Purpose of the Study. Resting CD4+ T cells are a primary reservoir for HIV. In these cells the HIV is in a latent form and not a target of current antiviral agents. The chromatin-remodeling enzyme histone deacetylase 1 (HDAC1) maintains latency of integrated HIV. This study tested the hypothesis that an inhibitor of HDAC1, valproic acid, would result in depletion of latently infected resting CD4+ T cells. Study Population. Four human volunteers with HIV receiving highly active antiretroviral therapy. Methods. The individual subjects’ antiretroviral therapies were intensified with enfuvirtide, a fusion inhibitor, to minimize the spread of HIV during potential release from latency. The subjects then were treated with oral valproic acid, 500 to 750 mg twice daily, in addition to their antiretroviral therapy, and they were followed for 3 months. Latently infected resting T cells were quantified before and after augmentation of treatment with limiting-dilution culture of resting cells after ex vivo activation. Results. The frequency of resting CD4+ T-cell infection was stable before the addition of enfuvirtide and valproic acid but declined thereafter. This decline was significant in 3 or 4 patients, with a mean reduction of 75% in circulating HIV-infected resting CD4+ T cells. There were no complications of the additional treatments except for the expected injection-site reactions to enfuvirtide. Conclusions. Combination therapy with an HDAC inhibitor and very potent antiretroviral therapy accelerated the reduction in HIV-infected resting T cells. This suggests a new approach to the management of HIV that eventually may result in clearance of HIV from infected individuals. Reviewer Comments. This study received a fair amount of media coverage at the time it was published. It begs the question, can HIV be cured? A 75% reduction in the resting T-cell reservoir seems impressive. However, this was a very short-term study, and the kinetics and degree to which the resting T-cell reservoir was replenished after discontinuation of valproic acid was not reported. In addition, valproic acid, a widely used anticonvulsant, is potentially highly toxic and has “black-box” warnings for hepatotoxicity, teratogenicity, and pancreatitis. Despite the authors’ optimistic conclusions, “this finding, though not definitive, suggests that new approaches will allow the cure of HIV in the future,” use of the “C word” is likely premature.

https://pediatrics.aappublications.org/content/pediatrics/118/Supplement_1/S51.2.full.pdf

Depletion of Latent HIV-1 Infection in Vivo: A Proof-of-Concept Study

Rates of and Factors Associated With Placebo Response in Trials of Pharmacotherapies for Nonalcoholic Steatohepatitis: Systematic Review and Meta-analysis

The first clinical study to investigate effects of dipeptidyl peptidase-4 (DPP-4) inhibition was published in 2002, and since then, numerous randomized controlled trials (RCTs) have shown that DPP-4 inhibitors are efficacious, safe and well-tolerated. This review will focus upon RCTs which have investigated DPP-4 inhibitors in patient groups which are often under-represented or excluded from typical phase 3 clinical trials. Large cardiovascular (CV) safety outcome trials in patients with established CV disease have confirmed that DPP-4 inhibitors are not associated with any additional CV risk in these already-at-high-risk individuals, while raising awareness of any uncommon adverse events, such as heart failure hospitalization seen in one of the trials. Studies in patients with kidney disease have shown DPP-4 inhibitors to be efficacious without increasing the risk of hypoglycaemia, irrespective of the degree of renal impairment, while data from the large CV trials as well as smaller RCTs have even pointed towards potential renoprotective effects such individuals. The use of DPP-4 inhibitors with insulin when therapy requires intensification may be beneficial without affecting the incidence or severity of hypoglycaemia, with these effects also being replicated in patients with chronic kidney disease, for whom other agents may not be suitable. Attention is now turning towards exploring the potential utility of DPP-4 inhibitors in other circumstances, including for in-hospital management of hyperglycaemia and in other metabolic disorders. Together, these RCTs raise the possibility that in the future, DPP-4 inhibitors may have a broader use which may extend beyond glycaemic control in the typical type 2 diabetes mellitus (T2DM) patient seen in general practice and may encompass conditions other than T2DM.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/dom.13135

A review of dipeptidyl peptidase-4 inhibitors. Hot topics from randomized controlled trials.

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in Western societies and a major cause of hepatic disease worldwide. Its more severe type, namely nonalcoholic steatohepatitis (NASH), may result in the development of cirrhosis and hepatocellular carcinoma. NAFLD, and especially NASH, are also associated with increased cardiovascular morbidity and mortality. Type 2 diabetes mellitus (T2DM) predisposes to NAFLD development and progression via insulin resistance and hyperglycemia. It has also been reported that the majority of T2DM patients have NAFLD/NASH, thus potentially further increasing their cardiometabolic risk. Current guidelines recommend to screen for NAFLD in all T2DM patients and vice-versa. Lifestyle remains the first-line therapeutic option for NAFLD/NASH. Among antidiabetic drugs, pioglitazone was shown to improve histological features of NASH. More recently, there is an increasing interest regarding the effects of newer anti-diabetic drugs, such as dipeptidyl peptidase 4 inhibitors (DPP-4i), sodium glucose cotransporter 2 inhibitors (SGLT2i), and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) on NAFLD/NASH. The present narrative review considers the up-to-date data on the impact of DPP-4i, SGLT2i, and GLP-1 RAs on biochemical and/or histological markers of NAFLD/NASH. The potential clinical implications of these findings in daily practice are also discussed. Taking into consideration the global increasing prevalence of NAFLD/NASH, therapeutic options that can prevent or treat this disease will exert considerable benefits on human health.

Effects of newer antidiabetic drugs on nonalcoholic fatty liver and steatohepatitis: Think out of the box!

The effects of green tea (GT) in obese subjects have been evaluated in different studies, but no consensus has been obtained due to the heterogeneity of the results. The dosage, the type of extract, and the duration of the intervention are the main contributors to the heterogeneity of the results. Therefore, the present systematic review and meta-analysis aimed to evaluate the efficacy and dose-response relationship of GT. Several databases were searched from inception to September 2019 to identify clinical trials that examined the influence of GT supplements on obesity indices in humans. Combined results using the random-effects model indicated that body weight (WMD: -1.78 kg, 95% CI: -2.80, -0.75, p = .001) and body mass index (BMI) (WMD: -0.65 kg/m2 , 95% CI: -1.04, -0.25, p = .001) did change significantly following GT administration. The reduction in waist circumference (WC) after GT consumption was significant in subjects in trials employing GT ≥800 mg/day (WMD: -2.06 cm) and with a treatment duration <12 weeks (WMD: -2.39 cm). Following the dose-response evaluation, GT intake did alter body weight, with a more important reduction when the GT dosage was <500 mg/day and the treatment duration was of 12 weeks. The results of present meta-analysis study support the use of GT for the improvement of obesity indices. Thus, we suggest that the use of GT can be combined with a balanced and healthy diet and regular physical exercise in the management of obese patients.

The effect of green tea supplementation on obesity: A systematic review and dose–response meta‐analysis of randomized controlled trials

Background and objective Increased neutrophil lymphocyte ratio (NLR) is a marker as well as predictor of various cardiac and non cardiac disorders. Our aim was to assess the relationship between NLR and different level of glycemic control in type 2 diabetic patients. Methods An observational study was conducted at diabetic clinic of Sheikh Zayed Medical College/Hospital, Rahim Yar Khan from September 2016 to February 2017 in which 330 type 2 diabetic patients were randomly divided in to three groups based upon diabetes control according to ADA criteria. Patients in group A with HbA1c ≤ 7% (excellent control), group B HbA1c 7.0-9.0 % (poor control) and group C HbA1c ≥ 9 %(worst control). Patients were assessed in terms of complete blood count and C - reactive protein. Results As compared to excellent control (Group A) patients with worst control (Group C)showed a high leukocyte count (p.001), high neutrophil count (P.003) and lower lymphocyte count (P 0.44) while patients in poor control (Group B)did not differ significantly. Similarly value of NLR was also significantly higher in worst control (Group C) as compared to poor control(Group B) and excellent control (Group A) diabetes (4.3±2.8, 2.7±1.0 and2.0±0.5(p.001). NLR were found independent predictor of worst diabetes control (OR: 1.809, 95% CI: 1.459-2.401) along with fasting blood sugar (OR: 0.938, 95% CI: 0.995-0.982) and CRP (OR: 1.020, 95% CI: 1.003-1.028). Conclusion Increased NLR level is associated with elevated HbA1c and poor glycemic control in patients of type 2 diabetes mellitus. It can be used as a disease monitoring tool during the follow up of diabetic patients.

Neutrophil lymphocyte ratio (NLR): A well assessment tool of glycemic control in type 2 diabetic patients.

Background and objective NAFLD affecting up to 30% of the population globally. Drug treatment options are limited with disappointing results. The dietary supplementation in the form of green tea is another option. Our objective was toinvestigate the effect of Green tea extract (GTE) supplementation on various parameters innon-alcoholicfatty liver disease (NAFLD) patients. Methods This study was conducted Dept. of Medicineof Sheikh Zayed Medical College/Hospital, Rahim Yar Khan from 15 April 2016 to 15 July 2016. Eighty overweight, non diabeticand dyslipidemic patients of NAFLD, diagnosed on the basis of ultrasound and aminotransferases level were randomized for treatmentwith capsule GTE500mg (n=40)and capsule placebo (n=40) twice a day for twelve weeks. Anthropometric parameters, liver enzymes, inflammatory markers and liver ultrasound imaging were estimated by SPSS-16 pre and post treatment. Results As compared to placebo, GTE caused a significant improvement in body weight (29.5±3.8 to 27.2±3.2 kg/m2 p=0.03), BMI (86±10.5 to 80±12.4 kg p=0.026), HOMA-IR(4.32±2.25 to 3.16± 1.6 p=0.0081) lipid profile (i.e. TC: L242.5±20.5 to 215.4±18.6 mg/dl p=0.005; TG: 175±22.6 to145±18 mg/dlp=0.003; LDL-C:155±12.5 to 140±16.7 mg/dl p=0.011; HDL-C: 36.8±6.7 to46.4±5.8 mg/dl p =0.001, Aminotransferases (i.e. ALT: 70.4±15.8to52.8±12.2 IU/L p=0.04; AST: 65.8±12.4 to 44.3± 8.5U/L p =0.002) and Inflammatory markers (hs-CRP: 3.14±0.58 to 2.18±0.32 p =0.023 Adiponectin: 8.46±1.02 to 10.55±3.42μg/ml p =0.003)GTE also caused a 67.5% regression of fatty liver changes on ultrasound as compared to placebo which is 25%only. Conclusion GTEtherapy resulted in significant improvement in metabolic, chemical, inflammatory and radiological parameters of non-alcoholic fatty liver disease patients who were non-diabetic anddyslipidemic.

Therapeutic benefits of green tea extract on various parameters in non-alcoholic fatty liver disease patients.

Background: Non-alcoholic Fatty Liver disease (NAFLD) is the most common cause of progressive liver disorders worldwide. Drug options are limited with varying results. Nigella sativa in the form of herbal medicine could be another option because of its strong historical background. The objective of the study was to evaluate the effect Nigella sativa on various parameters in patients of NAFLD. Methods: A randomized controlled trial was conducted at outpatient clinic of medical unit-1 of Sheikh Zayed Medical College/Hospital, Rahim Yar Khan, in which seventy patients of NAFLD were divided in to interventional and non-interventional groups. The interventional group was given cap Nigella sativa 1g twice a day while non-interventional group was given cap placebo in a same way for three months. Body weight, BMI, liver enzymes and ultrasound finding of fatty liver were assayed before and after treatment. Results: After 12 weeks treatment with Nigella sativa body weight decreased significantly from 86±13.8 to76±12.6 kg vs placebo ( p =0.041). BMI also reduced significantly from 29.06±4.6 to 26.25±6.2kg/m 2 vs placebo( p =0.012). There is remarkable reduction in aminotransferases level after treatment with Nigella sativa vs placebo (ALT: 78.05±5.52 to 52.6±5.65 IU/L vs 76.48±4.95–74.32±5.58 IU/L ( p =0.036). AST: 65.54±4.56–44.56±5.52 IU/L vs 63.25±5.43–59.43±3.39 IU/L ( p =0.021). There was overall 57.14 % patient had normal fatty liver grading on ultrasound after 12 weeks treatment with Nigella sativa as compared to placebo ( p =0.002). Conclusion: Nigella sativa improves bio chemical and fatty liver changes in NAFLD patients. Its use in early stages of NAFLD is recommended in order to prevent its life-threatening complication. Keywords: NAFLD; Nigella sativa ; Body weight; ALT; AST; Fatty liver grading

Effects of nigella sativa on various parameters in Patients of non-alcoholic fatty liver disease.

OBJECTIVE To determine the effect of Vildagliptin in non-alcoholic, fatty liver disease patients with dyslipidemia. METHODS A randomized placebo controlled trial was conducted at outpatient clinic of Medical Unit-I of Sheikh Zayed Medical College/Hospital, Rahim Yar Khan, in which fifty eight patients of NAFLD with dyslipidemia were divided in to two, case and control groups. The case group was given tablet Vildagliptin 50mg twice a day for twelve weeks and control group was given placebo in same way. Body weight, body mass index (BMI), lipid profile, liver enzymes and ultrasound finding of fatty liver were assayed before and after treatment. RESULTS After 12 weeks treatment of vildagliptin there was significant improvement in following parameters. Body weight and BMI decreased significantly from 88 ± 11 to79 ± 12 kg (p0.036) and 30±4to 27±5 kg/m2 (p 0.005) respectively. Notable reduction in the value of TC, TG and LDL-C (TC:252±24 to 220±20mg/dl (p 0.031); TG: 190±24 to115±22 mg/dl (p 0.005); LDL-C 160±15 to 145±13mg/dl (p 0.004). HDL-C level increased significantly from 29±5to45±4 mg/dl (p 0.001). There was remarkable reduction in aminotransferases level (ALT: 78± 17 to 48±14IU/L (p 0.036). AST: 63.3±13 to41±11IU/L (p 0.002). There was overall 65.5% improvement in fatty liver grading on ultrasound with vildagliptin while non significant effects were seen in placebo group in all of the above parameters. CONCLUSION Vildagliptin exhibited beneficial effects in non-alcoholic fatty liver disease, Non-diabetic patients with dyslipidemia.

Vildagliptin ameliorates biochemical, metabolic and fatty changes associated with non alcoholic fatty liver disease.

There are still no FDA approved drugs for NAFLD so far. Vitamin D may be a good therapeutic option for NAFLD patients due to its insulin sensitizing and anti-inflammatory properties. The purpose is to investigate the effect of oral vitamin D supplementation on various parameters in NAFLD patients. In this double blind randomized placebo controlled trial, 109 patients of NAFLD diagnosed by abdominal ultrasound and liver enzymes were divided into two groups for treatment with oral capsule of vitamin D3 50,000 IU and capsule placebo weekly for a period of 12 weeks. Anthropometric, chemical, metabolic and inflammatory parameters were assessed pre and post treatment by using SPSS 16. After 12 weeks oral treatment with vitamin D , its level increased significantly in vitamin D group from 12.5±4.2 to 24.5±3.8 ng/ml p =0.003 vs placebo group. This rise was further accompanied by decrease in HOMA-IR (4.56±1.6 to 3.26± 1.8 p=0.003) liver enzymes (i.e. ALT: 72.±17.6 to 54.5±14.5 IU/L p=0.04; AST: 68±14.5 to 46.± 10.5 p =0.002) serum CRP 3.25±0.68 to 2.28±0.44 mg/L p =0.06 and increase in serum adiponectin 8.56 ±1.12 to 10.44±2.35 mg/L p =0.03 as compared to placebo group. However non significant changes were observed in both groups in terms of body weight, BMI, and serum lipid profiles. Vitamin D supplementation not only improved its own status but also caused a significant amelioration in metabolic, chemical and inflammatory parameters in NAFLD patients. So it should be consider as an adjunctive therapy in NAFLD patients.

Lubna Akhtar

Papers

Neutrophil lymphocyte ratio (NLR): A well assessment tool of glycemic control in type 2 diabetic patients.

Therapeutic benefits of green tea extract on various parameters in non-alcoholic fatty liver disease patients.

Effects of nigella sativa on various parameters in Patients of non-alcoholic fatty liver disease.

Vildagliptin ameliorates biochemical, metabolic and fatty changes associated with non alcoholic fatty liver disease.

Effect of vitamin D supplementation on various parameters in non-alcoholic fatty liver disease patients.