External validation of BIA equations to estimate appendicular skeletal muscle mass in older adults: Importance of the bias analysis and derivation of correction factors to achieve agreement.

There are several equations based on bioelectrical impedance analysis (BIA) to estimate with high precision appendicular skeletal muscle mass (ASM). However, most of the external validation studies have reported that these equations are inaccurate or biased when applied to different populations. Furthermore, none of the published studies has derived correction factors (CFs) in samples of community-dwelling older adults, and none of the published studies have assessed the influence of the dual-energy X-ray absorptiometry (DXA) model on the validation process. This study assessed the agreement between six BIA equations and DXA to estimate ASM in non-Caucasian older adults considering the DXA model and proposed a CF for three of them. This analysis included 547 non-institutionalized subjects over 60 years old from the northwest of Mexico who were physically independent and without cognitive impairment: 192 subjects were measured using DXA Hologic, while 355 were measured by DXA Lunar. The agreement between each of the equations and DXA was tested considering the DXA model used as a reference method for the design of each equation, using the Bland and Altman procedure, a paired t test, and simple linear regression as objective tests. This process was supported by the differences reported in the literature and confirmed in a subsample of 70 subjects measured with both models. Only six published BIA equations were included. The results showed that four equations overestimated ASMDXA, and two underestimated it (p < 0.001, 95% CI for Kim's equation:-5.86--5.45, Toselli's:-0.51--0.15, Kyle's: 1.43-1.84, Rangel-Peniche's: 0.32-0.74, Sergi's: 0.83-1.23, and Yoshida's: 4.16-4.63 kg). However, Toselli's, Kyle's and Rangel-Peniche's equations were the only ones that complied with having a homogeneous bias. This finding allowed the derivation of CFs, which consisted of subtracting or adding the mean of the differences from the original equation. After estimating ASM applying the respective CF, the new ASM estimations showed no significant bias and its distribution remained homogeneously distributed. Therefore, agreement with DXA in the sample of non-Caucasian was achieved. Adding valid CFs to some BIA equations allowed to reduce the bias of some equations, making them valid to estimate the mean values of ASM at group level.

Habitability, Resilience, and Satisfaction in Mexican Homes to COVID-19 Pandemic.

Following the 2020 confinement due to the COVID-19 pandemic, housing has become the only safe place and this has exposed inequity in habitability. This research on the reality of confined households and the perception of their homes in the Mexican republic is based on a mixed participatory study, combining quantitative and qualitative approaches. The online questionnaire consisted of 58 questions in the quantitative approximation. The qualitative part required the provision of an image of the workspace, with testimonies and personal reflections. During the lockdown, all participants saw an increase in overall energy consumption; more than half reported not being in thermal comfort; and a third declared deficiencies in noise insulation. Regarding the perception of the telework/tele-study space, we found the following categories: bedrooms, living/dining rooms, studies and others. In addition, respondents had often adapted the workspace for both individual and shared use. In general, the households were satisfied with the size of their houses but would like landscaped spaces or better views outside. Confinement made housing the protective element against the pandemic. The consequences will have an effect globally, so new architectural design paradigms need to be rethought.

Sarcopenia: Influence of Regional Skeletal Muscle Cutoff Points and Fat-Free Mass in Older Mexican People-A Pilot Study.

BACKGROUND: Variation in the prevalence of sarcopenia is related to the skeletal muscle index cutoff points applied. The objective of this pilot study was to examine the recruitment process for testing different sarcopenia definitions (ASMI cutoffs) in older Mexican adults. It explored whether the prevalence of sarcopenia decreased by applying ethnic- and gender-specific, DXA-derived appendicular skeletal muscle index (ASMI)-cutoff points in the definitions, as well as some associated factors in a sample of community-dwelling older Mexican people. METHODS: This is a pilot feasibility study that included a convenience sample of 217 community-dwelling older adults. Volunteers underwent DXA measurements and an assessment of functional status based on hand grip strength and physical performance. Six definitions were formed based on the 2010 EWGSOP criteria, but using different cutoff points for each of the three components, including regional cutoff points for ASMI derived from young Mexican adults. Several risk factors for sarcopenia were also assessed. RESULTS: The prevalence of sarcopenia varied according to the different definitions applied. The lowest level was found with the definition that applied regional ASMI-cutoff points (p < 0.01). The sarcopenic older adults had significant lower body weight, fat mass, and fat-free mass (FFM) than the nonsarcopenic subjects. The risk of sarcopenia increased with age and low FFM (p < 0.001). CONCLUSION: The present study demonstrates the feasibility of the main study, and our data support the notion that using regional ASMI cutoff points resulted in a low prevalence of sarcopenia. Therefore, it is preferable to estimate the prevalence of this condition using ethnic- and gender-specific cutoff points and to explore associated factors such as low FFM.

Riesgo de desnutrición y factores asociados en una muestra de adultos mayores en la comunidad e institucionalizados de Yucatán, México / Malnutrition risk and associated factors in a sample of older adults in the community and institutionalized in Yucatan, Mexico

Evaluar la prevalencia de riesgo de desnutrición (RD) en adultos mayores de dos municipios de Yucatán, México, e identificar algunos factores asociados. Estudio transversal con muestreo intencional no probabilístico en 6 centros de atención geriátrica, una clínica universitaria y visitas domiciliares. Noventa y seis adultos mayores de 60 años (76% mujeres), 42 residentes de estancias geriátricas y 54 no institucionalizados. Se evaluó el RD con la escala de Valoración Mínima del Estado de Nutrición (VMEN), junto con variables demográficas, de funcionalidad, comorbilidades, depresión y apetito. La composición corporal se evaluó con ecuaciones basadas en antropometría e impedancia bioeléctrica. Se realizaron análisis descriptivos, t de Student, Kolmogorov-Smirnov, chi cuadrado, análisis univariado y análisis de regresión múltiple. El 47,9 % (46 sujetos; 37 mujeres y 9 varones) presentaron RD de acuerdo con la VMEN y 52,1% de los participantes fueron clasificados con estado nutricio normal de acuerdo con dicha escala. Los valores promedio de la masa corporal libre de grasa y la masa muscular esquelética en extremidades de sujetos con RD, fueron más bajos que en aquellos con estado de nutrición normal (p< 0,05). El análisis de regresión logístico múltiple ajustado por género indicó que la edad (OR=1,08, p=0,005) y la depresión (OR=3,79, p=0,017) fueron factores predictores asociados con RD. El 47,9 % de los participantes presentaron RD. Se requieren acciones para diagnosticar y atender el RD y evitar que progrese a desnutrición. La edad y la depresión se debieran incluir como posibles marcadores tempranos de desnutrición en futuros estudios poblacionales e intervenciones nutricionales en adultos mayores en comunidad e institucionalizados en Yucatán(AU)

To assess the prevalence of Malnutrition Risk (MR) in older adults from two municipalities of Yucatan, Mexico, and to identify some associated factors. Cross-sectional study, using non-probabilistic sample in six geriatric care centers, a university clinic, and home visits. Ninety-six adults over 60 years (76% women), 42 residents of geriatric care homes, and 54 non-institutionalized. The MR was assessed by the Mini Nutritional Assessment scale (MNA), along with demographic, functionality, comorbidities, depression, and appetite variables. Body composition was also assessed by bioelectrical impedance analysis. Descriptive analyzes, Student's t, Kolmogorov-Smirnov, chi-square, univariate, and multiple regression analysis were performed. Of the total sample, 47.9% (46 subjects; 37 women and 9 men) presented RD according to the VMEN and 52.1% of the participants were classified with normal nutritional status according to the scale. Mean values of fat-free mass and appendicular skeletal muscle mass were lower in subjects with MR than in those with normal nutritional status (p <0.05). The multiple logistic regression analysis adjusted by gender indicated that age (OR = 1.08, p = 0.005) and depression (OR = 3.79, p = 0.017) were predictor associated factors with MR. Almost forty eight percent of the participants present MR. Actions are required to diagnose and treat MR, avoiding progressing to malnutrition. Age and depression should be included as possible early markers of malnutrition in future population studies and nutritional interventions, in the community and institutionalized older adults in Yucatan(AU)

The fat mass index, not the fat-free mass index, is associated with impaired physical performance in older adult subjects: Evidence from a cross-sectional study.

BACKGROUND: Impaired physical performance (IPP) and physical disability (PD) are two serious public health problems in older adult populations worldwide. While studies show that changes in body composition are important risk factors for developing these conditions, there is little evidence that the fat-free mass (FFM) and fat mass (FM) indices (FFMI and FMI, respectively) are associated with IPP in older men and women. This study assessed the association among FFMI, FMI, and IPP using Short Physical Performance Battery (SPPB) in Mexican men and women aged over 60 years. METHODS: This cross-sectional study included 217 older people (men 34.6%, women 65.4%; 60-92 years). FFM and FM were assessed by dual X-ray absorptiometry, assuming a two-compartment model. FFM and FM were adjusted by height squared and the indices were obtained. After assessment of physical performance by SPPB, subjects with scores ≤6 were classified as having IPP. Associations were tested by multiple logistic regression analysis in separated models. RESULTS: IPP prevalence was 14.3%. Women were affected more than men. Regression analysis showed no significant association between FFMI and IPP, but FMI was strongly-associated, as for each unit increase in FMI, the risk of IPP rose significantly (OR: 1.14), and this result remained significant after adjusting for age, comorbidity, polypharmacy, and the appendicular skeletal muscle mass index (OR: 1.23; p ≤ 0.001). These results emphasize the importance of preventing increases in FM and avoiding overweight and obesity in older men and women.

Differences in Body Composition in Older People from Two Regions of Mexico: Implications for Diagnoses of Sarcopenia and Sarcopenic Obesity.

BACKGROUND: Mexico is a country that is rich in ethnicity and cultural diversity, divided into three well-defined socioeconomic, ecological, and epidemiological areas. However, we do not know the influence that these factors may have on body composition. Therefore, this study was designed to assess body composition and compare appendicular skeletal muscle mass (ASM) in older people from two areas of the country. METHODS: This is a cross-sectional study that included 430 subjects ≥60 years of age from northwestern and central Mexico. Body composition, including ASM, was measured by dual-energy X-ray absorptiometry, while anthropometry, handgrip strength, demographic variables, health status/chronic conditions, and energy expenditure data were all included. RESULTS: Men and women from the northwestern region had 5.9 kg and 3.8 kg more body fat, respectively, and 3.9 kg more as a group than their counterparts from central Mexico (p ≤ 0.0001). While there were no significant differences across gender or region in terms of ASM, the older subjects from central Mexico had a significantly higher ASM index (ASMI) than the sample from the northwest. When ASM was adjusted for age, body weight, height, health status/chronic conditions, estimated energy expenditure, and demographic variables, the subjects from central Mexico had significantly higher adjusted mean values of ASM and ASMI than their counterparts from the northwest. CONCLUSION: Older people from two regions of Mexico had significantly different estimates of body composition. Our findings highlight the importance of regionalizing estimates of ASM and ASMI if they are to be used for diagnostic purposes. It is also important to emphasize that appendicular skeletal muscle mass, or the ASM index, should be adjusted for other associated biological variables.

A Loss-of-Function Splice Acceptor Variant in IGF2 Is Protective for Type 2 Diabetes.

Type 2 diabetes (T2D) affects more than 415 million people worldwide, and its costs to the health care system continue to rise. To identify common or rare genetic variation with potential therapeutic implications for T2D, we analyzed and replicated genome-wide protein coding variation in a total of 8,227 individuals with T2D and 12,966 individuals without T2D of Latino descent. We identified a novel genetic variant in the IGF2 gene associated with ∼20% reduced risk for T2D. This variant, which has an allele frequency of 17% in the Mexican population but is rare in Europe, prevents splicing between IGF2 exons 1 and 2. We show in vitro and in human liver and adipose tissue that the variant is associated with a specific, allele-dosage-dependent reduction in the expression of IGF2 isoform 2. In individuals who do not carry the protective allele, expression of IGF2 isoform 2 in adipose is positively correlated with both incidence of T2D and increased plasma glycated hemoglobin in individuals without T2D, providing support that the protective effects are mediated by reductions in IGF2 isoform 2. Broad phenotypic examination of carriers of the protective variant revealed no association with other disease states or impaired reproductive health. These findings suggest that reducing IGF2 isoform 2 expression in relevant tissues has potential as a new therapeutic strategy for T2D, even beyond the Latin American population, with no major adverse effects on health or reproduction.

Daclatasvir and Peginterferon/Ribavirin for Black/African-American and Latino Patients with HCV infection.

 Background. Patient race and ethnicity have historically impacted HCV treatment response. This phase 3 study evaluated daclatasvir with peginterferon-alfa-2a/ribavirin (pegIFN alfa-2a/RBV) in treatment-naive black/African American (AA), Latino, and white non-Latino patients with chronic HCV genotype 1 infection. MATERIAL AND METHODS: In this single-arm, open-label study, 246 patients received daclatasvir plus pegIFN alfa-2a and weight-based RBV. Patients with an extended rapid virologic response (eRVR; undetectable HCV-RNA at treatment weeks 4 and 12) received 24 weeks of treatment; those without eRVR received an additional 24 weeks of treatment with pegIFN alfa-2a/RBV. The primary endpoint was sustained virologic response at post-treatment week 12 (SVR12; HCV-RNA < 25 IU/mL) compared with the cohort historical rate. RESULTS: Most patients were IL28B non-CC (84.4% black/AA; 77.6% Latino) genotype 1a-infected (72.7%; 81.3%), with HCV-RNA ≥ 800,000 IU/mL (81.3%; 64.5%). SVR12 rates were 50.8% (65/128; 95% confidence interval [CI], 42.1-59.4) for black/AA and 58.9% (63/107; 95% CI, 49.6-68.2) for Latino patients. The majority (55.5%; 58.9%) received 24 weeks treatment; rapid reductions (> 4-log10) in HCV-RNA levels were observed. Only 60.9% (78/128) of black/AA and 63.6% (68/107) of Latino patients completed treatment. On-treatment serious adverse events (SAEs) occurred in 21 patients. Discontinuations due to adverse events (AEs) occurred in 9 black/AA and 6 Latino patients. CONCLUSION: SVR12 rates for black/AA (50.8%) and Latino (58.9%) cohorts treated with daclatasvir plus pegIFN alfa-2a/RBV and the lower bound of the 95% CIs were higher than the estimated historical control (black/AA, 26% SVR; Latino, 36% SVR) treated with pegIFN alfa-2a/RBV. These data support daclatasvir use in all-oral direct-acting antiviral combinations.

Sofosbuvir for chronic hepatitis C virus infection genotype 1-4 in patients coinfected with HIV.

BACKGROUND: Chronic hepatitis C virus (HCV) infection is a major cause of morbidity and mortality among HIV-infected patients. Sofosbuvir is a first-in-class HCV NS5B inhibitor with potent pan-genotypic antiviral activity. We report a 2-part study that assessed the efficacy and safety of sofosbuvir in HCV/HIV-coinfected patients. Part A examined potential drug interactions between sofosbuvir and antiretrovirals (efavirenz, emtricitabine, tenofovir, zidovudine, lamivudine, atazanavir, ritonavir, darunavir, and raltegravir). Part B was a pilot study of sofosbuvir plus peginterferon-ribavirin administered for 12 weeks. METHODS: We enrolled noncirrhotic patients with chronic HCV infection (genotype, 1-6) and stable HIV. Part A followed a 5-cohort, open-label, multiple-dose, single-sequence design; part B followed an open-label, single-arm design. The primary end point of part B was sustained virologic response (defined as undetectable HCV RNA) 12 weeks after end of treatment (SVR12). This study is registered with ClinicalTrials.gov, number NCT01565889. FINDINGS: Thirty-eight patients were enrolled in part A and 23 in part B. In part A, no clinically significant drug interactions were observed between sofosbuvir and any of the antiretrovirals evaluated. In part B, 21 (91.3%) patients achieved SVR12. Two patients relapsed but none experienced on-treatment HCV virologic failure. Two patients discontinued study treatment because of adverse events (altered mood and anemia). No serious adverse events, HIV viral breakthrough, or decreases in CD4 percentage were reported in either part A or part B. INTERPRETATION: Sofosbuvir may be coadministered safely with many commonly used antiretrovirals. The addition of sofosbuvir to peginterferon-ribavirin was highly effective as assessed by SVR in HCV/HIV-coinfected patients.

Amerindian-specific regions under positive selection harbour new lipid variants in Latinos.

Dyslipidemia and obesity are especially prevalent in populations with Amerindian backgrounds, such as Mexican-Americans, which predispose these populations to cardiovascular disease. Here we design an approach, known as the cross-population allele screen (CPAS), which we conduct prior to a genome-wide association study (GWAS) in 19,273 Europeans and Mexicans, in order to identify Amerindian risk genes in Mexicans. Utilizing CPAS to restrict the GWAS input variants to only those differing in frequency between the two populations, we identify novel Amerindian lipid genes, receptor-related orphan receptor alpha (RORA) and salt-inducible kinase 3 (SIK3), and three loci previously unassociated with dyslipidemia or obesity. We also detect lipoprotein lipase (LPL) and apolipoprotein A5 (APOA5) harbouring specific Amerindian signatures of risk variants and haplotypes. Notably, we observe that SIK3 and one novel lipid locus underwent positive selection in Mexicans. Furthermore, after a high-fat meal, the SIK3 risk variant carriers display high triglyceride levels. These findings suggest that Amerindian-specific genetic architecture leads to a higher incidence of dyslipidemia and obesity in modern Mexicans.

Association of a low-frequency variant in HNF1A with type 2 diabetes in a Latino population.

IMPORTANCE: Latino populations have one of the highest prevalences of type 2 diabetes worldwide. OBJECTIVES: To investigate the association between rare protein-coding genetic variants and prevalence of type 2 diabetes in a large Latino population and to explore potential molecular and physiological mechanisms for the observed relationships. DESIGN, SETTING, AND PARTICIPANTS: Whole-exome sequencing was performed on DNA samples from 3756 Mexican and US Latino individuals (1794 with type 2 diabetes and 1962 without diabetes) recruited from 1993 to 2013. One variant was further tested for allele frequency and association with type 2 diabetes in large multiethnic data sets of 14,276 participants and characterized in experimental assays. MAIN OUTCOME AND MEASURES: Prevalence of type 2 diabetes. Secondary outcomes included age of onset, body mass index, and effect on protein function. RESULTS: A single rare missense variant (c.1522G>A [p.E508K]) was associated with type 2 diabetes prevalence (odds ratio [OR], 5.48; 95% CI, 2.83-10.61; P = 4.4 × 10(-7)) in hepatocyte nuclear factor 1-α (HNF1A), the gene responsible for maturity onset diabetes of the young type 3 (MODY3). This variant was observed in 0.36% of participants without type 2 diabetes and 2.1% of participants with it. In multiethnic replication data sets, the p.E508K variant was seen only in Latino patients (n = 1443 with type 2 diabetes and 1673 without it) and was associated with type 2 diabetes (OR, 4.16; 95% CI, 1.75-9.92; P = .0013). In experimental assays, HNF-1A protein encoding the p.E508K mutant demonstrated reduced transactivation activity of its target promoter compared with a wild-type protein. In our data, carriers and noncarriers of the p.E508K mutation with type 2 diabetes had no significant differences in compared clinical characteristics, including age at onset. The mean (SD) age for carriers was 45.3 years (11.2) vs 47.5 years (11.5) for noncarriers (P = .49) and the mean (SD) BMI for carriers was 28.2 (5.5) vs 29.3 (5.3) for noncarriers (P = .19). CONCLUSIONS AND RELEVANCE: Using whole-exome sequencing, we identified a single low-frequency variant in the MODY3-causing gene HNF1A that is associated with type 2 diabetes in Latino populations and may affect protein function. This finding may have implications for screening and therapeutic modification in this population, but additional studies are required.

A phase 2 study of filibuvir in combination with pegylated IFN alfa and ribavirin for chronic HCV.

OBJECTIVES: Filibuvir is a non-nucleoside inhibitor of hepatitis C virus (HCV) polymerase. This study evaluated the safety and efficacy of filibuvir plus pegylated interferon alfa-2a (pegIFN)/ribavirin. MATERIAL AND METHODS: Treatment-naïve, HCV genotype-1 patients were randomized to receive filibuvir 300 or 600 mg twice daily (BID) or placebo plus pegIFN (180 µg/wk) and ribavirin (1,000/1,200 mg BID) for 24 weeks. Filibuvir patients who achieved defined response through week 24 discontinued therapy at week 24. All other patients continued on open-label pegIFN/ribavirin through week 48. The primary endpoint was the proportion of patients who achieved sustained virologic response (SVR) defined as HCV RNA < 15 IU/mL at end of treatment (weeks 24 or 48) and week 72. RESULTS: Overall, 288 patients were randomized and treated. SVR was achieved by 41.7, 39.6, and 45.8% of patients in the filibuvir 300 mg, 600 mg, and placebo arms, respectively. While the addition of filibuvir to pegIFN/ribavirin improved on-treatment virologic response parameters, this did not translate into improved SVR rates due to a high rate of virologic relapse following completion of therapy (300 mg: 35.9%; 600 mg: 42.9%; placebo: 25.4%). The most commonly reported adverse events were nausea, fatigue, headache, and insomnia, and were reported at similar rates across arms. CONCLUSIONS: Filibuvir plus pegIFN/ribavirin did not improve the percentage of patients achieving SVR compared with administration of pegIFN/ribavirin alone. However, the agent was well tolerated and was associated with higher on-treatment virologic response parameters. Further evaluation of filibuvir in combination with other direct-acting antiviral agents may be considered.

Combination of vaniprevir with peginterferon and ribavirin significantly increases the rate of SVR in treatment-experienced patients with chronic HCV genotype 1 infection and cirrhosis.

BACKGROUND & AIMS: The combination of vaniprevir (a NS3/4A protease inhibitor) with peginterferon and ribavirin was shown to increase rates of sustained virologic response (SVR) significantly, compared with peginterferon and ribavirin alone, in treatment-experienced patients with chronic hepatitis C virus (HCV) genotype 1 infection without cirrhosis. We performed a blinded, randomized, controlled trial of the effects of vaniprevir with peginterferon and ribavirin in patients with cirrhosis who did not respond to prior therapy with peginterferon and ribavirin. METHODS: Treatment-experienced patients (88% white and 35% prior null responders) with HCV genotype 1 infection and compensated cirrhosis were assigned randomly to groups given vaniprevir (600 mg twice daily) with peginterferon and ribavirin for 24 weeks (n = 16), vaniprevir (600 mg twice daily) for 24 weeks with peginterferon and ribavirin for 48 weeks (n = 14), vaniprevir (300 mg twice daily) with peginterferon and ribavirin for 48 weeks (n = 15), vaniprevir (600 mg twice daily) with peginterferon and ribavirin for 48 weeks (n = 15), or placebo with peginterferon and ribavirin for 48 weeks (n = 14, control). Cirrhosis was documented by liver biopsy (84%) or noninvasive methods (16%). Before randomization, participants were stratified based on their historical response to peginterferon and ribavirin. RESULTS: In the primary analysis, SVR rates among patients in the respective vaniprevir groups were 9 of 15 (60.0%), 9 of 13 (69.2%), 8 of 15 (53.3%), and 10 of 13 (76.9%), compared with 2 of 14 (14.3%) in the control group (pairwise P values ≤ .016). Cirrhotic patients with null or partial responses to prior therapy achieved SVR less often than patients with prior breakthrough or relapse, although 42.1% of prior null responders in the vaniprevir groups achieved SVRs. Patients in the vaniprevir groups more frequently experienced mild-moderate nausea, vomiting, and diarrhea than controls; 5% developed grade 2 anemia compared with none in the control group (no patient developed grade 3 or 4 anemia). Among patients in the vaniprevir groups who experienced virologic failure, resistance-associated variants were detected predominantly at positions 155, 156, and 168 in the HCV protease gene. CONCLUSIONS: In a controlled phase 2B trial, vaniprevir with peginterferon and ribavirin significantly increased rates of SVR among treatment-experienced patients with chronic HCV genotype 1 infection, compared with re-treatment with peginterferon and ribavirin alone. Vaniprevir generally was well tolerated for up to 48 weeks in patients with compensated cirrhosis. ClinicalTrials.gov number, NCT00704405.

A double-blind, randomized, placebo-controlled study to assess the safety, antiviral activity and pharmacokinetics of GSK2336805 when given as monotherapy and in combination with peginterferon alfa-2a and ribavirin in hepatitis C virus genotype 1-infected treatment-naive subjects.

BACKGROUND & AIMS: GSK2336805 is a HCV NS5A inhibitor for chronic hepatitis C (CHC). In a prior Phase I study, GSK2336805 was well tolerated and had an antiviral and pharmacokinetic profile suitable for once-daily administration. This 28-day, double-blind, randomized, placebo-controlled study evaluated once daily GSK2336805 60 mg alone or in combination with peginterferon alfa-2a (180 µg per week) and ribavirin (1000-1200 mg daily) (PEG/RIBA) in treatment-naive genotype 1 CHC subjects. METHODS: Five centres enrolled 16 subjects in the USA and Puerto Rico who received GSK2336805 + PEG/RIBA or placebo + PEG/RIBA. RESULTS: Following a single monotherapy dose of GSK2336805 on day 1, median reduction from baseline in HCV RNA was -2.96 log10 (N = 11) vs. -0.13 log10 (N = 4) for placebo. With the addition of PEG/RIBA on day 2, subjects receiving GSK2336805 exhibited greater decreases in viral load over the 28-day treatment period as compared with placebo. At day 28, median reduction from baseline was -4.86 log10 (N = 9) in the GSK2336805 + PEG/RIBA group as compared with -1.98 log10 (N = 4) in the placebo + PEG/RIBA group. At day 28, rapid virological response (RVR) occurred in 8/11 (73%) of the GSK2336805 + PEG/RIBA subjects as compared with 1/4 (25%) of the placebo + PEG/RIBA subjects. Adverse events were consistent with those reported in clinical trials of peginterferon and ribavirin, and no unique adverse events appeared to be associated with GSK2336805. CONCLUSIONS: GSK2336805 is a potent NS5A inhibitor that showed a substantial antiviral effect as a monotherapy and in combination with peginterferon and ribavirin. ClinicalTrials.gov Identifier: NCT01439373.

Focus on drug interactions: the challenge of treating hepatitis C virus infection with direct-acting antiviral drugs in the HIV-positive patient.

PURPOSE OF REVIEW: Successful treatment of hepatitis C virus (HCV) infection is necessary for the survival of HIV-infected patients. This review covers the outcomes of current therapy, first-generation HCV direct-acting antivirals (DAAs) and their drug-to-drug interactions (DDIs). Understanding DDIs between HIV antiretroviral therapy (ART) and the DAAs in development is important to assure the best management of the HIV/HCV coinfected individuals. RECENT FINDINGS: The two first-in-class DAAs were approved for clinical use in 2011. The first trials with boceprevir or telaprevir added to standard therapy in HIV/HCV coinfected patients revealed triple therapy to be efficacious with significantly improved sustained virological response rates. However, these DAAs were associated with more and worse adverse effects, as well as with significant DDIs with multiple drugs, including ART. Early data on DAAs in development suggest improved efficacy and safety and the potential for lesser DDIs. SUMMARY: Anti-HCV therapy is fundamental in coinfected patients, but the approved therapies are suboptimal. The first-generation of approved HCV DAAs improved efficacy of therapy in coinfected patients, but have multiple safety concerns, including potentially serious drug interactions with ART. Early results from newer DAAs are promising.

Sofosbuvir (GS-7977) plus peginterferon/ribavirin in treatment-naïve patients with HCV genotype 1: a randomized, 28-day, dose-ranging trial.

BACKGROUND & AIMS: Sofosbuvir (formerly GS-7977) is a pyrimidine nucleotide analog inhibitor of the hepatitis C virus (HCV) NS5B polymerase. We assessed the safety, tolerability, antiviral activity, and pharmacokinetics of sofosbuvir plus pegylated-interferon (PegIFN)/ribavirin (RBV) in a 28-day, dose-ranging trial in treatment-naïve patients infected with genotype 1 HCV. METHODS: In this double-blind study, 64 patients were randomized (1:1:1:1) to receive one of three once-daily doses of oral sofosbuvir (100, 200, or 400mg) or placebo plus PegIFN/RBV for 28 days, after which all patients continued to receive PegIFN/RBV alone for a further 44 weeks. RESULTS: Patients in the sofosbuvir/PegIFN/RBV groups experienced mean reductions in HCV RNA >5 log10 IU/ml (-5.3 for 100 mg, -5.1 for 200 mg and -5.3 for 400 mg) vs. -2.8 log10 IU/ml for placebo/PegIFN/RBV after 28 days. Rapid virologic response (RVR) rates were markedly higher after sofosbuvir treatment (88-94%) than placebo (21%), as were rates of sustained virologic response (SVR) at post-treatment Week 24 (56%, 83%, and 80% for sofosbuvir 100, 200, and 400 mg, respectively, vs. 43% for placebo). The number of patients experiencing virologic breakthrough and post-treatment relapse was higher in the sofosbuvir 100 mg group than sofosbuvir 200 and 400 mg groups. Sofosbuvir was well tolerated; the most frequent adverse events were fatigue and nausea. CONCLUSIONS: These results support further studies with sofosbuvir at 200 mg and 400 mg to determine the optimal dose and treatment duration of sofosbuvir in HCV genotype 1.

The epidemiologic burden of hepatitis C virus infection in Latin America .

Chronic infection with hepatitis C virus (HCV) is a major and growing public health concern worldwide, including in Latin America. With more efficacious therapies becoming available, decision-makers will require accurate estimates of disease prevalence to assess the potential impact of new treatments. However, few estimates of the epidemiologic burden, either overall or by country, are available for Latin America; and the potential impact of currently-available treatments on the epidemiologic burden of HCV in Latin America has not been assessed. To address this, we systematically reviewed twenty-five articles presenting population-based estimates of HCV prevalence from general population or blood donor samples, and supplemen- ted those with publically-available data, to estimate the total number of persons infected with HCV in Latin America at 7.8 million (2010). Of these, over 4.6 million would be expected to have genotype 1 chronic HCV, based on published data on the risk of progression to chronic disease and the HCV genotype distribution of Latin America. Finally, we calculated that between 1.6 and 2.3 million persons with genotype 1 chronic HCV would potentially benefit from current treatments, based on published estimates of genotype-specific treatment responsiveness. In conclusion, these estimates demonstrate the substantial present epidemiologic burden of HCV, and quantify the impending societal and clinical burden from untreated HCV in Latin America.

Contribution of common genetic variation to the risk of type 2 diabetes in the Mexican Mestizo population.

Several studies have identified nearly 40 different type 2 diabetes susceptibility loci, mainly in European populations, but few of them have been evaluated in the Mexican population. The aim of this study was to examine the extent to which 24 common genetic variants previously associated with type 2 diabetes are associated in Mexican Mestizos. Twenty-four single nucleotide polymorphisms (SNPs) in or near genes (KCNJ11, PPARG, TCF7L2, SLC30A8, HHEX, CDKN2A/2B, CDKAL1, IGF2BP2, ARHGEF11, JAZF1, CDC123/CAMK1D, FTO, TSPAN8/LGR5, KCNQ1, THADA, ADAMTS9, NOTCH2, NXPH1, RORA, UBQLNL, and RALGPS2) were genotyped in Mexican Mestizos. A case-control association study comprising 1,027 type 2 diabetic individuals and 990 control individuals was conducted. To account for population stratification, a panel of 104 ancestry-informative markers was analyzed. Association to type 2 diabetes was found for rs13266634 (SLC30A8), rs7923837 (HHEX), rs10811661 (CDKN2A/2B), rs4402960 (IGF2BP2), rs12779790 (CDC123/CAMK1D), and rs2237892 (KCNQ1). In addition, rs7754840 (CDKAL1) was associated in the nonobese type 2 diabetic subgroup, and for rs7903146 (TCF7L2), association was observed for early-onset type 2 diabetes. Lack of association for the rest of the variants may have resulted from insufficient power to detect smaller allele effects.

Hepatitis C viral kinetics in Latino patients: a comparison to African American and Caucasian patients.

INTRODUCTION: Response to hepatitis C treatment is known to differ by race; and, limited data suggests by ethnicity as well. A lower efficacy of HCV therapy in Latinos has been observed; whether higher doses may improve the response is unknown. MATERIAL AND METHODS: This study used the available data from the patients enrolled in the PROGRESS study and stratified it by race and ethnicity. The primary objectives were to evaluate the early viral kinetic pattern in Latino patients and to assess whether it was improved by higher doses of Peg-IFN alfa-2a and/or RBV, as compared to Caucasian and African American patients. RESULTS: From a total of 1145 patients, 51 (4%) were classified Latino, 886 (77%) Caucasian, 124 (11%) African American and 84 (7%) other. Latinos had a similar virological response between the treatment groups at week 4; but by week 12, achieved a greater response with the higher intensified dose of peginterferon alfa-2a, and remained so at week 72. Caucasians had a greater response at week 4 and week 12 with the intensified dose; but by week 72, the response became similar between the treatment groups. The virological responses for African Americans were unaffected by the doses; and by week 12, were lower than both Latinos and Caucasians. In conclusion, this retrospective analysis provides further evidence for racial/ethnic differences in the response to peginterferon alfa-2a (40KD) plus ribavirin therapy in patients with HCV. Although the sample sizes in this analysis are small for generalized conclusions, the findings are of importance to physicians treating Latinos.

Balapiravir plus peginterferon alfa-2a (40KD)/ribavirin in a randomized trial of hepatitis C genotype 1 patients.

INTRODUCTION: Balapiravir (R1626, RG1626) is the prodrug of a nucleoside analogue inhibitor of the hepatitis C virus (HCV) RNA-dependent RNA polymerase (R1479, RG1479). This phase 2, double-blind international trial evaluated the optimal treatment regimen of balapiravir plus peginterferon alfa-2a (40KD)/ribavirin. MATERIAL AND METHODS: Treatment-naive genotype 1 patients (N = 516) were randomized to one of seven treatment groups in which they received balapiravir 500, 1,000, or 1,500 mg twice daily, peginterferon alfa-2a (40KD) 180 or 90 µg/week and ribavirin 1,000/1,200 mg/day or peginterferon alfa-2a (40KD)/ribavirin. The planned treatment duration with balapiravir was reduced from 24 to 12 weeks due to safety concerns. RESULTS: The percentage of patients with undetectable HCV RNA was consistently higher in all balapiravir groups from week 2 to 12. However, high rates of dose modifications and discontinuations of one/all study drugs compromised the efficacy assessment and resulted in similar sustained virological response rates in the balapiravir groups (range 32-50%) and the peginterferon alfa-2a (40KD)/ribavirin group (43%). Balapiravir was discontinued for safety reasons in 28-36% of patients (most often for lymphopenia) and the percentage of patients with serious adverse events (especially hematological, infection, ocular events) was dose related. Serious hematological adverse events (particularly neutropenia, lymphopenia) were more common in balapiravir recipients. Two deaths in the balapiravir/peginterferon alfa-2a/ribavirin combination groups were considered possibly related to study medication. CONCLUSION: Further development of balapiravir for the treatment of chronic hepatitis C has been halted because of the unacceptable benefit to risk ratio revealed in this study (www.ClinicalTrials.gov NCT 00517439).