Primary resistance to integrase strand-transfer inhibitors in Europe.

OBJECTIVES: The objective of this study was to define the natural genotypic variation of the HIV-1 integrase gene across Europe for epidemiological surveillance of integrase strand-transfer inhibitor (InSTI) resistance. METHODS: This was a multicentre, cross-sectional study within the European SPREAD HIV resistance surveillance programme. A representative set of 300 samples was selected from 1950 naive HIV-positive subjects newly diagnosed in 2006-07. The prevalence of InSTI resistance was evaluated using quality-controlled baseline population sequencing of integrase. Signature raltegravir, elvitegravir and dolutegravir resistance mutations were defined according to the IAS-USA 2014 list. In addition, all integrase substitutions relative to HXB2 were identified, including those with a Stanford HIVdb score ≥ 10 to at least one InSTI. To rule out circulation of minority InSTI-resistant HIV, 65 samples were selected for 454 integrase sequencing. RESULTS: For the population sequencing analysis, 278 samples were retrieved and successfully analysed. No signature resistance mutations to any of the InSTIs were detected. Eleven (4%) subjects had mutations at resistance-associated positions with an HIVdb score ≥ 10. Of the 56 samples successfully analysed with 454 sequencing, no InSTI signature mutations were detected, whereas integrase substitutions with an HIVdb score ≥ 10 were found in 8 (14.3%) individuals. CONCLUSIONS: No signature InSTI-resistant variants were circulating in Europe before the introduction of InSTIs. However, polymorphisms contributing to InSTI resistance were not rare. As InSTI use becomes more widespread, continuous surveillance of primary InSTI resistance is warranted. These data will be key to modelling the kinetics of InSTI resistance transmission in Europe in the coming years.

Antiretroviral activity of two polyisoprenylated acylphloroglucinols, 7-epi-nemorosone and plukenetione A, isolated from Caribbean propolis.

OBJECTIVES: Polyisoprenylated acylphloroglucinols have recently emerged as antitumoral agents. This study aims at elucidating the antiretroviral activity of two such compounds which were isolated from Caribbean propolis: 7-epi-nemorosone and plukenetione A, the structure of which is based on an adamantane moiety. Plukenetione A is for the first time shown to have antiretroviral activity. MATERIAL AND METHODS: The isolation of both small molecules was carried out using RP-HPLC. Their antiretroviral activity was studied based on lentiviral particles produced in HEK293T cells from the SIV-based vector VLDBH; their cytotoxicity was monitored by MTT proliferation assay. The antiviral activity of 7-epi-nemorosone was studied in CEMx174-SEAP infected with the HIV-1-strain pNL4.3wt. Reverse transcriptase inhibition was determined by a standard two-step RT-PCR using MMLV RT. RESULTS: 7-epi-nemorosone and plukenetione A were found to be potent antilentiviral agents in the employed system, inhibiting viral infection at concentrations below 1 µM/2 µM, respectively. Whereas 7-epi-nemorosone was not able to inhibit the reverse transcriptase in vitro (IC50 > 25 µM), plukenetione A effectively inhibited its enzymatic activity at an IC50 of 1.75 µM. CONCLUSIONS: Despite 7-epi-nemorosone and plukenetione A sharing some structural core elements, the mechanism of action involved in their antiretroviral activity seems to be different. We propose that 7-epi-nemorosone inhibits the viral replication by interrupting the Akt/PKB signaling cascade, as was demonstrated previously in various cell lines. Since plukenetione A effectively inhibits the enzymatic activity of MMLV reverse transcriptase at concentrations that show antilentiviral activity, we suggest that this small molecule acts by interfering with the enzyme's catalytic site.

Impact of transmission of drug-resistant HIV on the course of infection and the treatment success. Data from the German HIV-1 Seroconverter Study.

BACKGROUND: Data on the clinical course of infection in patients with transmitted drug-resistant HIV before and after initiation of treatment are scarce. PATIENTS AND METHODS: Genotypic resistance was analysed in 504 therapy-naïve individuals with a known date of infection. Resistance was predicted using the Stanford algorithm. Clinical parameters for 80 individuals with transmitted drug-resistant HIV and for 424 patients with susceptible virus were analysed. RESULTS: In 16% of the individuals transmitted drug-resistant HIV was found. Detection of drug-resistant HIV was more likely in individuals with acute primary HIV infection [odds ratio (OR)=1.529; 95% confidence interval (95% CI) 1.001; 2.236]. At the time of infection patients with an acute infection with resistant HIV had lower viral loads. CD4 cell counts tended to be higher and the CD4 cell loss more pronounced in the group with resistant HIV. Suppression of the viral load below the detection limit was achieved in 64% of the group with resistant HIV and in 85% of the group with susceptible HIV 6 months after initiation of therapy (P=0.199). The majority of the group with resistant HIV (74%) received at least one compromised drug. CONCLUSION: First-line treatment including drugs with predicted resistance can impair virological success in some patients. Factors influencing the decision to include compromised drugs need to be investigated.

[Late septic complications of internal fixations (author's transl)]. / Osteosynthesisek késöi, lappangó fertözéses szovodményei.

The review of the authors' 5 year material (from 1971 to 1975) showed 5 late latent septic complications. The average time in which septic signs became evident, was 7.7 months in their cases. Attention is drawn to certain inadequacies during operations, which may have a role in the aetiology of these infections, and to the importance of the correct assessment of the follow-up X-rays.

[Analysis of femoral shaft fractures (author's transl)]. / A combcsont diaphysis töréseinek elemzése.

Authors after having reviewed the literature analyse 157 healed cases from their own material of 198 femoral shaft fractures. Fractures between the subtrochanteric and supracondylar region has been considered. 2/3 part of the injured have been victims of traffic accidents, 1/6 part suffering severe polytraumatisation. From among the healed patients in 88 per cent an operation was carried out 76.8 per cent of which were medullary nailing following a broadened indication. In their patients treated surgically the fractures healed within 6 months in 75.4 per cent of cases. It is concluded that in the treatment of femoral shaft fractures the usual operative measures yield fast healing with good function. For multiple or comminuted fractures the use of other newer methods seems inevitable.

[Infectious complications of 227 open fractures of the leg]. / 557 nyílt lábszártörés fertözéses szövödményei

Out of 557 open fractures of the leg we have analysed 472 cases in respect of recovery. We tried to discrive the relationship between the infection and the severity of the lesion and the methods of treatment resp. We have analysed also the further course of the infect.on. In our material considerable risk of the infections in the case of open leg fractures was found, since the incidence of all infections corresponded--in accordance with the data of the literature--to 16,7% of the appreciable cases. Significant relationship between the occurrence of infections and the severity of the lesion was found. In the material analysed according to the ACD code the incidence of infections is in the severely injured patients three times as much as in the case of slight or moderately severe groups. The occurrence of posttraumatic osteitis corresponds to 9,11%--this latter is similarly in relation with the severity of the lesion. The infection leads to the protraction of the osseous union,--however, no convincing data were found in the authors' material in respect of the relationship between the infection and the methods of treatment. The course and the proportion of healing of the infected cases correspond to the mean values reported in the literature. On the basis of their great material it is stated by the authors that only in the case of lesions with identical or at the least similar severity comparison of the results of recovery or of the complications is possible and suitable.