[Profile of Kaposi sarcoma patients in the competence network HIV/AIDS]. / Profil der Kaposi-Sarkom-Patienten im Kompetenznetz HIV/AIDS.

BACKGROUND: Kaposi's sarcoma (KS) represents the most common AIDS-defining neoplasm. Only very few studies regarding the course and treatment of human immunodeficiency virus (HIV)-associated KS have been carried out in Germany. OBJECTIVE: In this study the course of HIV-associated KS was observed in patients from the cohort database of the competence network for HIV/AIDS. MATERIAL AND METHODS: Data from HIV-associated KS patients from 9 German core centers from 1987 to 2011 were retrospectively collected. Kaplan-Meier curves for the recurrence and survival probability were calculated. RESULTS: In 222 patients KS was diagnosed at a median age of 38.5 ± 10.1 years. Men were almost exclusively affected (97.7%). The HIV viral load at the time of diagnosis was in 7.4% <50 copies/ml. Of the patients 55.5% developed KS with a CD4 cell count of <200 cells/µl and 9.5% with >500 cells/µl. In 68 patients KS therapy consisted exclusively of the optimization or initiation of antiretroviral therapy (ART). In addition, 71 patients were treated with pegylated liposomal doxorubicin. During the median follow-up period of 8.9 ± 4.9 years, 80.2% of the patients were free of KS recurrence. Survival rates after 5 and 10 years were 96.8% and 91.3%, respectively. CONCLUSION: Even with a good immune status HIV-associated KS occurred. An effective ART was the most important mainstay of therapy. With appropriate therapy, HIV-positive patients with KS showed a good survival rate.

The male ScreenING Study: prevalence of HPV-related genital and anal lesions in an urban cohort of HIV-positive men in Germany.

BACKGROUND: Human papillomaviruses (HPV) induce condylomata, anogenital cancers and their precursor lesions as anal or penile intraepithelial neoplasia (AIN/PIN). HIV-positive individuals have an increased risk for the development of anogenital HPV-induced lesions. OBJECTIVE: Estimation of the prevalence of HPV-related anogenital benign and malignant lesions in HIV-infected men attending a screening programme. METHODS: Four hundred HIV-positive men [98% men who have sex with men (MSM)] were enrolled in this prospective study from 2008 to 2011. All patients received an inspection of the anogenital region, digital rectal examination, high-resolution anoscopy (HRA), anal cytology, anal/penile histology if required, and HPV-typing of anal and penile swabs. RESULTS: At baseline, 75% (n = 302) of the men had abnormal anal cytological/histological results. 41% presented with low-grade (n = 164), 24% with high-grade anal dysplasia (n = 95) and two men with invasive anal cancer. 2.3% had PIN (n = 9) and one patient had penile cancer at baseline. Throughout the study period, 75% had anal dysplasia (low-grade n = 177, high-grade n = 125), 3.3% (n = 13) had PIN and two further patients developed anal cancer. Within the study period, 52.8% (n = 211) had condylomata (49% anal, 15% penile, 11% anal plus penile condylomata). At baseline, 88.5% of anal and 39.3% of penile swabs were HPV-DNA positive, and 77.8% of anal and 26.5% of penile swabs carried high-risk HPV-types. HPV16 was the most frequent HPV-type. CONCLUSION: HIV-positive MSM have a high risk for HPV-induced condylomata, (pre)malignant anogenital lesions and anogenital cancers. Screening for HPV-induced dysplasia is crucial to avoid progression to invasive carcinomas. Additionally, HPV-vaccination recommendations should be extended to high-risk populations.

Contribution of APOBEC3G/F activity to the development of low-abundance drug-resistant human immunodeficiency virus type 1 variants.

Plasma drug-resistant minority human immunodeficiency virus type 1 variants (DRMVs) increase the risk of virological failure to first-line non-nucleoside reverse transcriptase inhibitor antiretroviral therapy (ART). The origin of DRMVs in ART-naive patients, however, remains unclear. In a large pan-European case-control study investigating the clinical relevance of pre-existing DRMVs using 454 pyrosequencing, the six most prevalent plasma DRMVs detected corresponded to G-to-A nucleotide mutations (V90I, V106I, V108I, E138K, M184I and M230I). Here, we evaluated if such DRMVs could have emerged from apolipoprotein B mRNA editing enzyme, catalytic polypeptide 3G/F (APOBEC3G/F) activity. Out of 236 ART-naive subjects evaluated, APOBEC3G/F hypermutation signatures were detected in plasma viruses of 14 (5.9%) individuals. Samples with minority E138K, M184I, and M230I mutations, but not those with V90I, V106I or V108I, were significantly associated with APOBEC3G/F activity (Fisher's P < 0.005), defined as the presence of > 0.5% of sample sequences with an APOBEC3G/F signature. Mutations E138K, M184I and M230I co-occurred in the same sequence as APOBEC3G/F signatures in 3/9 (33%), 5/11 (45%) and 4/8 (50%) of samples, respectively; such linkage was not found for V90I, V106I or V108I. In-frame STOP codons were observed in 1.5% of all clonal sequences; 14.8% of them co-occurred with APOBEC3G/F signatures. APOBEC3G/F-associated E138K, M184I and M230I appeared within clonal sequences containing in-frame STOP codons in 2/3 (66%), 5/5 (100%) and 4/4 (100%) of the samples. In a re-analysis of the parent case control study, the presence of APOBEC3G/F signatures was not associated with virological failure. In conclusion, the contribution of APOBEC3G/F editing to the development of DRMVs is very limited and does not affect the efficacy of non-nucleoside reverse transcriptase inhibitor ART.

An analysis of the impact of previous laparoscopic hysterectomy experience on the learning curve for robotic hysterectomy.

To analyze and compare the safety and perioperative outcomes of newly trained robotic surgeons with previous laparoscopic hysterectomy experience (TLH Exp) and those without previous laparoscopic hysterectomy experience (Non-TLH Exp). The purpose is to determine the effect of previous advanced laparoscopic skills on the performance in robotic assisted laparoscopic surgery. We will also compare the perioperative outcomes between the total laparoscopic hysterectomies (TLH), and robotic assisted laparoscopic hysterectomies (RALH) of a single experienced (TLH Exp) robotic surgeon. The purpose is to determine benefits and/or risks, if any, of one approach over the other in the hands of an experienced laparoscopic surgeon. Prospective data were collected on the first consecutive series of RALH performed by (TLH Exp) and (Non-TLH Exp) surgeons, with perioperative outcomes and morbidity being evaluated. In addition, retrsopective data were collected on a consecutive series of patients in a TLH group and compared with the outcomes in the robotic group for benign hysterectomies by the same surgeon. The parameters that were analyzed for associations with these two groups were estimated blood loss (EBL), Hb drop, length of hospital stay (LOS), procedure time, pain medication use, and complications. The (TLH Exp) group had 64 patients, and the (Non-TLH Exp) group had 72 patients. When comparing patients in the (TLH Exp) group with patients in (Non-TLH Exp) group, the mean age was 44 and 45 (P = 0.8), mean BMI was 27.7 and 29.5 kg/m(2) (P = 0.2), mean procedure time was 121 and 174 min (P < 0.05), mean console time was 70 and 119 min (P < 0.05), mean EBL was 64 and 84 ml (P = 0.3), with a Hb drop 1.7 and 1.33 (P = 0.2), uterine weight was 192 and 205 gms (P = 0.7), and length of stay was 1.07 and 1.33 days (P = 0.2), respectively. The (TLH Exp) surgeons had a lower OR, procedure and console time, but a higher hemoglobin drop, with no difference in EBL. There were no operative deaths, or conversions in either group. Morbidity occurred in two patients (3 %) in each group, with no statistically significant difference between the groups. In the (TLH Exp) group it included a blood transfusion and a readmission for a postoperative ileus. In the (Non-TLH Exp), the complications included a blood transfusion and a return to the OR for a vaginal cuff dehiscence. When comparing a single (TLH Exp) surgeon's own TLH versus RALH, there were 64 RALH and 49 TLH cases. There was a statistically significant difference in the mean procedure time 121.1 versus 88.8 min (P < 0.05), mean Hb drop 1.7 versus 2.3 (P < 0.05), and mean EBL 64.2 versus 158 ml (P < 0.05), respectively. The RALH group had a longer procedure time, but lower Hb drop, and less estimated blood loss. There were no operative deaths, or conversions in either group. Morbidity occurred in 2 patients in the robotic group, and included one blood transfusion, and one postoperative ileus. There were no complications noted in the laparoscopic hysterectomy group. Previous advanced laparoscopic skills appear to only significantly impact the length of the procedure, but not other variables. Robotic surgery may level the playing field between the basic and advanced laparoscopic surgeon for robotic assisted laparoscopic hysterectomy. In comparing the outcomes of RALH versus TLH by a single surgeon, the robotic assistance appeared to lengthen the procedure time, but reduce the amount of blood loss. Robotic surgery may offer a benefit of reduced blood loss at the expense of longer operating time. Similar studies including different surgeons are needed to validate these points, and thereby determine the risk-benefit balance between the two approaches for benign simple hysterectomies.

Impact of earlier HAART initiation on the immune status and clinical course of treated patients on the basis of cohort data of the German Competence Network for HIV/AIDS.

PURPOSE: Hitherto, studies on highly active antiretroviral therapy (HAART) initiation have shown partly inconsistent results. Our study investigated the clinical course and course of immune status after HAART initiation at CD4-cell-count/µl of treated patients between 250 and 349 (group 1), compared to 350-449 (group 2), on the basis of the cohort of the Competence Network for HIV/AIDS (KompNet cohort). METHODS: Patients had to be HAART-naïve. Medication had to start at the earliest in 1996, being at least triple combination therapy. The primary endpoints of death, first AIDS-defining illness and first drop of CD4-cell-count/µl below 200 were evaluated as censored event times between the initiation of HAART (t (0)) and the date of the first event/date of last observation. Probabilities of event-free intervals since t (0) were calculated by Kaplan-Meier estimation, compared by logrank tests. The results were adjusted for confounders using Cox regression. Additionally, incidences were estimated. RESULTS: A total of 822 patients met the inclusion criteria (group 1: 526, group 2: 296), covering 4,133 patient years (py) overall. In group 1, 0.64 death cases/100 py were found, with the corresponding vale being 0.17 in group 2. In group 1, 1.38 AIDS-defining events/100 py occurred, whereas it was 0.78 in group 2. In group 1, 2.64 events of first drop of CD4-cell-count/µl below 200 occurred per 100 py, compared to 0.77 in group 2. Kaplan-Meier estimations showed borderline significant differences regarding death (p = 0.063), no differences regarding first AIDS-defining illness (p = 0.148) and distinct differences regarding the first drop of CD4-cell-count/µl below 200 (p = 0.0004). CONCLUSIONS: The results gave a strong hint for a therapy initiation at higher CD4-cell-count/µl regarding the outcome of death in treated patients. A distinct benefit was shown regarding the first decline of CD4-cell-count/µl below 200.

Mechanistic model for prediction of formate dehydrogenase kinetics under industrially relevant conditions.

Formate dehydrogenase (FDH) from Candida boidinii is an important biocatalyst for the regeneration of the cofactor NADH in industrial enzyme-catalyzed reductions. The mathematical model that is currently applied to predict progress curves during (semi-)batch reactions has been derived from initial rate studies. Here, it is demonstrated that such extrapolation from initial reaction rates to performance during a complete batch leads to considerable prediction errors. This observation can be attributed to an invalid simplification during the development of the literature model. A novel mechanistic model that describes the course and performance of FDH-catalyzed NADH regeneration under industrially relevant process conditions is introduced and evaluated. Based on progress curve instead of initial reaction rate measurements, it was discriminated from a comprehensive set of mechanistic model candidates. For the prediction of reaction courses on long time horizons (>1 h), decomposition of NADH has to be considered. The model accurately describes the regeneration reaction under all conditions, even at high concentrations of the substrate formate and thus is clearly superior to the existing model. As a result, for the first time, course and performance of NADH regeneration in industrial enzyme-catalyzed reductions can be accurately predicted and used to optimize the cost efficiency of the respective processes.

Epidemiological composition, clinical and treatment characteristics of the patient cohort of the German Competence Network for HIV/AIDS.

OBJECTIVE: As its central basis for research, the Competence Network for HIV/AIDS (KompNet) established a nationwide cohort study on HIV-positive patients being in medical care in Germany. In this paper, we describe the epidemiological composition, and clinical as well as treatment characteristics of the KompNet cohort over time. METHODS: The KompNet cohort is an open, retrospective and prospective, multi-center, disease-specific and nationwide cohort study that started gathering data in June 2004. Semiannually, follow up visits of the patients are documented, covering a wide range of clinical and sociodemographic data. At enrollment and three years afterwards, an EDTA-sample is taken; a serum-sample is taken at every follow up. RESULTS: As of 20.10.2008, a total of 15,541 patients were enrolled by 44 documenting sites. In September 2007, the cohort size was reduced to ten outpatient clinics and fifteen private practitioners, covering a total of 9,410 patients. The documentation of these patients comprised 24,117 years of follow up-time since enrollment (mean: 2.6 years), 62,862 person years inclusive data documented retrospectively on course of HIV-infection and antiretroviral therapy (ART, mean: 6.7 years). Due to the short period of recruitment till now, rates of death (0.3%-0.8%) and losses to follow up (1.1%-5.5%) were low. 84.9% of patients were men. Main risk of transmission was sex between men (MSM: 62.9%). Mean age was 45 years. About two third of patients were classified as CDC-stage B or C. Therapy regimens of currently treated patients complied with recent guidelines. Trends of mean CD4 cell count/microl regarding the initial therapy and concerning the population under treatment reflected the developments and the changing standards of antiretroviral therapy over time. CONCLUSION: The KompNet cohort covers about a quarter of all patients estimated as being under treatment in Germany. Its composition can be accounted approximately representative for the situation of clinical care and treatment in the scope of HIV/AIDS in Germany. Therefore, it is an important instrument for measuring the course of HIV/AIDS, the reality of use of antiretroviral therapy and its clinical and psychosocial outcomes in Germany.

The Patient Cohort of the German Competence Network for HIV/AIDS (KompNet): a profile.

OBJECTIVE: In this paper, we describe the main objectives, the study design and the onset of the patient cohort of the German Competence Network for HIV/AIDS (KompNet) (www.kompetenznetz-hiv.de). Furthermore, we depict sociodemographic and clinical baseline characteristics and an estimation of the coverage and representativity as to the composition of persons living with HIV/AIDS (PLWHA) in Germany. METHODS: The KompNet cohort is an open, retrospective and prospective, multicenter, disease-specific and nationwide cohort study that started gathering data in June 2004. Semi-annually, follow up visits of the patients are documented, covering clinical and sociodemographic data. At enrolment and three years afterwards, an EDTA-sample is taken; a serum-sample is taken at every follow up visit. RESULTS: As of 14.9.2008, a total of 15,541 patients were enrolled by 44 documenting sites. In September 2007, the cohort size was reduced to 10 outpatient clinics and fifteen private practitioners, covering a total of 9,410 patients. The documentation of these patients comprises 24,117 years of follow up-time since enrolment (mean: 2.6 years), 62,862 person years inclusive data documented retrospectively on course of HIV-infection and combined antiretroviral therapy (cART, mean: 6.7 years). 1,008 patients (10.7%) were lost to follow up and 175 (1.9%) died since enrolment. 84.9% of patients were men. Main risks of transmission were sex between men (MSM: 62.9%), heterosexual contacts (18.4%), intravenous drug use (IVDU: 7.0%) and origin from a high prevalence country (HPL: 5.2%). Mean age was 45 years. CONCLUSION: The KompNet cohort covers about a quarter of all patients being under treatment in Germany. The composition of the cohort represents well the most important risks of transmission in Germany. The cohort contains a high proportion of patients being older than 49 years (28.1%). On basis of its comprehensive database and its biomaterials banks, the KompNet cohort serves as an important instrument to monitor and analyse the effects of combined antiretroviral therapy (cART) in Germany, interdigidating basis, clinical and psychosocial research in view to translational research.