Introduction Of Triple Therapy Research Articles

The preclinical discovery and development of the combination of ivacaftor + tezacaftor used to treat cystic fibrosis

ABSTRACT Introduction Cystic Fibrosis (CF) is caused by mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene. The most common mutation, F508del, induces protein misprocessing and loss of CFTR function. The discovery through in vitro studies of the CFTR correctors (i.e. lumacaftor, tezacaftor) that partially rescue the misprocessing of F508del-CFTR with the potentiator ivacaftor is promising in giving an unprecedented clinical benefit in affected patients. Areas covered Online databases were searched using key phrases for CF and CFTR modulators. Tezacaftor–ivacaftor treatment has proved to be safer than lumacaftor–ivacaftor, although clinical efficacy is similar. Further clinical efficacy has ensued with the introduction of triple therapy, i.e. applying second-generation correctors, such as VX-569 and VX-445 (elexacaftor) to tezacaftor–ivacaftor. The triple combinations will herald the availability of etiologic therapies for patients for whom no CFTR modulators are currently applied (i.e. F508del/minimal function mutations) and enhance CFTR modulator therapy for patients homozygous for F508del. Expert opinion CF patient-derived tissue models are being explored to determine donor-specific response to current approved and future novel CFTR modulators for F508del and other rare mutations. The discovery and validation of biomarkers of CFTR modulation will complement these studies in the long term and in real-life world.

Emerging Trends in Non-Interferon-Based Genotype-Specific Antiviral Agents: Pharmaceutical Perspectives.

Hepatitis C virus (HCV) presents a serious global health threat. Initially, the health-care community mainly focused on interferon (IFN)-based therapeutic options to eradicate HCV, but with the passage of time, these applications became unsuitable due to some serious side effects related to the use of IFN. In recent years, research conducted on different phases of HCV's life cycle has opened a new gateway for the use of a direct-acting new generation of anti-HCV agents. Their safer and ultrarapid response has made possible the introduction of triple therapy and use of IFN-free therapeutic treatment strategies. However, the high cost of these successful therapies has raised serious concerns, particularly in low-income countries, and this has forced pharmaceutical scientists to explore more cost-effective IFN-free alternatives for the treatment of HCV. In this article, we have briefly summarized the latest data regarding the research and development of non-IFN-based antiviral agents. The studies mentioned in this article highlight the significance of non-IFN-based direct-acting antiviral (DAA) agents. Economical alternative anti-HCV agents are expected to become available in the near future for better and more cost-effective treatments of HCV.

Cost-effectiveness analysis of simeprevir in combination with peginterferon and ribavirin for treatment-naïve chronic hepatitis C genotype 1 patients in Japan

Aim:Simeprevir (SMV), a protease inhibitor, recently became available for the treatment of chronic hepatitis C (HCV) genotype 1 patients in Japan. The introduction of triple therapy using SMV in combination with peginterferon and ribavirin (PR) significantly improves the cure rate. The aim was to assess the cost-effectiveness of SMV with PR (SMV/PR) compared to telaprevir with PR (TVR/PR), PR alone, or no treatment in treatment-naïve patients in Japan.Methods:A Markov model was developed to reflect the natural disease progression of HCV and to estimate the average life years and lifetime healthcare costs per patient. Sustained virologic response rates were obtained from a network meta-analysis including randomized clinical trials conducted in Japan. Patient baseline characteristics, HCV progression rates, mortality, medical resource utilization, and unit costs were obtained from Japanese sources. Outcomes were reported as incremental cost-effectiveness ratios as well as incremental cost and life years. Various sensitivity analyses were conducted to assess the uncertainty around model outcomes.Results:SMV/PR was estimated to be a cost-effective treatment option as more life years were gained by 0.235 and 0.873 years at a reduced cost by ¥263,037 and ¥776,900 compared to TVR/PR and PR alone, respectively. The results were robust to sensitivity analyses, in particular in the comparison of SMV/PR with PR alone. The multivariate probabilistic sensitivity analyses showed that the probability of SMV/PR being cost-effective was relatively constant at ∼87% at any willingness to pay.Conclusions:SMV/PR is estimated to be the most cost-effective treatment strategy for treatment-naïve HCV genotype 1 patients in Japan.

Time to AIDS from 1992 to 1999 in HIV-1-infected subjects with known date of infection.

To estimate the change in AIDS incubation time during three periods characterized by different availability of antiretroviral treatments, data from the French Hospital Database on HIV of 4702 HIV-1-positive subjects with a documented date of infection were analyzed. Times from seroconversion to AIDS were compared in three periods: period 1 from January 1992 to June 1995 (monotherapy); period 2 from July 1995 to June 1996 (dual therapy); and period 3 from July 1996 to June 1999 (triple therapy). Nonparametric survival analyses were performed to account for staggered entries in the database and during each period. From periods 1 to 3, antiretroviral treatments were initiated earlier after infection, more subjects were treated, and the nature of regimens changed (25.6% of subjects were treated with monotherapy in period 1, 34.6% were treated with dual therapy in period 2, and 53.4% were treated with triple therapy in period 3). Compared with period 1, the relative hazard (RH) of AIDS was 0.31 in period 3 (95% confidence interval [CI]: 0.24-0.39). When comparing period 3 with period 2, the RH of AIDS was 0.36 (CI: 0.29-0.45). Assuming a log normal distribution, the median time to AIDS was estimated as 8.0 years in period 1 (CI: 6.0-10.6), 9.8 years in period 2 (CI: 8.5, 11.2), and 20.0 years in period 3 (CI: 17.1-23.3). This lengthening in time to AIDS from 1992 to 1999 was particularly marked in the period after the introduction of triple therapy, including protease inhibitors.

Consortium management of triple therapy cost pressures for HIV/AIDS in the North East of England

Reviews NHS policy for the introduction of new technology and drug developments into the NHS with reference to HIV therapy. Also reviews current policy issues related to NHS rationing and priority setting with reference to commissioning services for HIV infection and AIDS. Confirms the destabilisation of HIV contracts in the North East of England caused by the introduction of double therapy in 1996 and triple therapy in 1997 in relation to the above policy areas. Also reviews purchaser and provider contracting following the introduction of triple therapy for HIV infection. Finally, concludes by reviewing local policy and management arrangements and recommendations for change.

Changing trends in cytomegalovirus retinitis with triple therapy.

Cytomegalovirus retinitis (CMVR) has been the most common cause of visual loss in AIDS patients. We investigate whether the pattern of disease has changed since the introduction of triple therapy. We reviewed the records of all patients with CMVR in one teaching hospital HIV unit over a 2 year period (n = 24). This included the opthalmic and systemic findings, HIV and CMV treatment, survival after diagnosis and CD4 results. There has been a marked decrease in the number of patients developing new CMVR: from 21 eyes (15 patients) to 4 eyes (4 patients) in two consecutive 12 month periods between January 1996 and December 1997, coinciding with the introduction of triple therapy in October 1996. Median survival has increased from 376 days in the deceased patients to 598 days in the survivors on triple therapy. Median time to CMVR relapse has lengthened from 79 to 179 days in the triple therapy cohort. The pattern of ocular morbidity in the 11 eyes of the 7 surviving patients is also changing, with no new zone 1 disease, and a marked rise in the incidence of uveitis, maculopathy and cataracts. Results suggest that triple therapy is associated with an increase in survival, a decrease in CMVR relapse and changes in ocular features. This transition has implications for current screening and treatment protocols.

Different Outcome in the First Two Patients with an HIV-1 Multinucleoside Drug-Resistant T69SSS Insertion in Spain

A novel multidrug-resistance mechanism has been described in human immunodeficiency virus type 1 (HIV-1), which involves the insertion of 6 bp between codons 69 and 70 in the reverse transcriptase (RT) gene. Herein, we report the first two patients in Spain carrying viral populations with the 69-SS insert coupled to the T69S mutation. Both patients were selected because of the lack of signal at positions 69/70 in the LiPA RT test despite being reactive to the remaining probes on the LiPA strip. The presence of the T69SSS complex was confirmed by sequence analysis. A common feature for both subjects was their past history with zidovudine monotherapy and zidovudine plus either didanosine or zalcitabine later on in the presence of persistent virus replication. Remarkably, the introduction of triple therapy in patient 1 soon after the emergence of the insert-containing viral strain produced its total displacement, which correlated with a sustained suppression in viral load.