Early Therapeutic Failure Research Articles

Esophageal two-phase supine/standing scintigraphy and balloon dilatation in achalasia: 20 years of experience

Background/Aim. The most frequent therapeutic method for achalasia is balloon dilatation (BD). Esophageal scintigraphy is potentially the most convenient method for the evaluation of achalasia by quantifying esophageal transit. The aim of this study was to present the results of esophageal scintigraphy (ES) in achalasia treated by BD for a long period of time, from 1997 to 2016, and to set parameters suitable for predicting treatment outcomes. Methods. Two-phase ES in anterior projection was performed. The first phase involved swallowing 10 mL of water with 18.5 MBq 99mTc in a supine position. The second phase was performed in a standing position after swallowing 100 mL of water. The retention index (RI) of esophageal radioactivity was calculated after the imaging using registered esophageal and gastric counts. ES was performed in 52 patients (34 males and 18 females, aged 22?75 years, the median age 44 years) before and after BD. In 31 patients, only two scintigraphies were performed. In the remaining 21 patients, follow-up and repeated scintigraphies were continued including the patients with therapeutic failure and repeated BD. BD was repeated in 8 patients, and those were followed up and evaluated over time. Modified BD was performed with Rigiflex balloon dilators. Results. A typical scintigraphic finding in the supine position was passive esophageal filling without the evidence of motility, and in most patients, 43 of them (83%), radionuclide elimination in the stomach was absent. Evaluating values before and long after the first BD, it was shown that certain values of RI indicated remission or relapse of the disease. The RI difference higher than 50% after BD was a reliable indicator of a longer remission. The age and gender of patients had no impact on the outcome of dilatation, but younger patients were with a higher risk of early failure (6 patients during the first year after BD). ES showed that the first BD was initially successful in 50 patients and after the follow-up in 41 (79%) patients. Conclusion. A two-phase supine/standing ES is most suitable for diagnosing and the follow-up of achalasia. RI represents an important parameter for the evaluation and prediction of therapeutic response. The RI difference of more than 50% after BD is a reliable predictor of a longer remission. Age and gender have no impact on dilatation outcome, but patients younger than 40 years have a higher risk of early therapeutic failure.

Abstract 4236: A subtype-specific T-cell transcriptomic atlas reveals determinants of T-cell dysfunction in CAR T-cell therapy resistance

Abstract Chimeric Antigen Receptor (CAR) T-cell therapy has been a major success for B-cell Acute Lymphoblastic Leukemia (B-ALL), yet recent clinical trials suggest that approximately 20% of patients do not respond to therapy and 40% of initial responders relapse within a year. We hypothesize that intrinsic T-cell factors are a major contributor to early therapeutic failure to CAR T-cell therapy. In particular, since most protocols do not select for T-cell subtypes, the heterogeneity in T-cell composition likely plays a major role in CAR T-cell engineering and confounds functional and clinical correlative studies. In order to characterize the molecular phenotypes of T-cells underlying therapeutic response, we performed subtype-specific transcriptomic profiling of clinical T-cell populations in 71 patients treated with CAR T-cell therapy at the Children's Hospital of Philadelphia. We obtained clinical T-cells via clinical leukapheresis prior to CAR T-cell engineering, used FACS to separate T-cells into five subtypes per patient (Naive, Stem Cell Memory, Central Memory, Effector Memory, and Effector), and performed RNA-Sequencing on all 355 samples. To our knowledge, this is the largest and most comprehensive transcriptomic profiling of clinical T-cells in CAR T-cell therapy to date. We found that a higher proportion of CCR7+CD62L+ naive and early memory T-cell phenotypes associates with longer clinical T-cell persistence (HR: 3.25 [1.37-7.89], P = 0.006), and that combining proportions of these populations with CCR7-CD62L-CD45RO+CD95+ effector memory T-cells has the greatest prognostic value (HR: 4.82 [1.89-12.32], P < 0.001). Apoptotic signaling pathways were enriched in effector and effector memory T-cell lineages (FDR < 0.001), suggesting that programmed cell death limits the contribution of these phenotypes to long-term CAR T-cell persistence. Maintenance of naive and early memory T-cell phenotypes associates positively with expression of transcription factors TCF7 and LEF1 (FDR < 0.001) and negatively with TBX21, EOMES, and ZEB2 (FDR < 0.001). Within T-cell subtypes, mixed-effects regression and integrative network analysis identified genes and network modules that discriminate between clinical responders and non-responders. We found that higher expression of CRTAM and SLAMF6 in naive and stem cell memory T-cells associates positively with clinical CAR T-cell persistence (FDR = 0.0088-0.019), suggesting that these lineage-determining factors direct T-cell fates toward effective CAR T-cell lineages. Finally, we identify an enrichment of type I interferon response pathways among patients with poor CAR T-cell persistence (F-test P < 0.001), suggesting a role of the chronic interferon response network in T-cell dysfunction. Together, these data shed light on the critical role of pre-infusion T-cell populations in CAR T-cell therapy, and may inform clinical prognosis and the development of improved CAR T-cell therapies. Citation Format: Gregory M. Chen, Changya Chen, Rajat K. Das, Yang-Yang Ding, Bing He, Hannah Kim, David M. Barrett, Kai Tan. A subtype-specific T-cell transcriptomic atlas reveals determinants of T-cell dysfunction in CAR T-cell therapy resistance [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4236.

Abstract PR3: Development of a transcriptomic T-cell atlas highlights the differential role of T-cell subpopulations in CAR T-cell therapy resistance

Abstract Chimeric antigen receptor (CAR) T-cell therapy has been a major breakthrough in B-cell acute lymphoblastic leukemia (B-ALL), yet therapeutic resistance remains an important clinical challenge. Given that approximately 20% of patients do not respond to therapy and 40% of initial responders relapse within a year, there is a pressing need to understand the basis of therapy resistance in order to identify prognostic biomarkers and improve the therapeutic modality. We hypothesize that intrinsic T-cell factors are a major contributor to early therapeutic failure to CAR T-cell therapy. Most protocols do not select for specific T-cell subtypes, leading to the use of heterogeneous T-cell populations for CAR T-cell engineering. In order to characterize the molecular phenotypes of T cells underlying therapeutic response, we performed subtype-specific transcriptomic profiling of clinical T-cell populations in patients subsequently treated with anti-CD19 CAR T-cell therapy. We identified 71 patients with B-ALL treated with CAR T-cell therapy at the Children’s Hospital of Philadelphia, and obtained T cells via clinical leukapheresis prior to CAR T-cell engineering. We used FACS to separate T cells into five subtypes per patient (Naive, Stem Cell Memory, Central Memory, Effector Memory, and Effector), and performed bulk RNA-sequencing on all 355 samples. To our knowledge, this is the largest and most comprehensive transcriptomic profiling of clinical T cells in CAR T-cell therapy to date. We find that a higher proportion of CCR7+CD62L+ naive and early memory T-cell phenotypes associates with longer clinical T-cell persistence (HR=3.25 [1.37-7.89], p=0.006), and that combining proportions of these populations with CCR7−CD62L−CD45RO+CD95+ effector memory T cells has the greatest prognostic value (HR: 4.82 [1.89-12.32]; p<0.001). We identified global transcriptomic markers of early and differentiated T-cell populations and identified differentially expressed genes that discriminated between clinical responders and nonresponders. Single-sample gene set enrichment analysis identified an enrichment of T-cell exhaustion pathways among the clinical nonresponders, which was predominant in the early lineage T-cell phenotypes (p=0.018-0.095) but not in the effector T-cell phenotypes (p=0.15-0.37). Together, these data shed light on the critical role of preinfusion T-cell populations in CAR T-cell therapy, and may inform clinical prognosis and the development of improved CAR T-cell therapies. This abstract is also being presented as Poster A65. Citation Format: Gregory M. Chen, Changya Chen, Rajat K. Das, Yang-Yang Ding, Bing He, Hannah Kim, David M. Barrett, Kai Tan. Development of a transcriptomic T-cell atlas highlights the differential role of T-cell subpopulations in CAR T-cell therapy resistance [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr PR3.

Treatment Stratification of Patients with Metastatic Castration-Resistant Prostate Cancer by Machine Learning.

SummaryProstate cancer is the most common cancer in men in the Western world. One-third of the patients with prostate cancer will develop resistance to hormonal therapy and progress into metastatic castration-resistant prostate cancer (mCRPC). Currently, docetaxel is a preferred treatment for mCRPC. However, about 20% of the patients will undergo early therapeutic failure owing to adverse events induced by docetaxel-based chemotherapy. There is an emergent need for a computational model that can accurately stratify patients into docetaxel-tolerable and docetaxel-intolerable groups. Here we present the best-performing algorithm in the Prostate Cancer DREAM Challenge for predicting adverse events caused by docetaxel treatment. We integrated the survival status and severity of adverse events into our model, which is an innovative way to complement and stratify the treatment discontinuation information. Critical stratification biomarkers were further identified in determining the treatment discontinuation. Our model has the potential to improve future personalized treatment in mCRPC.

Sensibilidad antimicrobiana en aislamientos de líquido peritoneal de niños intervenidos por abdomen agudo e infección intraabdominal

Introducción. La apendicitis aguda es causa frecuente de infección intraabdominal en pediatría. La elección del antibiótico se basa en los hallazgos quirúrgicos macroscópicos, el criterio médico, las guías locales o internacionales y, en pocas ocasiones, en el resultado de los aislamientos bacterianos en cultivos de líquido peritoneal y las tasas locales de resistencia. Se analizaron la frecuencia y la sensibilidad microbiológica de los cultivos de muestras de líquido peritoneal de pacientes de un mes a 16 años de edad con manejo quirúrgico por abdomen agudo con sospecha de infección intraabdominal. Materiales y métodos. Se llevó a cabo un estudio prospectivo de cohorte con análisis de las historias clínicas y de resultados de laboratorio de niños sometidos a cirugía por abdomen agudo, en la que el cirujano tomó muestra del líquido peritoneal para la tipificación y determinación de los perfiles de sensibilidad de los microorganismos aislados. Los datos se analizaron con el programa Stata™, versión15.0. Resultados. Se identificaron 303 casos, de los cuales el 93,6 % recibió profilaxis antibiótica con ampicilina-sulbactam y clindamicina-amikacina. El 95,3 % de los procedimientos fueron apendicectomías. Se tomó cultivo del 50 % de las apendicitis perforadas. Se aislaron 48 microorganismos; el más frecuente (2,7 %) fue Escherichia coli positiva para BLEE. El 100 % de los microorganismos resultaron ser sensibles a la amikacina, el 97,2 % al meropenem, y el 94,4 %, a la ciprofloxacina, el cefepime y el ceftazidime. La resistencia más frecuente (37,1 %) fue contra la combinación de ampicilina y sulbactam, en los gérmenes Gram negativos. Discusión. La evaluación de la sensibilidad antimicrobiana de los aislamientos de líquido peritoneal de los procedimientos quirúrgicos en pediatría, es una buena práctica clínica que orienta al cirujano en la adecuada selección del esquema antibiótico y, además, disminuye el riesgo de falla terapéutica temprana y la posibilidad de mayor resistencia o complicaciones infecciosas.

P1.04-76 Predictive Factors of Early Therapeutic Failure to Immunotherapy in Patients with Metastatic NSCLC

P1.04-76 Predictive Factors of Early Therapeutic Failure to Immunotherapy in Patients with Metastatic NSCLC

Treatment for human visceral leishmaniasis: a cost-effectiveness analysis for Brazil.

To estimate the cost-effectiveness of strategies for the treatment of VL in Brazil. Cost-effectiveness study comparing three therapeutic options: meglumine antimoniate (MA), liposomal amphotericin B (LAMB) and a combination of LAMB plus MA (LAMB plus MA), from public health system and societal perspectives. An analytical decision-making model was used to compare strategies for the following outcomes: early therapeutic failure avoided at 30days, days of hospitalisation avoided and VL cure at 180days. The efficacy and safety parameters of the drugs came from a randomised, open-label trial and the cost data came from a cost-of-illness study, both carried out in Brazil. For all outcomes analysed, the LAMB strategy was more effective. The MA strategy was inferior to the LAMB plus MA strategy for the outcomes early therapeutic failure avoided and cure. When only LAMB and MA were compared from a societal perspective, a cost of US$ 278.56 was estimated for each additional early therapeutic failure avoided, a cost of US$ 26.88 for each additional day of hospitalisation avoided and a cost of US$ 89.88 for each additional case of cured VL, for the LAMB strategy vs. MA. In Brazil, the LAMB strategy proved to be cost-effective for treating VL, considering a GDP per capita as the willingness-to-pay threshold, for all of the outcomes analysed in comparison to MA.

Evaluation of Two Techniques for Viral Load Monitoring Using Dried Blood Spot in Routine Practice in Vietnam (French National Agency for AIDS and Hepatitis Research 12338).

Background. Although it is the best method to detect early therapeutic failure, viral load (VL) monitoring is still not widely available in many resource-limited settings because of difficulties in specimen transfer, personnel shortage, and insufficient laboratory infrastructures. Dried blood spot (DBS) use, which was introduced in the latest World Health Organization recommendations, can overcome these difficulties. This evaluation aimed at validating VL measurement in DBS, in a laboratory without previous DBS experience and in routine testing conditions.Methods. Human immunodeficiency virus (HIV)-infected adults were observed in a HIV care site in Hanoi, and each patient provided 2 DBS cards with whole blood spots and 2 plasma samples. Viral load was measured in DBS and in plasma using the COBAS Ampliprep/TaqMan and the Abbott RealTime assays. To correctly identify those with VL ≥ 1000 copies/mL, sensitivity and specificity were estimated.Results. A total of 198 patients were enrolled. With the Roche technique, 51 plasma VL were ≥1000 copies/mL; among these, 28 presented a VL in DBS that was also ≥1000 copies/mL (sensitivity, 54.9; 95% confidence interval [CI], 40.3–68.9). On the other hand, all plasma VL < 1000 copies/mL were also <1000 copies/mL in DBS (specificity, 100; 95% CI, 97.5–100). With the Abbott technique, 45 plasma VL were ≥1000 copies/mL; among these, 42 VL in DBS were also ≥1000 copies/mL (sensitivity, 93.3%; 95% CI, 81.7–98.6); specificity was 94.8 (95% CI, 90.0–97.7).Conclusions. The Abbott RealTime polymerase chain reaction assay provided adequate VL results in DBS, thus allowing DBS use for VL monitoring.

Evaluation of the efficacy and safety of three 2-drug combinations for the treatment of uncomplicated Plasmodium falciparum malaria in Senegal: artesunate-amodiaquine, dihydroartemisinin-piperaquine, and artemether-lumefantrine

Since 2006, artemisinin-based combination therapies (ACT) have been used to treat uncomplicated Plasmodium falciparum malaria in Senegal, as recommended by WHO. Recently, decreased parasite clearance with artemisinin derivatives has been reported in Cambodia and Thailand. The effectiveness of artemisinin derivatives in Africa must be monitored. This study was conducted to evaluate the efficacy and the tolerability of three ACT widely used in Senegal. From October 2010 to February 2011, a descriptive and analytical sequential study was conducted in adults and children to evaluate these three combinations: artemether-lumefantrine (AL), artesunate-amodiaquine (ASAQ), and dihydroartemisinin-piperaquine (DHAPQ). The study took place at the health posts of Deggo and Pikine and the health center of Guédiawaye, in the suburbs of Dakar. The primary endpoint was the PCR-corrected adequate clinical and parasitological response (ACPR) at day 28 (D28); the secondary endpoints included ACPR at D42, clearance times for parasites, fever, and gametocytes, and the incidence of adverse events. The study included 393 patients: 139 in the AL group, 130 in the ASAQ group, and 124 in the DHAPQ group. In the intent-to-treat population, PCR-corrected ACPR at day 28 was 92.8% in the AL, 89.2% in the ASAQ, and 91.1% in the DHAPQ (p = 0.58) groups, and in the per-protocol population, 98.4%, 98.3%, and 100% respectively (p = 0.39). At D42, ACPR was 99.2% in the AL, and 99.1% in each of the ASAQ and DHAPQ arms (p = 1). No early therapeutic failure (ETF) was observed. The combinations were well tolerated, with no serious adverse events reported during the follow-up period. These combinations are still effective and well-tolerated. Continued monitoring is nonetheless essential to detect early artemisinin resistance in Africa.

Routinely Established Skewed Thiopurine Metabolism Leads to a Strikingly High Rate of Early Therapeutic Failure in Patients With Inflammatory Bowel Disease.

The conventional thiopurines azathioprine and mercaptopurine are considered maintenance immunosuppressive drugs of choice in the treatment of inflammatory bowel disease (IBD). Unfortunately, treatment is often discontinued because of adverse events (AEs) or refractoriness, retrospectively associated with the high levels of the thiopurine metabolites 6-methylmercaptopurine ribonucleotides (6-MMPR). Patients with a clinically "skewed" thiopurine metabolism may be particularly at risk for therapy failure. We determined the predictive value of this pharmacological phenomenon in patients with IBD during regular thiopurine therapy. Clinical effectiveness and tolerability of weight-based thiopurine therapy were determined in all patients with IBD displaying a skewed metabolism [ratio 6-MMPR/6-thioguanine nucleotide (6-TGN) >20]. All samples were routinely assessed between 2008 and 2012, as part of standard clinical follow-up after initiation of conventional thiopurine therapy. Forty-one (84%) of 49 included patients with IBD discontinued thiopurines (55% female, 53% with Crohn disease) with a median duration of 14 weeks (range, 7-155). The majority of patients with a skewed metabolism discontinued thiopurines because of adverse events (55%) or refractoriness (12%). The most commonly observed adverse event was hepatotoxicity (18 patients, 37%). Median 6-TGN level was 159 pmol/8 × 10 RBC (range, 46-419), median 6-MMPR level was 11,020 pmol/8 × 10 RBC (range, 3610-43,670), and the median 6-MMPR/6-TGN ratio was 72 (range, 29-367). Thiopurine therapy failure was associated with a ratio above 50 (P < 0.03). Hepatotoxicity occurred more frequently in patients with an extremely skewed metabolism (6-MMPR/6-TGN ratio >100) (P < 0.01). This study demonstrates that a routinely established skewed metabolism is a major risk factor for future thiopurine failure in patients with IBD. These observations imply that routine thiopurine metabolite measurements may be used as a prognostic tool to identify those patients with an aberrant-skewed metabolism at an early stage, possibly benefitting from therapy adjustments.

HIV-1 variability and viral load technique could lead to false positive HIV-1 detection and to erroneous viral quantification in infected specimens

Viral load (VL) testing is used for early HIV diagnosis in infants (EID) and for detecting early therapeutic failure events, but can be affected by HIV genetic variability. Dried blood samples (DBS) increase VL access and EID in remote settings and when low blood volume is available. This study compares VL values using Siemens VERSANT HIV-1 RNA 1.0 kPCR assay (kPCR) and Roche CAP/CTM Quantitative test v2.0 (CAP/CTM v2.0) in 176 DBS carrying different HIV-1 variants collected from 69 Equatoguinean mothers and their infants with known HIV-1 status (71 infected, 105 uninfected). CAP/CTM v2.0 provided false positive VLs in 11 (10.5%) cases. VL differences above 0.5 log10 were observed in 42/49 (87.5%) DBS, and were above 1 log10 in 18 cases. CAP/CTM v2.0 quantified all the 41 specimens with previously inferred HIV-1 variant by phylogenetic analysis (68.3% recombinants) whereas kPCR only identified 90.2% of them, and was unable to detect 14.3% of 21 CRF02_AG viruses. CAP/CTM v2.0 showed higher sensitivity than kPCR (95.8% vs. 70.1%), quantifying a higher rate of viruses in infected DBS from subjects under antiretroviral exposure at sampling time compared to kPCR (94.7% vs. 96.2%, p-value<0.001). kPCR showed maximum specificity (100%) whereas for CAP/CTM v2.0 was 89.5%. VL assays should increase their sensitivity and specificity to avoid overestimated HIV-1 quantifications, which could be interpreted as virological failure events, or false negative diagnostic results due to genetic variability. We recommend using the same VL technique for each patient during antiretroviral therapy monitoring.

P343 Skewed thiopurine metabolism leads to early therapeutic failure in the majority of patients with inflammatory bowel disease

P343 Skewed thiopurine metabolism leads to early therapeutic failure in the majority of patients with inflammatory bowel disease

HIV-1 RNA Quantification from Dried Blood Spots and Plasma Using the Siemens VERSANT® HIV-1 RNA 1.0 Assay (kPCR)

HIV-1 RNA Quantification from Dried Blood Spots and Plasma Using the Siemens VERSANT® HIV-1 RNA 1.0 Assay (kPCR) Objective: Dried blood specimens (DBS) use simplifies the sample collection for viral load (VL) testing in some settings. We compared the VL quantification using DBS and the plasma using the Siemens VERSANT® HIV-1 RNA 1.0 (kPCR) Assay. Methods: Paired DBS/plasma samples were prepared from 62 HIV-1 infected patients harboring different HIV-1 subtypes and recombinants and HIV-1 RNA was quantified by kPCR in 62 paired specimens. DBS and plasma VL results were compared. Viraemia values in DBS were corrected for plasma volume differences assuming the hematocrit percentage in each patient. Results: The results showed a good correlation between corrected VL values in DBS and the results obtained in plasma. The intraclass correlation coefficient was 82.3%. The detection rate in DBS was 83.9%, while the sensitivity of the kPCR for DBS was 92.9%. Overall VL in DBS was, on average, 0.8 log (SD = 0.58) lower than in plasma. We observed overestimated VL in DBS specimens with less than 1,000 copies/ml in plasma. Conclusion: DBS can be used for HIV-1 quantification using kPCR and can be useful for the early therapeutic failure detection in treated subjects. However, VL in DBS can be overestimated in specimens with low VL in plasma, maybe due to a higher effect of proviral DNA in quantification. More studies including more HIV-1 variants are needed to define the kPCR performance.

Eficacia de la combinación amodiaquina más sulfadoxinapirimetamina y de la cloroquina para el tratamiento del paludismo en Córdoba, Colombia, 2006

The decrease in the efficacy of antimalarial drugs in the world and in Colombia hampers its control. The in vivo therapeutic efficacy of the amodiaquine+sulfadoxine-pyrimethamine combination was evaluated in the treatment of uncomplicated Plasmodium falciparum malaria and of chloroquine for P. vivax malaria. From May to November 2006, in vivo efficacy studies of malaria treatments were undertaken in Tierralta, Córdoba, northeastern Colombia. Standard protocols were followed as recommended by the World Health Organization/Panamerican Health Organization, with some modifications. Patients older than two years with single P. falciparum or P. vivax infection, with asexual parasitemia between 500 and 50,000 parasites/microl, were selected according to established inclusion and exclusion criteria. Supervised treatment was administered, and clinical and parasitological follow-up was carried out on days 0 (inclusion), 1, 2, 3, 7, 14, 21 and 28. The outcome was defined as adequate clinical and parasitological response, early therapeutic failure, or late therapeutic failure. Of 53 subjects selected, 50 (94.3%; CI 70%-100%) presented adequate clinical and parasitological response to the amodiaquine+sulfadoxine-pyrimethamine treatment for uncomplicated falciparum malaria. One patient presented early therapeutic failure, and two developed late therapeutic failure. All of the 50 patients (95%CI: 74%-100%) in the invivo efficacy study of chloroquine for vivax malaria presented adequate clinical and parasitological response. In Cordoba, the amodiaquine+sulfadoxine-pyrimethamine combination and chloroquine show a high efficacy for the treatment of uncomplicated falciparum and vivax malaria, respectively.

Relevance of early detection of HIV type 1 SI/CXCR4-using viruses in vertically infected children.

The aim of the study was to investigate the prevalence and persistence of syncytium-inducing (SI) strains in HIV-1-infected children along time of infection and to evaluate the influence of antiretroviral therapy and host factors on viral tropism. This is a retrospective analysis carried out in 267 HIV-1 vertically infected children from an Argentinean cohort. The viral phenotype was screened in MT-2 cells and coreceptor usage confirmed by the GHOST cell assay. Also, CD4(+) T cell count, viral load, antiretroviral therapy, and human CCR5-Δ32 and CCR2-64I genotypes were analyzed. A high frequency of HIV-1 SI/CXCR4-using variants (22%) was found among children within the first trimester of life, reaching 46% after 10 years of infection. At acute infection, zidovudine prophylaxis did not significantly affect the proportions of SI HIV-1 strains, while their presence was favored by the CCR5(+)/Δ32 genotype. Interestingly, the majority of the early SI strains did not persist over time, probably due to a higher susceptibility to antiretroviral (ARV) treatment or immunologic pressure. At the chronic stage, SI variants emerged even in the presence of HAART reaching 36% at 120 months of infection. Also the HIV-1 SI phenotype was associated with lower CD4(+) T cell counts all along the course of infection. These findings highlight the need to evaluate the presence of SI/CXCR4 variants early at primary infection. This will make it possible to optimize the use of CCR5 inhibitors in children who are apparently carriers of the R5 virus preventing early therapeutic failure due to the reemergence of SI strains from reservoirs.

Multicentric assessment of the efficacy and tolerability of dihydroartemisinin-piperaquine compared to artemether-lumefantrine in the treatment of uncomplicated Plasmodium falciparum malaria in sub-Saharan Africa

BackgroundThe choice of appropriate artemisinin-based combination therapy depends on several factors (cost, efficacy, safety, reinfection rate and simplicity of administration). To assess whether the combination dihydroartemisinin-piperaquine (DP) could be an alternative to artemether-lumefantrine (AL), the efficacy and the tolerability of the two products for the treatment of uncomplicated falciparum malaria in sub-Saharan Africa have been compared.MethodsA multicentric open randomized controlled clinical trial of three-day treatment of DP against AL for the treatment of two parallel groups of patients aged two years and above and suffering from uncomplicated falciparum malaria was carried out in Cameroon, Côte d'Ivoire and Senegal. Within each group, patients were randomly assigned supervised treatment. DP was given once a day for three days and AL twice a day for three days. Follow-up visits were performed on day 1 to 4 and on day 7, 14, 21, 28 to evaluate clinical and parasitological results. The primary endpoint was the recovery rate by day 28.ResultsOf 384 patients enrolled, 197 were assigned DP and 187 AL. The recovery rates adjusted by genotyping, 99.5% in the DP group and 98.9% in the AL group, were not statistically different (p = 0.538). No Early Therapeutic Failure (ETF) was observed. At day 28, two patients in the DP group and five in AL group had recurrent parasitaemia with Plasmodium falciparum. In the DP group, after PCR genotyping, one of the two recurrences was classified as a new infection and the other as recrudescence. In AL group, two recurrences were classified after correction by PCR as recrudescence. All cases of recrudescence were classified as Late Parasitological Failure (LPF). In each group, a rapid recovery from fever and parasitaemia was noticed. More than 90% of patients did no longer present fever or parasitaemia 48 hours after treatment. Both drugs were well tolerated. Indeed, no serious adverse events were reported during the follow-up period. Most of the adverse events which developed were moderate and did not result in the treatment being stopped in either treatment group.ConclusionsDihydroartemisinin-piperaquine was as effective and well-tolerated as artemether-lumefantrine in the treatment of uncomplicated falciparum malaria. In addition, dihydroartemisinin-piperaquine, a single daily dose, could be an advantage over artemether-lumefantrine in Africa because of better treatment observance.

Efficacité de l’artéméther dans le traitement du paludisme simple à Plasmodium falciparum chez l’enfant de 6 à 60 mois à Bangui (Centrafrique)

Transmission of malaria in the Central African Republic is holoendemic. The disease accounts for 40% of medical consultations and is the leading cause of morbidity and mortality. Central African Republic is classified by WHO in zone C for resistance to traditional anti-malaria drugs such as chloroquine, sulfadoxine-pyrimethamine, and amodiaquine. In this setting, our study sought to evaluate the therapeutic effectiveness and the feasibility (acceptability) of artemether in the treatment of uncomplicated malaria in young children in Bangui. This non-comparative, cross-sectional, open study included children aged from 6 months to 5 years of age treated for uncomplicated malaria at the Urban Health Center (CSU) of Bédé-Combatant from May through November 2005. All children had a specific Plasmodium falciparum infection and both parasitemia ranging from 2,000 to 100,000 parasites/microL in uncomplicated malaria and an axillary temperature of 37.5 degrees C or higher but lower than 39.5 degrees C. Epi info software, version 6.03, was used for the data analysis. The study included 53 children, only 49 of whom could be analysed. An adequate clinical and parasitological response (ACPR) was obtained for 47 (96%), early therapeutic failure was detected for 1 patient (on D2), and late parasitological failure on D14 for another. On the whole, only 4% could be qualified as early or late treatment failure. Tolerance was excellent. Artemether was well tolerated. This agent is an effective and safe alternative for the treatment of uncomplicated P. falciparum malaria in children in the Central African Republic.

TVT-Obturator: Short-Term Data on an Operative Procedure for the Cure of Female Stress Urinary Incontinence Performed on 300 Patients

ObjectivesTo evaluate the short-term therapeutic results of a novel minimally invasive anti-incontinence operative procedure—the tension-free vaginal tape (TVT)-obturator. MethodsWith this prospective, observational, and consecutive patient series, TVT-obturator surgery was performed, according to de Leval (2003), by the same surgeon on 300 patients with urodynamically proven stress urinary incontinence. Follow-up lasted 4–24 mo. ResultsThe demographic and therapeutic aspects of the patient group data were evaluated. The TVT-obturator required neither bladder catheterization nor intraoperative diagnostic cystoscopy. Half of the 18 (6%) patients with postoperative voiding difficulties had postoperative urethral bladder catheterization for 1–4 d, whereas the other 9 patients underwent a tape loosening procedure in theater under anesthesia. The early therapeutic failure rate for the TVT-obturator procedure was 2.7% (8 patients). Six of the latter patients underwent an interval TVT operation with satisfactory results. Neither bowel nor urethral injuries were recorded, and no evidence of bladder penetration was observed. With the TVT-obturator, no intraoperative bleedings, postoperative field infections, or postoperative pelvic floor relaxations were noted. ConclusionsUse of the TVT-obturator, a novel midurethral sling, seems to reduce the incidence of some of the operative complications associated with the TVT, primarily bladder penetration and postoperative outlet obstruction. The early therapeutic results and the cost-effectiveness of the novel TVT-obturator appear similar to those reported for common TVT surgery. However, long-term comparative data collection will be required to enable drawing solid conclusions regarding the appropriate position of this operative technique within the spectrum of anti-incontinence operations.

TVT and TVT-Obturator: Comparison of two operative procedures

AimTo compare two anti-incontinence operations: the tension-free vaginal tape (TVT) and the TVT-Obturator for the first two 75-patient groups. MethodsOne surgeon operated on two patient groups with urodynamically proven urinary stress incontinence. The first 75-patient group in 1998 included the first TVT procedures performed according to Ulmsten [Ulmsten U, Henriksson L, Johnson P, Varhos G. An ambulatory surgical procedure under local anesthesia for treatment of female urinary incontinence. Int Urogynecol J 1996;7:81–6]. Follow-up lasted for 5–6 years. The second 75-patient group in 2004 included the first TVT-Obturator operations performed according to [De Leval J. Novel surgical technique for the treatment of female stress urinary incontinence: transobturator vaginal tape inside-out. Eur. Urol. 2003;44:724–30]. Follow-up lasted for 6–13 months. ResultsThe two patient groups were similar from the demographic and therapeutic points of view. The TVT-Obturator procedure required neither bladder catheterization nor intra-operative diagnostic cystoscopy. TVT-related bladder penetration (8.0%), post-operative voiding difficulties (5.0%), intra-operative bleeding (4.0%), post-operative field infection (2.7%), and post-operative pelvic floor relaxation (1.3%) were not noted with the TVT-Obturator. The early therapeutic failure rates were 2.7% for the TVT and 1.3% for the TVT-Obturator, and neither bowel nor urethral injuries were recorded. ConclusionsThe surgeons’ learning curves of these two minimally invasive surgical procedures for the treatment of female urinary stress incontinence are comparable. The safety and cost-effectiveness of the TVT are well-established. The TVT-Obturator, a novel mid-urethral sling, was designed to overcome some of the TVT-related operative complications. The TVT-Obturator patients seem to have less intra-operative and post-operative surgical complications than the TVT patients. However, long-term comparative data collection is required prior to drawing solid conclusions concerning the superiority of one of these two operative techniques.

Dihydrofolate reductase mutations in Plasmodium vivax from Indonesia and therapeutic response to sulfadoxine plus pyrimethamine.

The target enzyme of pyrimethamine is dihydrofolate reductase (DHFR), but little is known about allelic variants of dhfr in Plasmodium vivax populations. Still less is known about associations between specific alleles and the failure of sulfadoxine/pyrimethamine (S/P) to clear the erythrocytic stages of P. vivax in vivo. We studied P. vivax dhfr mutations in 24 patients who received S/P therapy in Papua or Central Java, Indonesia, and we measured the resistance of the alleles in vitro in a dhfr yeast expression assay. Fourteen (58%) of 24 patients had an inadequate therapeutic response. Two of 6 alleles that were identified were novel. One allele that expressed 4 point mutations (57L+58R+61M+117T) correlated with a high risk of therapeutic failure. The 9 patients infected by P. vivax carrying this allele proved 23 times more likely to experience early therapeutic failure, compared with patients infected by P. vivax carrying other alleles (P=.003; 95% confidence interval, 2-450). This allele also conferred high levels of pyrimethamine resistance in vitro. The experimental antifolate WR99210 inhibited the allele in this system. The present study identified a strong correlation between specific mutations in P. vivax dhfr and S/P treatment failure. Our results suggest that WR99210 could provide effective therapy for S/P-resistant P. vivax.