Lamivudine-conjugated and efavirenz-loaded G2 dendrimers: Novel anti-retroviral nano drug delivery systems.

Infection with human immunodeficiency virus (HIV)-1 causes immunological disorders and death worldwide which needs to be further assisted by novel anti-retroviral drug delivery systems. Consequently, finding newer anti-retroviral pharmaceuticals by using biocompatible, biodegradable nanomaterials comprising a nanoparticle as core and a therapeutic agent is of high global interest. In this experiment, a second generation of a negatively charged nano-biopolymer linear globular G2 dendrimer was carefully conjugated and loaded with well-known anti-HIV drugs lamivudine and efavirenz, respectively. They were characterised by a variety of analytical methods such as Zetasizer, Fourier-transform infrared spectroscopy, elemental analysis and liquid chromatography-mass spectroscopy. Additionally, conjugated lamivudine and loaded efazirenz with globular PEGylated G2 dendrimer were tested on an HEK293 T cell infected by single-cycle replicable HIV-1 virion and evaluated using XTT test and HIV-1 P24 protein load. The results showed that lamivudine-conjugated G2 significantly decreased retroviral activity without any cell toxicity. This effect was more or less observed by efavirenz-loaded G2. These nano-constructs are strongly suggested for further in vivo anti-HIV assays.

Single-pill sofosbuvir and daclatasvir for treating hepatis C in patients co-infected with human immunodeficiency virus.

BACKGROUND: The current recommendation for treating hepatitis C virus (HCV) in HIV patients includes the combination of sofosbuvir (SOF) and daclatasvir (DCV). DCV should be used at different doses to compensate for interactions with antiretroviral therapy (ART). Up to three pills a day might be required which will significantly add to the pill burden of these patients. In this study, we have used a single-tablet approach to treating HCV-HIV coinfection. METHODS: Patients coinfected with HIV and HCV were prospectively enrolled from 10 centers throughout the country. Patients received a single once-daily fixed dose combination (FDC) pill containing 400 mg SOF and 30, 60 or 90 mg DCV depending on the type of ART they were receiving for 12 or 24 weeks. (ClinicalTrials.gov ID: NCT03369327). RESULTS: Two hundred thirty-three patients were enrolled from 10 centers. Twenty-three patients were lost to follow-up and two patients died from causes unrelated to treatment. Two hundred eight patients completed the treatment course of which 201 achieved SVR (96.6%). CONCLUSION: Single-tablet combination of DCV and SOF is an effective and safe treatment for patients coinfected with HIV and HCV. The combination works well in patients on ART in which dose adjustment is required. Patients with cirrhosis, previous treatment failure and various genotypes respond identically. The expenses of genotyping can be saved.

Novel delivery based anionic linear globular dendrimerg2-zidovudine nano-conjugate significantly decreased retroviral activity.

Human diseases like viral organisms for example, hepatitis, HIV and etc., attack the health and caused large mortality in populations by many years. So finding novel delivery vehicles based antiviral drugs employing nano-materials is of high universal interest. In current approach a very biocompatible biodegradable nano-biopolymer anionic linear globular dendrimer second generation G2 was elaborately conjugated to a well-known anti-HIV drug Azidovudine and thereafter was characterized by different analytical techniques like AFM, Zeta sizer, 1HNMR, FTIR and LC-Mass spectroscopy. Then, Anionic Linear Globular DendrimerG2-Zidovudine Nano-Conjugate was assessed on human normal cells (toxicity assay by XTT test) and also HIV cell model and the results showed that Anionic Linear Globular DendrimerG2-Zidovudine Nano-Conjugate Significantly Decreased Retroviral Activity without any human cell toxicity respectively. Based on current experimental data such nano-compositions is proposed for further in vivo anti-HIV assays as well.

Real-life efficacy of generic sofosbuvir/ledipasvir for treatment of Iranian patients with chronic hepatitis C: A cohort study.

BACKGROUND: Treatment of hepatitis C virus (HCV) infection with recently introduced direct-acting antiviral agents (DAA) is effective and safe, however there is little known regarding safety and efficacy of generic DAAs in the real-life clinical setting. This study aimed to evaluate the efficacy and safety of generic sofosbuvir/ledipasvir (SOF/LDV) in a real-life clinical experience. METHODS: In this prospective cohort study, patients with chronic HCV infection who referred to Middle East Liver Diseases (MELD) Center were included. Based on the patients' condition, they were treated with SOF/LDV fixed-dose combination with or without ribavirin (RBV) for 12 or 24 weeks. RESULTS: A total of 30 (M/F: 19/11) patients with chronic HCV genotype 1 infection with a mean age of 49.8 years were treated with generic SOF/LDV with (9 patients) or without (11 patients) RBV for 12 (27 patients) or 24 (3 patients) weeks. Ten (33.3%) had cirrhosis and 13 (43.3%) with a previous history of treatment with interferon (IFN)-based regimens. Among the 30 patients, 26 (86.7%, 95% CI=70.3%-94.7%) achieved a rapid virologic response, 30 (100%, 95% CI=88.7%-100%) achieved the end of treatment response and 30 (100%, 95% CI=88.7%-100%) achieved a sustained virologic response. No severe treatment adverse event was observed however, 6 (20%) patients experienced mild to moderate adverse events. CONCLUSION: The treatment of HCV genotype 1 infection with generic SOF/LDV found to be safe and effective even in patients with cirrhosis and previous history of treatment with IFN-based treatments.

Peg-interferon Plus Ribavirin Combination Therapy in HCV Mono-infected and HCV/HIV Co-infected Patients in Iran.

Background: Hepatitis C virus (HCV) infection is a cause of major liver complications, particularly in patients infected with human immunodeficiency virus (HIV). This study aimed to evaluate the efficacy of pegylated interferon (Peg-IFN) and a fixed dose of ribavirin treatment among Iranian HCV mono-infected and HCV/HIV-co-infected patients. Methods: A total of 214 HCV mono-infected and HCV/HIV co-infected patients attending Liver Disease Center in Tehran were assigned to receive treatment with Peg-IFN-α2a or -α2b plus ribavirin for 24-48 weeks. Sustained virologic response (SVR) was used as the primary efficacy endpoint of Peg-IFN and ribavirin therapy. Results: Treatment with Peg-IFN and ribavirin has been associated with a considerably higher rate of SVR (24 weeks for HCV genotype 3 and 48 weeks for HCV/HIV co-infected and HCV genotype 1 patients). Overall, the clearance of HCV-RNA at the end of therapy occurred in 48.6% of patients. Adverse events leading to treatment discontinuation were seen in 14% of patients. Conclusion: This retrospective study revealed a relatively well-tolerated response in both HCV mono-infected and HCV/HIV coinfected patients during treatment with Peg-IFN and ribavirin. However, the recent revolutionized interferon-free therapies for chronic HCV infection should be taken into account for achieving a greater response and minimal adverse events.

Interleukin 20 Gene Polymorphism (rs1518108) is not Associated with Sustained Virological Response in Iranian Patients with Hepatitis C Virus Infection.

METHODS: This case-control study, was performed on 136 blood samples based on 81 patients with chronic HCV genotypes 1 and 3 including 64 SVR positive and 17 negative and 55 healthy individual controls. DNA was isolated from the samples and the frequency of the polymorphism was analyzed using a PCR-RFLP method. Finally, the products were detected on 3.5% agarose gel electrophoresis. RESULTS: The analysis of the data for C/T polymorphism indicated that the CC genotype was found in 19 of 64 patients who achieved SVR, while the TT genotype was detected in 3 patients and SVR was achieved in 2. Finally, heterozygous CT was identified in 53 patients and 10 patients were resistant to treatment. CONCLUSIONS: The results did not support any significant effects of TT or CT genotypes on susceptibility to HCV infection (p = 0.935, OR = 1.031, CI = 0.464 - 2.026). Moreover, there was no significant correlation between SVR to PEG-IFN combined by ribavirin therapy in patients with genotype CC (p = 0.601, OR = 0.736, CI = 0.234 - 2.319).

Recommendations for the Clinical Management of Hepatitis C in Iran: A Consensus-Based National Guideline.

CONTEXT: Hepatitis C virus (HCV) infection is a major public health issue worldwide, including Iran. The new direct-acting antiviral agents (DAAs) with high efficacy have changed the landscape of HCV treatment. This guideline provides updated recommendations for clinical management of HCV infection in Iran. EVIDENCE ACQUISITION: The recommendations of this guideline are based on international and national scientific evidences and consensus-based expert opinion. Scientific evidences were collected through a systematic review of studies that evaluated efficacy and safety of DAA regimens, using PubMed, Scopus and Web of Science. Expert opinion was based on the consensus of Iran Hepatitis Scientific Board (IHSB) in the 3rd national consensus on management of Hepatitis C in Iran, held on 22nd of July 2016. RESULTS: Pegylated Interferon alpha (PegIFN), Ribavirin (RBV), Sofosbuvir (SOF), Ledipasvir (LDV) and Daclatasvir (DCV) are currently available in Iran. Pre-treatment assessments include HCV RNA level, HCV genotype and resistance testing, assessment of liver fibrosis, and underlying diseases. In HCV genotype 1 and 4, DCV/SOF and LDV/SOF are recommended. In HCV genotype 2, SOF plus RBV and in HCV genotype 3, DCV/SOF is recommended. Additional care for underlying diseases should be considered. CONCLUSIONS: Affordable new HCV treatment regimens are available in Iran, providing an opportunity for HCV elimination. Recommendations provided in this current national guideline can facilitate evidence-based management of HCV infection.

Lack of TNF-α Gene Polymorphism (rs1799724) Association with Sustained Virological Response in Iranian Patients with Chronic HCV Infection.

Infection with the hepatitis C virus is a major public health concern which can lead to carcinoma and liver failure. It has been shown that single nucleotide polymorphisms can affect the level of gene activity of tumor necrosis factor (TNF) which has an important role, especially in viral infections which can lead to apaptosis of infected hepatocellular cells. We investigated the impact of three possible genotypes for rs1800629 or A/G single nucleotide polymorphism located downstream of TNFα gene promoter in groups of control (n=76) and chronic hepatitis C patients (n=89) focusing on the response to treatment among sensitive and resistant groups. Genomic DNA was extracted from 500 µl prepheral whole blood and PCR and RFLP were used to amplify the region of interest and genotyping. With statistical analyzes a p-value <0.05 was considered meaningful. There was no significant difference in distribution of the possible three genotypes among healthy individuals and patients (P=0.906, OR=1.194, CI=0.063-22.790). However, the frequency of the G allele was higher in patients whereas A allele was more common among healthy individuals (p<0.0001). Further studies with more samples appears to be necessary.

Impact of TGF-ß1 Gene Polymorphism (rs1800469) on Treatment Response to Pegylated Interferon/Ribavirin in Iranian Patients with Hepatitis C.

BACKGROUND: Hepatitis C virus as a major cause of chronic liver disease affects more than 170 million people worldwide. Recent studies have claimed that single nucleotide polymorphisms (SNPs) for the transforming growth factor-ß1 (TGF-ß1) gene were strongly associated with the antiviral treatment response. Thus, the present study aimed at the determination of distribution of the rs1800469 (C/T) polymorphism among Iranian with chronic hepatitis C. METHODS: A total of 165 blood samples including 68 SVR positive and 21 non-responder samples from individuals suffering chronic hepatitis C and also 76 healthy individual controls were analyzed in this cross-sectional study. DNA was isolated from the samples using a DNA extraction standard kit. Then the frequency of the polymorphism was analyzed using PCR-RFLP method. Eventually, the products of interest were detected on 2.5% agarose gel electrophoresis. RESULTS: The distribution of the C/T polymorphism between healthy individuals and patients were obtained as TT: 22.4%, TC: 46%, CC: 31.6%, and TT: 19.1%, TC: 48.3%, CC: 32.6%, respectively. Furthermore, the CC genotype was identified in 20 patients of whom 68 achieved SVR, while the CT heterozygous was found in 43 patients and SVR was achieved in 38. Finally, the TT was detected in 17 patients, and 7 patients did not achieve SVR. CONCLUSIONS: We observed a significant difference of C allele frequency with SVR as compared to the T allele among patients (p = 0.064). On the other hand, there is no correlation between the polymorphism and susceptibility to HCV infection. However, further studies with more samples seem to be necessary.

Correlation Study Between IL-28B Gene Polymorphism (rs8099917SNP) and Sustained Virological Response in Iranian Patients with Chronic Hepatitis C.

BACKGROUND: The current standard treatment for hepatitis C is a combination of pegylated interferon alpha and ribavirin (peg-IFNα/RBV). Recent studies have shown that single nucleotide polymorphisms (SNPs) near the interleukin 28B (IL28B) gene coding for IFN-λ3 were associated with the antiviral treatment response. Therefore, in this study, we determined the distribution of the rs8099917 (T/G) polymorphism with sustained virological response (SVR) to chronic hepatitis C virus infection among Iranian patients. METHODS: This cross-sectional study was performed on 150 blood samples based on 93 patients with chronic HCV genotypes 1 and 3 including 71 SVR positive, 22 negative, and 57 healthy individual controls. DNA was extracted from the samples and the frequency of the polymorphism was analyzed the using PCR-RFLP method. Finally, the products were detected on 3.5% agarose gel electrophoresis. RESULTS: The analysis of the data for G/T polymorphism showed that the GG genotype was identified in 6 patients of 71 who achieved SVR, while the GT heterozygous was found in 33 patients and SVR was achieved in 19. Finally, the TT was detected in 53 patients and 7 patients were resistant to treatment. CONCLUSIONS: The results showed significant effects of G allele carriers on susceptibility to HCV infection com-pared to the other allele (T) in our studied population (p = 0.013, OR = 2.23, 95% CI = 1.18-4.21), but we did not find a significant correlation for SVR to therapy in patients with genotype TT (p = 0.055, OR = 0.48, 95% CI = 0.23-1.01). However, further studies with more samples are necessary.

Role of IL28-B Polymorphism (rs12979860) on Sustained Virological Response to Pegylated Interferon/Ribavirin in Iranian Patients With Chronic Hepatitis C.

BACKGROUND: The current medical treatment for hepatitis C virus (HCV) infection is pegylated interferon plus ribavirin, but just 50% of genotype 1 HCV patients and about 80% of HCV genotype 3 patients are treated completely. Recently, the rs12979860 C/T polymorphism, which is located 3 kb upstream of the IL28b gene that codes IFNλ3, shows a powerful association in response to the treatment in HCV patients. OBJECTIVES: The aim of this study was to evaluate the relationship between IL28b single nucleotide polymorphism (SNP) and treatment outcomes among chronic HCV patients in Iran. PATIENTS AND METHODS: In this cross-sectional study, 108 blood samples were collected from chronic patients in Iran; 50 unrelated healthy subject samples were also collected. Genomic DNA was extracted, and rs12979860 SNP was done by PCR-RFLP. Finally, products were detected on 12% polyacrylamide gel electrophoresis. RESULTS: The analysis of data for C/T SNP showed that the CC genotype is more common in the control group than in the group of patients. In contrast, the frequency of TT as a mutant genotype is more frequent in patients than in uninfected people. In addition, results showed a statistically significant relationship between CC, CT, and TT genotypes in sensitive and resistant groups (P value: < 0.001, Or: 0.003, CI: 0-0.047). This relationship was also examined in terms of allele frequency, to determine whether the possibility of resistance to treatment in patients with T allele is more than in patients who carry C allele (P value: < 0.001). CONCLUSIONS: These results showed a significant effect between rs12979860 SNP and sustained virological response (SVR) rate in Iranian patients with chronic HCV. To decrease the cost of long treatments and to prevent severe side effects, determining this polymorphism at the beginning of treatment can be very helpful for patients and physicians.