BACKGROUNDTenofovir disoproxil (TDF) is a promising salvage therapy for patients with chronic hepatitis B (CHB) who failed regimens of other nucleoside analogues (NAs). In this study, we aimed to investigate the clinical efficacy and safety of TDF monotherapy in Chinese CHB patients with genotypic resistance.

METHODSA total of 33 CHB patients who had failed treatment with other NAs and had genotypic resistance were switched to TDF monotherapy for 48 weeks. Patients' demographic data (age, sex, history of hepatitis B virus [HBV] therapy), laboratory testing results (hepatitis B e antigen [HBeAg] status, HBV DNA levels, alanine aminotransferase [ALT] levels, serum creatinine, urinary protein, genotypic assay), clinical symptoms, and liver color ultrasound examinations were collected for evaluation at day 0 (baseline) and the 12th, 24th, 36th, and 48th weeks after initiating treatment. Statistical analyses were carried out using rank sum test or rank correlation.

RESULTSWith regard to efficacy, the study found that all patients who switched to TDF monotherapy had undetectable HBV DNA levels after 48 weeks. In addition, patients with lower baseline HBV DNA levels realized earlier virological undetectability (rs = 0.39, P = 0.030). ALT levels were normal in 30 of 33 patients (91%). HBeAg negative conversion occurred in 7 of 25 patients (28%), among whom HBeAg seroconversion (12%) and HBeAg seroclearance (16%) occurred. The time of complete virological response was significantly affected by the number of resistance loci (rs = 0.36, P = 0.040). Concerning safety, the study found that no adverse events were observed during the 48 weeks.

CONCLUSIONTDF monotherapy is an effective and safe salvage treatment for CHB patients who are resistant to other NAs.

Adult ; Anti-HIV Agents ; adverse effects ; therapeutic use ; DNA, Viral ; genetics ; Drug Resistance, Viral ; Female ; Genotype ; Hepatitis B virus ; drug effects ; pathogenicity ; Hepatitis B, Chronic ; drug therapy ; Humans ; Male ; Middle Aged ; Prospective Studies ; Tenofovir ; adverse effects ; therapeutic use

OBJECTIVETo investigate distinctive features in drug-resistant mutations (DRMs) and interpretations for reverse transcriptase inhibitors (RTIs) between proviral DNA and paired viral RNA in HIV-1-infected patients.

METHODSForty-three HIV-1-infected individuals receiving first-line antiretroviral therapy were recruited to participate in a multicenter AIDS Cohort Study in Anhui and Henan Provinces in China in 2004. Drug resistance genotyping was performed by bulk sequencing and deep sequencing on the plasma and whole blood of 77 samples, respectively. Drug-resistance interpretation was compared between viral RNA and paired proviral DNA.

RESULTSCompared with bulk sequencing, deep sequencing could detect more DRMs and samples with DRMs in both viral RNA and proviral DNA. The mutations M184I and M230I were more prevalent in proviral DNA than in viral RNA (Fisher's exact test, P<0.05). Considering 'majority resistant variants', 15 samples (19.48%) showed differences in drug resistance interpretation between viral RNA and proviral DNA, and 5 of these samples with different DRMs between proviral DNA and paired viral RNA showed a higher level of drug resistance to the first-line drugs. Considering 'minority resistant variants', 22 samples (28.57%) were associated with a higher level of drug resistance to the tested RTIs for proviral DNA when compared with paired viral RNA.

CONCLUSIONCompared with viral RNA, the distinctive information of DRMs and drug resistance interpretations for proviral DNA could be obtained by deep sequencing, which could provide more detailed and precise information for drug resistance monitoring and the rational design of optimal antiretroviral therapy regimens.

Adult ; Antiviral Agents ; pharmacology ; China ; DNA, Viral ; genetics ; metabolism ; Drug Resistance, Viral ; genetics ; Female ; HIV Infections ; drug therapy ; HIV-1 ; drug effects ; genetics ; metabolism ; High-Throughput Nucleotide Sequencing ; Humans ; Male ; Middle Aged ; Mutation ; Proviruses ; genetics ; metabolism ; RNA, Viral ; genetics ; metabolism ; RNA-Directed DNA Polymerase

BACKGROUND/AIMS: To analyze the effects of preexisting lamivudine (LAM) resistance and applying antiviral treatment (adefovir [ADV] add-on LAM combination treatment) on long-term treatment outcomes, and comparing the clinical outcomes of antiviral-naïve chronic hepatitis B patients receiving entecavir (ETV) monotherapy. METHODS: This study enrolled 73 antiviral-naïve patients who received 0.5-mg ETV as an initial therapy and 54 patients who received ADV add-on LAM combination treatment as a rescue therapy from July 2006 to July 2010. RESULTS: During 24-month treatments, the decreases in serum log10HBV-DNA values (copies/mL) were significantly greater in the antiviral-naïve patients treated with ETV than the patients receiving ADV add-on LAM combination treatment. The biochemical response rates for alanine aminotransferase normalization at 6 months (ETV) and 12 months (ADV add-on LAM) were 90.4% (66/73) and 77.8% (42/54), respectively (P=0.048). A Kaplan-Meier analysis indicated that the rates of serologic response, viral breakthrough, and emergence of genotypic resistance did not differ significantly between the two patient groups. There were also no significant intergroup differences in the rates of disease progression (PD) and new development of hepatocellular carcinoma (HCC). CONCLUSION: The long-term clinical outcomes of antiviral-naïve patients treated with ETV and LAM-resistant patients receiving ADV add-on LAM combination treatment were comparable in terms of the emergence of HCC and disease progression.
Adenine/*analogs & derivatives/pharmacology/therapeutic use ; Adult ; Alanine Transaminase/blood ; Antibodies, Viral/blood ; Antiviral Agents/*therapeutic use ; DNA, Viral/blood ; Disease Progression ; Drug Resistance, Viral/drug effects ; Drug Therapy, Combination ; Female ; Follow-Up Studies ; Genotype ; Guanine/analogs & derivatives/pharmacology/therapeutic use ; Hepatitis B e Antigens/blood ; Hepatitis B virus/drug effects/genetics/isolation & purification ; Hepatitis B, Chronic/*drug therapy ; Humans ; Lamivudine/pharmacology/therapeutic use ; Male ; Middle Aged ; Organophosphonates/pharmacology/*therapeutic use ; Treatment Outcome

BACKGROUND/AIMS: Tenofovir disoproxil fumarate (TDF) exhibits similar antiviral efficacy against treatment-naïve and lamivudine (LAM)-resistant chronic hepatitis B (CHB). However, there are few clinical reports on the antiviral effects of TDF-LAM combination therapy compared to TDF monotherapy in patients with LAM-resistant CHB. METHODS: We investigated the antiviral efficacy of TDF monotherapy vs. TDF-LAM combination therapy in 103 patients with LAM-resistant CHB. RESULTS: The study subjects were treated with TDF alone (n=40) or TDF-LAM combination therapy (n=63) for ≥6 months. The patients had previously been treated with TDF-based rescue therapy for a median of 30.0 months (range, 8-36 months). A virologic response (VR) was achieved in 99 patients (96.1%): 95.0% (38/40) of patients in the TDF monotherapy group and 96.8% (61/63) of patients in the TDF-LAM combination therapy group. The VR rates were not significantly different between the TDF monotherapy and TDF-LAM combination therapy groups (88.9 vs. 87.3% at month 12, and 94.4 vs. 93.7% at month 24, log-rank p=0.652). Univariate and multivariate analyses revealed that none of the pretreatment factors were significantly associated with VR. CONCLUSIONS: TDF monotherapy was as effective as TDF-LAM combination therapy for maintaining viral suppression in the vast majority of patients with LAM-resistant CHB, which suggests that TDF add-on therapy with LAM is unnecessary.
Adult ; Aged ; Aged, 80 and over ; Antiviral Agents/pharmacology/*therapeutic use ; DNA, Viral/blood ; Drug Administration Schedule ; Drug Resistance, Viral/drug effects ; Drug Therapy, Combination ; Female ; Hepatitis B virus/genetics ; Hepatitis B, Chronic/*drug therapy ; Humans ; Kidney Function Tests ; Lamivudine/*therapeutic use ; Liver Function Tests ; Male ; Middle Aged ; Polymerase Chain Reaction ; Tenofovir/*therapeutic use ; Treatment Outcome

A549 Cells ; Animals ; Drug Evaluation, Preclinical ; Drug Resistance, Viral ; drug effects ; Humans ; Influenza A virus ; metabolism ; Mice, Inbred BALB C ; Orthomyxoviridae Infections ; drug therapy ; metabolism ; Sesterterpenes ; chemistry ; pharmacology

Animals ; Dogs ; Drug Resistance, Viral ; drug effects ; Female ; Humans ; Influenza A Virus, H7N9 Subtype ; Madin Darby Canine Kidney Cells ; Male ; Orthomyxoviridae Infections ; drug therapy ; Ribavirin ; pharmacology

This study is to evaluate the HAART pharmacodynamics with dolutegravir as the "anchor" in vitro. A nucleoside reverse transcriptase inhibitors (NRTIs) resistant recombinant virus model (VSVG/HIV-1(RT-D67N,K70R,T215F)) and an integrase inhibitors (INIs) resistant recombinant virus model (VSVG/HIV-1(IN-G140S,QI48H)) were constructed and established. The anti-viral pharmacodynamics was evaluated with drug combinations including two NRTIs along with one INI or one NNRTI. The results showed that the combination with an INI gave a stronger synergism on wild type HIV-1 replication comparing to that with an NNRTI. Comparing the two INIs as the "anchor" for HAART, DTG exhibited an equivalent CI to that of RAL on wild type HIV-1 replication; but a greater synergy than RAL on INI-resistant HIV-1 replication. Besides of the pharmacodynamics results of DTG-based drug combination, the results may contribute to clinical antiviral therapy.
Antiretroviral Therapy, Highly Active ; Cells, Cultured ; Drug Resistance, Viral ; HIV Integrase Inhibitors ; pharmacology ; HIV-1 ; drug effects ; physiology ; Heterocyclic Compounds, 3-Ring ; pharmacology ; Humans ; Virus Replication ; drug effects

Data based on the antiviral-resistant phenotyping characteristics of 884 influenza B viruses circulating in mainland China from October 2013 to March 2014 were analyzed to assess the susceptibility of influenza B viruses to neuraminidase inhibitors. All 884 viruses were sensitive to oseltamivir; two viruses (0.23%) had reduced sensitivity to zanamivir and all other viruses were sensitive to zanamivir. Among the 38 viruses with a B/Victoria lineage, B/Shandong-Kuiwen/1195/2014 exhibited a half-maximal inhibitory concentration (IC50) for zanamivir that was elevated by 5. 12-fold (1.78 nM) compared with neuraminidase inhibitors sensitive to the reference virus (0.34 nM), suggesting that it exhibited reduced inhibition by zanamivir. D35G, N59D and S402T (39, 64 and 399 with N2 number) amino-acid substitutions in the NA gene were detected with no previously reported antiviral-resistant substitutions. Among viruses with the 846 B/Yamagata lineage, B/Hunan-Lingling/350/2013 exhibited a 7.99-fold elevated IC50 for zanamivir (2.72 nM) compared with neuraminidase inhibitors sensitive to the reference virus (0.34 nM), suggesting that it exhibited reduced inhibition by zanamivir. D197N (N2 number), a previously reported antiviral resistant-related amino-acid substitution in the NA gene, was detected in B/Hunan-Lingling/350/2013. These data suggest that recently circulating influenza B viruses in mainland China have retained susceptibility to neuraminidase inhibitors.
Amino Acid Substitution ; Antiviral Agents ; pharmacology ; China ; epidemiology ; Drug Resistance, Viral ; Enzyme Inhibitors ; pharmacology ; Humans ; Influenza B virus ; drug effects ; enzymology ; genetics ; isolation & purification ; Influenza, Human ; epidemiology ; virology ; Microbial Sensitivity Tests ; Neuraminidase ; antagonists & inhibitors ; genetics ; metabolism ; Viral Proteins ; antagonists & inhibitors ; genetics ; metabolism

In order to investigate the mutation of HBV polymerase gene reverse transcription conserved region (P region) in chronic hepatitis B (CHB) patients, 212 CHB patients who took antiretroviral treatment with nucleotide analogues were chosen. The drug resistance mutations of HBV P region and HBV genotype were detected by Pyrosequencing. Sequence analysis showed that the drug resistance sites of HBV P region located at sites 173; 180; 181; 184; 204; 236 and 250. The main site of HBV P region drug resistance was 204 and 180, accounting for 35.8% and 23.5%, respectively. There were significant differences in the mutation rate of site 180 among different age groups. There were also significant differences in the mutation rate of site 204 among younger than 30 age group, 41 to 50 age group and 51 to 60 age group. (P < 0.05, P < 0.01). The mutation rate of site 180 combined with site 204 was 66.6%. The mutation rate of site 181 combined with site 236 was 23.3%. The age of C genotype infected patients was significantly older than B genotype infected patients (P < 0.01). M204V/I mutation mostly existed in the form of joint L180M mutation, the mutation rate was age-related. The detection of HBV genotypes and drug resistance sites of HBV P region have important clinical implications for the treatment and prognosis of patients with CHB.
Adult ; Aged ; Antiviral Agents ; pharmacology ; China ; Drug Resistance, Viral ; Female ; Gene Products, pol ; genetics ; Genotype ; Hepatitis B virus ; classification ; drug effects ; enzymology ; genetics ; Hepatitis B, Chronic ; drug therapy ; virology ; Humans ; Male ; Middle Aged ; Mutation, Missense ; Young Adult

OBJECTIVETo study the condition of HIV-1 drug resistance mutation among failures of first-line antiretroviral therapy in Henan province.

METHODThe sub platform of China's legal infectious disease monitoring information reporting system-HIV/AIDS integrated prevention and control data information management system was used to collect the information of patients experiencing first-line antiretroviral treatment failure (virus load ≥ 1 000 copies/ml) more than one year among nine cities of Henan in 2011. A total of 40 cases with no information and 212 cases with incomplete drug resistance results were deleted, and 1 922 cases were included in this study and genotype resistance testing was carried out. Non-conditional logistic regression analysis was used to analyse the influencing factors of drug resistance mutation.

RESULTSA total of 1 922 cases were included in the analysis. 1 039 cases were males, 833 cases were females, the age was (45.7 ± 12.1) years, 82.73% (1 590) were married, and 87.93% (1 690) were transmitted by blood. 64.20% (1 234) patients acquired drug resistance. Nucleoside reverse transcriptase inhibitor (NRTI), non-nucleoside reverse transcriptase inhibitor (NNRTI) and protease inhibitor (PI) resistance mutations were found in 62.59% (1 203), 49.74% (956) and 0.94% (18) of subjects, respectively. 42.09% (809) of patients harbored NRTI and NNRTI resistance mutations synchronously. ≥ 1TAM was the most commonly emerged NRTI resistance mutation (41.94% (806)), the prevalences of TAM-1 and TAM-2 were 8.48% (163) and 4.24% (81), respectively. K65R/N and Q151M complex existed in 23 and 4 patients, respectively. K103N/S was the most commonly emerged NNRTI resistance mutation (34.32% (659)). Non-conditional logistic regression analysis showed that, factors associated with high drug resistance were the following: transmitted by mother to child (OR = 9.05, 95% CI: 1.14-72.12), clinical stage was IV (OR = 1.70, 95% CI: 1.09-2.66) and 5-year-treated (OR = 1.59, 95% CI: 1.03-2.47). Factors associated with low drug resistance were the following: 1-year-treated (OR = 0.19, 95% CI: 0.13-0.27).

CONCLUSIONComplex patterns of HIV-1 drug resistance mutations were identified among individuals experiencing failure of first-line antiretroviral therapy in Henan province. Factors associated with high drug resistance were lived in Luohe, Shangqiu, Nanyang, Xinyang, transmitted by mother to child, clinical stage was IV, and 5-year-treated.

Adult ; China ; Drug Resistance, Viral ; genetics ; Female ; Genotype ; HIV Infections ; drug therapy ; HIV-1 ; drug effects ; genetics ; Humans ; Infectious Disease Transmission, Vertical ; Male ; Middle Aged ; Prevalence ; Protease Inhibitors ; therapeutic use ; Reverse Transcriptase Inhibitors ; therapeutic use