tertiary referral center in Lusaka, Zambia.

In settings of resource constraint, an understanding of HIV drug resistance can guide antiretroviral therapy (ART) at switch to second-line therapy. To determine the prevalence of such HIV drug resistance mutations (HIV DRM), we used an in-house sequencing assay in the pol gene (protease and partial reverse transcriptase) in a cohort of patients suspected of failing a first-line regimen, which in Zambia comprises two nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) and one non-nucleoside reverse transcriptase inhibitor (NNRTI). Our analysis cohort (n = 68) was referred to the University Teaching Hospital in Lusaka from November 2009 to October 2012. Median duration on first-line ART to suspected treatment failure was 3.2 years (IQR 1.7-4.7 years). The majority of patients (95%) harbored HIV-1 subtype C virus. Analysis of reverse transcriptase revealed M184V (88%), K103N/S (32%), and Y181C/I/V (41%) DRMs, with the latter conferring reduced susceptibility to the salvage therapy candidates etravirine and rilpivirine. Three patients (5%) had major protease inhibitor (PI) resistance mutations: all three had the V82A mutation, and one patient (Clade J virus) had a concurrent M46I, Q58E, and L76V DRM. HIV-1 genotyping revealed major and minor DRMs as well as high levels of polymorphisms in subtype C isolates from patients failing first-line antiretroviral therapy. Closer monitoring of DRM mutations at first-line failure can inform clinicians about future options for salvage therapy.

Risk of first-line antiretroviral therapy failure in HIV-infected Thai children and adolescents.

Adolescence may affect adherence and response to highly active antiretroviral therapy (HAART). Limited data are available regarding the long-term treatment outcomes of perinatal HIV-infected adolescents. Data from perinatally acquired HIV-infected Thai children who started first-line nonnucleoside analog-based HAART before 18 years of age and treated for ≥24 weeks were analyzed. Children were categorized by age at HAART initiation; age<3 years, 3-9 years, early adolescence (10-13 years) and middle adolescence (14-16 years). CD4 and HIV-RNA were monitored every 6-12 months. Virologic failure (VF) was defined as HIV-RNA≥1000 copies/mL after ≥24 weeks of HAART. Of 840 children, 68% were in pre-adolescence. Median baseline CD4% was 7.9%. Use of nevirapine versus efavirenz was 77:23%. Median duration of nonnucleoside reverse transcriptase inhibitor-based HAART was 5.6 years. No differences between groups were observed for rate of HIV-RNA<50 copies/mL (68%, P=0.18) and rate of VF (28%, P=0.82), median time to VF (22 months, P=0.13). Incidence of VF per 100 child-year in children age<3 years, 3-9 years, early adolescence and middle adolescence were 7.9, 4.7, 7.4 and 10.8, respectively (P=0.012). Median adherence by pill count was 97.3% (P=0.23). By multivariate analysis, predictors for VF were age at HAART initiation of <3 years (HR: 1.73, 95% CI: 1.18-2.55), age 10-16 years (HR: 1.47, 95% CI: 1.09-1.97), and nevirapine use (HR: 1.63, 95% CI: 1.14-2.32). VF rates were observed in one-third of long-term treated Thai children on first-line HAART. Age 3-9 years at HAART initiation was associated with less VF compared with those younger or older, whereas children who used nevirapine had higher VF.

Efficacy of second-line antiretroviral therapy among people living with HIV/AIDS in Asia: results from the TREAT Asia HIV observational database.

Roughly 4% of the 1.25 million patients on antiretroviral therapy (ART) in Asia are using second-line therapy. To maximize patient benefit and regional resources, it is important to optimize the timing of second-line ART initiation and use the most effective compounds available. HIV-positive patients enrolled in the TREAT Asia HIV Observational Database who had used second-line ART for ≥6 months were included. ART use and rates and predictors of second-line treatment failure were evaluated. There were 302 eligible patients. Most were male (76.5%) and exposed to HIV via heterosexual contact (71.5%). Median age at second-line initiation was 39.2 years, median CD4 cell count was 146 cells per cubic millimeter, and median HIV viral load was 16,224 copies per milliliter. Patients started second-line ART before 2007 (n = 105), 2007-2010 (n = 147) and after 2010 (n = 50). Ritonavir-boosted lopinavir and atazanavir accounted for the majority of protease inhibitor use after 2006. Median follow-up time on second-line therapy was 2.3 years. The rates of treatment failure and mortality per 100 patient/years were 8.8 (95% confidence interval: 7.1 to 10.9) and 1.1 (95% confidence interval: 0.6 to 1.9), respectively. Older age, high baseline viral load, and use of a protease inhibitor other than lopinavir or atazanavir were associated with a significantly shorter time to second-line failure. Increased access to viral load monitoring to facilitate early detection of first-line ART failure and subsequent treatment switch is important for maximizing the durability of second-line therapy in Asia. Although second-line ART is highly effective in the region, the reported rate of failure emphasizes the need for third-line ART in a small portion of patients.

A phase II trial of regorafenib as a single agent in patients with advanced and metastatic biliary tract carcinoma and first-line chemotherapy failure.

TPS498 Background: Biliary tract cancers (including cholangiocarcinomas) are rare but aggressive malignancies with limited options for treatment. Currently, the combination of gemcitabine and cisplatin is considered the upfront systemic chemotherapy for patients with advanced and metastatic diseases. There is no ‘standard’ for second-line treatment. Several signaling pathways have been identified that might play a role in the development of biliary tract cancer and that may represent targets for directed therapies. Overexpression of VEGF and alterations of the Ras/Raf pathway have been identified in the majority of cholangiocarcinoma; some studies have shown these mutations to be associated with metastasis and poorer prognosis. Regorafenib is an oral multikinase inhibitor of multiple angiogenic and oncogenic kinases (VEGFR1-3, TIE2, PDGFR-β, FGFR1, KIT, RET, RAF) which has shown efficacy as a single agent in multiple solid tumors. This study evaluates the efficacy of regorafenib in patients with advanced/metastatic biliary tract cancer following the failure of first-line chemotherapy. Methods: Enrollment in this phase II, single-arm trial is ongoing. Eligible patients have unresectable advanced or metastatic biliary tract adenocarcinoma, and have failed first-line systemic chemotherapy. Patients receive regorafenib 120 mg orally daily in a 21 days on, 7 days off cycle. Tumor measurements take place every 3 cycles by CT or MRI imaging. Patients continue on therapy until disease progression or unacceptable toxicities. The primary end point of this study is median progression-free survival (PFS). To evaluate for evidence of activity, defined as a median PFS of 3.5 months or greater, with 83% power (one-sided test, α=0.10), target enrollment is 37 patients. Secondary endpoints include safety, overall response rate, disease control rate, median overall survival, and changes in biomarker levels. The correlation of these biomarkers and of tumor mutations with response to treatment is built into the study as well. As of September 2014, 9 patients had been enrolled. ClinicalTrials.gov Identifier: NCT02053376. Clinical trial information: NCT02053376.

Second-line treatment options of adult immune thrombocytopenia

Immune thrombocytopenia (ITP) is an autoimmune disease characterized by the decrease of platelet count. In recent years, the pathogenesis, diagnosis and treatments of adult ITP have achieved significant progress. In particular, with wide clinical applications of rituximab, thrombopoietin (TPO) and TPO receptor agonist (TPORA) in ITP, the second-line treatment options have no longer limited to splenectomy. This article mainly discusses the second-line treatment options of adult ITP after first-line treatments failure, in order to provide individualized treatments. Key words: Thrombocytopenia; Adult; Splenectomy; Rituximab; Thrombopoietin; Thrombopoietin receptor agonist

Molecular analysis of sunitinib resistant renal cell carcinomacells after sequential treatment with RAD001(everolimus) or sorafenib.

Sequential application of target drugs is standard procedure after renal cell carcinoma (RCC) patients develop resistance. To optimize the sequence, antitumour effects of the mTOR inhibitor RAD001 or the tyrosine kinase inhibitor (TKI) sorafenib on RCC cells with acquired resistance to the TKI sunitinib was evaluated. RCC cells were exposed to 1 μM sunitinib for 24 hrs (as control) and for 8 weeks (to induce resistance) and then switched to RAD001 (5 nM) or sorafenib (5 μM) for a further 8 weeks. Tumour cell growth, cell cycle progression, cell cycle regulating proteins and intracellular signalling were then investigated. Short-term application of sunitinib (24 hrs) induced cell growth blockade with accumulation in the G2/M phase. RCC cells became resistant to sunitinib after 8 weeks, demonstrated by accelerated cell growth along with enhanced cdk1, cdk2, loss of p27, activation of Akt, Rictor and Raptor. Switching to sorafenib only slightly reduced growth of the sunitinib resistant RCC cells and molecular analysis indicated distinct cross-resistance. In contrast, full response was achieved when the cancer cells were treated with RAD001. p19 and p27 strongly increased, phosphorylated Akt, Rictor and Raptor decreased and the tumour cells accumulated in G0/G1. It is concluded that an mTOR-inhibitor for second-line therapy could be the strategy of choice after first-line sunitinib failure.

The combination of pill count and self-reported adherence is a strong predictor of first-line ART failure for adults in South Africa.

Suboptimal adherence to antiretroviral therapy (ART) is a strong predictor of virologic failure (VF) among people with HIV. Various methods such as patient self-report, pill counts and pharmacy refills have been utilized to monitor adherence. However, there are limited data on the accuracy of combining methods to better predict VF in routine clinical settings. We examined various methods to assess adherence including pill count, medication possession ratio (MPR), and self-reported adherence in order to determine which was most highly associated with VF after > 6 months on ART. We conducted a secondary analysis of data from a case-control study. At enrollment, pharmacy refill data were collected retrospectively from the medical chart, pill counts were completed to derive a pill count adherence ratio (PCAR) and a self-report questionnaire was administered to all participants. Parametric smooth splines and receiver operator characteristic (ROC) analyses were carried out to assess the accuracy of the adherence methods. 458 patients were enrolled from October 2010 to June 2012. Of these, 158 (34.50%) experienced VF (cases) and 300 (65.50%) were controls. The median (IQR) PCAR was 1.10 (0.99-1.14) for cases and 1.13 (1.08-1.18) for controls (p < 0.0001). The median MPR was 1.00 (0.97-1.07) for cases and 1.03 (0.96-1.07) for controls (p = 0.83). Combination of PCAR and self-reported questions was highly associated with VF. In this setting, a combination of pill count adherence and self-report adherence questions had the highest diagnostic accuracy for VF. Further validation of this simple, low-cost combination is warranted in large prospective studies.

High frequency of antiviral drug resistance and non-b subtypes in HIV-1 patients failing antiviral therapy in Cuba.

IntroductionEmergence of HIV-1 drug resistance may limit the sustained benefits of antiretroviral therapy (ART) in settings with limited laboratory monitoring and drug options. The objective is to implement the surveillance of drug resistance and subtypes in HIV-1 patients failing ART in Cuba.MethodsThis study compiled clinical and genotypic drug resistance data 588 ART-experienced HIV-1 patients attending a clinical center in Havana in 2009–2013. Drug resistance testing was performed as part of routine clinical care. Drug resistance mutations and levels were determined using Rega version 8.0.2.ResultsEighty-three percent received solely ART containing at least three drugs. Patients from 2009 to 2010 were longer treated (median: 4.9 vs 2.7 years) and exposed to more ART regimens (median: 4 vs 2 regimens) compared to patients from 2011–2013. Nucleoside reverse transcriptase inhibitor (NRTI), non-nucleoside RTI (NNRTI) and PI mutations were present in 83.5, 77.4 and 52.0%. Full-class resistance (FCR) to NRTI, NNRTI, PI and multidrug resistance (MDR) were detected in 25.0, 33.7, 11.4 and 6.3%. FCR to NRTI, NNRTI, PI and MDR were present in 12.8, 28.7, 0 and 0% after first-line failure (164 patients) and in 23.1, 34.6, 3.8 and 3.1% after second-line failure (130 patients). Subtype B (32.5%), BG recombinants (19.6%) and CRF19_cpx (16.2%) were the most prevalent genetic forms. Subtype distribution did not change significantly between 2009–2010 and 2011–2013, except for BG recombinants that increased from 12.2 to 21.3% (p=0.002).ConclusionsOur study found a high prevalence of drug resistance and supports the need for appropriate laboratory monitoring in clinical practice and access to drug options in case of virological failure.

Managing first-line failure.

WHO standard of care for failure of a first regimen, usually 2N(t)RTI's and an NNRTI, consists of a ritonavir-boosted protease inhibitor with a change in N(t)RTI's. Until recently, there was no evidence to support these recommendations which were based on expert opinion. Two large randomized clinical trials, SECOND LINE and EARNEST both showed excellent response rates (>80%) for the WHO standard of care and indicated that a novel regimen of a boosted protease inhibitor with an integrase inhibitor had equal efficacy with no difference in toxicity. In EARNEST, a third arm consisting of induction with the combined protease and integrase inhibitor followed by protease inhibitor monotherapy maintenance was inferior and led to substantial (20%) protease inhibitor resistance. These studies confirm the validity of the current recommendations of WHO and point to a novel public health approach of using two new classes for second line when standard first-line therapy has failed, which avoids resistance genotyping. Notwithstanding, adherence must be stressed in those failing first-line treatments. Protease inhibitor monotherapy is not suitable for a public health approach in low- and middle-income countries.

Effectiveness of medical treatment with methotrexate for interstitial pregnancy.

In the last three decades, systemic methotrexate (MTX) has become widely accepted as the primary treatment for unruptured tubal pregnancy. This has prompted investigations into the use of MTX in the management of interstitial pregnancy. To determine the effectiveness of methotrexate for treatment of interstitial pregnancy. We retrospectively reviewed 17 haemodynamically stable women admitted to our tertiary, university-affiliated medical centre with an intact interstitial pregnancy from January 2003 through February 2013. First-line treatment consisted of intramuscular MTX 1 mg/kg/day x4 alternating with folinic acid 0.1 mg/kg or, in cases of low beta-human chorionic gonadotropin (β-hCG) and no embryonic pole, one dose of 50 mg/m(2) body surface area. Uterine artery MTX injection was administered on the ipsilateral side of the pregnancy followed by uterine artery embolisation as second-line treatment. Failure criteria were <15% decrease in β-hCG or sonographic evidence of pregnancy development. Second-line failures were referred for surgery. Twelve women (70.5%) underwent successful first-line treatment and 5 (29.5%) required second-line treatment. Baseline characteristics were similar except for a higher rate of two previous ectopic pregnancies in the first-line failures (80% versus 8.3%, P = 0.01). Two women eventually required surgery, both with two previous ectopic pregnancies. Of the three women with fetal cardiac activity on admission, two had successful first-line treatment and one required surgery. Systemic MTX is effective for treatment of intact interstitial pregnancy in haemodynamically stable women. The success rate is increased with uterine artery MTX injection as second-line treatment.

High Prevalence of Cross-resistance to Rilpivirine in Subtype C HIV-1 Isolates from First-line ART Failures in South Africa

AIDS Research and Human RetrovirusesVol. 30, No. S1 Resistance and Treatment FailureHigh Prevalence of Cross-resistance to Rilpivirine in Subtype C HIV-1 Isolates from First-line ART Failures in South AfricaKerri J. Penrose, Carole L. Wallis, Maritsa Scoulos-Hanson, Raquel Viana, John W. Mellors, and Urvi M. ParikhKerri J. PenroseUniversity of Pittsburgh School of Medicine, Infectious Diseases, Pittsburgh, PA, United StatesSearch for more papers by this author, Carole L. WallisLancet Laboratories, Specialty Molecular Division, Johannesburg, South AfricaSearch for more papers by this author, Maritsa Scoulos-HansonUniversity of Pittsburgh School of Medicine, Infectious Diseases, Pittsburgh, PA, United StatesSearch for more papers by this author, Raquel VianaLancet Laboratories, Specialty Molecular Division, Johannesburg, South AfricaSearch for more papers by this author, John W. MellorsUniversity of Pittsburgh School of Medicine, Infectious Diseases, Pittsburgh, PA, United StatesSearch for more papers by this author, and Urvi M. ParikhUniversity of Pittsburgh School of Medicine, Infectious Diseases, Pittsburgh, PA, United StatesSearch for more papers by this authorPublished Online:30 Oct 2014https://doi.org/10.1089/aid.2014.5346.abstractAboutSectionsView articleView Full TextPDF/EPUB ToolsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail View article"High Prevalence of Cross-resistance to Rilpivirine in Subtype C HIV-1 Isolates from First-line ART Failures in South Africa." AIDS Research and Human Retroviruses, 30(S1), p. A166FiguresReferencesRelatedDetailsCited byCost-effectiveness of Injectable Preexposure Prophylaxis for HIV Prevention in South Africa18 May 2016 | Clinical Infectious Diseases, Vol. 63, No. 4Deciphering the Effects of Injectable Pre-exposure Prophylaxis for Combination Human Immunodeficiency Virus Prevention16 June 2016 | Open Forum Infectious Diseases, Vol. 3, No. 3 Volume 30Issue S1Oct 2014 InformationCopyright 2014, Mary Ann Liebert, Inc.To cite this article:Kerri J. Penrose, Carole L. Wallis, Maritsa Scoulos-Hanson, Raquel Viana, John W. Mellors, and Urvi M. Parikh.High Prevalence of Cross-resistance to Rilpivirine in Subtype C HIV-1 Isolates from First-line ART Failures in South Africa.AIDS Research and Human Retroviruses.Oct 2014.A166-A166.http://doi.org/10.1089/aid.2014.5346.abstractPublished in Volume: 30 Issue S1: October 30, 2014PDF download

Biologic choices after first-line anti-tumour necrosis factor failure in non-systemic juvenile idiopathic arthritis

Biologic choices after first-line anti-tumour necrosis factor failure in non-systemic juvenile idiopathic arthritis

Phenotypic characterization of virological failure following lopinavir/ritonavir monotherapy using full-length Gag-protease genes.

ObjectivesMajor protease mutations are rarely observed following first-line failure with PIs and interpretation of genotyping results in this context may be difficult. We performed extensive phenotyping of viruses from five patients failing lopinavir/ritonavir monotherapy in the MONARK study without major PI mutations by standard genotyping.MethodsPhenotypic susceptibility testing and viral infectivity assessments were performed using a single-cycle assay and fold changes (FC) relative to a lopinavir-susceptible reference strain were calculated.Results>10-fold reduced baseline susceptibility to lopinavir occurred in two of five patients and >5-fold in another two. Four of five patients exhibited phylogenetic evidence of a limited viral evolution between baseline and failure, with amino acid changes at drug resistance-associated positions in one: T81A emerged in Gag with M36I in the protease gene, correlating with a reduction in lopinavir susceptibility from FC 7 (95% CI 6–8.35) to FC 13 (95% CI 8.11–17.8). Reductions in darunavir susceptibility (>5 FC) occurred in three individuals.DiscussionThis study suggests both baseline reduced susceptibility and evolution of resistance could be contributing factors to PI failure, despite the absence of classical PI resistance mutations by standard testing methods. Use of phenotyping also reveals lower darunavir susceptibility, warranting further study as this agent is commonly used following lopinavir failure.

Drug susceptibility and resistance mutations after first-line failure in resource limited settings.

The development of drug resistance to nucleoside reverse transcriptase inhibitors (NRTIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs) has been associated with baseline human immunodeficiency virus (HIV)-1 RNA level (VL), CD4 cell counts (CD4), subtype, and treatment failure duration. This study describes drug resistance and levels of susceptibility after first-line virologic failure in individuals from Thailand, South Africa, India, Malawi, Tanzania. CD4 and VL were captured at AIDs Clinical Trial Group (ACTG) A5230 study entry, a study of lopinavir/ritonavir (LPV/r) monotherapy after first-line virologic failure on an NNRTI regimen. HIV drug-resistance mutation associations with subtype, site, study entry VL, and CD4 were evaluated using Fisher exact and Kruskall-Wallis tests. Of the 207 individuals who were screened for A5230, sequence data were available for 148 individuals. Subtypes observed: subtype C (n = 97, 66%) AE (n = 27, 18%), A1 (n = 12, 8%), and D (n = 10, 7%). Of the 148 individuals, 93% (n = 138) and 96% (n = 142) had at least 1 reverse transcriptase (RT) mutation associated with NRTI and NNRTI resistance, respectively. The number of NRTI mutations was significantly associated with a higher study screening VL and lower study screening CD4 (P < .001). Differences in drug-resistance patterns in both NRTI and NNRTI were observed by site. The degree of NNRTI and NRTI resistance after first-line virologic failure was associated with higher VL at study entry. Thirty-two percent of individuals remained fully susceptible to etravirine and rilpivirine, protease inhibitor resistance was rare. Some level of susceptibility to NRTI remained; however, VL monitoring and earlier virologic failure detection may result in lower NRTI resistance.

A comparison of computational models with and without genotyping for prediction of response to second‐line HIV therapy

We compared the use of computational models developed with and without HIV genotype vs. genotyping itself to predict effective regimens for patients experiencing first-line virological failure. Two sets of models predicted virological response for 99 three-drug regimens for patients on a failing regimen of two nucleoside/nucleotide reverse transcriptase inhibitors and one nonnucleoside reverse transcriptase inhibitor in the Second-Line study. One set used viral load, CD4 count, genotype, plus treatment history and time to follow-up to make its predictions; the second set did not include genotype. Genotypic sensitivity scores were derived and the ranking of the alternative regimens compared with those of the models. The accuracy of the models and that of genotyping as predictors of the virological responses to second-line regimens were compared. The rankings of alternative regimens by the two sets of models were significantly correlated in 60-69% of cases, and the rankings by the models that use a genotype and genotyping itself were significantly correlated in 60% of cases. The two sets of models identified alternative regimens that were predicted to be effective in 97% and 100% of cases, respectively. The area under the receiver-operating curve was 0.72 and 0.74 for the two sets of models, respectively, and significantly lower at 0.55 for genotyping. The two sets of models performed comparably well and significantly outperformed genotyping as predictors of response. The models identified alternative regimens predicted to be effective in almost all cases. It is encouraging that models that do not require a genotype were able to predict responses to common second-line therapies in settings where genotyping is unavailable.

DNA methylation biomarkers predict progression-free and overall survival of metastatic renal cell cancer (mRCC) treated with antiangiogenic therapies.

VEGF-targeted therapy increases both the progression-free (PFS) and overall survival (OS) of patients with metastasized renal cell cancer (mRCC). Identification of molecular phenotypes of RCC could improve risk-stratification and the prediction of the clinical disease course. We investigated whether gene-specific DNA hypermethylation can predict PFS and OS among patients undergoing anti-VEGF-based therapy. Primary tumor tissues from 18 patients receiving targeted therapy were examined retrospectively using quantitative methylation-specific PCR analysis of CST6, LAD1, hsa-miR-124-3, and hsa-miR-9-1 CpG islands. PFS and OS were analyzed for first-line and sequential antiangiogenic therapies using the log rank statistics. Sensitivity and specificity were determined for predicting first-line therapy failure. Hypermethylation of CST6 and LAD1 was associated with both a shortened PFS (log rank p = 0.009 and p = 0.004) and OS (p = 0.011 and p = 0.043). The median PFS observed for the high and low methylation groups of CST6 and LAD1 was 2.0 vs.11.4 months. LAD1 methylation had a specificity of 1.0 (95% CI 0.65–1.0) and a sensitivity of 0.73 (95% CI 0.43–0.90) for the prediction of first-line therapy. CST6 and LAD1 methylation are candidate epigenetic biomarkers showing unprecedented association with PFS and OS as well as specificity for the prediction of the response to therapy. DNA methylation markers should be considered for the prospective evaluation of larger patient cohorts in future studies.

Treatment Sequencing After Failure of the First Biologic in Cost-Effectiveness Models of Psoriasis: A Systematic Review of Published Models and Clinical Practice Guidelines

ObjectivesTo analyse the treatment sequencing assumptions after failure on a first-line biologic in cost-effectiveness models of treatment of moderate to severe plaque psoriasis, and to compare them with the most recent treatment guidelines.MethodsA systematic search of MEDLINE, Embase, EconLit and the Cochrane Library databases used free text and Medical Subject Headings terms including psoriasis, biologic therapies indicated for psoriasis, and all types of economic evaluations. Two researchers performed 2-level abstract screening for articles meeting pre-specified inclusion criteria. Assumptions about treatment pathways after first-line biologic failure in the cost-effectiveness models were analysed. A second systematic search was performed for psoriasis clinical practice guidelines. Sequence assumptions were compared with treatment guideline recommendations.ResultsOf 25 cost-effectiveness modelling studies identified, ten estimated the incremental cost per responder; time horizons varied (12 weeks–18 months) and treatment sequencing was not considered. In 15 studies where treatment sequencing was considered, with time horizons up to 10 years, five studies included only a switch to nonsystemic therapy or best supportive care after first-line biologic failure. Another five of the 15 treatment-pathway studies were available only as abstracts with no details of the sequence assumptions. In five of the 15 studies, first-line biologic failure was followed by second-line biologic monotherapy, one of the recommendations in current treatment guidelines. In only one of these five studies was the efficacy of the second-line biologic adjusted downwards, compared with first-line treatment. Only one of these studies considered dose titration with a first-line biologic and none combination therapy (biologic plus methotrexate or phototherapy) after first-line biologic failure, as recommended in some treatment guidelines.ConclusionsCost-effectiveness models of first-line biologics for moderate to severe plaque psoriasis either do not include subsequent treatment regimens or include only some of the regimens recommended in current treatment guidelines. Results may be sensitive to assumptions about treatment sequencing and the choice and efficacy of subsequent treatment regimens.Electronic supplementary materialThe online version of this article (doi:10.1007/s40273-014-0130-5) contains supplementary material, which is available to authorized users.