VOL. 9 - The Society of Physicians of Hong Kongsophysicianshk.org/Journal/2017_07.pdf · JUL 2017...

Journal of THE SOCIETY OF PHYSICIANS OF HONG KONG

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JULY 2017 • VOL. 9 • NO. 5

ISSN 2072-4209

JUL 2017 Journal of The Society of Physicians of Hong Kong | 58

Asthma and chronic obstructive pul-monary disease (COPD) manage-ment has evolved tremendously in

the past decade – a myriad of new drugs is now available to patients and physi-cians promising better efficacy and symp-tom control. Interestingly, most landmark randomized trials concerning these new treatments focus mainly on the drugs involved, without a comparable amount of attention to the devices. Yet, we all under-stand that magic bullets could never hit their targets without proper firearms. It is also obvious to us that many patients are either not using their devices properly or not using them at all.

Magnitude of inhaler device problems• 90% of patients make errors1

• 39% of patients have poor technique and 50% have poor technique and poor adherence2

• For both COPD and asthma, the presence of critical errors in using inhaler devices is associated with a 50% increase in the need for steroids, hospital admission or emergency visits3

Major types of inhaler devices used locally and their pitfallsMetered dose inhalers (MDI): This is the classical device developed by Riker Laboratories in 1955. Many of us have been using these devices since the days of Ventolin and Atrovent. However, due to its short propelling time of 0.1– 0.2 seconds,4 it is hard for most patients to achieve good hand-lung coordination to inhale the aerosols. Furthermore, hurried inhalation frequently induces turbulent flow that reduces the amount of drug delivered. Deep and slow inhalation with an adequate breath hold of 3 seconds afterwards is the key to correct usage. Ironically, the way that smokers inhale their cigarettes is akin to the correct way of using MDI.

MDI with spacer: A spacer is recognised for reducing the requirement for hand-lung coordination for children and the elderly, but its ability to hold the aerosols for 2 seconds, allowing time for slow inhalation even for adults, is frequently neglected. It also

reduces the direct impact of inhaled ste-roid and hence reduces oral side effects. Unfortunately, it is too often advised as a lazy option to replace proper training and education. Besides the need for training on the correct use of a spacer, the need for proper cleaning and the addition of extra steps to the whole inhalation pro-cess could be counter-productive, espe-cially for elderly patients with cognitive impairment.

Soft mist inhaler (SMI): Respimat is the only device in this cat-egory. This award-winning device has a clever mechanism that generates a slow mist that lasts for 1–1.5 seconds.4 This allows time for slow inhalation with lamellar flow to bring the drug deeply into the small airways. One problem for patients is the slightly complicated load-ing of a cartridge before use (needs to be done once a month) and the need to prime before its first use.

Dry powder inhalers (DPI): Diskus/Turbuhaler/HandiHaler/Ellipta/Genuair/Breezhaler In general, DPIs require high inspiratory flow to convert dry powder into small par-ticles. They are more convenient to use than the MDI or SMI. However, they also tend to have more oral impact and local side effects. Patients who can not clearly distinguish between inhalation and exha-lation or those who are unable to sustain a good inhalation effort should not be given a DPI.

Diskus/Turbuhaler: These older-generation DPIs are easy to use, but it is even easier to make one or two errors during the inhalation process.

Updates on Inhaler Devices for Airway Diseases: “Knowing Our Guns”

59 | Journal of The Society of Physicians of Hong Kong JUL 2017

About half to two-thirds of patients will make errors using these devices.5 Errors during the twist-and-click preparation of the dose, failure to hold the device in the right position before inhalation, blow-ing or shaking the device right before inhalation are common mistakes affecting their correct usage. The lack of a feedback system also makes it difficult to ascertain whether patients have taken the dose correctly.

HandiHaler: This device is simple to use; however, some patients could accidentally break the capsule when putting it into the device. It is also harder to inhale with the HandiHaler as the device has higher resistance than the newer DPIs Ellipta, Breezhaler and Genuair.

Ellipta:It is simple and convenient to use with a 2-step process (open and breathe). A study showed that most patients could use the device correctly after reading an information leaflet.5 This is also a low-resistance DPI that allows high flow with minimal inhalation effort.6

Genuair:This is a new device available locally since 2016. It has a clear colour mark to indicate successful inhalation, with reasonably low resistance. However, it still requires some training for most patients to under-stand the correct usage.

Breezhaler: This device is the only DPI that contains three feedback systems to indicate suc-cessful inhalation (whirring sound, sweet taste and empty capsule). It was found to have the lowest resistance among the newer DPIs (Table) and is the easiest to generate the required inspiratory flow.6 However, its small size and the need to insert the capsule into this compact device could occasionally cause problems for some elderly patients with visual or dexterity limitation.

In short, using the right device correctly is as important as prescribing the right drug for patients with asthma and COPD. Just as clearly stated by the Global Initia-tive for Asthma (GINA)7, a four-step pro-cess is needed to ensure correct device use:

1. Choose the right device2. Check (ask the patient to demonstrate,

assuming the technique to be poor until proven otherwise)

3. Correct (correct any error and demon-strate)

4. Confirm (ask the patient to return dem-onstration)

With the right gun and bullets, we allow these new drugs to exert their benefit as seen in multiple landmark trials, where compliance, adherence and technique are always optimized.

References1. Price D, Ryan DP, Gruffydd-Jones K et al. Assessment of potentially

important device errors performed by asthma patients in the global iHARP review service. Abstract presented at IPCRG 2014.

2. Crompton G, Barnes P, Broeders M, et al. Aerosol Drug Management Improvement Team. The need to improve inhalation technique in Europe: a report from the Aerosol Drug Management Improvement Team. Respir Med 2006;100:1479–94.

3. Melani AS, Bonavia M, Cilenti V, et al; Gruppo Educazionale Associazione Italiana Pneumologi Ospedalieri. Inhaler mishandling remains common in real life and is associated with reduced disease control. Respir Med 2011;105:930–8.

4. Hochrainer D, Hölz H, Kreher C, et al. Comparison of the aerosol velocity and spray duration of Respimat Soft Mist inhaler and pressurized metered dose inhalers. J Aerosol Med 2005;18:273–82.

5. van der Palen J, Thomas M, Chrystyn H, et al. A randomised open-label cross-over study of inhaler errors, preference and time to achieve correct inhaler use in patients with COPD or asthma: comparison of ELLIPTA with other inhaler devices. NPJ Prim Care Respir Med 2016;24;26:16079.

6. Krüger P, Ehrlein B, Zier M, Greguletz R. Inspiratory flow resistance of marketed dry powder inhalers (DPI). Eur Resp J 2014;44:4635.

7. Global initiative for asthma (GINA). GINA Report 2017. Available at http://ginasthma.org/2017-gina-report-global-strategy-for-asthma-management-and-prevention/.

Table. Resistance and therapeutic flow rates of various dry powder inhalers

DPI Inspiratory flow rate at 4.0 kPa pressure drop (L/min)

Inspiratory device resistance ( kPa mins/L)

Minimal therapeutic flow rate (L/min)

Minimal inspiratory force needed (kPa)

HandiHaler® 37 0.058 39 5.11

Turbuhaler® 58 0.035 45 2.48

Genuair® 64 0.031 45 1.95

Ellipta® 74 0.027 43.5 1.37

Breezhaler® 111 0.017 47 0.63


Type 2 diabetes is a chronic pro-gressive disease associated with cardiovascular-renal complications

and premature mortality. Optimizing glycaemic control reduces the risk of microvascular complications and, if implemented early, may also lower incident cardiovascular disease.1 Oral anti-diabetic drugs are the recommended first-line treatment for type 2 diabetes, but with natural disease progression and the decline in pancreatic beta cell function/glucose toxicity, insulin therapy becomes necessary to curb hyperglycaemia. The latest professional guidelines have addressed the importance of early insulin initiation.2,3

Reduce the psychological insulin resistance In clinical practice, insulin initiation is frequently delayed due to clinical

inertia from doctors and psychological resistance from patients.4 One large-scale epidemiological study revealed that more than 28% of type 2 diabetic patients expressed reluctance to start insulin if prescribed.5 Barriers to insulin initiation include the fear of injection, anticipated pain, side effects of hypoglycaemia and weight gain, as well as other misconcep-tions about insulin therapy.5,6 Contrary to common belief, several studies have reported the positive impact of insulin on quality of life, and improving anxiety in type 2 diabetes.7-9 As clinicians, we need to arm our type 2 diabetes patients with a better understanding of and fewer mis-conceptions about insulin, so that patients will have less psychological resistance to insulin and can benefit from earlier insulin use.

Other indications of insulin initiation in type 2 diabetesClinicians need to initiate insulin promptly at first presentation of type 2 diabetes if the patient presents with marked cata-bolic symptoms, such as marked weight loss, short history of polyuria/polydip-sia, or presence of moderate to severe ketonuria. Personally, I advocate starting insulin upon diagnosis when the present-ing HbA1c is greater than 10%. Once the catabolic symptoms subside and acute glucotoxicity resolves, it is possible to taper insulin entirely and change to oral anti-diabetic drugs.

Insulin should be also started in pregnant women with pre-existing type 2 diabetes and women contemplating pregnancy, when they fail to achieve stringent glycaemic control despite life-style intervention +/- metformin. Very

often, patients with significant renal or liver impairment need insulin because most oral anti-diabetic drugs are contra-indicated. Finally, insulin is the preferred drug for treating hyperglycaemia in the inpatient setting.

How to start basal insulinBasal insulin provides relatively stable coverage throughout the day and night. It keeps blood glucose to target by sup-pressing hepatic glucose production between meals and during sleep. For many patients with type 2 diabetes, basal insulin suffices to control blood glucose, especially when it is combined with oral anti-diabetic drugs. If fasting blood glu-cose is within target but the post-pran-dial glucose is still suboptimal, clinicians should consider adding a glucagon-like peptide 1 (GLP-1) receptor agonist or prandial insulin.3

The usual starting dose of insulin is 0.2 units/kg/day. For example, in a patient who weighs 50 kg, his/her starting dose of insulin should be 10 units per day. Increase the insulin dose by 2–4 units once every 3–4 days until the fasting blood glucose reaches a desired level. A more aggressive dose increment is nec-essary for more severe hyperglycaemia. If hypoglycaemia develops, reduce the insulin dose by 2–4 units (or by 10–20%, whichever is greater). For insulin han-dling/storage and injection techniques, I recommend readers refer to the cited article, as these topics are discussed in detail.10

Choices of basal insulinsIntermediate-acting insulin (neutral prot-amine Hagedorn [NPH] insulin), long- acting insulin analogues (insulin detemir

Insulin Initiation in Patients with Type 2 Diabetes


and glargine) and the newer long-acting insulin analogues (insulin glargine U300 and insulin degludec) can all be used as basal insulin. The pharmacological proper-ties of various basal insulins are summa-rized in the table below.

Due to cost constraints, NPH insu-lin is often the first-line insulin regimen in most public healthcare settings. Com-pared with long-acting basal analogues, NPH insulin has more intra-individual vari-ability in terms of absorption. It is asso-ciated with higher hypoglycaemia risk and more weight gain. NPH insulin has a peak action 4–6 hours after injection, and as such can be responsible for nocturnal hypoglycaemia (if given at bedtime) and for late-morning hypoglycaemia (if given before breakfast). Long-acting insulins are insulin analogues and a slight altera-tion in their molecular structure results in slower absorption and a more stable pharmacokinetic profile; hence, they cause less hypoglycaemia. They are cur-rently preferable to NPH insulin as basal insulin in non-pregnant patients.

Newer basal insulin: Less hypoglycaemia and even more stable pharmacokineticsHypoglycaemia is the most unwanted side effect of insulin therapy for patients and doctors. The newest long-acting insu-lins have the potential to minimize hypo-glycaemia. Having a longer duration of action (>24 hours), newer basal insulins demonstrate a relatively flat action profile with less hypoglycaemia risk even though they are as efficacious as the older gener-ations.11 Due to their very long action, we

should be aware that the effect of dosage reduction (in case of hypoglycaemia for instance) is not immediate for the newer insulin (in contrast to older insulins).

Two “newer basal insulins” were launched in Hong Kong last year: insu-lin glargine U300 and insulin degludec. Glargine U300 is the concentrated form of insulin glargine (glargine U100); the concentration of insulin glargine is usually 100 units/mL, while glargine U300 has a concentration of 300 units/mL. With the increased concentration, glargine U300 has a much more prolonged dissolution than glargine U100 and can provide a “more peakless” action. Its hypoglycae-mia risk is 25% lower than glargine U100 over a 6-month period.12

Insulin degludec has an even longer half-life (>40 hours). Given as once-daily dosing, its plasma concentration vari-ability is the lowest among the available long-acting insulins; therefore, it has a low hypoglycaemia risk in type 2 diabetes patients. Furthermore, its unique feature of flexible dosing may improve patients’ acceptance and adherence to insulin injection. Unlike the older basal insulins, which require injection at the same time of the day, insulin degludec allows daily injection at any time of the day without compromising its efficacy and safety pro-file.13 In my opinion, insulin degludec is a good option for patients who work shifts and elderly patients who may have diffi-culty with strictly adhering to the insulin injection schedule. A study has demon-strated that the absorption of degludec was not affected by injection sites (abdo-men, deltoid, thigh),14 giving further flexibility to patients. Finally, a recent

randomized control trial involving >7,500 patients confirmed insulin degludec was as cardiovascular-safe as insulin glargine, but had fewer hypoglycaemia events and could lower fasting glucose level more.15

In conclusion, the newer insulins provide a peakless action with less hypo-glycaemia and greater injection flexibility. These unique features can aid in over-coming clinical inertia and psychological resistance to initiating insulin therapy.

References1. Turner RC, Millns H, Neil HA, et al. Risk factors for coronary artery

disease in non-insulin dependent diabetes mellitus: United Kingdom Prospective Diabetes Study (UKPDS: 23). BMJ 1998;316:823–8.

2. Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycaemia in type 2 diabetes: a patient-centered approach. Position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetologia 2012;55:1577–96.

3. Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycemia in type 2 diabetes, 2015: a patient-centered approach: update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 2015;38:140–9.

4. Ishii H, Iwamoto Y, Tajima N. An exploration of barriers to insulin initiation for physicians in Japan: findings from the Diabetes Attitudes, Wishes And Needs (DAWN) JAPAN study. PLoS One 2012;7:e36361.

5. Polonsky WH, Fisher L, Guzman S, Villa-Caballero L, Edelman SV. Psychological insulin resistance in patients with type 2 diabetes: the scope of the problem. Diabetes Care 2005;28:2543–5.

6. Rubin RR, Peyrot M. Psychological issues and treatments for people with diabetes. J Clin Psychol 2001;57:457–78.

7. Fischer JS, McLaughlin T, Loza L, Beauchamp R, Schwartz S, Kipnes M. The impact of insulin glargine on clinical and humanistic outcomes in patients uncontrolled on other insulin and oral agents: an office-based naturalistic study. Curr Med Res Opin 2004;20:1703–10.

8. Houlden R, Ross S, Harris S, Yale JF, Sauriol L, Gerstein HC. Treatment satisfaction and quality of life using an early insulinization strategy with insulin glargine compared to an adjusted oral therapy in the management of Type 2 diabetes: the Canadian INSIGHT Study. Diabetes Res Clin Pract 2007;78:254–8.

9. Lee LJ, Fahrbach JL, Nelson LM, et al. Effects of insulin initiation on patient-reported outcomes in patients with type 2 diabetes: results from the durable trial. Diabetes Res Clin Pract 2010;89:157–66.

10. American Diabetes Association. Insulin administration. Diabetes Care 2004;27 Suppl 1:S106–9.

11. Pettus J, Santos Cavaiola T, Tamborlane WV, Edelman S. The past, present, and future of basal insulins. Diabetes Metab Res Rev 2016;32:478–96.

12. Ritzel R, Roussel R, Bolli GB, et al. Patient-level meta-analysis of the EDITION 1, 2 and 3 studies: glycaemic control and hypoglycaemia with new insulin glargine 300 U/ml versus glargine 100 U/ml in people with type 2 diabetes. Diabetes Obes Metab 2015;17:859–67.

13. Meneghini L, Atkin SL, Gough SC, et al. The efficacy and safety of insulin degludec given in variable once-daily dosing intervals compared with insulin glargine and insulin degludec dosed at the same time daily: a 26-week, randomized, open-label, parallel-group, treat-to-target trial in individuals with type 2 diabetes. Diabetes Care 2013;36:858–64.

14. Nosek L, Coester HV, Roepstorff C, et al. Glucose-lowering effect of insulin degludec is independent of subcutaneous injection region. Clin Drug Investig 2014;34:673–9.

15. Marso SP, McGuire DK, Zinman B, et al. Efficacy and safety of degludec versus glargine in type 2 diabetes. N Engl J Med 2017. Jun 12. doi: 10.1056/NEJMoa1615692. [Epub ahead of print]

Basal insulin (Trade name)

NPH insulin(Humulin N®)(Protaphane HM®)

Levemir(Detemir®)

Glargine U100(Lantus®)

Glargine U300(Toujeo®)

Degludec(Tresiba®)

Duration of action ~18 hours ~20 hours ~24 hours >24 hours >24 hours(up to 42 hours)

Peak 4–6 hours 7–14 hoursFlat(some peak at 4–12 hours)

Flat, no peak Flat, no peak

Frequency of administration Twice daily Twice daily in most patients

Daily(same time) Daily +/- 3 hours Daily

(any time of the day)

Pregnancy category Category B Category B Category C Category C Category C


Global response to viral hepatitis – Global Health Sector Strategy (GHSS) Viral hepatitis B and C infections cause serious health issues, with approximately 325 million infected persons worldwide leading to 1.34 million deaths in 2015. There is good evidence that eliminating viral hepatitis is technically feasible by strategies including: 1. Preventive measures with safe blood

supply, safe injections and universal precaution in healthcare settings

2. Good coverage of hepatitis B vacci-nation

3. Case finding and treatment of chronic hepatitis B and C with highly effective antiviral agents.

In 2016, the World Health Assembly adopted the WHO’s first “Global Health Sector Strategy (GHSS) on Viral Hepatitis”,

with elimination as its overarching vision. The target for 2030 is to reduce the rate of new infection by 90% and mortality by 65%.1

Morbidity and mortality from viral hepatitisChronic hepatitis B (CHB) and chronic hepatitis C (CHC) can lead to cirrhosis and hepatocellular carcinoma. These asymp-tomatic diseases can present at a late stage with high morbidity and mortality. Studies in Hong Kong noted that around 80% of liver cancer is related to CHB, 3–6% to CHC, and co-infection another 0.4–3%.2 In 2015, liver cancer was the fourth most common cancer in men and ninth most common cancer in women; amounting to 1,407 cases of males and 445 cases of females with liver cancer. In terms of cancer deaths, liver cancer was ranked third among men and accounted for 21.2% of all cancer deaths.3 There is a downward trend in age-standardized mortality rate for both sexes in the past decade, but this does not reflect the major advances during this time. From 1999 to 2000, 76 liver transplants were performed in Queen Mary Hospital due to cirrhosis; of these, 51 and 7 were related to CHB and CHC, respectively.4

Viral hepatitis B in Hong KongChanging hepatitis B virus epidemiologyHepatitis B virus (HBV) infection is endemic in Hong Kong, resulting in acute hepatitis B and CHB. In the annual Centre for Health Prevention (CHP) publication on viral hepatitis, acute hepatitis B had decreased from 121 in 2002 to 29 cases in 2015. CHB results from mother-to-child or early childhood transmission. CHB has four phases: (1) immune tolerance, (2) immune clearance, (3) quiescent,

and (4) hepatitis B antigen e (HBeAg)-negative hepatitis or reactivation. One in four patients has protracted immune clearance or HBeAg-negative hepatitis, which although asymptomatic can lead to an early death from complications of cirrhosis or hepatocellular carcinoma. To combat the cause of CHB, a universal HBV vaccination programme for new-borns was implemented in 1988, and additional hepatitis B immunoglobulin was prescribed for infants born to HBsAg- positive mothers. A study in 2009 showed HBsAg seroprevalence among teenagers declined from 10% to 0.78%. Increased vaccination coverage among adults, universal precautions practiced in healthcare settings, safe blood donation and safe sex promotion have contributed to the overall decline in HBsAg seropreva-lence from 15% in the 1980s to 5–7% at present.4

Are we harnessing HBV therapeutic advances to impact morbidity and mortality?

All HBsAg-positive individuals must be assessed with blood tests for HBeAg, HBV DNA and alanine aminotransfer-ase together with ultrasonography and Fibroscan. Therapeutic options for HBV have evolved from the less effec-tive pegylated interferon to more effec-tive, drug resistance-free and safer oral nucleos(t)ide analogues, namely enteca-vir and tenofovir.5 Additionally, tenofovir alafenamide, with an improved safety profile, will be available next year.6 Cur-rent therapy suppresses viral replica-tion but cannot eradicate the resilient covalently closed circular DNA (cccDNA) in the nucleus of the host hepatocytes. However, local data have previously dem-onstrated a significant reduction in the incidence of complications and hepatocel-lular carcinoma with long-term therapy.7-8

Elimination of Viral Hepatitis B and C


Despite the availability of these effective oral antiviral agents, the impact on the incidence and mortality rate of liver cancer is not satisfactory. The rea-son is that only half of those infected and in need of therapy are being treated at the moment. A major barrier is “service linkage failure”. Many patients informed of their HBsAg-positive status have not been counselled and assessed prop-erly. They label themselves as "carriers" 帶菌者 and do nothing further. Red Cross, antenatal clinics, premarital and pre- pregnancy checks, insurance companies and most medical checkups are impor-tant partners in this drive to eliminate hepatitis. They screen clients for HBsAg and are in the vital position to counsel and refer those who have tested positive for further counselling. Updated guidelines must be promulgated to the frontline doctors, healthcare communities and the public.

Further strategies to reduce new HBV infection and reduce disease burden

Since 2016, HBsAg-positive pregnant mothers are encouraged to have their HBV DNA levels tested. Those with over 200,000 IU/mL are advised to take anti-viral therapy (tenofovir, telbivudine or lamivudine) in the third trimester. This eliminates the 5–10% risk of mother-to-child transmission.9 New infection

reduction and treatment accessibility of impact can only be achieved by a territory-wide governmental healthcare initiative.

Viral hepatitis C in Hong KongHepatitis C virus (HCV) is transmitted by body fluids and has a chronicity rate of 70%. CHC is identified by anti-HCV blood test, and disease activity is defined by HCV RNA level, ALT, ultrasonography and Fibroscan.10 There are six HCV geno-types and surveys have shown that 0.5% of the Hong Kong population is infected. Anti-HCV has been found to be positive in injecting drug users (66.8%), haemophilia patients (56%) and haemodialysis users (4.6%). Sexual contact presents a low risk for HCV transmission. In a more recent analysis of HCV-positive blood donors, a history of blood transfusion (43.7%) was the most common risk factor, followed by intravenous drug use (34.9%) and tattoos (28.6%). HIV/AIDS patients, with a pro-portion being injecting drug users, have a comparatively high HCV prevalence. Chinese HIV-infected men who have sex with men (MSM) are also at risk. Cirrhosis and hepatocellular carcinoma are likely sequelae of CHC.4 Fortunately, breakthrough therapeutic advances can eradicate the virus with an 8–12 week course of oral antiviral combination therapy. The initial prohibitively expensive

cost is likely to be rapidly reduced with more agents being approved. More effective pan-genotypic antiviral combina-tion therapies are also in the pipeline.11

ConclusionHong Kong has made good progress in the prevention and treatment of viral hepatitis B and C. We are in a position to achieve the WHO target for 2030 of 90% reduction in new infection and 65% reduction in mortality if government-led initiatives can coordinate all the stake-holders.

References1. Wiktor, S. Towards the Elimination of Hepatitis B and C by 2030. The

draft WHO Global Hepatitis Strategy, 2016-2021 and global elimination targets. http://www.viralhepatitisaction.org/sites/default/files/Stefan%20Wiktor_The%20draft%20WHO%20Global%20Hepatitis%20Strategy,%202016-2021%20and%20global%20elimination%20targets.pdf.

2. Leung NW, Tam JS, Lai JY, et al. Does hepatitis C virus infection contribute to hepatocellular carcinoma in Hong Kong? Cancer 1992;70:40–4.

3. Ten most common cancers in Hong Kong in 2014. Hong Kong Cancer Registry. http://www3.ha.org.hk/cancereg/.

4. Surveillance of Viral Hepatitis in Hong Kong -2015 Update report. Special Prevention Programme, Centre for Health Protection, Department of Health, December 2016. http://www.chp.gov.hk/files/pdf/hepsurv15.pdf.

5. WHO Guidelines for protection, care and treatment for persons with chronic hepatitis B. http://www.who.int/hepatitis/publications/hepatitis-b-guidelines/en/2015.

6. Scott LJ, Chan HLY. Tenofovir alafenamide: a review in chronic hepatitis B. Drugs 2017;77:1017–28.

7. Wong GL, Tse YK, Chan HL, et al. Oral nucleos(t)ide analogues reduce recurrence and death in chronic hepatitis B-related hepatocellular carcinoma. Aliment Pharmacol Ther 2016;43:802–13.

8. Wong GL, Tse YK, Wong VW, et al. Long-term safety of oral nucleos(t)ide analogs for patients with chronic hepatitis B: A cohort study of 53,500 subjects. Hepatology 2015;62:684–93.

9. Pan CQ, Duan Z, Dai E, et al; China Study Group for the Mother-to-Child Transmission of Hepatitis B.Tenofovir to prevent hepatitis B transmission in mothers with high viral load. N Engl J Med 2016;374:2324–34

10. WHO Guidelines for the screening, care and treatment of persons with hepatitis C infection http://www.who.int/hiv/pub/hepatitis/hepatitis-c-guidelines/en/2014.

11. D'Ambrosio R, Degasperi E, Colombo M, Aghemo A. Direct-acting antivirals: the endgame for hepatitis C? Curr Opin Virol 2017;24:31–7.


Introduction Moisturisers are bland oleaginous sub-stances that are applied to the skin by rubbing. They are used to replace natural skin oils, to cover tiny fissures in the skin, and to provide a soothing protective film. They may slow evaporation of the skin’s moisture, thereby maintaining hydra-tion, and improving the appearance and tactile properties of dry and aging skin. The current "bricks and mortar" model

of the stratum corneum reflects its role as more than a simple layer. It is a highly dynamic chemical and biological antimi-crobial shield. Loss of intercellular lipids, ie, ceramides, cholesterol and fatty acids that form bilayers, damages the water-barrier function. The natural moisturising factor (NMF), a natural mixture of amino acids, lactates, urea and electrolytes that helps the stratum corneum retain water, is also essential for hydration. Dry skin is noted when the moisture content is less than 10%, and there is loss of con-tinuity of the stratum corneum. Example ingredients in emollients include mineral oil, lanolin, shea butter, fatty acids, cho-lesterol, squalene and structural lipids. Long-chain, saturated fatty acids and fatty

alcohols are commonly used in topical pharmaceuticals and cosmetic formula-tions. They exert their benefits through effects on the skin barrier and on perme-ability. Examples include stearic, linoleic, linolenic, oleic and lauric acids, which can be found in palm oil, coconut oil and wool fat. Fatty acids and fatty alcohols can change the properties of intracel-lular lipids or the stratum corneum, with medium-chain, saturated hydrocarbons or longer-chain, unsaturated hydrocarbons being the most effective. Essential fatty acids (ie, linoleic and alpha-linoleic acids) influence skin physiology and pathology via their effects on skin barrier functions, eicosanoid production, membrane fluid-ity and cell signaling. Structural lipids,

Updates on the Current Use of Moisturisers

Advisory board on atopic dermatitis and the use of moisturisers, Asian Medical Experts Academy, 2017


ie, intracellular lipids comprising mul-tilamellae, which are located between stratum cornea cells, play a considerable role in the water-holding potential of the stratum corneum. Ceramide is a major component of the inner cellular lipids and plays a major role in generating multila-mellae architecture, and has been shown to be clinically effective in preventing and improving dry skin. Moisturisers contain-ing collagen and other proteins, ie, keratin and elastin, claim to rejuvenate the skin by replenishing its essential proteins. These protein molecules are limited by their size to penetrate the dermis. Protein additives may provide temporary relief of dry skin by filling irregularities in the stra-tum corneum; like emollients, when they dry, they shrink slightly, leaving a protein film that appears to smooth the skin and stretch out some of the fine wrinkles.1

A moisturiser describes the nature of being able to hydrate the stratum cor-neum, while an emollient describes the ability to make skin smooth, supple and lubricated. In daily practice, both terms can be used interchangeably indicating the non-medicated nature in the design and the ingredients.2

An ideal moisturiserWe agreed that an ideal moisturiser should contain most, if not all, of the following characteristics:1. Effectively hydrates the stratum

corneum, reduces and prevents tran-sepidermal water loss (TEWL)

2. Aids in restoring the lipid barrier, ie, duplicating and enhancing the skin’s natural moisture retention mech-anisms

3. Demonstrated clinical efficacy 4. Useful for all age groups with good

safety profiles5. Able to reduce patient’s reliance on

therapeutic agents making them less susceptible to potential side effects

6. Cosmetically elegant and acceptable7. Well tolerated in patients with sen-

sitive skin conditions – ie, hypo- allergenic, nonsensitizing, fragrance

free, non-comedogenic, no preser-vative with potential toxic effects like parabens

8. Offered at an affordable price9. Long-lasting effects10. Fast onset11. Durable stability in the formulation12. Absorbed rapidly providing immediate

hydration without unwanted side effects like irritation, contact der-matitis, occlusion folliculitis

Possible roles of moisturisers in atopic dermatitisThe use of moisturisers at all stages of atopic dermatitis (AD) diseases was given the strongest ‘strength of recommenda-tion’ of A and highest ‘level of evidence’ of I among all current evidenced-based treatment options.2,3 AD is a clinically defined, highly pruritic, chronic inflamma-tory skin disease of children and adults. The diagnosis is made using evaluated clinical criteria. AD is associated with skin barrier anomalies that facilitate an easier allergen penetration into the skin with an increased tendency to irritation and subsequent cutaneous inflammation. A lack of important stratum corneum inter-cellular lipids and an inadequate ratio of lipid compounds (cholesterol, essential fatty acids, and ceramides), as well as filaggrin defects, enhance TEWL, leading to epidermal microfissuring, which may cause direct exposure of Langerhans cell dendrites and nerve endings to the environment.4

1. Prevention of water loss and repair of skin barrier

High-quality moisturisers were developed as baseline treatments in the early 21st century. We have a plethora of data to sustain the consensus for the daily use of moisturisers to prevent the worsening of AD.5 A basic principle of treatment of AD is optimal skin care that adequately addresses the skin barrier defect that manifests as an increase in TEWL and increased penetration of allergens and

infectious agents, leading to inflamma-tion and intense pruritus. Contributing to this abnormality is a disturbed epidermal terminal differentiation leading to filag-grin deficiency and reduced natural skin lipids. A good moisturiser should restore the ability of the intercellular lipid bilayers to absorb, retain and redistribute water by contributing to the reorganization of the structure of the skin layers. The changes in hydration and lessening of TEWL can be scientifically measured and have been shown to correlate with a better clinical outcome.

Novel moisturisers are gradually replacing aqueous creams, as they have superior efficacy in repairing the skin barrier. Their active ingredients provide good support in the form of emollients, humectants and/or occlusives. Clinicians now readily prescribe these moisturisers and educate their patients so that these creams or lotions will be liberally applied to reduce irritation caused by atopy or those of idiopathic origins (eg, side effects of applied drugs).

Only moisturisers can guarantee that epidermal hydration can be main-tained in the distorted microenvironment produced by AD inflammation. In order to eliminate the urge for patients with AD to scratch and subsequently induce further inflammation, the use of moisturisers with suitable active ingredients is essen-tial to their recovery.

2. Steroid-sparing, proactive treatment and prescribed emollients

New and novel emollient creams have ingredients with proposed moisturising, anti-inflammatory and anti-pruritic proper-ties and can be the primary treatment for mild cases of AD. They are an important component as adjunctive or maintenance therapy in inflammatory dermatoses and may help to limit the use of drugs.3

Proactive treatment has been advo-cated for cost-saving benefits and to minimize the use of therapeutic agents, thus producing fewer side effects. In the


traditional approach, anti-inflammatory topical therapy was only administered to lesional skin and was stopped or tapered down once visible lesions were cleared. In the last decade, this traditional, reac-tive approach has been complemented by the proactive treatment concept, which is a combination of predefined, long-term, low-dose, anti-inflammatory treatment applied to previously affected areas of skin, in combination with use of emol-lients on the entire body and a predefined appointment schedule for clinical control examinations. The proactive approach usually consists of a twice-weekly topi-cal treatment of the previously affected areas. This is started only after all visible lesions have successfully been treated, in addition to ongoing daily emollient therapy for both previously affected and unaffected skin.

Prescription emollient devices are a newer class of topical agents designed to target specific defects in skin barrier func-tion observed in AD. They include prepa-rations with various combinations and ratios of lipids, ceramides, fatty acids and filaggrin breakdown products that mimic endogenous compositions and creams containing glycyrrhetinic acid, hydrolipids and other ingredients.3,6 Some of these products are more costly than conven-tional emollients. In the future, more extensive clinical trials are expected to show a greater benefit in the disease management and superiority compared with other emollients.

3. Prevention of atopic dermatitisIn global studies, moisturisers have the strongest evidence of efficacy for the treatment of AD.7 Published clinical tri-als from 2000 onwards provide strong scientific evidence of the epidermal interactions and clinical benefits from regular use of moisturisers.7 Short-term application of corticosteroids is helpful in dealing with sensitization of dendritic cells. However, TEWL seems to be a more prominent issue that requires clinical attention when attempting to ameliorate

the mechanical damage of the skin barrier in AD patients.

A new picture emerges from recent findings, in which the natural history of AD has three phases. The initial phase is the non-atopic form of dermatitis in early infancy, when sensitization has not yet occurred. Next, in 60–80% of patients, genetic factors influence the induction of IgE-mediated sensitization to food, environmental allergens or both – this is the transition to true AD. Third, scratching damages skin cells, which release auto-antigens that induce IgE autoantibodies in a substantial proportion of patients with AD. In children, before and after the diagnosis of IgE-mediated sensitization, measures that prevent exposure to aller-gens could be beneficial. When applied early in infancy, it could potentially help to reduce later sensitization to environmen-tal antigens and autoallergens.8-10

ClassificationsMoisturisers can be classified by the functional design:1. Occlusive: Physically block TEWL, like

petroleum products and oils2. Humectants: Attract water to stratum

corneum, such as glycerin, sorbitol, urea, shea butters, hyaluronic acid

3. Formulated emollients: In the past 10 years, many innovative ingredients have been developed to create products with better functional benefits by con-taining cholesterol, squalene and fatty acids. Some of them also offer a re-pairing, protective and soothing role. Examples include vitamins C and E, antioxidants like tocopheryl acetate, vitis vinifera, telmesteine, anti-inflam-matory and anti-pruritic substances like glycyrrhetinic acid and others.

4. Protein rejuvenators: Replenish es-sential proteins like collagen, keratin, elastin

Alternatively, they can be categorized by their formulated physical nature:1. Lotions contain more water and less

fat than creams. Lotions spread very

easily and are cooling, but are not that effective at moisturising very dry skin. This is because they are not thick enough to repair the skin barrier. They are useful for hairy areas and weeping eczema, or for quick absorption if time is short.

2. Creams contain a mixture of fat and water, and feel light and cool on the skin. They are quite easy to spread over sore and weeping skin and are not greasy, so many people prefer them to ointments for daytime use.

3. Hydrating gels are relatively light and non-greasy, despite having a reasonably high oil content.

4. Sprays are made by dissolving emollient substances like liquid paraffin and oil in volatile media like silicone or butane, which evaporate on application to the skin. Emollient spray is particularly useful to treat hard-to-reach places.

5. Ointments are often stiff and greasy. They are very effective at holding water in the skin and repairing the skin barrier. They are useful for very dry and thickened areas, under wet wraps, or if a heavier emollient is required at night.1,3

Proper applications of moisturisersThe emollient of choice should be used frequently – ideally, this will be every few hours, but should be at least twice a day, and every few hours if the eczema is flaring. • Bath/shower: Pat your skin dry after-

wards with a soft towel and im-mediately re-apply your leave-on emollient.

• Application: Apply emollient gently in the direction of hair growth. Never rub up and down vigorously as this could trigger itching, block hair follicles and create more heat in the skin. It is a good idea to dot blobs of emollient around the limbs and trunk first, as this helps to ensure that all areas of skin are moisturised.

Continued on p.70


Introduction There are 175 million people infected with hepatitis C worldwide, with a prevalence rate of 0.4% in Hong Kong and 1% in China. Oral, direct-acting antiviral regi-mens for chronic hepatitis C virus (HCV) infection have been developed over the past 2 years. In particular, sofosbuvir and velpatasvir have revolutionized the treat-ment of HCV infection. This is the first regimen with well-established efficacy for all genotypes (Figures 1 and 2), even in patients with cirrhosis or prior treatment failure with interferon-based regimens.

HCV genotype in Hong KongRegimen selection varies by genotype and other patient factors. Genotypic stud-ies in Hong Kong have identified that 1b and 6a were the most prevalent HCV gen-otypes locally, a scenario different from that in Western countries where 1a domi-nates.1 In a study of 212 blood donors who tested anti-HCV-positive from 1991 to 1994, the most commonly detected genotype was 1b (58.8%), followed by 6a (27.0%).2 The prevalence of genotypes

1a, 2a, 2b and 3a were 6.2%, 1.4%, 1.4% and 1.9%, respectively. In this review, the treatment of genotypes 1, 2, 3 and 6 will be discussed.

Treatment of chronic HCVRegimen selection for patients with HCV infection should take into account the effi-cacy, duration and adverse effect profile of the regimen, potential drug interac-tions, the patient’s prior treatment and the stage of fibrosis. For each individual patient, insurance and financial issues will also be important considerations.

Genotype 1 Sofosbuvir-velpatasvir is a pangenotypic regimen prescribed for the vast majority of patients with chronic HCV infection. It is available in a once-daily, fixed-dose combination tablet of the nonstructural protein 5B (NS5B) inhibitor, sofosbuvir (400 mg) and the NS5A inhibitor, velpa-tasvir (100 mg). The usual regimen is 12 weeks of treatment. It is highly effective for both treatment-naive and experienced patients with genotype 1 infection.

In a randomized, placebo-controlled trial that included 328 genotype 1-infected

Sofosbuvir and Velpatasvir for All Genotypes of Chronic Hepatitis C Infection

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Adapted from http://hcp.epclusainfo.com/.GT, genotype.


patients who received sofosbuvir- velpatasvir for 12 weeks, 98% and 99% of 1a- and 1b-infected patients, respec-tively, achieved a sustained virologic response (SVR).3 Response rates were similar regardless of treatment history or the presence of cirrhosis. Among patients who had previously failed treatment with a protease inhibitor plus peginter-feron and ribavirin, the SVR rates in two separate studies were 100% (of 37 patients) and 96% (of 28 patients).3,4

Sofosbuvir-velpatasvir has been shown to be well tolerated, with <1% of trial participants discontinuing a 12-week regimen due to adverse events. The most common adverse events were fatigue, headache, nausea and insomnia.

In patients with decompensated cirrhosis, antiviral treatment should only be undertaken by, or in close consulta-tion with, an expert in the management of such patients, preferably at a trans-plant centre. In one study that included 68 patients with genotype 1 infection and Child-Pugh class B cirrhosis, SVR rates with sofosbuvir-velpatasvir plus ribavi-rin for 12 weeks were 94% and 100% for subtypes 1a and 1b, respectively.5 Although serious adverse events were common, few were deemed related to the treatment.

Levels of sofosbuvir and its metab-olite are substantially higher in patients with severe renal impairment (estimated glomerular filtration rate <30 mL/min/1.73 m2) or end-stage renal disease on dialysis than in patients who have normal renal functions, so the safety of sofosbuvir-containing regimens in such patients has not been established.

Genotype 2Treatment with sofosbuvir-velpatasvir for 12 weeks is the preferred regimen for patients with genotype 2 infection with-out cirrhosis or with compensated cir-rhosis, regardless of treatment history.6 It has been shown to be extremely effec-tive against genotype 2, was more effec-tive than the alternative of sofosbuvir

plus weight-based ribavirin, and has the advantage of omission of ribavirin.

A randomized, placebo-controlled trial reported SVR in 100% of 104 geno-type 2-infected individuals (10 with cir-rhosis and 25 with previously failed treatment).3 In another trial that enrolled 266 patients with genotype 2 infection (14% with cirrhosis and 14% with prior treatment failure), the SVR rate was 99% with sofosbuvir-velpatasvir treatment for 12 weeks compared with 95% with sofosbuvir plus ribavirin treatment for the same time period.7 There were no virologic failures among patients receiv-ing sofosbuvir-velpatasvir. One patient with sofosbuvir-velpatasvir discontinued therapy on day 1 due to adverse effects (anxiety, headache and difficulty concen-trating).

Genotype 3Patients without cirrhosis Sofosbuvir-velpatasvir for 12 weeks is the recommended treatment regimen for patients with genotype 3 infection without cirrhosis.

In a randomized trial that included 197 genotype 3-infected patients without

cirrhosis who received 12 weeks of sofosbuvir-velpatasvir, SVR rates were 98% and 91% among treatment-naive (n=163) and peginterferon-ribavirin- experienced (n=34) patients, respectively. In treatment-experienced patients, the addition of ribavirin to the regimen is rec-ommended when the Y93H mutation is detected. The presence of baseline NS5A RASs (and particularly the Y93H muta-tion) is associated with lower SVR rates. In a small study, the addition of ribavirin to sofosbuvir-velpatasvir was associated with higher SVR rates in a difficult-to-cure genotype 3-infected population.8 The most commonly reported adverse events were headache, fatigue and nausea.

Patients with cirrhosisA sofosbuvir-velpatasvir-based regimen for 12 weeks is the recommended treatment regimen for patients with genotype 3 infection with compensated cirrhosis, with a SVR of 93%. If the Y93H mutation is present, sofosbuvir-velpatasvir plus weight-based ribavirin is given for 12 weeks.9

Patients who have failed peg-interferon plus ribavirin should receive

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Figure 2. Sustained virological response among patients with HCV genotype 3, according to cirrhosis status and previous treatment

Adapted from Foster GR, et al. N Engl J Med 2015;373:2608–17.


sofosbuvir-velpatasvir plus weight-based ribavirin for 12 weeks. In a study that enrolled 42 patients, there was a trend towards higher SVR rates with the addi-tion of ribavirin to sofosbuvir-velpatasvir for 12 weeks (96% versus 88% without ribavirin).8

Genotype 6 HCV genotype 6 has been found primar-ily in South China, Hong Kong, Taiwan, Macao and Southeast Asia, including Sin-gapore, Malaysia, Vietnam, Thailand and Myanmar.

In a trial that included 41 genotype 6-infected patients (6 with cirrhosis and 3 treatment-experienced), sofosbuvir- velpatasvir for 12 weeks resulted in SVR in 100%.3

HBV coinfectionReactivation of HBV infection has been reported in patients receiving direct-acting antiviral (DAA) therapy. Among 29 reported cases of HBV reactivation, two were fatal and one required a liver

transplant.10 Reactivation occurred at an average of 53 days into DAA treatment and was not associated with a particular HCV genotype or DAA regimen. Patients who experienced reactivation had at least one of the following HBV character-istics at baseline: detectable HBV DNA, positive HBV surface antigen (HBsAg), or HBV core antibody (HBcAb)-positive in the setting of a negative surface antibody (HBsAb). Before initiating treatment with DAA, patients should be tested for evi-dence of current or prior HBV infection.

Antiviral therapy for HBV should be initiated for HBV patients who war-rant treatment. Otherwise, those with evidence of HBV infection (ie, with posi-tive HBcAb and negative HBsAb) should be monitored for HBV reactivation during HCV treatment.

Follow-up after treatmentFollow-up after treatment includes check-ing the viral load 12 weeks after the cessa-tion of therapy to evaluate the patient for an SVR. Patients with advanced fibrosis

or cirrhosis need continued screening for hepatocellular carcinoma, regardless of antiviral treatment success.11

ConclusionsSofosbuvir-velpatasvir is the first and only pan-genotypic, once-daily, single-tablet regimen. It is indicated for the treatment of chronic HCV genotype 1, 2, 3, 4, 5 or 6 infection without cirrho-sis or with compensated cirrhosis, and in combination with ribavirin for those with de-compensated cirrhosis. The overall SVR rate was 98%. Sofosbuvir- velpatasvir has been shown to be well tolerated with low rates of discontinua-tions (0.2%) and adverse events across clinical trials. In HCV/HBV co-infected patients, there is a risk of hepatitis B reactivation. Appropriate management for HBV infection should be initiated.

References1. Delwart E, Slikas E, Stramer SL, et al. Genetic Diversity of Recently

Acquired and Prevalent HIV, Hepatitis B Virus and Hepatitis C Virus Infections in US Blood Donars. JID 2012; 205:875-85.

• Combining with other treatments: Use moisturisers alongside other pre-scribed treatments, such as topical steroids and topical calcineurin in-hibitors. There are no standard rules on whether to apply a topical steroid before or after using an emollient. Some people use an emollient first to prepare the skin, followed by the topical steroid.

• Swimming and water recreation: Apply a thicker-than-usual layer of emollient (the greasier the better) before swimming to help protect the skin from the drying and irritant effects of swimming pool water. After swimming, shower and apply your usual leave-on moisturiser.

• Protect your hands with emollient (and perhaps wear gloves) before handling substances such as sand, certain

foods, paint or clay, so they don’t ir-ritate your skin.

• Continue to use the emollient, even when the eczema has improved. This will help prevent flare-ups.

• Apply the emollient to all of your skin, not just the area with eczema.1,11,12

Consensus on the current use of moisturisersPrescription of emollients or moisturis-ers is an evidence-based practice in the management of AD. The application is a strong integral part in active disease treat-ment, maintenance and prevention. Effec-tive management of AD should always involve the treatment of a defective skin barrier. AD is a chronic and relapsing dis-ease; thus, active use of moisturisers can minimize any possible side effects from long-term drug use. As pruritus and

constant scratching is the most impor-tant perpetuating factor, effective use of moisturisers can minimize such symp-toms and the resulting barrier damage. Chronicity and severity of AD, along with patient age, treatment compliance and economic background should all be taken into account when selecting an appropri-ate moisturiser for AD patients. Other considerations include adjuvant proper-ties of the product, cosmetic accept-ability and availability over the counter. Well-defined clinical phenotypes of AD could optimally benefit from specific moisturisers.

References1. Lynde CW. Moisturizers: what they are and how they work. Skin Therapy

Lett 2001;6:3–5.

Continued from p.67

A complete list of references can be downloaded from www.SOPHYSICIANSHK.org

A complete list of references can be downloaded from www.SOPHYSICIANSHK.org

JSPHK July 2017 issue Page 65 – Updates on the Current Use of Moisturisers

Dr Hau Kwun Cheung (侯鈞翔醫生) Dr Chan Chun Yin, Johnny (陳俊彥醫生) Dr Chan Kam Tin, Michael (陳錦添醫生) Dr Ho Ka Keung (何家強醫生) Prof Hon Kam Lun, Ellis (韓錦倫醫生) Dr Lam Ka Man, Carmen (林嘉雯醫生) Dr Lau Ka Fai, Tony (劉家輝醫生)

References:

1. Lynde, C. W., MD, FRCPC. (2015). Skin Therapy Letter. Moisturizers: What They Are And How They Work. Retrieved June 26, 2017, from http://www.skintherapyletter.com/2001/6.13/2.html.

2. Giam, Y. C., Hebert, A. A., Dizon, M. V., Van Bever, H., Tiongco-Recto, M., Kim, K. H., ... & Luk, D. C. K. (2016). A review on the role of moisturizers for atopic dermatitis. Asia Pacific Allergy, 6(2), 120.

3. Eichenfield, L. F., Tom, W. L., Berger, T. G., Krol, A., Paller, A. S., Schwarzenberger, K. ... & Cordoro, K. M. (2014). Guidelines of care for the management of atopic dermatitis: section 2. Management and treatment of atopic dermatitis with topical therapies. Journal of the American Academy of Dermatology, 71(1), 116-132.

4. Wollenberg, A., et al. "ETFAD/EADV Eczema task force 2015 position paper on diagnosis and treatment of atopic dermatitis in adult and paediatric patients."Journal of the European Academy of Dermatology and Venereology 30.5 (2016): 729-747.

5. Rawlings, A. V. (2010). Recent advances in skin ‘barrier’ research. Journal of Pharmacy and Pharmacology, 62(6), 671-677.

6. Krakowski, A. C., MD, & L. B., PA-C, MMSC. (2015). An update on topical management options and adjuvant interventions for this common condition. Topical Therapies for Atopic Dermatitis. Retrieved June 26, 2017, from http://practicaldermatology.com/2015/03/topical-therapies-for-atopic-dermatitis

7. Nankervis, H., Thomas, K. S., Delamere, F. M., Barbarot, S., Rogers, N. K., & Williams, H. C. (2016). Scoping systematic review of treatments for eczema.Programme Grants for Applied Research, 4(7), 1-480

8. Simpson, E. L., Chalmers, J. R., Hanifin, J. M., Thomas, K. S., Cork, M. J., McLean, W. I., ... & Williams, H. C. (2014). Emollient enhancement of the skin barrier from birth offers effective atopic dermatitis prevention. Journal of Allergy and Clinical Immunology, 134(4), 818-823.

9. Bieber. T., MD., Ph.D. (2010). Ann Dermatol. Atopic Dematitis , 22(2), 125-137. doi:10.5021/ad.2010.22.2.125 10. Bieber, T., M.D, Ph.D. (2008). The NEW ENGLAND JOURNAL of MEDICNE REVIEW ARTICLE.MECHANISMS OF

DISEASE Atopic Dermatitis, 358(14), 1483-1494. 11. Ring, J., Alomar, A., Bieber, T., Deleuran, M., Fink-Wagner, A., Gelmetti, C., ... & Schäfer, T. (2012). Guidelines

for treatment of atopic eczema (atopic dermatitis) Part I. Journal of the European Academy of Dermatology and Venereology, 26(9), 1176-1193.

12. National Eczema Society. (2016). FACTSHEET. EMOLLIENTS, 1-10. Retrieved June 26, 2017.

JSPHK July 2017 issue Page 68 – Sofosbuvir and Velpatasvir for All Genotypes of Chronic Hepatitis C Infection

Dr Ng Fook Hong (吳福康醫生) Dr Cheung Sai Wah (張世華醫生)

References:

1. Delwart E, Slikas E, Stramer SL, et al. Genetic Diversity of Recently Acquired and Prevalent HIV, Hepatitis B Virus and Hepatitis C Virus Infections in US Blood Donars. JID 2012; 205:875-85.

2. Prescott LE, Simmonds P, Lai CL, et al. Detection and clinical features of hepatitis C virus type 6 infections in blood donors from Hong Kong. J Med Virol 1996;50:168-75.

3. Feld JJ, Jacobson IM, Hézode C, Asselah T, Ruane PJ, Gruener N, Abergel A, Mangia A, Lai CL, Chan HL, Mazzotta F, Moreno C, Yoshida E, Shafran SD, Towner WJ, Tran TT, McNally J, Osinusi A, Svarovskaia E, Zhu Y, Brainard DM, McHutchison JG, Agarwal K, Zeuzem S, ASTRAL-1 Investigators. Sofosbuvir and Velpatasvir for HCV Genotype 1, 2, 4, 5, and 6 Infection. N Engl J Med. 2015;373(27):2599.

4. Pianko S, Flamm SL, Shiffman ML, Kumar S, Strasser SI, Dore GJ, McNally J, Brainard DM, Han L, Doehle B, Mogalian E, McHutchison JG, Rabinovitz M, Towner WJ, Gane EJ, Stedman CA, Reddy KR, Roberts SK Sofosbuvir Plus Velpatasvir Combination Therapy for Treatment-Experienced Patients With Genotype 1 or 3 Hepatitis C Virus Infection: A Randomized Trial. Ann Intern Med. 2015;163(11):809.

5. Curry MP, O'Leary JG, Bzowej N, Muir AJ, Korenblat KM, Fenkel JM, Reddy KR, Lawitz E, Flamm SL, Schiano T, Teperman L, Fontana R, Schiff E, Fried M, Doehle B, An D, McNally J, Osinusi A, Brainard DM, McHutchison JG, Brown RS Jr, Charlton M, ASTRAL-4 Investigators. Sofosbuvir and Velpatasvir for HCV in Patients with Decompensated Cirrhosis. N Engl J Med. 2015;373(27):2618.

6. http://www.hcvguidelines.org Published on Recommendations for Testing, Managing, and Treating Hepatitis C (Assessed in July 2017)

7. Foster GR, Afdhal N, Roberts SK, Bräu N, Gane EJ, Pianko S, Lawitz E, Thompson A, Shiffman ML, Cooper C, Towner WJ, Conway B, Ruane P, Bourlière M, Asselah T, Berg T, Zeuzem S, Rosenberg W, Agarwal K, Stedman CA, Mo H, Dvory-Sobol H, Han L, Wang J, McNally J, Osinusi A, Brainard DM, McHutchison JG, Mazzotta F, Tran TT, Gordon SC, Patel K, Reau N, Mangia A, Sulkowski M, ASTRAL-2 Investigators, ASTRAL-3 Investigators Sofosbuvir and Velpatasvir for HCV Genotype 2 and 3 Infection. N Engl J Med. 2015;373(27):2608.

8. Pianko S, Flamm SL, Shiffman ML, Kumar S, Strasser SI, Dore GJ, McNally J, Brainard DM, Han L, Doehle B, Mogalian E, McHutchison JG, Rabinovitz M, Towner WJ, Gane EJ, Stedman CA, Reddy KR, Roberts SK . Sofosbuvir Plus Velpatasvir Combination Therapy for Treatment-Experienced Patients With Genotype 1 or 3 Hepatitis C Virus Infection: A Randomized Trial. Ann Intern Med. 2015;163(11):809.

9. Recommendations for Testing, Managing, and Treating Hepatitis C. Joint panel from the American Association of the Study of Liver Diseases and the Infectious Diseases Society of America. http://www.hcvguidelines.org/ (Accessed on July 08, 2016).

10. Bersoff-Matcha SJ, Cao K, Jason M, Ajao A, Jones SC, Meyer T, Brinker A. Hepatitis B Virus Reactivation Associated With Direct-Acting Antiviral Therapy for Chronic Hepatitis C Virus: A Review of Cases Reported to the U.S. Food and Drug Administration Adverse Event Reporting System.Ann Intern Med. 2017.

11. http://www.hcvguidelines.org/ (Assessed in Aug 2016)

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