Concurrent treatment of HIV, disseminated Mycobacterium avium complex and HCV-infection.

Patients with HIV-infection diagnosed at late stages usually have significant immunosuppression and demand simultaneous antiretroviral therapy and treatment of opportunistic infections. The presence of HCV coinfection makes treatment even more challenging because of possible adverse effects and drug-drug interactions. HCV cure in such clinical situations not only prevents fibrosis progression, but can also enhance virologic and/or immunologic response to antiretrovirals and thus effective treatment of opportunistic infections. Thorough consideration of all existing diseases and drug interactions of the combined therapy makes simultaneous treatment of HIV, chronic hepatitis C, and opportunistic infections not only possible but the best way to improve outcomes in a complex clinical situation.

NMR study of dyadic and triadic splitting in copoly(arylene)phthalides based on diphenyl oxide and diphenyl sulfide.

All 13 C NMR signals of the poly(arylene) polymers, O-1, S-7, OS-4, OOS-3, OOOS-2, SSO-5, and SSSO-6 (where O is a diphenyleneoxiphthalide unit and S is a diphenylenethiophthalide unit) in dyads and triads were assigned unequivocally with two-dimensional NMR techniques (ge-2D [1 H-1 H] COSY, ge-2D [1 H-13 C] HSQC, and ge-2D [1 H-13 C] HMBC), and for each atom, the increments of the shifts are determined. For structurally similar carbon atoms of the phthalide cycle and heteroaromatic fragments of the skeletal chain, additive signal splitting schemes in phthalide centered dyads and in diphenylene oxide and in diphenylene sulfide centered triads are considered, based on taking into account the contributions to their shielding of adjacent and distant substituents. It was shown that the nature of the splitting of the signals of each of the 20 carbon atoms in 3,3-bisphenylphthalide fragments is determined by the type of carbon atom (tertiary or quaternary, even or odd), the type of heteroatoms in adjacent heteroaromatic fragments, their distance from the identified carbon nucleus, and their polyad symmetry. The results obtained in this article will greatly facilitate our further studies and, in particular, will allow us to study the microstructure of statistical copolymers based on the asymmetric OS monomer at the dyad and triad levels.

Genetic structure of a regionally endangered orchid, the dark red helleborine (Epipactis atrorubens) at the edge of its distribution.

The genetic structure and diversity of species is determined by both current population dynamics and historical processes. Population genetic structure at the edge of the distribution is often expected to differ substantially from populations at the centre, as these edge populations are often small and fragmented. In addition, populations located in regions that have experienced repeated glaciations throughout the Pleistocene, may still carry imprints from the genetic consequences of frequent distribution shifts. Using chloroplast DNA sequences and nuclear microsatellite markers we studied the genetic structure of Epipactis atrorubens at the northern edge of its distribution. Contrary to populations in the centre of the distribution, populations at the northern range are regionally endangered as they are small and disjunct. Sequence data of 2 chloroplast loci and allelic data from 6 nuclear microsatellite markers were obtained from 297 samples from Finland, Estonia and Russia. We sought for genetic indicators of past population processes, such as post-glacial colonisation history of E. atrorubens. As expected, we observed low genetic variation, in terms of numbers of substitutions, haplotypes and alleles, and significant levels of differentiation, especially pronounced in the chloroplast DNA. These features suggest that the edge populations could be prone to extinction.

Clinical significance of the UGT1A1*28 allele detection in HIV-infected patients.

INTRODUCTION: The UGT1A1*28 (rs8175347) polymorphism is associated with hyperbilirubinemia. The presence of 6 TA-repeats in the UGT1A1 gene promoter region corresponds to normal UGT1TA1 activity. A detection of 7 TA-repeats in hetero- or homozygous individuals [(TA)6/(TA)7 and (TA)7/(TA)7] is associated with lower UGT1TA1 activity, which may eventually result in the development of Gilbert syndrome and/or modified individual response to drugs metabolized by this enzyme. ATV contributes to the decreased levels of UGT1A1, which may lead to elevations of indirect bilirubin, jaundice and even to therapy discontinuation. We evaluated the prevalence of the UGT1A1*28 among HIV-infected patients and the dependence of the frequency and severity of AE during ATV treatment on individual genetic characteristics. MATERIALS AND METHODS: 47 HIV-infected patients was screen for UGT1A1 genotype and the presence of UGT1A1*28. All patients received ATV in the HAART regimen for 48 weeks. Changes in the total, direct and indirect bilirubin, ALT, AST, GGT and jaundice were evaluated. Statistical analysis was performed using Microsoft Office Excel for Windows XP Professional 2007 and Biostat. RESULTS: All patients were followed up in the AIDS Center (males 72.3%, median age 33 years, median CD4+ count-282 cells/µl (19.5%)). HBV/HCV was in 36.2% patients. Ten patients had risk factors that could affect bilirubin turnover (chronic cholecystitis, biliary dyskinesia, etc.). Genotype (TA)6/(TA)6 was found in 42.6% patients, (TA)6/(TA)7-42.6% and (TA)7/(TA)7-14.9%. Overall prevalence of UGT1A1*28 was 57.4%, and homozygous allele frequency was 14.9%. G3/4 of indirect bilirubin were detected in 36.2% patients [(TA)6/(TA)6 in 10-20%, (TA)6/(TA)7-25-40%, (TA)7/(TA)7-72-86%], and significant jaundice in 10.6% [80% with (TA)7/(TA)7]. The OR for hyperbilirubinemia>40 µmol/L in patients with heterozygous UGT1A1*28 was increased 3 times over patients without this allele (OR 3.07, 95% CI 1.54-4.6) and 34 times as compared with homozygotes (OR 33.9, 95% CI 31.45-36.35). The presence of additional risk factors increased the probability of G3/4 hyperbilirubinemia. No significant changes in the ALT, AST, and GGT levels were observed. CONCLUSIONS: The risk of severe hyperbilirubinemia during ATV treatment is minimal for patients without UGT1A1*28 and no more than one additional risk factor and for patients with UGT1A1*28 and no additional risk factors; patients with homozygous genotype UGT1A1*28 are at the highest risk.

Effect of HIV infection-related factors on SVR rate in HCV treatment in HIV-infected patients.

INTRODUCTION: Factors that have an effect on the rate of sustained virological response (SVR) in chronic hepatitis C (CHC) patients include: genotype of hepatitis C virus (HCV); level of HCV RNA replication and rate of its reduction in the course of treatment; original hepatic fibrosis level; genotype of Interleukin-28B (especially for Genotype 1 HCV - G1); daily ribavirin (RBV) dose. This study evaluated the effect of the HIV infection-related factors on the SVR rate in HCV treatment in patients with concurrent infection (HIV/HCV). METHODS: The follow-up included 232 HIV/HCV-infected patients. Ninety-nine of 232 patients with HIV/HCV-infection received antiretroviral therapy (ART) for at least three months before the initiation of the CHC treatment. Before the HCV therapy, the median of CD4+cells was 406/mm(3) (with ART) and 507/mm(3) (without ART). Patients received HCV treatment with pegylated interferon (PEG-IFN) and RBV (1000/12,000 mg/day) during 24-48 weeks. RESULTS: SVR was received in 50% of patients with G1 HCV, and 80.1% of patients with Genotypes 2/3 (G2/3; p<0.0001). The SVR rate in the group of patients without ART was reliably higher, 74.4% (with ART - 58.6%; p=0.0053). No significant differences in the SVR rate (62.3% and 69.6%, accordingly) were detected after the differentiation of patients based on the initial absolute values of CD4+cells count (<350 cells/mm(3) and >350 cells/mm(3)). In 127 patients with the HIV/HCV-infection, the percentage of CD4+cells before the CHC treatment was >25% and more (Group 1 [Gr. 1]), and in 105 patients ≤25% (Group 2 [Gr. 2]). The SVR rate for Gr. 1 patient was 74.6%, and for Gr. 2 patients -58.1% (p=0.0023). The SVR rate in patients with G1 HCV was 56.8% (Gr. 1) and 44.2% (Gr. 2; p=0.1095), whereas the rate for G2 and 3 was 85.5% and 71.7%, accordingly (p=0.0242). Forty patients in Gr. 1 and 59 patients in Gr. 2 received ART. The comparison of the SVR rate for these patients showed no significant differences: 60% and 57.6%, accordingly. SVR rate in the patients without ART demonstrated that for Gr.1 patients (CD4+>25%) was reliably higher, 82.8% (compared to Gr.2 with 58.7%; p=0.0012). CONCLUSIONS: Along with factors related to HCV and the patient, the SVR rate in the HCV treatment with PEG-IFN and RBV may be affected in patients with the concurrent infection by the use of ART and original relative content of CD4+cells. The maximum SVR rate was achieved in the patients without ART and with the CD4+cells >25% (baseline). When indicted, it is reasonable to provide HCV treatment to HIV-infected patients as long as the percentage of CD4+cells remains high and there is no need of ART.