1.Effects of proteasome inhibitors on leukemias.
Shu-Qing LÜ ; Jian-Min YANG ; Jian-Min WANG
Journal of Experimental Hematology 2007;15(4):896-900
The proteasome is primarily responsible for intracellular protein degradation. The abnormality of its activity is sign of tumorigenesis. It was confirmed that proteasome inhibitors have activities against a variety of malignancies. Bortezomib, the first proteasome inhibitor, obtained permission of clinical trial and on sale. Multiple myeloma patients treated with bortezomib have gained a high overall response rate and complete remission rate. A lot of studies on effects of proteasome inhibitors on leukemias, including plasma cell leukemia; chronic lymphocytic leukemia, adult T cell lymphoma/leukemia, chronic myeloid leukemia and acute myeloid leukemia, were reviewed in this article.
Animals
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Boronic Acids
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therapeutic use
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Bortezomib
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Humans
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Leukemia
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drug therapy
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enzymology
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Multiple Myeloma
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drug therapy
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Protease Inhibitors
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therapeutic use
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Proteasome Inhibitors
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Pyrazines
;
therapeutic use
2.Role of proteasome inhibition in sensitized transplant candidates.
Matthew J EVERLY ; Jason J EVERLY ; Paul I TERASAKI
Chinese Medical Journal 2011;124(5):771-774
OBJECTIVETo review this efficacy and safety of bortezomib, a proteasome inhibitor, in the setting of the sensitized transplant candidate.
DATA SOURCESThe data used in this review were from articles published (PubMed) between 2000 to 2010. Additionally abstracts from medical meetings related to transplant were also used.
STUDY SELECTIONArticles were selected if they were trial results or case studies for the use of bortezomib in the sensitized patient population.
RESULTSThe early data using bortezomib as a part of desensitization regimens has shown success. Although one cycle (4 doses) of bortezomib seems to have affect on many patients, it also seems likely that to provide complete desensitization multiple cycles will be required. Regarding safety, bortezomib has been shown to have minimal side effects. The most common side effects reported are those of thrombocytopenia and anemia. These side effects are dose related and self limiting upon discontinuation of the treatment.
CONCLUSIONSBortezomib with plasmapheresis is a promising new alternative to desensitization protocols that use either high dose intravenous immune globulin (IVIG) or low dose IVIG and plasmapheresis. The efficacy on antibody reduction looks to be batter that that of the IVIG based regimens without significant addition toxicity. The results of ongoing prospective trials are positive and their complete results are greatly anticipated.
Boronic Acids ; therapeutic use ; Bortezomib ; Graft Rejection ; immunology ; prevention & control ; Humans ; Protease Inhibitors ; therapeutic use ; Proteasome Endopeptidase Complex ; metabolism ; Pyrazines ; therapeutic use ; Transplants ; adverse effects
3.Genetic Subtypes and Pretreatment Drug Resistance in the Newly Reported Human Immunodeficiency Virus-Infected Men Aged≥50 Years Old in Guangxi.
Ning-Ye FANG ; Wen-Cui WEI ; Jian-Jun LI ; Ping CEN ; Xian-Xiang FENG ; Dong YANG ; Kai-Ling TANG ; Shu-Jia LIANG ; Yu-Lan SHAO ; Hua-Xiang LU ; He JIANG ; Qin MENG ; Shuai-Feng LIU ; Qiu-Ying ZHU ; Huan-Huan CHEN ; Guang-Hua LAN ; Shi-Xiong YANG ; Li-Fang ZHOU ; Jing-Lin MO ; Xian-Min GE
Acta Academiae Medicinae Sinicae 2023;45(3):399-404
Objective To analyze the genetic subtypes of human immunodeficiency virus (HIV) and the prevalence of pretreatment drug resistance in the newly reported HIV-infected men in Guangxi. Methods The stratified random sampling method was employed to select the newly reported HIV-infected men aged≥50 years old in 14 cities of Guangxi from January to June in 2020.The pol gene of HIV-1 was amplified by nested reverse transcription polymerase chain reaction and then sequenced.The mutation sites associated with drug resistance and the degree of drug resistance were then analyzed. Results A total of 615 HIV-infected men were included in the study.The genetic subtypes of CRF01_AE,CRF07_BC,and CRF08_BC accounted for 57.4% (353/615),17.1% (105/615),and 22.4% (138/615),respectively.The mutations associated with the resistance to nucleoside reverse transcriptase inhibitors (NRTI),non-nucleoside reverse transcriptase inhibitors (NNRTI),and protease inhibitors occurred in 8 (1.3%),18 (2.9%),and 0 patients,respectively.M184V (0.7%) and K103N (1.8%) were the mutations with the highest occurrence rates for the resistance to NRTIs and NNRTIs,respectively.Twenty-two (3.6%) patients were resistant to at least one type of inhibitors.Specifically,4 (0.7%),14 (2.3%),4 (0.7%),and 0 patients were resistant to NRTIs,NNRTIs,both NRTIs and NNRTIs,and protease inhibitors,respectively.The pretreatment resistance to NNRTIs had much higher frequency than that to NRTIs (2.9% vs.1.3%;χ2=3.929,P=0.047).The prevalence of pretreatment resistance to lamivudine,zidovudine,tenofovir,abacavir,rilpivirine,efavirenz,nevirapine,and lopinavir/ritonavir was 0.8%, 0.3%, 0.7%, 1.0%, 1.3%, 2.8%, 2.9%, and 0, respectively. Conclusions CRF01_AE,CRF07_BC,and CRF08_BC are the three major strains of HIV-infected men≥50 years old newly reported in Guangxi,2020,and the pretreatment drug resistance demonstrates low prevalence.
Male
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Humans
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Middle Aged
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Reverse Transcriptase Inhibitors/therapeutic use*
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HIV Infections/drug therapy*
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Drug Resistance, Viral/genetics*
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China/epidemiology*
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Mutation
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HIV-1/genetics*
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Protease Inhibitors/therapeutic use*
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Genotype
4.New treatments for chronic hepatitis C.
Jae Young JANG ; Raymond T CHUNG
The Korean Journal of Hepatology 2010;16(3):263-277
Treatments for chronic hepatitis C has evolved significantly in the past 15 years. The standard of care (SOC) is peginterferon alfa-2a/-2b with ribavirin for 48 weeks or 24 weeks in patients infected with HCV genotype 1 or 2/3, respectively. The treatment duration can be individualized based on the baseline viral load and the speed of the virologic response during treatment. However, current therapies are associated with side effects, complications, and poor patient tolerability. Therefore, there is an urgent need to identify better strategies for treating this disease. An improved sustained virologic response (SVR) can be achieved with new HCV-specific inhibitors against NS3/4A and NS5B polymerases. Recent trials have found SVR rates in patients with HCV genotype 1 infection of 61~68% and 67~75% for combining the SOC with the protease inhibitors telaprevir and boceprevir, respectively. Several new HCV-specific inhibitors such as protease inhibitors and nucleoside and non-nucleoside polymerase inhibitors as well as non-HCV-specific compounds with anti-HCV activity are currently in clinical evaluation. In this review we discuss these new treatments for chronic hepatitis C.
Antiviral Agents/*therapeutic use
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DNA-Directed RNA Polymerases/antagonists & inhibitors/metabolism
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Hepatitis C, Chronic/*drug therapy
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Humans
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Interferons/therapeutic use
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Nucleotides/chemistry/therapeutic use
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Protease Inhibitors/*therapeutic use
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Viral Nonstructural Proteins/antagonists & inhibitors/metabolism
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Virus Internalization/drug effects
5.Recent Advances in Management of Acute Pancreatitis.
The Korean Journal of Gastroenterology 2015;66(3):135-143
Acute pancreatitis is common but remains a condition with significant morbidity and mortality. Despite a better understanding of the pathophysiology of acute pancreatitis achieved during the past few decades, there is no specific pharmacologic entity available. Therefore, supportive care is still the mainstay of treatment. Recently, novel interventions for increasing survival and minimizing morbidity have been investigated, which are highlighted in this review.
Acute Disease
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Antioxidants/therapeutic use
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Bacteremia/complications
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Cholangiopancreatography, Endoscopic Retrograde
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Fluid Therapy
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Gallstones/complications
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Humans
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Necrosis
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Pancreatitis/mortality/*pathology/therapy
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Protease Inhibitors/therapeutic use
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Renal Dialysis
6.Salvage therapy with proteasome inhibitor bortezomib for relapsed and refractory multiple myeloma.
Wen-Rong HUANG ; Rong LI ; Yu JING ; Yi-Zhuo ZHANG ; Xiao-Xiong WU ; Chun-Ji GAO ; Jian BO ; Li YU ; Quang-Shun WANG ; Wan-Ming DA
Journal of Experimental Hematology 2006;14(6):1146-1150
Multiple myeloma is a malignant disease with high incidence in middle-aged and old-aged population. Bortezomib is a proteasome inhibitor which target mainly is NF-kappaB. This observation is to study the clinical treatment effect of bortezomib in one relapsed multiple myeloma (MM) patient and one primary refractory MM patient. The first patient diagnosed as IgA IIIA stage, whose state of disease became worse after 8 months of autologous peripheral blood stem cell transplantation. And the disease became further aggressive with 4 courses of chemical therapy regimen including methylprednisolone, Arsenic trioxide, dexamethasone, cyclophosphamide, mitoxantrone, VM-26. Myeloma cells in bone marrow and abnormal monoclonal immunoglobulin in blood plasma both increased. Bone destruction became severe, and there was a plasmacytoma about 5 x 6 cm on the patient's right upper chest wall. Therefore, the patient received therapy of bortezomib combined with doxrubicin, dexamethasone and thalidomide (VADT). After one course of therapy with this VADT regimen, IgA in blood plasma decreased from 54 g/L to 6.6 g/L, and abnormal plasma cells in bone marrow decreased from 40% to 0.6%, and plasmacytoma on the patient's right upper chest wall almost absorbed. But there was no obvious clinical effect after the second course of therapy of VADT, and the disease status became progressive again. The second patient was MM patient with a light chain kappa type, III B stage. There was no any effect after two courses of VAD therapy and one course of MOFP therapy. The patient acquired near complete remission after one course of treatment with VADT. Quantity of kappa protein in urine reduced from 24 - 30 g/24 hours to 1.12 g/24 hours. Blood creatinine reduced from 475.3 micromol/L to 124.2 micromol/L. Beta2-MG reduced from 161g/L to 64 g/L. And this patient got complete remission after three consecutive VADT therapy. The mainly side effects of the bortezomib regimen in the first patient include markedly lassitude, diarrhea, numbness of the end of extremities, marked increase of LDH. All the side effects could be tolerated and became disappeared after contraposing treatment and stopping the bortezomib regimen therapy. The second patient complicated with severe subacute left hemiplegia after the bortezomib dose had been increased to 1.45 mg/m2 at the third time of the first VADT course and the complication became worst at the following day. The upper limb muscle strength was only 1 grade and the lower limb muscle strength was 2 grade. Then the condition improved with the support therapy and gradually recovered after two weeks. Therefore, bortezomib is an effective target drug for therapy in refractory multiple myeloma, and more attentions to the side effects should be paid in order to deal with those side effects in time.
Adult
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Antineoplastic Agents
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therapeutic use
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Boronic Acids
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therapeutic use
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Bortezomib
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Humans
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Male
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Middle Aged
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Multiple Myeloma
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drug therapy
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Neoplasm Recurrence, Local
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drug therapy
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Protease Inhibitors
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therapeutic use
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Pyrazines
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therapeutic use
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Salvage Therapy
7.Advances in novel anti-HIV-1 drugs and drug candidates: 2005-2008.
Pu-rong ZHENG ; Hai XUE ; Zhi-yan XIAO ; Gang LIU
Acta Pharmaceutica Sinica 2010;45(2):154-164
HIV and AIDS remain as the crucial global health concern, therefore, research and development of novel anti-HIV-1 chemical therapeutics is still of paramount significance, which may be illuminated by cases of successful marketed drugs. Herein, we document the discovery and biological profile of new anti-HIV-1 drugs approved by FDA between 2005 and 2008 and some drug candidates are also discussed.
Acquired Immunodeficiency Syndrome
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drug therapy
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Anti-HIV Agents
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chemistry
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pharmacology
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therapeutic use
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HIV Fusion Inhibitors
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chemistry
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pharmacology
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therapeutic use
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HIV Infections
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drug therapy
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HIV Integrase Inhibitors
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chemistry
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pharmacology
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therapeutic use
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HIV Protease Inhibitors
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chemistry
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pharmacology
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therapeutic use
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HIV-1
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drug effects
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Humans
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Molecular Structure
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Reverse Transcriptase Inhibitors
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chemistry
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pharmacology
;
therapeutic use
8.The development of anti-HIV-1 drugs.
Acta Pharmaceutica Sinica 2010;45(2):165-176
Human immunodeficiency virus type 1 (HIV-1) is the causative agent of acquired immunodeficiency disease syndrome (AIDS). After over 26 years of efforts, there is still not a therapeutic cure or an effective vaccine against HIV/AIDS. The clinical management of HIV-1 infected people largely relies on antiretroviral therapy (ART). Although highly active antiretroviral therapy (HAART) has provided an effective way to treat AIDS patients, the huge burden of ART in developing countries, together with the increasing incidence of drug resistant viruses among treated people, calls for continuous efforts for the development of anti-HIV-1 drugs. Currently, four classes of over 30 licensed antiretrovirals (ARVs) and combination regimens of these ARVs are in use clinically including: reverse transcriptase inhibitors (RTIs) (e.g. nucleoside reverse transcriptase inhibitors, NRTIs; and non-nucleoside reverse transcriptase inhibitors, NNRTIs), protease inhibitors (PIs), integrase inhibitors and entry inhibitors (e.g. fusion inhibitors and CCR5 antagonists). Here, we intend to provide updated information of currently available antiretroviral drugs for ART to promote the development of novel anti-HIV-1 drugs.
Acquired Immunodeficiency Syndrome
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drug therapy
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Anti-HIV Agents
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chemistry
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pharmacology
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therapeutic use
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HIV Fusion Inhibitors
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chemistry
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pharmacology
;
therapeutic use
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HIV Infections
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drug therapy
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HIV Integrase Inhibitors
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chemistry
;
pharmacology
;
therapeutic use
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HIV Protease Inhibitors
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chemistry
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pharmacology
;
therapeutic use
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HIV-1
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drug effects
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Humans
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Molecular Structure
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Reverse Transcriptase Inhibitors
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chemistry
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pharmacology
;
therapeutic use
9.Prevalence of drug resistance mutations among antiretroviral drug-naive HIV-1-infected patients in China.
Xue-feng SI ; Hai-long HUANG ; Min WEI ; Qi GUAN ; Yan-hui SONG ; Peng-fei MA ; Yu QUAN ; Hui XING ; Yi-ming SHAO
Chinese Journal of Experimental and Clinical Virology 2004;18(4):308-311
OBJECTIVETo collect background information on drug-resistant HIV-1 strains in various regions before the start of nation-wide antiretroviral therapy in China.
METHODSTwenty percent of the 2,000 blood samples from antiretroviral therapy naive patients collected for the 2nd national HIV molecular epidemiology survey (NHMES) in 2002 were randomly sampled for this study. The entire protease gene and 20-230 amino acids of the reverse transcriptase gene were amplified by PCR from provirus DNA and sequenced. The results were analyzed with HIV db-Drug Resistance Algorithm and genotypic resistance mutations were determined to particular anti-HIV drugs.
RESULTSTotally 164 protease gene sequences and 138 reverse transcriptase gene sequences were obtained from patients; 0.61% of 164 sequences displayed primary resistance mutations in the protease gene, whereas 99.39% carried 1 or more secondary mutations. Genotypic resistance to at least one nucleoside reverse transcriptase inhibitors (NRTI) was present in 5.80%,and resistance to at least one non-nucleo side reverse transcriptase inhibitors (NNRTI) was present in 1.45% of samples.
CONCLUSIONThe prevalence of genotypic drug resistance is very low in drug-naive HIV infected patients from 21 provinces of China tested in this study. Laboratories participated in the NHMES have organized a network to provide drug resistance monitoring service in the current nation-wide antiviral treatment program in China.
Anti-HIV Agents ; therapeutic use ; China ; epidemiology ; Drug Resistance, Viral ; Genotype ; HIV Infections ; drug therapy ; epidemiology ; virology ; HIV Protease ; genetics ; HIV Protease Inhibitors ; therapeutic use ; HIV Reverse Transcriptase ; genetics ; HIV-1 ; genetics ; Humans ; Mutation ; Reverse Transcriptase Inhibitors ; therapeutic use ; Sentinel Surveillance
10.Emerging Therapies for Hepatitis C.
Do Young KIM ; Sang Hoon AHN ; Kwang Hyub HAN
Gut and Liver 2014;8(5):471-479
The combination of pegylated interferon (PEG-IFN) and ribavirin (RBV), the current therapy for hepatitis C virus (HCV) infection, has saved the lives of many HCV-infected patients. Direct-acting antivirals (DAAs) target several sites of HCV nonstructural proteins, resulting in the cessation of viral replication. The first NS3/4A protease inhibitors consisted of boceprevir and telaprevir, which have shown superior efficacy against genotype 1 HCV infection when combined with PEG-IFN/RBV compared with the standard therapy in both treatment-naive and -experienced patients. Simeprevir, faldaprevir, and asunaprevir are second-wave, first-generation NS3/4A inhibitors that have already been or will soon be approved. Second-generation protease inhibitors are in clinical trials. Daclatasvir is the first approved DAA belonging to the class of NS5A replication complex inhibitors. The potency of daclatasvir is very high, and this drug is an important and essential component of combination regimens for all genotypes. Sofosbuvir, the first approved NS5B polymerase inhibitor, is characterized by high potency and genetic barriers to resistance. Sofosbuvir combined with RBV achieved an interferon-free regimen in genotype 2 or 3 patients with a reduced treatment duration. It can also be used in combination with PEG-IFN/RBV in genotype 1 patients for 12 weeks. DAAs have provided new hope for curing HCV infections with a short treatment duration and acceptable adverse events.
Antiviral Agents/*therapeutic use
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Drug Therapy, Combination
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Hepacivirus/drug effects/genetics
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Hepatitis C/*drug therapy
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Humans
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Protease Inhibitors/therapeutic use
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Viral Nonstructural Proteins/antagonists & inhibitors
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Virus Replication/drug effects