PDF superior New approaches in the treatment of hepatitis C.

16 Lawitz E, Lalezari JP, Hassanein T, Kowdley KV, Poordad FF, Sheikh AM, Afdhal NH, Bernstein DE, Dejesus E, Freilich B, Nelson DR, Dieterich DT, Jacobson IM, Jensen D, Abrams GA, Darling JM, Rodriguez-Torres M, Reddy KR, Sulkowski MS, Bzowej NH, Hyland RH, Mo H, Lin M, Mader M, Hindes R, Albanis E, Symonds WT, Berrey MM, Muir A. Sofosbuvir in combination with peginterferon alfa-2a and ribavirin for non- cirrhotic, treatment-naive patients with genotypes 1, 2, and 3 hepatitis C infection: a randomised, double-blind, phase 2 trial. Lancet Infect Dis 2013; 13: 401-408 [PMID: 23499158 DOI: 10.1016/S1473-3099(13)70033-1]

nary approach helps ensure these psychiatric complica- tions are adequately treated. Before the implementation of multidisciplinary management, our hepatologists treat- ed mild psychiatric disorders themselves with antide- pressants or benzodiazepines, sometimes after delays. Antiviral treatment was discontinued when patients de- veloped severe psychiatric complications. Including a psychiatrist in the multidisciplinary team enabled us to detect and treat psychiatric complications promptly, pre- venting the development of more severe symptoms that would have required us to stop antiviral treatment. Other studies have shown that HCV-infected patients with sta- ble psychiatric disease can be safely treated with pegylat- ed interferon plus ribavirin. 22,24,25 Cabré, et al. 22 showed

The presence of hepatitis C virus (HCV) can be demonstrated by direct detection techniques using monoclonal antibodies that recognize specific viral antigens. Chemiluminescent substrates and photometry are used frequently, given the high sensitivities achieved. Although HCV infection does not induce high viremia, attempts to develop procedures for antigen detection in serum date back to 1992 (Katayama et al., 1992; Tanaka et al., 1995; Kashiwakuma et al., 1996; Orito et al., 1996; Tanaka et al., 1996; Jolivet-Reynaud et al., 1998; Masalova et al., 1998; Kobayashi et al., 1998). The target of these assays was the core protein of HCV, since it is the most abundant protein in the virion and its immunodominant epitopes are well-conserved in different strains. Although the performance of these methods seemed promising, it was not until 1999 that the first useful report was published. In the original description (Aoyagi et al., 1999), this method was able to detect antigen concentrations of up to 0.06 pg/ml, roughly 500 copies per ml. Moreover, it was able to detect infections in any serotype. The correlations with the PCR techniques ranged from 94% to 96%. The presence in the sample of substances, such as anticoagulants, hemoglobin, rheumatoid factor, bilirubin or lipids, that could possibly interfere with these assays had no effect on the method. The linear response range was broad and the coefficient of variation between 4% and 7.9%. After the optimization and standardization of the use of detergents (Peterson et al., 2000), a new method for the detection of core antigen in serum was developed. This method was able to detect viremia in all stages of infection and not only in the antibody negative window phase. In the first studies, the cutoff value was 2.3 pg/ml, which was equivalent to 50,000 IU/ml, measured by PCR (Icardi et al., 2001). However, more recent studies have demonstrated that it is possible to reduce the cutoff value of the assay to 1.5 pg/ml without loss of specificity (Zanetti et al., 2002; Picchio, 2002). The present study aims to assess the clinical usefulness of this new technique for monitoring patients under treatment for chronic HCV infection.

The relationship between the change in inflamma- tion and the change in fibrosis for patients with SVR is illustrated in figure 5. A decline in the inflammation score was associated with a linear de- cline in hepatic fibrosis. Seventeen percent (20/122) of patients either had no change or an increase of 1-4 points (6 patients) in the hepatic inflammation score after being HCV RNA undetectable in serum for at least 5 years. Only 4 of these 20 patients had a decline in the fibrosis score. No baseline features differentiated patients who failed to have a decline in hepatic inflammation from those that did have a decline in inflammation after achieving SVR. Specifi- cally, there were no significant differences in base- line serum ALT, serum HCV RNA level, the total inflammation score, piecemeal necrosis score or fi- brosis score. All patients who failed to have a decline in inflammation also remained persistently HCV RNA undetectable in serum by Taqman PCR.

CD81, a member of the tetraspanin superfamily of cell surface molecules and expressed on virtually all cells, is the putative receptor for HCV entry into the host cell, since this molecule strongly interacts with E2 as well as virus particles in vitro. The virus may also be able to enter the cell by binding to low-density lipo- protein (LDL) receptors. But whether interaction with the LDL receptor or CD81 leads to internalization and a productive infection remains to be determined. Based on comparison with fusion peptides of paramyxoviruses, E1 may be involved in membrane fusion. The low pH within the endosomal compart- ment may induce a major structural rearrangement of the E1, resulting in exposure of a fusion peptide which destabilizes membranes, leading to membrane fusion and particles entry into the cytoplasm. 4

In 2004, Shu, et al. reported their success in trea- ting 11 renal transplant recipients with active hepa- titis C with “ultra-low dose” interferon-alpha (1 x 10 units subcutaneously three times/week) and riba- virin (600 mg/day). After 48 weeks of treatment, all patients except one (91%) had a biochemical respon- se, with normalization of serum ALT level at a me- dian of 1.1 months post-treatment. Five patients (45%) were HCV RNA negative at the end of treat- ment, while three (27%) had a sustained virological response. No histopathologic data was reported, as no liver biopsies were taken. Only one patient (9%) terminated the treatment due to acute graft failure, who was subsequently treated using methylpredni- solone with restoration of graft function. The au- thors concluded that ultra-low dose interferon-alpha and ribavirin was relatively safe for the treatment of chronic HCV infection in renal transplant reci- pients, with a significant portion of patients achie- ving a sustained biochemical and virological response. 59 In 2006, Sharma, et al. administered in-

The goal of treatment for chronic hepatitis C viral (HCV) infection is to cure the infection rather than suppress the virus. Historically, a sustained virological response (SVR) defined as undetectable HCV RNA at 24 weeks following the completion of treatment was considered the gold standard to define successful eradication of the virus as a primary endpoint in clinical trials. SVR measured at 12 weeks post-treatment has been shown to be highly concordant with SVR24 in trials of pegylated interferon and ribavirin. The appropriateness and durability of SVR12 as the efficacy endpoint with new oral direct-acting antivirals is less established. A literatu- re search was performed using PubMed, EMBASE and CENTRAL databases to identify any studies that examined the concordance between SVR24 and earlier time points. Two studies and 4 abstracts were found that performed concordance analyses using positive and negative predictive values. Overall, SVR4 and SVR12 were highly concordant with SVR24 with high positive (> 97%) and negative (> 94%) predictive values; however there was a higher risk of HCV relapse occurring after post-treatment week 4. The majority of the data focused on SVR12 and demonstrated that SVR12 reliably predicted SVR24 in several populations infected with HCV (treatment-naïve, prior null responders, different genotypes) using various new oral direct-acting antiviral regimens. In conclusion, the available data suggests that SVR12 is a reliable assessment of HCV eradication and could be used instead of SVR24 for drug development clinical trials assessing efficacy of new direct-acting antivirals. Data on the long-term durability of SVR12 is still needed. Key words.

elicit an efficient immune response. Passive, antigen- specific immunotherapies involve the use of the immune system components that are already able to promote an immune response against a specific antigen. Cell-based and antibody-based approaches have been developed for this purpose. The adoptive cell transfer basically com- prises the transfer of TILs to patients because there is wide evidence that these immune cells participate in tumour regression in different solid tumours. 51 TILs are obtained from tumours and are cultured with IL-2 to promote the expansion of the tumour antigen-specific T cells. After 6 or 8 weeks of culture, the increased number of cells can be transferred into the host where TILs local- ize to the tumour and start an in situ anti-tumour reac- tion. 35 The use of antibodies generated ex vivo against a particular antigen works also as an adoptive transfer of immunity that generates a specific humoral response. This approach has been widely used for the treatment of diverse types of cancer as will be discussed below. The active specific treatments require host immune- competence and involve the use of vaccines. Several types of vaccines are being developed, from purified antigen vaccines to polyvalent antigen vaccines, depending on the immunotherapy purpose. The main challenge is to gener- ate an immune response to a variety of tumour antigens at the same time. Briefly, the main vaccine subtypes developed so far are (i) tumour antigen-based, (ii) pep- tide-based, (iii) dendritic cell-based, (iv) vector-based and (v) idiotype-based vaccines (for an exhaustive revision see ref. 35). Hobo et al., 52 developed a dendritic cell (DC)-based vaccine with improved immunogenic poten- tial by transfecting DCs with the small-interfering RNAs (siRNAs) of PD-1 ligands combined with a target antigen mRNA electroporation. They could specifically silence PD-L1 and PD-L2 with high efficiency and keep the phe- notype and migratory capacity of DCs using a lipid

5. (a) Vaquero, J. J.; Alvarez-Builla, J. Advances in Nitrogen Heterocycles; 2000; Vol. 4, pp 159–250; (b) Valenciano, J.; Cuadro, A. M.; Vaquero, J. J.; Alvarez-Builla, J. Tetrahedron Lett. 1999, 40, 763–766; (c) Crabb, D. L.; McCullough, K. J.; Preston, P. N.; Rosair, G. M.; Bishop, B. C.; Wright, S. H. B.; Clegg, W.; Coles, S. J. Chem. Soc., Perkin Trans. 1 1999, 1517–1526; (d) Bishop, B. C.; Marley, H.; Preston, P. N.; Wright, S. H. B. J. Chem. Soc., Perkin Trans. 1 1999, 1527–1532; (e) Schmidt, A.; Martin, N. Heterocycles 2001, 55, 827–834; (f) Butler, N. R.; Wallace, L. M. J. Chem. Soc., Perkin Trans. 1 2001 , 1778–1784; (g) Valenciano, J.; Sanchez-Pavon, E.; Cuadro, A. M.; Vaquero, J. J.; Alvarez-Builla, J. J. Org. Chem. 2001 , 66, 8528– 8536; (h) Schmidt, A. J. Heterocycl. Chem. 2002, 39, 949–956; (i) Kappel, J. C.; Yokum, T. S.; Barany, G. J. Comb. Chem. 2004, 6, 746–752; (j) Dietrich, M.; Matthias, N. Heterocycles 2004, 63, 2605–2614; (k) Butler, R. N.; Fahy, A. M.; Fox, A.; Stephens, J. C.; Cunningham, D.; Ryder, A. J. Org. Chem. 2006, 71, 5679–5687; (l) Moderhack, D.; Noreiks, M. Heterocycles 2006, 68, 2113–2122; (m) Valenciano, J.; Sanchez-Pavon, E.; Cuadro, A. M.; Alvarez-Builla, J.; Vaquero, J. J. Eur. J. Org. Chem. 2007 , 15, 2423–2429.

APROVVIE is a multicenter, observational study per- formed by the Association Nationale des Gastroentéro- logues des Hôpitaux généraux (ANGH) in French general hospitals. This study included consecutive adult patients (≥ 18 years old) treated for chronic hepatitis C (CHC) to evaluate the efficacy of and tolerance to treatment in real- life conditions. This study began on October 10, 2012. Af- ter July 4, 2014, investigators could include patients treated with new DAAs, first for early access programs, and then in daily practice.

molecular level, HCV decreases glucose transport into cells by down-regulating glucose transporter receptor (GLUT2). The virus also up-regulates expression of genes for phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6P-ase), which are integral en- zymes within the hepatic gluconeogenesis pathway. HCV also induces degradation of insulin receptor substrate (IRS), which blocks intracellular insulin signaling. Clear- ance of the virus has been shown to result in improved IR as measured by reduction in homeostasis model of assess- ment (HOMA) value, suggesting the virus itself plays a significant role in mediating IR. 1,13,15

We face the opposite problem in patients with HCV- genotype 1 who are still difficult to treat. Extending the treatment duration beyond 48 weeks is one strategy that may improve response rates in these difficult-to-treat pa- tients. The rationale is to extend the time of HCV-RNA negativity, especially in patients with a slow viral decline (first time HCV-RNA negative between TW12 and TW24) to reduce the relapse rate in these patients. Sever- al studies investigated the efficacy and safety of 48 weeks versus 72 weeks of treatment with PEG-IFN plus ribavi- rin in patients with chronic hepatitis C. Sanchez-Tapias and colleagues reported a benefit of an extended therapy in patients who were HCV-RNA positive at treatment week 4. The relapse rate after 72 weeks of therapy was significantly reduced in these patients. 14 However, a treat-

In summary, all HIV-positive persons with chronic HCV infection should be considered as potential candi- dates for anti-HCV therapy, given their higher risk of pro- gression to end-stage liver disease and increased risk of liver toxicity after beginning antiretroviral therapy, com- pared to HIV-negatives. The timing for anti-HCV treat- ment should be decided on an individual basis. Severe neuropsychiatric disorders, alcohol and drug abuse and advanced liver cirrhosis contraindicate current anti-HCV treatment. However, methadone use and early cirrhosis are not contraindications for therapy. Treatment of pa- tients with CD4 counts below 200 cells/mm 3 is risky and

Besides simeprevir and sofosbuvir, several other DAA agents are currently in late stages of development. Most will be used without interferon and some even without ribavirin. The majority will not use response guided therapy and will de- pend on a fixed regimen with a total duration of usually no more than 12 weeks. Side effect profile looks very promising, but the number of patients tested is still small and few cirrhotics have been included. At the moment of this writing, none of these second and third wave agents has yet sent the “new drug application” request to the FDA. Notwithstanding, it is a fact that many of them are also receiving the fast-track analysis status from the FDA and could be commercially availa- ble, at least in the United States and parts of Europe, as early as the end of 2014 or early 2015. The main companies and drug combinations that make the bulk of the third wave anti-HCV DAA agents are listed below:

appeared to be almost completely equivalent clinically. No clinical evidence was found to indicate that African Americans should more often than other racial groups be deemed ineligible for HCV treatment. The findings sug- gest that an underlying contributor to the HCV treatment eligibility disparity disfavoring African Americans could be racial discrimination. Future research should seek to determine if clinicians are inadvertently allowing their own subjective and socially-constructed biases about Afri- can Americans that are contrary to empirical data to influ- ence their decision-making in HCV treatment eligibility determination. Identifying and correcting such as- sumptions among HCV clinicians may be needed to counter this discriminatory pattern. Racially discriminatory practice in the allocation of HCV treatment represents an important area of research, because barriers that inhibit equal opportunity for African American HCV patients to receive curable benefits of DAAs must be addressed and corrected. Otherwise, African Americans will continue to suffer from HCV-related liver complications and death at a greater rate than other racial groups in the US.

The other study was performed by Siebert and Sroc- zynsky as part of the German team for hepatitis C mod- el (GEHMO), as commissioner of Federal Germany Health and Social Security Ministery. This systematic review of published evidence was undertaken to deter- mine the efficacy and cost-effectiveness of antiviral treatment with interferon or pegylated interferon com- bined with ribavirin in treatment-naïve patients chron- ically infected with HCV. A series of meta-analyses was made, and evidence tables were constructed. The Markov model of hepatitis C was applied to determine the long-term clinical efficacy, costs, and cost effec- tiveness of the therapeutic strategies. The model pa- rameters were derived from German databases consist- ing of nine controlled randomized studies, two health technology evaluations, a Cochrane review, two meta- analyses, and seven economic evaluations. The meta- analysis showed that the proportion of nonresponders was reduced by 17% by the combination of pegylated interferon and ribavirin, which had an adjusted in- creasing cost of •9,800 per AVAC. This suggests that in treatment-naïve, chronic hepatitis C virus carriers, the combination of pegylated interferon and ribavirin is the most efficient and cost-effective treatment (Ta- ble II) and that it increases survival and improves quality of life. 34

showed that age ≥ 60 years was predictive of poor treatment response. Controversy exists whether older age unfavorably affects the response to HCV treatment12. A wide variation in SVR rates among older patients has been reported in the literature (22 to 52%). These discrepant results can be attributed to study heterogeneity, different age limits, and small sample size, among others. Surprisingly, Huang, et al. 3 reported an SVR rate of 51.9% in 27 patients ol-

Background and aim. Grazoprevir is an NS3/4A protease inhibitor (PI), while elbasvir is an NS5A inhibitor. We performed this meta-analysis to directly compare grazoprevir plus elbasvir and ribavirin regimen vs. grazoprevir and elbasvir without ribavirin in the treatment of hepatitis C virus genotype 1 infection and to precisely evaluate the efficacy of the latter regimen in cirrhotic, IL28 CC genotype patients and those coinfected with human immunodeficiency virus. Material and methods Material and methods Material and methods Material and methods Material and methods. A computer literature search of PubMed, Scopus, EBSCO, Embase, and Cochrane central was conducted. Studies were screened for eligibility. Sus- tained virologic response (SVR) rates were pooled using OpenMeta [Analyst] software for windows. A subgroup analysis was per- formed to stratify the treatment efficacy according to the different baseline characteristics of HCV patients. Results. Results. Results. Results. Results. Eight randomized controlled trials (n = 1,297 patients) were pooled in the final analysis. The overall SVR rate was 96.6% with 95% CI [95.5% to 98%]. For cirrhotic patients, the SVR rate was 95.7% with 95% CI [93.9% to 97.5%] and for non-cirrhotic patients, the SVR rate was 97% with 95% CI [95.9% to 98.4%]. Furthermore, the addition of ribavirin (RBV) to the treatment regimen did not significantly improve the SVR (RR 1.003, 95% CI [0.944 to 1.065]).The dual regimen was effective in patient populations with NS3 resistance-associated substitution (RAS). However, this regimen achieved lower SVR rates (< 90%) in patients with NS5A RAS. Conclusions.

In practice, much depends on the sympathy of the ministry involved, the degree of influence enjoyed by women’s advocates and NGOs, and the objectives of the programmes concerned. While feminist NGOs have pioneered projects that incorporate equality principles, and have been able to develop their own research capacity considerably in recent years allowing closer attention to women’s needs, the evidence shows that they have less impact on policy than on local or small-scale project design. Women’s organizations find it hard to make an impact on social policy provision and on the fast-proliferating antipoverty programmes, and many do not even try, preferring to remain “outside power”. A history of co-option and clientelization of women’s movements by political parties, exemplified in the Peruvian case examined later, tends to deepen the divisions between those who work “in the state” and “against the state”, limiting the scope for cooperation in this vital area for equality interventions. It remains the case in the Latin American region that most policy makers see no need to incorporate a gender analysis in their poverty programmes, reasoning that policies benefiting the poor “necessarily benefit women”, eliding women with poverty in a simple reduction that exports gender analysis altogether. This attitude reportedly surfaced even in a context of an active feminist movement in relation to Brazil’s Bolsa Escola programme. Yet, as Jackson (1998:39) has argued, the concept of poverty cannot serve as a “proxy for the subordination of women”. It would not be unfair, given this scenario, to conclude that despite the formal recognition of the gender- poverty link, many antipoverty programmes have remained for the most part innocent of gender analysis; there is little to distinguish them in this regard from their antecedents in the “women and poverty” approach identified by Moser (1993), which was premised on the assumption that it was enough to integrate women into development programmes. Yet, if programmes fail to problematize gender relations, they risk perpetuating gender inequalities not least by remaining locked into norms of public culture based on conceptions of femininity and gender relations that fail to correspond to the realities of most poor women’s lives.

Hepatitis A virus (HAV) is the most common cause of acute viral hepatitis worldwide. The virus is mainly transmitted via the fecal- oral route and, the incidence of infection is closely related to low socioeconomic conditions and poor sanitation. Mexico, previously categorized an area of high endemicity for HAV infection, is undergoing epidemiological transition. However, a limited number of HAV-related scientific reports regarding to virus burden is available. According to the local government health agency (Secretaría de Salud, SSA in Spanish), from 1994 to 2017 a reduction in the incidence of hepatitis related to HAV has been reported. However, HAV is still the most common cause of viral hepatitis in the country, and the pediatric population is the most prone to be infected with this virus. The analysis of the SSA data reveals that most of the reported cases from 1994 to 2017 were found in highly indus- trialized states. This information contradicts the documented relationship between the highest prevalence of infection and the lowest socio-economic status, and supports the necessity of viral detection and notification of HAV cases. Moreover, in spite that four HAV vaccines are available in Mexico and universal vaccination has been shown to be beneficial in developing countries in terms of declining endemicity, HAV vaccination is not mandatory in Mexico. In this review, preventive strategies including appropriate diagno- sis, vaccination and public health policies on the basis of the epidemiologic status of HAV in Mexico are discussed.