Complete Viral Response Research Articles

The effect of nucleos(t)ide analogues on clinical outcomes of patients treated with transarterial chemoembolization and radiofrequency ablation for hepatitis B virus-related hepatocellular carcinoma.

Because hepatitis B virus (HBV) replication has been known to play an important role in cancer recurrence after curative treatment of HBV-related hepatocellular carcinoma (HCC), we examined whether treatment based on nucleos(t)ide analogues (NAs) might decrease the recurrence rate and improve patient survival. The retrospective cohort study enrolled 73 patients with chronic hepatitis B who were treated with transarterial chemoembolization (TACE) and radiofrequency ablation (RFA) with curative intent for HCC. Among those, 30 and 43 patients were treated with tenofovir disoproxil fumarate (TDF) and entecavir (ETV), respectively. Of the 73 patients, 51 experienced HCC recurrence, and 14 patients were dead during a follow-up of 73±34 months. Multivariate analyses showed that tumor size (hazard ratio [HR], 1.590; 95% confidence-interval [CI], 1.106-2.285; P=0.012) and Child-Pugh class B (vs. class A/non cirrhosis; HR, 5.794; 95% CI, 2.311-14.523; P=0.001) was significantly associated with HCC recurrence, and Child-Pugh class B (HR, 7.357; 95% CI, 2.100-25.777; P=0.002) was an independent unfavorable prognostic factor for survival. During NAs therapy, TDF was superior to ETV for complete viral response at 1 year after the date of combination of TACE and RFA (P=0.016). However, the risks of HCC recurrence and survival were not significantly different between those treated with TDF versus ETV. TDF was superior to ETV for achieving complete viral response. However, the recurrence and mortality after TACE and RFA for HBV-related HCC were not significantly different between patients treated with TDF versus ETV.

Study on early predictive factors of an incomplete viral response with 48 week-entecavir therapy in HBeAg-positive chronic hepatitis B patients

Objective: To study the virological and serological indicators before treatment and 24 weeks after treatment to predict the partial virological response (PVR) of 48-week entecavir (ETV) treatment, and formulate early clinical adjustment treatment plans for HBeAg-positive CHB patients. Methods: HBeAg-positive CHB-naïve patients diagnosed in the Department of Infectious Diseases, Shengjing Hospital, China Medical University, who were treated with oral ETV monotherapy from January 2018 were enrolled. The groups were divided according to the test results of HBV DNA at 48 weeks. Among them, HBV DNA < 20 IU/ml was the complete viral response (CVR) group, and HBV DNA ≥ 20 IU/ml was the PVR group. The virological and serological indexes of the two groups before treatment and 24 weeks after treatment were compared. ROC curve univariate analysis and multivariate logistic regression were performed to find out the early predictors of PVR in HBeAg-positive CHB patients receiving ETV therapy for 48 weeks. Results: As of July 2020, a total of 90 cases had completed 48 weeks of treatment, including 50 cases of CVR (55.56%) and 40 cases of PVR (44.44%). Before treatment and at 24 weeks of treatment, HBsAg, HBeAg and HBV DNA in the PVR group were significantly higher than those in the CVR group (P < 0.001). Univariate analysis showed that HBV DNA quantification (AUC = 0.961, P < 0.001, PPV = 97.06%, NPV = 87.50%) and HBeAg quantification (AUC = 0.883, P < 0.001, PPV = 90.63%, NPV = 81.03%) had higher predictive value at 24 weeks of treatment. Multivariate analysis showed that HBeAg > 1.952 log(10) S/CO (OR = 3.177, 95% CI: 1.261 ~ 8.267, P = 0.018) and HBV DNA > 2.205 log(10) IU / ml (OR = 43.197, 95% CI: 6.858 ~ 272.069, P < 0.001) were independent predictors of PVR at 24 weeks of treatment, and their combination had the best predictive effect. Conclusion: In HBeAg-positive CHB patients receiving ETV treatment for 48 weeks, HBV DNA combined with HBeAg quantification can be an early predictor of PVR at 24 weeks. Additionally, patients with both HBV DNA and HBeAg > 2 log(10) at 24 weeks of treatment must wait 48 weeks to obtain CVR, so it is recommended that treatment strategies should be adjusted at this time.

Tenofovir is a more suitable treatment than entecavir for chronic hepatitis B patients carrying naturally occurring rtM204I mutations.

BACKGROUNDHepatitis B virus (HBV) DNA polymerase mutations usually occur to long term use of nucleos(t)ide analogues (NAs), but they can occur spontaneously in treatment-naïve chronic hepatitis B (CHB) patients. The naturally occurring HBV DNA polymerase mutations might complicate antiviral therapy with NAs, leading to the generation of drug-resistant viral mutants and disease progression. The most common substitutions are known to be YMDD-motif mutations, but their prevalence and the influence on antiviral therapy is unclear.AIMTo investigate prevalence of the naturally occurring rtM204I mutations in treatment-naïve CHB genotype C2 patients and their influence on antiviral therapy.METHODSA total of 410 treatment-naïve CHB patients infected with HBV genotype C2 strains were enrolled in this retrospective study. Among the 410 patients, 232 were treated with NAs for at least 12 mo. Significant fibrosis was defined as fibrosis-4 index > 3.25 or aspartate aminotransferase to platelet ratio index > 1.5. Complete viral response (CVR) during NAs was defined as undetectable serum HBV DNA (< 24 IU/mL). The rtM204I variants were analyzed by a newly developed locked nucleotide probe (LNA probe) based real-time PCR (LNA-RT-PCR) method.RESULTSThe LNA-RT-PCR could discriminate rtM204I mutant-type (17 patients, 4.2%) from rtM204 wild-type (386 patients, 95.8%) in 403 of 410 patients (98.3% sensitivity). Multivariate analysis showed that naturally occurring rtM204I variants were more frequently detected in patients with significant fibrosis [odd-ratio (OR) 3.397, 95% confidence-interval (CI) 1.119-10.319, P = 0.031]. Of 232 patients receiving NAs, multivariate analysis revealed that achievement of CVR was reversely associated with naturally occurring rtM204I variants prior to NAs treatment (OR 0.014, 95%CI 0.002-0.096, P < 0.001). Almost patients receiving tenofovir achieved CVR at 12 mo of tenofovir, irrespective of pre-existence of naturally occurring rtM204I mutations (CVR rates: patients with rtM204I, 100%; patients without rtM204I, 96.6%), whereas, pre-existence of naturally-occurring rtM204I-mutations prior to NAs significantly affects CVR rates in patients receiving entecavir (at 12 mo: Patients with rtM204I, 16.7%; patients without rtM204I, 95.6%, P < 0.001).CONCLUSIONThe newly developed LNA-RT-PCR method could detect naturally occurring rtM204I mutations with high-sensitivity. Theses mutations were more frequent in patients with liver fibrosis. Tenofovir is a more suitable treatment than entecavir for CHB patients carrying the naturally occurring rtM204I mutations.

Step-down Strategy in Antiviral Resistant Chronic Hepatitis B Patients Who Achieved Viral Suppression With Rescue Combination Therapy

In the treatment of chronic hepatitis B (CHB) patients with drug resistance, rescue combination therapy leads to viral suppression in almost all patients. However, once it is achieved, lifelong maintenance especially, by using combination therapy is not always possible in a significant proportion of patients. At present, there is no consensus on whether it is possible to switch to monotherapy from combination therapy. However, there is robust evidence to support step-down therapy, which involves switching from combination therapy to monotherapy in antiviral resistant CHB patients who achieve complete viral response from combination therapy. We review the evidence in favor of switching to monotherapy in antiviral resistant CHB patients who achieve complete viral response by combination therapy.

Efficacy of tenofovir disoproxil fumarate therapy in Chinese chronic hepatitis B patients after multiple antiviral failures.

In this prospective study, we aimed to evaluate the efficacy and safety of tenofovir disoproxil fumarate (TDF) in Chinese chronic hepatitis B (CHB) patients after multiple nucleoside/nucleotide analog (NA) treatment failures. A total of 115 Chinese CHB patients with suboptimal response to two or more NA treatments were included in this study. All patients were changed to TDF (300 mg/day, oral administration) antiviral treatment for at least 72 weeks. Hepatitis B virus (HBV) polymerase (P) gene mutation screening for each patient was performed. In addition, virological, biochemical responses and estimated glomerular filtration rate (eGFR) of each patient at weeks 12, 24, 48 and 72 of TDF treatment were evaluated. Seventy-six out of 115 patients had drug-resistance mutations (R(+) ), including 27 with adefovir (ADV)-associated mutations (35.5%) and 49 with lamivudine (LMV)-associated mutations (64.5%). For all included patients, complete viral response (CVR) of HBV DNA (<100 IU/mL) was 57.4%, 69.6%, 74.8% and 86.1% at weeks 12, 24, 48 and 72 of TDF treatment, respectively. Alanine aminotransferase normalization and hepatitis B e-antigen seroclearance occurred in 77.3% and 23.2%, respectively, after 72-week TDF treatment. CVR at weeks 12, 24 and 48 was observed more commonly in patients with baseline HBV DNA of less than 10(6) IU/mL. There was no significant reduction of eGFR induced by the TDF treatment. Seventy-two-week treatment with TDF in Chinese CHB patients with previously multiple NA treatment failures exhibited effective and safe outcomes, which were independent of baseline mutations conferring ADV or LMV resistance.

Prediction of prognosis to lamivudine in patients with spontaneous reactivation of hepatitis B virus-related acute-on-chronic liver failure: Using virologic response at week 4

Background/aimsCurrent results had demonstrated lamivudine (LAM) contributed to improve liver function and short-term prognosis in patients with hepatitis B virus-related acute-on-chronic liver failure (ACLF), but data concerning the outcome of long-term prognosis are limited. Our objective was to explore the prediction value of early viral response for prognosis and LAM resistance in ACLF patients with lamivudine treatment within 96weeks. MethodsOne hundred and forty consecutive subjects were recruited, 76 patients were treated with LAM and supportive treatment (LAM group) and 64 patients only received supportive treatment (non-NAs group). All the patients were followed up until death or 96weeks. The primary end point was overall survival rate at 96weeks, as well as the relationship between the virologic response at weeks 4 or 12 and prognosis and resistance at 96weeks. ResultsAt 96weeks, the cumulative survival was higher in the LAM group than that in the non-NA group (43/76 (56.58%) vs 9/64 (14.06%), respectively, p=0.000). The survival rate of patients achieved complete viral response (CVR) at week 4 was higher than that of those with partial virologic response (PVR) during the 96-week follow-up (27/29 [93.10%] vs 16/45 [35.56%], p=0.000). In CVR patients, there was a significant improvement in model for end-stage liver failure (MELD) scores compared to PVR. Logistic recurrence indicated that both 4-week CVR and MELD scores were an independent predictor of the 96-week survival. Twelve patients developed LAM resistance (22.22%); all of them came from the PVR at 4weeks. ConclusionLAM can significantly improve the long-term survival rate, and 4weeks CVR can predict the long-term clinical outcome and LAM-resistant in patients with HBV-related ACLF.

Dynamics of lamivudine-resistant hepatitis B virus strains in patients with entecavir rescue therapy

Entecavir rescue therapy is frequently used in patients with lamivudine-resistant hepatitis B virus (HBV) strains. The aim of this study was to investigate evolutionary patterns of HBV quasispecies during entecavir rescue therapy and evaluate their impacts on therapeutic efficacy. We enrolled 21 chronic hepatitis B patients who failed to respond to lamivudine therapy and were switched to entecavir treatment. Measurement of serum HBV DNA and sequence analysis of HBV reverse transcriptase were done up to 144 weeks. Four patients of this series showed a reversion to wild-type HBV after entecavir treatment and in three of them, a complete viral response (<2.6 log10 copies/ml) was achieved. An additional five patients developed entecavir genotypic resistance, with prior occurrence of lamivudine-resistant mutation (L180 M ± M204 V/I). A viral breakthrough was observed in four of the five patients with entecavir-resistant mutants. The remaining 12 patients of this series showed dominance of lamivudine-resistant mutants throughout the entecavir rescue therapy, and five of them achieved a complete viral response at the end of follow-up. The average HBV DNA level was significantly lower in patients with a reversion to wild-type HBV than in those without it (P < 0.05). In conclusion, reversion to wild-type HBV is a favorable indicator for response to entecavir rescue therapy in lamivudine-refractory patients with chronic hepatitis B. The presence of lamivudine-resistant mutations contributes to the development of entecavir resistance.

Regression of a case of Multiple Myeloma with antiviral treatment in a patient with chronic HCV infection

We report a case of a 54 year old patient with Multiple Myeloma (MM) and chronic HCV infection. In 2005 MM was diagnosed and a chemotherapy was prescribed. Before starting treatment a chronic HCV infection was found. When she came to our Institution for a second opinion, chemotherapy treatment was not considered immediately necessary so the patient was treated for the HCV chronic infection (Pegilated alpha-Interferon 180μg/week and Ribavirin 1000mg p.o./day). After one month of treatment she presented a reduction of Bence Jones protein (BJ) that further decreased in the following three months. The antiviral treatment was suspended after six months and a re-evaluation showed a complete viral response and a regression of MM. Sixty-eight months after the end of antiviral treatment the patient is asymptomatic and presents a condition compatible with an M-GUS. While the association between HCV infection and non-Hodgkin's lymphoma is consolidated and it is clearly demonstrated that antiviral treatment in these patients can induce a high proportion of partial and complete remission, a similar effect was never described in MM. The response obtained in our patient may suggest a possible a role of HCV in the pathogenesis of MM.

Etravirine: A Guide to Its Use in Treatment-Experienced Pediatric Patients with HIV-1 Infection in the US

Etravirine (Intelence®), an oral next-generation non-nucleoside reverse transcriptase inhibitor (NNRTI), is approved for the treatment of HIV-1 infection in treatment-experienced patients. In the US, the approved use of etravirine in patients who have evidence of viral replication and harbor HIV-1 strains resistant to other antiretroviral agents has recently been expanded to include pediatric patients aged ≥ 6 to <18 years. At 24 and 48 weeks in an open-label trial, etravirine 5.2 mg/kg twice daily (maximum dosage 200 mg twice daily) plus an optimized background therapy regimen achieved complete viral response (defined as HIV-1 RNA <50 copies/mL) in approximately half of treatment-experienced children and adolescents with HIV-1 infection and evidence of viral replication, and had an acceptable tolerability profile.

Clinical course and predictive factors of virological response in long‐term lamivudine plus adefovir dipivoxil combination therapy for lamivudine‐resistant chronic hepatitis B patients

The aims of this study were to assess the long-term efficacy of lamivudine (LAM) plus adefovir dipivoxil (ADV) combination therapy in patients with chronic hepatitis B resistant to LAM, to identify predictive factors of complete viral response (HBV-DNA <2.6 log copies/ml at 12 months of combination therapy), and to analyze amino acid substitutions associated with treatment resistance in the hepatitis B virus (HBV) genome. Seventy-two patients who received ADV in addition to LAM for breakthrough hepatitis were enrolled. Undetectable HBV-DNA was observed in 61%, 74%, 81%, 84%, and 85% at 12, 24, 36, 48, and 60 months of combination therapy, respectively. On multivariate analysis, undetectable HBV-DNA during the preceding LAM monotherapy (P < 0.0001), alanine aminotransferase value ≥ the upper limit of normal × 6 (P = 0.006) and HBV-DNA level < 6.0 log copies/ml at the initiation of combination therapy (P = 0.007) were independent significant predictors of complete viral response. The cumulative rate of undetectable HBV-DNA was significantly higher in patients with response to the preceding LAM monotherapy than in those with poor response to it. Breakthrough hepatitis occurred in three patients without complete viral response and with poor response to the preceding LAM monotherapy, and rtA181A/V substitution was detected in one of the three patients. In conclusion, undetectable HBV-DNA during the LAM monotherapy was the strongest independent predictor of complete viral response to the following combination therapy. The efficacy of LAM plus ADV combination therapy may be determined by viral response to the preceding LAM monotherapy.

Maraviroc in treatment-experienced patients with HIV-1 infection - experience from routine clinical practice

ObjectiveFew data are available about the efficacy of maraviroc (MVC) during routine use. We characterized indications for MVC use and the efficacy of MVC in clinical practice.MethodsThirty-two patients treated with MVC at our institution between 2006 and 2009 were included. Genotypic (n = 31) and phenotypic (n = 13) tropism analysis was performed. We determined indications for MVC use, characteristics of antiretroviral combination partners and treatment outcome.ResultsComplete suppression of viral replication was achieved in 78% after 6 months. A median increase of 124 CD4+ cells/μl after 6 months was observed. Concordance between phenotypic and genotypic tropism was found in 75%. Indications for MVC treatment included treatment failure (n = 15), intolerance to previous antiretrovirals (n = 6) and add-on MVC for intensification without changing the current regimen (n = 11). The add-on strategy was used in patients with a relatively low viremia in order to achieve complete viral load suppression or in situations with suppressed viral load but judged as unstable due to an extensive resistance pattern. Salvage drugs most frequently combined with MVC were darunavir (n = 14) and raltegravir (n = 14).The genotypic assay had predicted CXCR4 tropism in 5 patients, using a false positive rate (FPR) of 20%. Lowering the FPR to 5% predicted CCR5 tropism in 4 cases, still resulting in sustained complete viral response under MVC use.ConclusionsMVC containing salvage regimens achieve relevant CD4 cell increases and high viral response rates. In patients with few remaining treatment options it may be justified to lower the FPR-cutoff to 5% when predicting the coreceptor usage. Hereby, MVC could still be applied in selected patients with otherwise limited treatment options.

Emergence of hepatitis B virus quasispecies with lower susceptibility to nucleos(t)ide analogues during lamivudine treatment

We studied the impact of hepatitis B virus (HBV) polymerase/reverse transcriptase (Pol/Rt) heterogeneity on adefovir rescue therapy in 34 consecutive chronic hepatitis B patients with viral breakthrough during lamivudine monotherapy. The Pol/Rt A-F domains were directly sequenced in all patients at baseline, and 12 and 24 months. Response to therapy was evaluated at 3, 6, 12 and 24 months by quantitative HBV-DNA. Primary treatment failures did not occur. At 6 months 24/34 (70.6%) patients had viraemia<10(4) copies/mL [initial viral response (IVR)]; at 12 and 24 months 23 (71.9%) and 26 (81.3%) of 32 had HBV-DNA<200 copies/mL [complete viral response (CVR)]. IVR or CVR patients did not show viral breakthroughs, which occurred in one of the six remaining patients. All but three patients had baseline rtM204I/V substitutions associated with rtL180M in 23, rtL80I/V in 14, rtV173L in 4, rtT184S in 3, rtQ215S in 2 and rtA181S in 2 cases. rtA181S without rtM204I/V was found in one patient. Four of the six patients (67%) without 24 month CVR showed rtA181S or rtT184S substitutions either alone or with typical lamivudine resistance profiles. Baseline HBV-DNA levels were negatively associated with IVR (univariate analysis, P=0.023). At least one of rtA181S and rtT184S substitutions correlated negatively with IVR and CVR (univariate analysis, P=0.001) and was independently associated with absence of CVR (P = 0.016). Lamivudine monotherapy favours the emergence of viral quasispecies that influence the response rate to adefovir rescue therapy independently from baseline viraemia and lower the susceptibility to other nucleos(t)ide analogues.

Changes in hypervariable region 1 in patients with chronic hepatitis C of genotype 1b with biochemical response to interferon

Background/aims: The outcome of interferon (IFN) therapy of hepatitis C virus (HCV) infection can be classified as a complete viral response (CR), biochemical response (BR), or no response (NR). Why alanine aminotransferase (ALT) activity decreases in patients with BR despite viral persistence is unknown. Methods: Of 158 patients infected with HCV genotype 1b, all 20 patients with BR and 20 of the 114 patients with NR, matched for viral load to the BR group, were studied. We sequenced nucleotides in the hypervariable region (HVR) of serum HCV RNA, and analyzed quasispecies of this region by the polymerase chain reaction and single-strand conformation polymorphism (PCR-SSCP). Results: In HVR 1, SSCP patterns differed after therapy; the major clone before therapy disappeared with therapy in eight of the 20 BR patients, but in none of the 20 NR patients ( P=0.0033; Fisher's exact test). PCR products of HVR 1 from six patients were cloned before and after therapy, and 40 clones from each patient were sequenced each time. Results of cloning and sequencing were generally consistent with those of SSCP. For the six patients, a major clone could be identified both before and after therapy. In two patients with BR, there were many changes in the amino acid sequence of the major clone after IFN; in one patient with NR, mutations were not found. Conclusion: Changes in the major viral clone with IFN treatment may be related to the decrease in ALT activity in some patients, in spite of the continued presence of HCV RNA.