STG hospital level adult 2019_v2.0.pdf

Standard Treatment Guidelines and Essential Medicines List for South Africa Hospital Level, Adults 2019 Edition Electronic copies are available on National Department of Health Website: http://www.health.gov.za/edp.php Mobile versions can be downloaded as “EML Clinical Guide” smartphone app from...

Standard Treatment Guidelines and Essential Medicines List for South Africa Hospital Level, Adults 2019 Edition Electronic copies are available on National Department of Health Website: http://www.health.gov.za/edp.php Mobile versions can be downloaded as “EML Clinical Guide” smartphone app from the relevant app stores - available for iOS and Android. Print copies may be obtained from: The Directorate: Affordable Medicines Private Bag X828 Pretoria 0001 First printed 1998 Second edition 2006 Third edition 2012 Fourth edition 2015 Fifth edition 2019 ISBN: 978-1-990938-49-8 NOTE: The information presented in these guidelines conforms to the current medical, nursing and pharmaceutical practice. Contributors and editors cannot be held responsible for errors, individual responses to medicines and other consequences. © Copyright 2019, The National Department of Health. Any part of this material may be reproduced, copied or adapted to meet local needs, without permission from the Committee or the Department of Health, provided that the parts reproduced are distributed free of charge or at no cost – not for profit. Suggested citation: National Department of Health, South Africa. Essential Drugs Programme. Hospital level (Adults) Standard Treatment Guidelines and Essential Medicines List. 5th ed. 2019. Published and funded by: The National Department of Health, Pretoria, Republic of South Africa.  ACKNOWLEDGEMENTS This edition of the Adult Hospital Level Standard Treatment Guidelines is evidence of the dedication, technical expertise, skills, and considerable time offered up by the Adult Hospital Level Expert Review Committee. The Committee has enthusiastically evolved with the review process, embracing Health Technology Assessment principles as South Africa journeys towards Universal Health Coverage. Collaboration with various stakeholders was strengthened and we thank all for your constructive engagement. We recommend continuous participation in the peer review consultative process and encourage the dissemination and implementation of these guidelines. In particular, we would like to thank each Committee Member for their valuable contributions, and the Chairpersons of the Adult Hospital Level Expert Review Committee, Dr Black and Dr Dawood, for their unwavering commitment and support during this review process. NATIONAL ESSENTIAL MEDICINES LIST COMMITTEE (2017 - present) Prof A Parrish (Chairperson) Mr K Mahlako Dr G Reubenson (Vice Chairperson) Mrs N Makalima Prof L Bamford Ms E Maramba Dr A Black (resigned) Ms T Matsitse Prof S Boschmans (resigned) Ms N Mazibuko Dr RC Chundu Prof M Mendelson (resigned) Dr K Cohen Ms N Mokoape (resigned) Dr D Dawood (2019-current) Ms N Mpanza Dr R de Waal Dr L Mvusi Mr M Dheda Mr R Naidoo Dr N Dlamini (resigned) Dr N Ndjeka Ms D du Plessis Dr N Ndwamato (resigned) Ms S Dube Dr L Padayachee Prof M Freeman (resigned) Dr Z Pinini Ms T Furumele (2019-current) Mr W Ramkrishna (resigned) Mr A Gray Ms S Ramroop (resigned) Dr G Grobler Ms R Reddy Ms N Gumede Ms Z Rhemtula (2019-current) Dr P Holele (resigned) Dr A Robinson (resigned) Prof B Hoek (2020-current) Prof P Ruff Ms Y Johnson Mr G Steel (resigned) Brig Gen T Kgasago (resigned) Prof M Tshifularo (resigned) Dr T Kredo (2019-current) Mr G Tshitaudzi Ms F Loonat Dr K Vilakazi-Nhlapo (2019-current) Dr J Lotter (resigned) Mr R Wiseman Prof G Maartens Ms C Zeelie (resigned) iii  ACKNOWLEDGEMENTS ADULT HOSPITAL LEVEL EXPERT REVIEW COMMITTEE (2017-2020) Dr A Black - Chair (resigned 2019) Dr H Dawood - Chair (2019-2020) Dr E Bera - Vice Chair Prof PJC Commerford Dr A Sherriff Dr RP Kaswa Dr S Takuva Dr AS Rossouw Dr GA Timothy Prof GS Gebhardt Prof R Coetzee Dr L Robertson Mr JM Nabyoma Dr R Griesel (resigned 2018) Dr Y Hookamchand (resigned 2018) Dr V Mpongoshe (resigned 2019) TECHNICAL AD HOC SUPPORT TO THE ADULT HOSPITAL LEVEL COMMITTEE (2017-2020) Dr K Balme Dr J Nel Dr H Gunter Dr MFP van Jaarsveld Prof S Honikman Prof L Wallis Dr R Kularatne Dr L Weich Ms J Mueller MEDICINE REVIEW AUTHORS/PEER REVIEWERS Dr K Balme Dr H Gunter Prof AG Parrish Prof L Bamford Dr RP Kaswa Ms J Patterson Dr E Bera Dr SR Krause Dr G Reubenson Dr A Black Dr T Kredo Dr L Robertson Prof R Coetzee Ms TD Leong Dr AS Rossouw Prof K Cohen Ms P Letsoane Dr S Takuva Prof PJC Commerford Prof A Moodley Dr GA Timothy Dr H Dawood Dr MA Moorhouse Dr MFP van Jaarsveld Dr R de Waal Ms L Mopelo Ms M Wilkinson Prof GS Gebhardt Dr V Mpongoshe Mr R Wiseman Mr A Gray Mr JM Nabyoma Dr R Griessel Dr J Nel Evidence reviews (78) developed during this review cycle are accessible at: http://www.health.gov.za/index.php/standard-treatment-guidelines-and-essential-medicines-list/category/286- hospital-level-adults COSTINGS/ ECONOMIC ANALYSES Dr E Bera Ms V Mutyambizi (UCT) Ms E Chanikira (UCT) Dr J Miot (HE2RO) Prof GS Gebhardt Ms R Rapiti (Priceless-SA) Miss TD Leong Ms M Wilkinson (Cochrane-SA) Dr L Chola (Priceless-SA) Mr T Wilkinson (Priceless-SA/ UCT) Ms K Macquilkan (Priceless SA) Mr A Winch (Priceless SA) Costing/ economic analyses (12) developed during this review cycle are accessible at: http://www.health.gov.za/index.php/standard-treatment-guidelines-and-essential-medicines-list/category/286- hospital-level-adults iv  ACKNOWLEDGEMENTS COMMENTS AND CONTRIBUTIONS Dr K Balme Prof L Jenkins Dr V Pillay-Fuentes Lorente Dr T Boltina Ms Y Johnson Dr F Pirie Dr M Braithwaite Dr W Jooste Dr P Raubenheimer Dr N Brey Dr T Kalk Dr G Reubenson Dr K Brouard Dr J Kanku Prof B Rayner Prof A Bryer Dr T Kemp Ms R Reddy Prof J Carr Dr D Kettles Dr M Redelinghuys Dr A Chin Ms B Koopman Prof G Richards Dr Chundu Ms S Kirsten Prof P Ruff Dr A Coetzee Dr L Lai King Dr A Scheibe Dr R Coetzee Dr R Krause Prof A Schutte Prof K Cohen Dr R Kularatne Mr R Setshedi Dr M Conradie Prof G Lamacraft Dr S Singh Dr T Crede Dr N Lister Prof M Sonderup Dr J Cunningham Prof V Louw Prof W Spearman Dr J Dave Prof D Lubbe Dr J Stanford Dr H Dawood Ms E Maramba Dr D Stanton Dr A de Villiers Dr K Mawson Dr C Stephen Prof K Dheda Dr S Meiring Dr J Taljaard Dr P Douglas-Jones Prof K Mlisana Dr A Thornton Prof A Doubell Dr S Mohangi Ms N Thipe Ms A du Toit Dr L Molife Dr N Tsabedze Dr R du Toit Prof J Moodley Dr IS Ukpe Prof S Dyer Dr MA Moorhouse Dr A Vachiat Dr R Freercks Prof A Motala Dr E van Duuren Ms M Gijzelaar Dr F Moti Dr MFP van Jaarsveld Prof AGS Gous Ms L Muller Dr R van Rensburg Prof N Govender Dr N Ndjeka Prof R van Zyl-Smit Dr T Hardcastle Dr SC Nyoka-Mokgalong Ms C Vedalanker Ms H Hayes Prof AP Parrish Dr L Visser Dr E Hodgson Dr I Paruk Mr F Vorster Dr B Hodkinson Dr M Patel Dr S Walaza Ms H Hoffman Dr AJK Pecararo Prof L Wallis Dr N Horn Dr L Pein Dr L Weich Dr N Ismail Dr Petro Ms L Whitelaw Allergan Pharmaceuticals South Africa (Pty) Ltd National Committee on Confidential Enquiries into Maternal Deaths Novartis South Africa Pfizer Laboratories (Pty) Ltd Private Healthcare Information Standards Committee (PHISC) Psychological Society of South Africa: Sexuality & Gender Division South African HIV Clinicians Society Society for Endocrinology, Metabolism and Diabetes in South Africa South African Rheumatism Arthritis Association South African Gastroenterology Society v  ACKNOWLEDGEMENTS South African Medical Association South African Society of Anaesthesiologists South African Society of Clinical Pharmacy South African Society of Ophthalmology CLINICAL EDITORS Prof PJC Commerford Dr R de Waal Prof GS Gebhardt Prof G Maartens EDITORIAL Ms TD Leong Dr J Jugathpal Ms G Mngola Ms A Brewer Ms S Putter SECRETERIATE Ms TD Leong Dr J Jugathpal Dr J Riddin Dr R Lancaster Ms S Govender LOGISTICS Ms P Ngobese Mr M Molewa DIRECTOR: AFFORDABLE MEDICINES Ms K Jamaloodien vi  TABLE OF CONTENTS Foreword i Introduction ii Acknowledgements iii Table of contents vii The Essential Medicines Concept xxiii How to use these guidelines xxiv A guide to patient education in chronic diseases xxxiii CHAPTER 1: ALIMENTARY TRACT 1.1 1.1 Gastrointestinal disorders 1.1 1.1.1 Bowel preparations 1.1 1.1.2 Diverticulosis 1.1 1.1.3 Gastro-oesophageal reflux disease (GORD) 1.2 1.1.4 Hiatus hernia 1.4 1.1.5 Inflammatory bowel disease 1.4 1.1.6 Pancreatitis, acute 1.4 1.1.7 Pancreatitis, chronic 1.5 1.1.8 Peptic ulcer 1.6 1.2 Hepatic disorders 1.7 1.2.1 Hepatitis, non-viral 1.8 1.2.2 Liver failure, acute 1.9 1.2.3 Portal hypertension and cirrhosis 1.10 1.2.4 Hepatitis, viral 1.11 1.2.4.1 Hepatitis B, acute 1.12 1.2.4.2 Hepatitis B, chronic (non-HIV coinfection) 1.13 1.2.4.3 Hepatitis B, chronic (HIV coinfection) 1.15 1.2.5 Liver abscess, pyogenic 1.15 1.2.6 Liver abscess, amoebic 1.15 1.2.7 Cholecystitis, acute and cholangitis, acute 1.16 1.3 Diarrhoea 1.16 1.3.1 Cholera 1.16 1.3.2 Dysentery (acute inflammatory diarrhoea) 1.17 1.3.3 Diarrhoea, acute non-inflammatory 1.17 1.3.4 Clostridum difficle diarrhoea 1.18 1.3.5 Amoebic dysentery 1.19 1.3.6 Giardiasis 1.20 1.3.7 Typhoid 1.20 vii  TABLE OF CONTENTS 1.3.8 Bacterial peritonitis 1.20 CHAPTER 2: BLOOD AND BLOOD FORMING ORGANS 2.1 2.1 Anaemia 2.1 2.1.1 Anaemia, iron deficiency 2.1 2.1.2 Anaemia, megaloblastic 2.3 2.1.3 Anaemia, chronic disorder 2.5 2.1.4 Anaemia, haemolytic 2.5 2.1.5 Anaemia, aplastic 2.7 2.1.6 Anaemia, sickle cell 2.7 2.2 Febrile neutropenia 2.9 2.3 Myelodysplastic syndromes 2.10 2.4 Bleeding disorders 2.11 2.4.1 Haemophilia A and B, von willebrand’s disease 2.11 2.5 Immune thrombocytopenia (ITP) 2.15 2.6 Thrombotic thrombocytopenic purpura-haemolytic uraemic syndrome (TTP-HUS) 2.16 2.7 Acquired coagulation defects 2.17 2.7.1 Disseminated intravascular coagulation (DIC) 2.17 2.8 Venous thrombo-embolism 2.18 CHAPTER 3: CARDIOVASCULAR SYSTEM 3.1 3.1 Ischaemic heart disease and atherosclerosis, prevention 3.1 3.2 Acute coronary syndromes 3.5 3.2.1 ST elevation myocardial infarction (STEMI) 3.5 Non-ST elevation myocardial infarction (NSTEMI) and Unstable 3.2.2 angina (UA) 3.9 3.2.3 Chronic management of STEMI / NSTEMI / UA 3.11 3.2.4 Angina pectoris, stable 3.12 3.2.5 Atherosclerotic peripheral arterial disease 3.13 3.3 Cardiac dysrhythmias 3.14 3.3.1 Narrow QRS complex (supraventricular) tachydysrhythmias 3.14 3.3.1.1 Atrial fibrillation 3.15 3.3.1.2 Atrial flutter 3.18 3.3.1.3 AV junctional re-entry tachycardias 3.18 3.3.2 Wide QRS (ventricular) tachyarrhythmias 3.20 3.3.2.1 Regular wide QRS tachycardias 3.20 Sustained (>30 seconds) irregular wide QRS 3.3.2.2 tachycardias 3.21 Non-sustained (20000 Elevated » Treatment required. chronic hepatitis positive B (Immune » HBeAg Clearance) positive 3. HBeAg-negative » HBsAg 2000 Elevated » Treatment required. chronic hepatitis positive B (Immune » HBeAg Escape) negative 5. Occult hepatitis B » HBsAg 50 mL/minute. LoE:IIIxxi AIMS OF TREATMENT HBeAg-positive disease » Sustained HBsAg loss off therapy, with/without the development of anti- HBs, and » Suppression of HBV DNA to undetectable or low (5–20 x 109/L, then platelet transfusion is not necessary. Replacement therapy for thrombocytopenia should consist of 1 apheresis single donor unit or 1 pooled random donor unit. In chronic DIC, or in the 2019 2.17 CHAPTER 2 BLOOD AND BLOOD FORMING ORGANS absence of bleeding, platelet transfusions should not be given merely to correct the thrombocytopenia. For hypofibrinogenaemia:  Cryoprecipitate, IV, 1 unit/10 kg. For depletion of other coagulation factors:  Lyophilised plasma, IV, 15 mL/kg as initial dose. o Volume: ±200 mL/unit. OR FFP, IV, 15 mL/kg as initial dose. o Volume: ±280 mL/unit. LoE:IIxx Repeat replacement therapy 8 hourly or less frequently, with adjustment according to the clinical picture and laboratory parameters. Monitor response with frequent estimation of the platelet count and coagulation screening tests. 2.8 VENOUS THROMBO-EMBOLISM I80.0-3/I80.8-9/I81/I82.0-3/I8.8-9/I26.0/I26.9 DESCRIPTION Venous thromboembolism (VTE) should be seen as a spectrum from calf deep venous thrombosis (DVT) to pulmonary thrombo-embolism. All patients should be seen as potentially high risk. Differential diagnosis includes: » cellulitis » ruptured popliteal (Baker’s) cyst » superficial thrombophlebitis » calf muscle pull or tear » lymphoedema » internal derangement of the knee » chronic venous insufficiency Diagnosis is primarily clinical and confirmed with imaging studies, e.g. Duplex Doppler. GENERAL MEASURES Strategies for prevention include: lifestyle modifications like avoiding obesity and inactivity, avoiding dehydration, avoiding cigarette smoking, maintaining normal blood pressure, and mechanical measures like vascular compression stockings and intermittent pneumatic compression boots. LoE:IIIxxi Acute management Thrombolytic therapy may be indicated in patients with confirmed early pulmonary embolism where haemodynamic stability cannot be achieved. Discuss with a specialist. 2019 2.18 CHAPTER 2 BLOOD AND BLOOD FORMING ORGANS MEDICINE TREATMENT PROPHYLAXIS Risk Assesement Risk assessment is essential, and treatment needs to be individualised. Risk factors for VTE can be divided into predisposing factors (i.e. patient characteristics) and exposing factors (i.e. underlying medical conditions, nature of surgical intervention, etc.). SUBCATEGORIES OF VTE RISK IN SURGICAL AND NON-SURGICAL PATIENTS Surgical patients Medical patients Low VTE risk » Surgery lasting 20% risk of developing a CVD event in 10 years) should switch to atazanavir/ritonavir and repeat the fasting lipid profile in 3 months. » Patients with persistent dyslipidaemia despite switching, qualify for lipid lowering therapy. Criteria for initiating lipid lowering therapy are the same as for HIV-uninfected patients. Many statins (including simvastatin) cannot be used with protease inhibitors, as protease inhibitors inhibit the metabolism of the statin resulting in extremely high blood levels. » Patients who fail to respond to lifestyle modification and have dyslipidaemia treat with:  Atorvastatin, oral, 10 mg at night. REFERRAL » Random cholesterol >7.5 mmol/L. » Fasting (14 hours) triglycerides >10 mmol/L. 3.2 ACUTE CORONARY SYNDROMES These conditions should be managed in a high care setting with continuous ECG and frequent BP monitoring. Reference guide for ECG analysis: “ECG APPtitude” smartphone app can be downloaded from the relevant app stores - available for iOS and Android. 3.2.1 ST ELEVATION MYOCARDIAL INFARCTION (STEMI) I21.0-I21.4/I21.9/I22.0-1/I22.8-9 DESCRIPTION Ischaemic chest pain that is prolonged, or associated with nausea, sweating and syncope or associated with persistent ST elevation or new or presumed new left bundle branch block (LBBB). Repeat ECG at 20-30 minute intervals if the initial ECG is not diagnostic. MEDICINE TREATMENT LoE:Ivii  Oxygen if saturation 75 years of age), omit IV loading dose and reduce SC dose: o Loading dose: SC, 0.75 mg/kg as a single dose. o Maintenance dose: SC, 1.5 mg/kg daily or 1 mg/kg LoE:Ixiii 12 hourly. Pain not responsive to thrombolytics may suggest ongoing unresolved ischaemia.  Nitrates, e.g.: LoE:IIIxiv  Isosorbide dinitrate, SL, 5 mg immediately as a single dose. o May be repeated at 5-minute intervals for 3 or 4 doses. For ongoing chest pain, to control hypertension or treat pulmonary oedema:  Glyceryl trinitrate, IV, 5–200 mcg/minute, titrated to response. o Start with 5 mcg/minute and increase by 5 mcg/minute every 5 minutes until response or until the rate is 20 mcg/minute. o No response after 20 mcg/minute, increase by 20 mcg/minute every 5 minutes until a pain response or medicine is no longer tolerated. o Flush the PVC tube before administering the medicine to patient. o Monitor BP carefully. Dilution of Glyceryl trinitrate: Volume of diluent Glyceryl trinitrate Concentration of 5mg/mL dilution 5 mL (25 mg) 100 mcg/mL 250 mL 10 mL (50 mg) 200 mcg/mL 20 mL (100 mg) 400 mcg/mL 10 mL (50 mg) 100 mcg/mL 500 mL 20 mL (100 mg) 200 mcg/mL 40 mL (200 mg) 400 mcg/mL Solution 100 mcg/mL 200 mcg/mL 400 mcg/mL Concentration solution solution solution (mcg/mL) 2019 3.7 CHAPTER 3 CARDIOVASCULAR SYSTEM Dose (mcg/min) Flow rate (microdrops/min = mL/hour) 5 3 — — 10 6 3 — 15 9 — — 20 12 6 3 30 18 9 — 40 24 12 6 60 36 18 9 80 48 24 12 100 60 30 15 120 72 36 18 160 96 48 24 200 – 60 30 For severe pain unresponsive to nitrates:  Morphine, IV, to a total maximum dose of 10 mg (See Appendix II, for individual dosing and monitoring for response and toxicity). o Ongoing severe pain despite all appropriate treatment above is an indication for urgent referral. When clinically stable without signs of heart failure, hypotension, bradydysrhythmias or history of asthma:  Cardio-selective -blocker, e.g.:  Atenolol, oral, 50 mg daily.  HMGCoA reductase inhibitors (statins), e.g.:  Simvastatin, oral, 40 mg at night. LoE:Ixv Patients on protease inhibitor:  Atorvastatin, oral, 10 mg at night. LoE:Ixvi Patients on amlodipine (and not on a protease inhibitor):  Simvastatin, oral, 10 mg at night. LoE:IIIxvii If patient complains of muscle pain: Reduce dose:  HMGCoA reductase inhibitors (statins), e.g.:  Simvastatin, oral, 10–20 mg at night. OR Consult specialist for further management. LoE:IIIxviii For LV dysfunction following myocardial infarction, heart failure or ejection fraction 1 week) therapy. xlvi Precautions: LoE:III o If on warfarin, halve the dose of warfarin and monitor INR closely, until INR is stable. o Avoid concomitant digoxin. o Monitor thyroid function every 6 months for thyroid abnormalities. o Ophthalmological examination every 6 months. 3.3.2.2 SUSTAINED (>30 SECONDS) IRREGULAR WIDE QRS TACHYCARDIAS I47.0-2/I47.9 These tachycardias are usually due to atrial fibrillation with bundle branch block, or pre-excitation (WPW syndrome). If the QRS complexes have a pattern of typical right or left bundle branch block, with a rate 170 bpm, and/or the complexes are atypical or variable, the likely diagnosis is WPW syndrome with atrial fibrillation, conducting via the bypass tract. Treat with DC conversion. Do not treat with medication. Verapamil and digoxin may precipitate ventricular fibrillation by increasing the ventricular rate. If in doubt as to the nature of a tachycardia, and in all patients with haemodynamic compromise, DC cardioversion under IV sedation is the safest option. DC cardioversion, 200 J, after sedation with:  Midazolam, IV, 1–2.5 mg, administered over 2-3 minutes. o Monitor and repeat dose after 2-3 minutes, as necessary. o If 200 J fails, use 360 J. LoE:III 3.3.2.3 NON-SUSTAINED (1 week) therapy. Precautions: o If on warfarin, halve the dose of warfarin and monitor INR closely, until INR is stable. o Avoid concomitant digoxin. o Monitor thyroid function every 6months as thyroid abnormalities may develop. o Ophthalmological examination every 6 months. OR Only in haemodynamically stable patients:  Lidocaine (lignocaine), IV, 50–100 mg (1–2 mg/kg) initially and at 5 minute intervals if required to a total of 200–300 mg. Thereafter, for recurrent ventricular tachycardia only:  Lidocaine (lignocaine), IV infusion, 1–3 mg/minute for 24–30 hours. » Lidocaine will only terminate ± 30% of sustained ventricular tachycardias, and may cause hypotension, heart block or convulsions. » For emergency treatment of ventricular tachycardia, DC cardioversion is first line therapy, even if stable. In the absence of acute ischaemia or infarction, consider torsades de pointes, due to QT prolonging medicines. 3.3.2.4 TORSADES DE POINTES VENTRICULAR TACHYCARDIA (VT) I47.0-2/I47.9 Torsades de pointes Ventricular Tachycardia (VT) has a twisting pattern to the QRS complexes and a prolonged QT interval in sinus rhythm. It is usually due to a QT-prolonging medication, active myocardial ischaemia and/or hypokalaemia and/or a history of alcohol abuse/malnutrition. GENERAL MEASURES Defibrillation, as necessary. Torsades complicating bradycardia: temporary pacing. MEDICINE TREATMENT Stop all QT-prolonging medicines (a list of medicines that cause QT prolongation can be viewed at https://www.sads.org.uk/drugs-to- avoid/?doing_wp_cron=1585301751.3996679782867431640625 Correct serum potassium.  Magnesium sulphate, IV, 2 g administered over 5–10 minutes. If recurrent episodes after initial dose of magnesium sulphate:  Magnesium sulphate, IV, 2 g administered over 24 hours. LoE:III 2019 3.22 CHAPTER 3 CARDIOVASCULAR SYSTEM Torsades complicating bradycardia:  Adrenaline (epinephrine) infusion to raise heart rate to >100 bpm (if temporary pacing unavailable). REFERRAL All cases of wide QRS tachycardia, after resuscitation and stabilization. 3.3.3 HEART BLOCK (SECOND OR THIRD DEGREE) I44.1/I44.2 DESCRIPTION The majority of cases occur in patients >60 years of age and are idiopathic, with an excellent long-term prognosis, provided a permanent pacemaker is implanted. Acute, reversible AV block commonly complicates inferior myocardial infarction. Heart block may also be induced by metabolic and electrolyte disturbances, as well as by certain medicines. GENERAL MEASURES Emergency cardio-pulmonary resuscitation (if necessary). External pacemaker should be available in all secondary hospitals and must be preceded by appropriate analgesia. MEDICINE TREATMENT Analgesia if external pacemaker:  Morphine, IM, 10–15 mg 3–6 hourly. Apply relevant precautions as indicated in Appendix II (i.e. monitoring for response and toxicity). AV nodal block with narrow QRS complex escape rhythm only:  Atropine, IV bolus, 0.6–1.2 mg. o May be repeated as needed until a pacemaker is inserted. o Use in patients with inferior myocardial infarct and hypotension and second degree AV block, if symptomatic. o It is temporary treatment of complete AV block before referral (urgently) for pacemaker. OR For resuscitation of asystole in combination with CPR: I46.0-1/I46.9+(I44.1-2)  Adrenaline (epinephrine) 1:10 000, slow IV, 5 mL (0.5 mg). o Used as temporary treatment of complete heart block when other medicines are not effective. REFERRAL » All cases with a heart rate 600 mcg) as a possible non-infectious cause of postpartum fever. GENERAL MEASURES Prevent deep vein thrombosis. Complete evacuation of uterine contents. Hysterectomy may be indicated in severe uterine sepsis. Attention to breast engorgement. MEDICINE TREATMENT Antibiotic treatment, where appropriate, should be guided by the presumed source of infection. Empiric antibiotic therapy  Amoxicillin/clavulanic acid, IV, 1.2 g 8 hourly, until patient apyrexial for 24 hours. Follow with: LoE:III  Amoxicillin/clavulanic acid, oral, 875/125 mg 12 hourly. REFERRAL » No clinical response in 48 hours of antibiotic treatment. » Septic shock. 6.19 POSTPARTUM HAEMORRHAGE O72.1-3 + (Z51.2) DESCRIPTION Blood loss >500 mL after birth of the baby or any blood loss which results in haemodynamic instability (tachycardia and/or hypotension). GENERAL MEASURES Bimanual compression of the uterus. Ensure delivery of placenta is complete. Check for local causes of bleeding. Balloon tamponade of the uterine cavity should be considered if the patient is to be transferred to another facility. MEDICINE TREATMENT Prevention Z29.2 Active management of the 3rd stage of labour:  Oxytocin, IM, 10 units. Note: » Delay cord clamping and cutting (after 1 minute) » Deliver the placenta by controlled cord traction. 2019 6.25 CHAPTER 6 OBSTETRICS Treatment Resuscitate. Put up two IV lines of crystalloid, one of which should contain oxytocin 20 IU. Cross match and hold blood for transfusion. Monitor BP and pulse, and response to uterotonics every 15 minutes.  Oxytocin, IV, 20 units in 1 L sodium chloride 0.9% at 250 mL/hour. If uterus remains atonic (palpable above the umbilicus): ADD  Ergometrine, IM, 0.5 mg. OR  Oxytocin, IM, 5 units. AND  Ergometrine, IM, 0.5 mg. o Avoid ergometrine in women with hypertension or cardiac disease, except in severe cases where the benefit is considered to outweigh the risk (discuss with a specialist). o Repeat ergometrine 0.5 mg IM after 15 minutes if no response If still no response after 15 minutes:  Tranexamic acid 1 g, IV, slowly over 10 minutes. LoE:Ixxxviii o Repeat after 30 minutes if there is ongoing vaginal bleeding. In settings where oxytocin had NOT been administered as prophylaxis at birth:  Misoprostol, sublingual, or rectal, 600 mcg as a single dose. LoE:Ixxxix 6.20 THE RHESUS NEGATIVE WOMAN O36.0 + (Z29.1) GENERAL MEASURES Maternal serum antibodies absent Prevention Test for maternal serum antibodies at ‘booking’, 28 and 34 weeks’ gestation. During pregnancy, give prophylactic anti-D immunoglobulin to the mother within 72 hours of a potentially sensitising event. MEDICINE TREATMENT After a termination of pregnancy (TOP), miscarriage, ectopic pregnancy or amniocentesis 48 hours requiring referral: Chapman AS, Bakken JS, Folk SM, Paddock CD, Bloch KC, Krusell A, et al: Tickborne Rickettsial Diseases Working Group; CDC. Diagnosis and management of tickborne rickettsial diseases: Rocky Mountain spotted fever, ehrlichioses, and anaplasmosis--United States: a practical guide for physicians and other health-care and public health professionals. MMWR Recomm Rep. 2006 Mar 31;55(RR-4):1-27. https://www.ncbi.nlm.nih.gov/pubmed/16572105 xxxiii Ceftriaxone, IV: Acharya G, Butler T, Ho M, Sharma PR, Tiwari M, Adhikari RK, Khagda JB, Pokhrel B, Pathak UN. Treatment of typhoid fever: randomized trial of a three-day course of ceftriaxone versus a fourteen-day course of chloramphenicol. Am J Trop Med Hyg. 1995 Feb;52(2):162-5. http://www.ncbi.nlm.nih.gov/pubmed/7872445 Ceftriaxone, IV: Smith MD, Duong NM, Hoa NT, Wain J, Ha HD, Diep TS, Day NP, Hien TT, White NJ. Comparison of ofloxacin and ceftriaxone for short-course treatment of enteric fever.Antimicrob Agents Chemother. 1994 Aug;38(8):1716-20. http://www.ncbi.nlm.nih.gov/pubmed/7986000 Ceftriaxone, IV: Wallace MR, Yousif AA, Mahroos GA, Mapes T, Threlfall EJ, Rowe B, Hyams KC. Ciprofloxacin versus ceftriaxone in the treatment of multiresistant typhoid fever. Eur J ClinMicrobiol Infect Dis. 1993 Dec;12(12):907-10. http://www.ncbi.nlm.nih.gov/pubmed/8187784 Ceftriaxone, IV: Islam A, Butler T, Kabir I, Alam NH. Treatment of typhoid fever with ceftriaxone for 5 days or chloramphenicol for 14 days: a randomized clinical trial. Antimicrob Agents Chemother. 1993 Aug;37(8):1572-5. http://www.ncbi.nlm.nih.gov/pubmed/8215265 Ceftriaxone, IV: Lasserre R, Sangalang RP, Santiago L. Three-day treatment of typhoid fever with two different doses of ceftriaxone, compared to 14-day therapy with chloramphenicol: a randomized trial. J AntimicrobChemother. 1991 Nov;28(5):765-72. http://www.ncbi.nlm.nih.gov/pubmed/1778879 Ceftriaxone, IV: Islam A, Butler T, Nath SK, Alam NH, Stoeckel K, Houser HB, Smith AL. Randomized treatment of patients with typhoid fever by using ceftriaxone or chloramphenicol. J Infect Dis. 1988 Oct;158(4):742-7. http://www.ncbi.nlm.nih.gov/pubmed/3171225 xxxiv Antiviral, oral (active against herpes zoster) therapeutic class: McDonald EM, De Kock J, Ram FS. Antivirals for management of herpes zoster including ophthalmicus: a systematic review of high-quality randomized controlled trials. Antiviral Therapy 2012; 17(2): 255-264. https://www.ncbi.nlm.nih.gov/pubmed/22300753 xxxvAntivirals to treat herpes zoster (therapeutic class): McDonald EM, De Kock J, Ram FS. Antivirals for management of herpes zoster including ophthalmicus: a systematic review of high-quality randomized controlled trials. Antiviral Therapy 2012; 17(2): 255-264.https://www.ncbi.nlm.nih.gov/pubmed/22300753 xxxvi Aciclovir, IV - dose adjustment in renal impairment:: South African Medicines Formulary. 12th Edition. Division of Clinical Pharmacology. University of Cape Town. 2016. 2019 9.21  CHAPTER 10 HIV AND AIDS Consult the most recent HIV Guidelines from the National Department of Health. https://www.knowledgehub.org.za/elibrary/2019-art-clinical-guidelines- management-hiv-adults-pregnancy-adolescents-children-infants 10.1 ANTIRETROVIRAL THERAPY B24 Antiretroviral therapy (ART) consists of combinations of antiretroviral medicines that are capable of suppressing HIV replication (defined as an undetectable viral load). Continued use of ART with a detectable viral load results in the development of resistance to some or all of the medicines in the regimen. High levels of adherence are essential for long-term success with ART. The current recommended first-line ART regimen contains two nucleoside reverse transcriptase inhibitors (NRTIs) together with an integrase inhibitor (InSTI) dolutegravir. Previously a non-nucleoside reverse transcriptase inhibitor (NNRTI), efavirenz or nevirapine, together with two NRTIs, were recommended for first-line ART. Dolutegravir is better tolerated than the NNRTIs and has a much higher barrier to the development of resistance. Dolutegravir, together with two NRTIs, is also recommended in second-line ART after failing an NNRTI-based first-line regimen. Previously a protease inhibitor (PI), together with two NRTIs, was recommended for second-line ART, but dolutegravir is better tolerated than PIs. Switching people, established on ART to the newer dolutegravir-based ART regimens needs to be carefully done to reduce the risk of the emergence of resistance (refer to National Department of Health HIV Guidelines). ELIGIBILITY FOR ART Eligibility to start ART: All adults with confirmed HIV infection, irrespective of CD4 count or WHO clinical stage. Where a patient is willing and ready, ART should be initiated on the same day as HIV diagnosis, except in patients with TB or cryptococcal meningitis (see Timing of ART initiation below). LoE: Ii Immediate initiation: ART should be initiated immediately in pregnancy and during breastfeeding. LoE:IIIii Fast tracking (within 7 days): Patients with CD4 200 cells/mm3 on ART.  Cotrimoxazole 160/800 mg, oral daily. 2019 10.24 CHAPTER10 HIV AND AIDS 10.2.8 MYCOBACTERIOSIS – DISSEMINATED NON- TUBERCULOUS B20.0 DESCRIPTION Disseminated infection due to non-tuberculous mycobacteria, usually Mycobacterium avium complex. Diagnosis must be by culture from sterile sources, e.g. blood, tissue or bone marrow. Note that culture from a single sputum specimen is not adequate to make the diagnosis as this often reflects colonisation rather than disease. Non-tuberculous mycobacteria can cause limited pulmonary disease, which is diagnosed if the sputum culture is positive repeatedly and there is a worsening pulmonary infiltrate. Disseminated disease is AIDS-defining (WHO clinical stage 4). MEDICINE TREATMENT  Azithromycin, oral, 500 mg daily. AND LoE:IIxl  Ethambutol, oral, 15–20 mg/kg daily. Treatment can be stopped when treatment has been continued for at least 12 months AND the CD4 count has increased to >100 cells/mm3 on ART. 10.2.9 PNEUMOCYSTIS PNEUMONIA B20.6 DESCRIPTION Interstitial pneumonitis due to Pneumocystis jirovecii (formerly carinii). AIDS- defining illness (WHO clinical stage 4). MEDICINE TREATMENT All patients:  Cotrimoxazole 80/400 mg, oral, 6 hourly for 21 days. o 200 cells/mm3. Diagnosis is confirmed by a clinical response to therapy, which occurs in 7–14 days. CT scan improvement usually occurs within 14–21 days. Interpreting the response to therapy may be difficult if steroids have been given concomitantly. Steroid therapy should only be given for life-threatening peri-lesionaloedema. MEDICINE TREATMENT  Cotrimoxazole 160/800, oral, 2 tablets 12 hourly for 28 days, followed by 1 tablet 12 hourly for 3 months. Secondary prophylaxis Continue for at least 6 months and until CD4 count increases to > 200 cells/mm3 on ART.  Cotrimoxazole 160/800 mg, oral, 2 tablets daily. See cotrimoxazole desensitisation: Page 10.23. REFERRAL/CONSULTATION Specialist or tertiary Intolerance to cotrimoxazole. Note: Attempt desensitisation first (see section 10.2.9: Pneumocystis pneumonia). 10.3 HIV AND KIDNEY DISEASE B23.8 + (N28.9) DESCRIPTION A number of kidney disorders are associated with HIV infection. Acute kidney injury due to sepsis, dehydration or nephrotoxicity from medicines occurs commonly. The commonest chronic kidney disorder is HIV-associated nephropathy (HIVAN). Typical features of HIVAN are: » Heavy proteinuria. » Rapidly progressive chronic kidney disease with preserved kidney size on imaging. » ART slows progression of chronic kidney disease. Early detection of kidney disease is important in order to implement interventions that may slow kidney disease progression, and for adjusting the 2019 10.27 CHAPTER10 HIV AND AIDS dose of relevant medicines. Risk factors for HIV renal disease: » CD4 count 0.15 g/mmol discuss with a specialist).  Serum creatinine and eGFR. Dose adjustment of ART in renal impairment: Refer to table: Dosing of ART for renal adjusted doses in section 10.1: Antiretroviral therapy. 10.4 KAPOSI SARCOMA (KS) B21.0 DESCRIPTION Kaposi Sarcoma (KS) is a malignancy of lymphatic endothelial origin associated with Human Herpes Virus-8, also known as KS Herpes Virus, infection. KS may involve the skin, oral cavity, lymph nodes or viscera (especially lung and GIT). Most patients have multiple lesions. Lymphoedema is a common complication. 10–20% of cases of visceral KS will have no oral or skin involvement. KS is an AIDS-defining illness (WHO clinical stage 4). Although most cases are diagnosed on the typical macroscopic appearance of skin and oral lesions, biopsy confirmation is necessary for atypical lesions and if chemotherapy is considered. One important differential diagnosis is bacillary angiomatosis, which develops more rapidly. MEDICINE TREATMENT All patients with KS should be commenced on ART (see section 10.1: Antiretroviral therapy) and cotrimoxazole prophylaxis (see section 10.2.2: Opportunistic infection prophylaxis, with cotrimoxazole) regardless of CD4 count. Many patients with limited mucocutaneous KS will have complete resolution or substantial regression on ART alone. REFERRAL Prior to referral, all patients must be started on ART. » Radiotherapy/intralesional chemotherapy for symptomatic local lesions. » Systemic chemotherapy is indicated in patients with poor prognostic factors: - more than 25 skin lesions, 2019 10.28 CHAPTER10 HIV AND AIDS - rapidly progressive disease, - visceral involvement, - extensive oedema, or - “B” symptoms, i.e. fever, night sweats, significant constitutional symptoms. » Failure of KS to respond to ART. 10.5 POST-EXPOSURE PROPHYLAXIS National HIV Health Care Worker Hotline: 0800 212 506 or 021 406 6782. 10.5.1 POST-EXPOSURE PROPHYLAXIS, OCCUPATIONAL S61.0 + (W46.22 + Z20.6 + Z29.8) DESCRIPTION Antiretroviral therapy may prevent the risk of acquiring HIV following a significant occupational exposure. It is essential to document occupational exposures adequately for possible subsequent compensation. Other blood borne infections (hepatitis B and C) should also be tested for in the source patient and appropriate prophylaxis instituted in the case of hepatitis B. Assessing the risk of occupational exposures The risk of acquiring HIV following occupational exposure is determined by the nature of the exposure and the infectiousness of the source patient. High-risk exposures involve exposure to a larger quantity of viruses from the source patient, either due to exposure to larger quantity of blood or because the amount of virus in the blood is high. Any one of the following associated with an increased risk of HIV transmission: » deep percutaneous sharps injuries » percutaneous exposure involving a hollow needle that was used in a vein or artery » visible blood on the sharp instrument involved in a percutaneous injury » the source patient has terminal AIDS or is known to have a high viral load, i.e. >100 000 copies/mL In instances when the risk of infection is extremely low or non-existent, post- exposure prophylaxis (PEP) is not indicated, as the risks of PEP will far outweigh the benefits. PEP is NOT indicated when: » The material the healthcare worker was exposed to is not infectious for HIV in the occupational setting, e.g. vomitus, urine, faeces or saliva, unless these are visibly blood stained. » The exposure was on intact skin. » The source patient is HIV negative, unless there are clinical features to suggest seroconversion illness, in which case PEP should be commenced until further tests are done – consult with a virologist or infectious diseases 2019 10.29 CHAPTER10 HIV AND AIDS specialist. » The healthcare worker is HIV infected, as this person should be assessed for ART initiation. PEP REGIMENS PEP should be commenced as soon as possible after the injury. Do not delay initiating PEP while awaiting confirmatory test results on the source patient and health care worker. PEP should be considered up to 72 hours after exposure and, in exceptional circumstances involving high-risk exposures, PEP may be considered up to 7 days after exposure. When PEP is indicated:  Tenofovir, oral, 300 mg daily for 4 weeks (provided baseline eGFR is >50 mL/minute). and  Lamivudine, oral, 200 mg daily for 4 weeks and  Dolutegravir, oral 50 mg once daily for 4 weeks. LoE:IIIxli In WOCP, pregnant women 50 mL/minute). and  Emtricitabine, oral, 200 mg daily for 4 weeks. and LoE:IIIxlii  Atazanavir/ritonavir 300/100 mg daily for 4 weeks. Or  Lopinavir/ritonavir 200/50 mg, oral, 2 tablets 12 hourly for 4 weeks. If tenofovir is contraindicated or if source patient is known to be failing a tenofovir based regimen, replace tenofovir and emtricitabine with:  Zidovudine, oral, 300 mg 12 hourly for 4 weeks. and  Lamivudine, oral, 150 mg 12 hourly for 4 weeks. PEP is generally not well tolerated. Adverse effects occur in about half of cases and therapy is discontinued in about a third. Efavirenz is not recommended as it is very poorly tolerated in PEP. Zidovudine often causes nausea and headache. If zidovudine is not tolerated, switch to tenofovir (check baseline eGFR as above). Lopinavir/ritonavir often causes diarrhoea. If lopinavir/ritonavir is not tolerated switch to atazanavir/ritonavir. Atazanavir/ritonavir often causes unconjugated jaundice, which is benign but may not be tolerated, in which case switch to lopinavir/ritonavir. 2019 10.30 CHAPTER10 HIV AND AIDS Recommendations for post exposure prophylaxis (PEP) after occupational exposure to infectious material (includes blood, CSF, semen, vaginal secretions and synovial/pleural/ pericardial/ peritoneal/amniotic fluid) from HIV seropositive patients are given in the table, below. PEP for healthcare worker following occupational HIV exposure: Exposure HIV Status of source patient Negative Unknown or Positive Intact skin no PEP no PEP Mucosal splash no PEP 3-drug regimen (PI-based) or non-intact skin or percutaneous injury When the source patient is known to be failing ART, modify the PEP regimen: » If the patient is on zidovudine , use tenofovir. » If the patient is on tenofovir then use zidovudine. Patients failing 2nd line ART usually have no resistance to protease inhibitors, so lopinavir/ritonavir should still be effective, but consultation with a virologist or infectious diseases physician is recommended for advice on which ARVs to use for PEP in this setting. PEP for healthcare workers following hepatitis B exposure Source patient HBsAg positive HbsAg HBsAg negative unknown Unvaccinated  HBIG, IM, 500  Initiate Hep B  HBIG, IM, 500 or units* vaccination units* vaccination  Hep B vaccine (month 0, 1  Hep B vaccine Vaccination incomplete (3 doses at and 6) (3 doses at status monthly intervals) monthly and intervals) antibody Vaccinated AND No treatment No treatment No treatment response known to have status of HBsAb HCW >10 units/mL# Vaccinated AND  HBIG, IM, 500 No treatment  HBIG, IM, 500 HBsAb units * units* 10 units/mL 1 – 2 months after the last vaccine dose. 2019 10.31 CHAPTER10 HIV AND AIDS Monitoring in occupational exposures Source Exposed health care worker patient Baseline Baseline 2 weeks 6 weeks 4 months HIV Rapid test Rapid test ELISA ELISA PLUS PLUS ELISA ELISA Hepatitis B Surface Surface antigen antibody* Hepatitis C HCV HCV antibody* HCV PCR* antibody Syphilis RPR/ RPR/TP RPR/TP TP antibody antibody* antibody* Creatinine If TDF part of If TDF PEP part of PEP FBC If AZT part of If AZT PEP part of PEP *Only if source patient was positive. 10.5.2 NON OCCUPATIONAL POST EXPOSURE PROPHYLAXIS, SEXUAL ASSAULT Z29.8 PEP should be offered to rape survivors who present within 72 hours (management is the same as for occupational HIV exposure. See section 10.4.1 Post-exposure prophylaxis, occupational). A patient presenting ≥72 hours since the alleged incident should not be given PEP, but should be counselled about the possible risk of transmission, with HIV testing provided at the time of presentation and 4 months later. Rape survivors who test HIV seropositive should be initiated on ART– see section 10.1: Antiretroviral therapy. Other important aspects of care for the rape survivor should not be forgotten, i.e. contraception, treatment for sexually transmitted infections, counseling and forensic specimens. Emergency contraception after pregnancy is excluded Do a pregnancy test in all women and female adolescents. Children must be tested and given Emergency contraception from Breast Tanner Stage III, if unsure of staging, give Emergency contraception when you detect any breast development (DO NOT REGARD MENARCHE AS AN INDICATION).  Levonorgestrel 1.5 mg, oral, as a single dose as soon as possible after unprotected intercourse. LoE:IIIxliii o Repeat the dose, if woman vomits within 2 hours. 2019 10.32 CHAPTER10 HIV AND AIDS CAUTION Emergency contraceptive tablets must be taken as soon as possible, preferably within 72 hours of unprotected intercourse, and not later than 5 days. Enzyme inducers (including efavirenz, carbamazepine) cause a significant reduction in levonorgestrel concentrations. Women on these medicines should double the dose of levonorgestrel, because of significant reduction of levonorgestrel. Women > 80 kg or BMI ≥ 30 should also be given twice the standard dose. LoE:IIIxliv An anti-emetic:  Metoclopramide oral, 10 mg 8 hourly as needed. LoE:IIIxlv STI prophylaxis  Ceftriaxone, IM, 250 mg as a single dose. o For ceftriaxone IM injection: Dissolve ceftriaxone 250 mg in 0.9 mL lidocaine 1% without epinephrine (adrenaline). AND  Azithromycin, oral, 1 g, as a single dose. AND  Metronidazole, oral, 2 g immediately as a single dose. LoE:IIIxlvi Inadvertent (non-occupational) exposure to infectious material from HIV sero- positive persons often requires clinical judgement and includes: » human bites (requires hepatitis B, but not HIV prophylaxis) » sharing of needles during recreational drug use » consensual sexual exposure, burst condoms » contact sports with blood exposure LoE:IIIxlvii 10.5.3 NON OCCUPATIONAL POST EXPOSURE PROPHYLAXIS, INADVERTENT NON- OCCUPATIONAL Z29.8 Management of inadvertent (non-occupational) HIV exposure is the same as for occupational HIV exposure. See section 10.4.1 Post-exposure prophylaxis, occupational. 2019 10.33 CHAPTER10 HIV AND AIDS References: iEligibility for ART: INSIGHT START Study Group, Lundgren JD, Babiker AG, Gordin F, Emery S, Grund B, Sharma S, Avihingsanon A, Cooper DA, Fätkenheuer G, Llibre JM, Molina JM, Munderi P, Schechter M, Wood R, Klingman KL, Collins S, Lane HC, Phillips AN, Neaton JD. Initiation of Antiretroviral Therapy in Early Asymptomatic HIV Infection. N Engl J Med. 2015 Aug 27;373(9):795-807. http://www.ncbi.nlm.nih.gov/pubmed/26192873 Eligibility for ART: TEMPRANO ANRS 12136 Study Group. A Trial of Early Antiretrovirals and Isoniazid Preventive Therapy in Africa. N Engl J Med. 2015 Aug 27;373(9):808-22. http://www.ncbi.nlm.nih.gov/pubmed/26193126 Eligibility for ART- Immediate initiation of ART: Rosen S, Maskew M, Fox MP, Nyoni C, Mongwenyana C, Malete G, Sanne I, Bokaba D, Sauls C, Rohr J, Long L. Initiating Antiretroviral Therapy for HIV at a Patient's First Clinic Visit: The RapIT Randomized Controlled Trial. PLoS Med. 2016 May 10;13(5):e1002015. https://www.ncbi.nlm.nih.gov/pubmed/27163694 Eligibility for ART- Immediate initiation of ART: National Department of Health. 2019 ART Clinical Guidelines for the Management of HIV in Adults, Pregnancy, Adolescents, Children, Infants and Neonates. https://www.knowledgehub.org.za/elibrary/2019-art-clinical-guidelines-management-hiv-adults-pregnancy- adolescents-children-infants ii Immediate initiation of ART, pregnant and breastfeeding women: South African National Department of Health South Africa. Guideline for the Prevention of Mother to Child Transmission of Communicable Infections, October 2019. https://www.knowledgehub.org.za/elibrary/guideline-prevention-mother-child-transmission-communicable- infections Immediate initiation of ART, pregnant and breastfeeding women: WHO. Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection, June 2013.Web annexes: Chapter 7 Clinical guidance across the continuum of care: antiretroviral therapy guidelines; Section 7.1.2: When to start ART in pregnant andbreastfeeding women and GRADE tables. http://www.who.int/hiv/pub/guidelines/arv2013/annexes/en/index2.html iii Fast tracking: CD4 < 200: National Department of Health. 2019 ART Clinical Guidelines for the Management of HIV in Adults, Pregnancy, Adolescents, Children, Infants and Neonates. https://www.knowledgehub.org.za/elibrary/2019-art-clinical-guidelines-management-hiv-adults-pregnancy- adolescents-children-infants ivTiming of ART initiation (pulmonary TB): Uthman OA, Okwundu C, Gbenga K, Volmink J, Dowdy D, Zumla A,Nachega JB. Optimal Timing of Antiretroviral Therapy Initiation for HIV-Infected Adults With Newly Diagnosed Pulmonary Tuberculosis: A Systematic Review and Meta-analysis. Ann Intern Med. 2015 Jul 7;163(1):32- 9.http://www.ncbi.nlm.nih.gov/pubmed/26148280 vTiming of ART initiation (tuberculous meningitis): Török ME, Yen NT, Chau TT, Mai NT, Phu NH, Mai PP, Dung NT, Chau NV, Bang ND, Tien NA, Minh NH, Hien NQ, Thai PV, Dong DT, Anh do TT, Thoa NT, Hai NN, Lan NN, Lan NT, Quy HT, Dung NH, Hien TT, Chinh NT, Simmons CP, de Jong M, Wolbers M, Farrar JJ. Timing of initiation of antiretroviral therapy in human immunodeficiency virus (HIV)--associated tuberculous meningitis. Clin Infect Dis. 2011 Jun;52(11):1374-83. http://www.ncbi.nlm.nih.gov/pubmed/21596680 vi Timing of ART initiation: National Department of Health. 2019 ART Clinical Guidelines for the Management of HIV in Adults, Pregnancy, Adolescents, Children, Infants and Neonates. https://www.knowledgehub.org.za/elibrary/2019-art-clinical-guidelines-management-hiv-adults-pregnancy- adolescents-children-infants vii Dolutegravir, oral (risk of NTDs): Zash R, Holmes L, Diseko M, Jacobson DL, Brummel S, Mayondi G, Isaacson A, Davey S, Mabuta J, Mmalane M, Gaolathe T, Essex M, Lockman S, Makhema J, Shapiro RL. Neural-Tube Defects and Antiretroviral Treatment Regimens in Botswana. N Engl J Med. 2019 Aug 29;381(9):827-840. https://www.ncbi.nlm.nih.gov/pubmed/31329379 Dolutegravir, oral (risk of NTDs): National Department of Health. 2019 ART Clinical Guidelines for the Management of HIV in Adults, Pregnancy, Adolescents, Children, Infants and Neonates. https://www.knowledgehub.org.za/elibrary/2019-art-clinical-guidelines-management-hiv-adults-pregnancy- adolescents-children-infants viiiDolutegravir, oral (first-line ART): National Department of Health: Affordable Medicines, EDP-Adult Hospital level. Medicine Review: Dolutegravir in HIV-infected patients commencing first-line antiretroviral therapy, updated 11 February 2019. http://www.health.gov.za/ Dolutegravir, oral (first-line ART): Rutherford GW, Horvath H. Dolutegravir Plus Two Nucleoside Reverse Transcriptase Inhibitors versus Efavirenz Plus Two Nucleoside Reverse Transcriptase Inhibitors As Initial Antiretroviral Therapy for People with HIV: ASystematic Review. PLoS One. 2016 Oct 13;11(10):e0162775. https://www.ncbi.nlm.nih.gov/pubmed/27736859 Dolutegravir, oral (first-line ART): National Department of Health. 2019 ART Clinical Guidelines for the Management of HIV in Adults, Pregnancy, Adolescents, Children, Infants and Neonates. https://www.knowledgehub.org.za/elibrary/2019-art-clinical-guidelines-management-hiv-adults-pregnancy- adolescents-children-infants Dolutegravir, oral (risk of NTDs): Zash R, Holmes L, Diseko M, Jacobson DL, Brummel S, Mayondi G, Isaacson A, Davey S, Mabuta J, Mmalane M, Gaolathe T, Essex M, Lockman S, Makhema J, Shapiro RL. Neural-Tube Defects and Antiretroviral Treatment Regimens in Botswana. N Engl J Med. 2019 Aug 29;381(9):827-840. https://www.ncbi.nlm.nih.gov/pubmed/31329379 Dolutegravir, oral (risk of NTDs): National Department of Health. 2019 ART Clinical Guidelines for the Management of HIV in Adults, Pregnancy, Adolescents, Children, Infants and Neonates. https://www.knowledgehub.org.za/elibrary/2019-art-clinical-guidelines-management-hiv-adults-pregnancy- adolescents-children-infants 2019 10.34 CHAPTER10 HIV AND AIDS ix Abacavir: Cruciani M, Mengoli C, Malena M, Serpelloni G, Parisi SG, Moyle G, Bosco O. Virological efficacy of abacavir: systematic review and meta-analysis. J Antimicrob Chemother. 2014 Dec;69(12):3169- 80.http://www.ncbi.nlm.nih.gov/pubmed/25074854 x Dual therapy – dolutegravir/lamivudine: Cahn P, Madero JS, Arribas JR, Antinori A, Ortiz R, Clarke AE, et al; GEMINI Study Team. Dolutegravir plus lamivudine versus dolutegravir plus tenofovir disoproxil fumarate and emtricitabine in antiretroviral-naive adults with HIV-1 infection (GEMINI-1 and GEMINI-2): week 48 results from two multicentre, double-blind, randomised, non-inferiority, phase 3 trials. Lancet. 2019 Jan 12;393(10167):143-155. https://www.ncbi.nlm.nih.gov/pubmed/30420123 Dual therapy – dolutegravir/lamivudine: Hidalgo-Tenorio C, Cortés LL, Gutiérrez A, Santos J, Omar M, Gálvez C, et al. DOLAMA study: Effectiveness, safety and pharmacoeconomic analysis of dual therapy with dolutegravir and lamivudine in virologically suppressed HIV-1 patients. Medicine (Baltimore). 2019 Aug;98(32):e16813. https://www.ncbi.nlm.nih.gov/pubmed/31393412 xi FDC formulations currently available in public sector: Contract circular RT71-2019ARV. http://www.health.gov.za/ xiiTenofovir, oral (Renal function in HIV infected patients on nephrotoxic medicines): Kenyon C, Wearne N, Burton R, Meintjes G. The Risks of Concurrent Treatment with Tenofovir and Aminoglycosides in Patients with HIV-Associated Tuberculosis. South Afr J HIV Med 2011;12(1):43–45. http://www.ncbi.nlm.nih.gov/pubmed/21695064 xiiiEmtricitabine, oral (red cell aplasia adverse drug reaction): Cohen K, Viljoen C, Njuguna C, Maartens G. Emtricitabine-associated red cell aplasia. AIDS. 2019 May 1;33(6):1095-1096. https://www.ncbi.nlm.nih.gov/pubmed/30946164 xivEfavirenz, oral (encephalopathy adverse drug reaction): Variava E, Sigauke FR, Norman J, Rakgokong M, Muchichwa P, Mochan A, Maartens G, Martinson NA. Brief Report: Late Efavirenz-Induced Ataxia and Encephalopathy: A Case Series. J Acquir Immune Defic Syndr. 2017 Aug 15;75(5):577-579. https://www.ncbi.nlm.nih.gov/pubmed/28520619 xv Dosing of ART and ADRs: South African Medicines Formulary. 12th Edition. Division of Clinical Pharmacology. University of Cape Town, 2016. Dosing of ART and ADRs: National Department of Health. 2019 ART Clinical Guidelines for the Management of HIV in Adults, Pregnancy, Adolescents, Children, Infants and Neonates. https://www.knowledgehub.org.za/elibrary/2019-art-clinical-guidelines-management-hiv-adults-pregnancy- adolescents-children-infants Dosing of ART and ADRs: Datapharm Ltd. Electronic medicines compendium (emc). [Internet][Accessed 28 November 2019] https://www.medicines.org.uk/emc/ Dosing of ART (renal impairment): Lucas GM, Ross MJ, Stock PG, Shlipak MG, Wyatt CM, Gupta SK, Atta MG, Wools-Kaloustian KK, Pham PA, Bruggeman LA, Lennox JL, Ray PE, Kalayjian RC; HIV Medicine Association of the Infectious Diseases Society of America. Clinical practice guideline for the management of chronic kidney disease in patients infected with HIV: 2014 update by the HIV Medicine Association of the Infectious Diseases Society of America. Clin Infect Dis. 2014 Nov 1;59(9):e96- 138.http://www.ncbi.nlm.nih.gov/pubmed/25234519 Dosing of ART (renal impairment): MeintjesG (chairperson),Black J, Conradie F, Cox V, Dlamini S, Fabian J, Maartens G, Manzini T, Mathe M, Menezes C, Moorhouse M, Moosa Y, Nash J, Orrell C, Pakade Y, Venter F, Wilson D (expert panel members). Adult antiretroviral therapy guidelines 2014 By the Southern African HIV Clinicians Society. S Afr J HIV Med 2014;15(4):121- 143.http://www.sahivsoc.org/upload/documents/2014%20Adult%20ART%20Guideline.pdf xvi ART-rifampicin drug interaction: National Department of Health. 2019 ART Clinical Guidelines for the Management of HIV in Adults, Pregnancy, Adolescents, Children, Infants and Neonates. https://www.knowledgehub.org.za/elibrary/2019-art-clinical-guidelines-management-hiv-adults-pregnancy- adolescents-children-infants xviiRifabutin: Zhang J, Zhu L, Stonier M, Coumbis J, Xu X, Wu Y, Arikan D, Farajallah A, Bertz R. Determination of rifabutin dosing regimen when administered in combination with ritonavir-boosted atazanavir. J Antimicrob Chemother. 2011 Sep;66(9):2075-82. http://www.ncbi.nlm.nih.gov/pubmed/21712242 Rifabutin: Molina JM, Andrade-Villanueva J, Echevarria J, Chetchotisakd P, Corral J, David N, Moyle G, Mancini M, Percival L, Yang R, Thiry A, McGrath D; CASTLE Study Team. Once-daily atazanavir/ritonavir versus twice-daily lopinavir/ritonavir, each in combination with tenofovir and emtricitabine, for management of antiretroviral-naive HIV-1- infected patients: 48 week efficacy and safety results of the CASTLE study. Lancet. 2008 Aug 23;372(9639):646-55. http://www.ncbi.nlm.nih.gov/pubmed/18722869 Rifabutin (dosing): Lan NT, Thu NT, Barrail-Tran A, Duc NH, Lan NN, Laureillard D, Lien TT, Borand L, Quillet C, Connolly C, Lagarde D, Pym A, Lienhardt C, Dung NH, Taburet AM, Harries AD. Randomised pharmacokinetic trial of rifabutin with lopinavir/ritonavir-antiretroviral therapy in patients with HIV-associated tuberculosis in Vietnam. PLoS One. 2014 Jan 22;9(1):e84866. http://www.ncbi.nlm.nih.gov/pubmed/24465443 Rifabutin (dosing): Centers for Disease Control and Prevention. Managing Drug Interactions in the Treatment of HIV- Related Tuberculosis [online]. 2013. www.cdc.gov/tb/TB_HIV_Drugs/default.htm Rifabutin (dosing): Ramachandran G, Bhavani PK, Hemanth Kumar AK, Srinivasan R, Raja K, Sudha V, Venkatesh S, Chandrasekaran C, Swaminathan S. Pharmacokinetics of rifabutin during atazanavir/ritonavir co-administration in HIV-infected TB patients in India. Int J Tuberc Lung Dis. 2013 Dec;17(12):1564-8. https://www.ncbi.nlm.nih.gov/pubmed/24200269 xviii Drug interactions with dolutegravir: National Department of Health. 2019 ART Clinical Guidelines for the Management of HIV in Adults, Pregnancy, Adolescents, Children, Infants and Neonates. https://www.knowledgehub.org.za/elibrary/2019-art-clinical-guidelines-management-hiv-adults-pregnancy- adolescents-children-infants xix Atazanavir-PPI/H2-anatagonist interaction: University of Liverpool HIV Drug Interaction online tool. https://www.hiv- druginteractions.org/checker 2019 10.35 CHAPTER10 HIV AND AIDS Atazanavir-PPI interaction: Khanlou H, Farthing C. Co-administration of atazanavir with proton-pump inhibitors and H2 blockers. J Acquir Immune Defic Syndr. 2005 Aug 1;39(4):503. https://www.ncbi.nlm.nih.gov/pubmed/16010179 Atazanavir-PPI interaction: European Medicines Agency. Public Statement: Important new pharmacokinetic data demonstrating that REYATAZ(atazanavir sulfate) combined with NORVIR (ritonavir) and omeprazole should not be co- administered, 21 December 2004. https://www.ema.europa.eu/en/documents/public-statement/important-new- pharmacokinetic-data-demonstrating-reyataz-atazanavir-sulfate-combined-norvir_en.pdf xx LAM urine testing (DS-TB): National Department of Health. Guidance on the use of the lipoarabinomannan lateral flow assay (LF-LAM) for the diagnosis of tuberculosis in people living with HIV, July 2017. http://www.health.gov.za/ LAM urine testing (DS-TB): Bjerrum S, Schiller I, Dendukuri N, Kohli M, Nathavitharana RR, Zwerling AA, Denkinger CM, Steingart KR, Shah M. Lateral flow urine lipoarabinomannan assay for detecting active tuberculosis in people living with HIV. Cochrane Database Syst Rev. 2019 Oct 21;10:CD011420. https://www.ncbi.nlm.nih.gov/pubmed/31633805 xxiUrine dipstick: Han TM, Naicker S, Ramdial PK, Assounga AG. A cross-sectional study of HIV-seropositive patients with varying degrees of proteinuria in South Africa. Kidney Int. 2006 Jun;69(12):2243-50. http://www.ncbi.nlm.nih.gov/pubmed/16672914 Screen for Cryptococcus antigen: Southern African HIV Clinician’s Society. Guideline for the prevention, diagnosis and management of cryptococcal meningitis among HIV-infected persons:2013 update. S Afri HIV Med 2013;14(2):76- 86.http://www.sajhivmed.org.za/index.php/hivmed/article/view/82/128 xxiiAbacavir: South African Medicines Formulary. 12th Edition. Division of Clinical Pharmacology. University of Cape Town, 2016. xxiiiManagement of drug-induced liver injury: Jong E, Conradie F, Berhanu R, Black A, John MA, Meintjes G, Menezes C. Consensus Statement: Management of drug-induced liver injury in HIV-positive patients treated for TB. S Afri HIV Med 2013;14(3): 113-119.http://www.sajhivmed.org.za/index.php/hivmed/article/view/63 Management of drug-induced liver injury: Sharma SK, Singla R, Sarda P, Mohan A, Makharia G, Jayaswal A, Sreenivas V, Singh S. Safety of 3 different reintroduction regimens of antituberculosis drugs after development of antituberculosis treatment-induced hepatotoxicity. Clin Infect Dis. 2010 Mar 15;50(6):833-9. https://www.ncbi.nlm.nih.gov/pubmed/20156055 xxivPrednisone, oral (TB-IRIS on ART): Meintjes G, Stek C, Blumenthal L, Thienemann F, Schutz C, Buyze J, Ravinetto R, van Loen H, Nair A, Jackson A, Colebunders R, Maartens G, Wilkinson RJ, Lynen L; PredART Trial Team. Prednisone for the Prevention of Paradoxical Tuberculosis-Associated IRIS. N Engl J Med. 2018 Nov 15;379(20):1915- 1925. https://www.ncbi.nlm.nih.gov/pubmed/30428290 xxvIsoniazid (IPT) - 12-month therapy: Rangaka MX, Wilkinson RJ, Boulle A, Glynn JR, Fielding K, van Cutsem G, Wilkinson KA, Goliath R, Mathee S, Goemaere E, Maartens G. Isoniazid plus antiretroviral therapy to prevent tuberculosis: a randomised double-blind placebo-controlled trial. Lancet 2014;384(9944):682-90. http://www.ncbi.nlm.nih.gov/pubmed/24835842 xxvi Isoniazid (IPT) – Pregnant women: Gupta A, Montepiedra G, Aaron L, Theron G, McCarthy K, Bradford S, Chipato T, Vhembo T, Stranix-Chibanda L, Onyango-Makumbi C, Masheto GR, Violari A, Mmbaga BT, Aurpibul L, Bhosale R, Mave V, Rouzier V, Hesseling A, Shin K, Zimmer B, Costello D, Sterling TR, Chakhtoura N, Jean-Philippe P, Weinberg A; IMPAACT P1078 TB APPRISE Study Team. Isoniazid Preventive Therapy in HIV-Infected Pregnant and Postpartum Women. N Engl J Med. 2019 Oct 3;381(14):1333-1346. https://www.ncbi.nlm.nih.gov/pubmed/31577875 Isoniazid (IPT) – Pregnant women: Akolo C, Adetifa I, Shepperd S, Volmink J. Treatment of latent tuberculosis infection in HIV infected persons. Cochrane Database Syst Rev. 2010 Jan20;(1):CD000171. https://www.ncbi.nlm.nih.gov/pubmed/20091503 Isoniazid (IPT) – Pregnant women: Kalk E, Heekes A, Mehta U, de Waal R, Jacob N, Cohen K, Myer L, Davies MA, Maartens G, Boulle A. Safety and Effectiveness of Isoniazid Preventive Therapy in HIV-Positive Pregnant Women on Art: An Observational Study using Linked Population Data. Clin Infect Dis. 2020 Jan 4. pii: ciz1224. https://www.ncbi.nlm.nih.gov/pubmed/31900473 xxviiCotrimoxazole, oral (pregnancy): World Health Organisation. Guidelines on post-exposure prophylaxis for HIV and the use of co-trimoxazole prophylaxis for HIV-related infections among adults, adolescents and children: recommendations for a public health approach. December 2014 supplement to the 2013 consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection. https://www.who.int/hiv/pub/cotrimoxazole/en/ Cotrimoxazole, oral (pregnancy): National Department of Health: Affordable Medicines, EDP-Adult Hospital level. Evidence summary: Is co-trimoxazole safe to use in pregnancy, March 2011. http://www.health.gov.za/ xxviiiCotrimoxazole, oral: National Department of Health. 2019 ART Clinical Guidelines for the Management of HIV in Adults, Pregnancy, Adolescents, Children, Infants and Neonates. https://www.knowledgehub.org.za/elibrary/2019- art-clinical-guidelines-management-hiv-adults-pregnancy-adolescents-children-infants Cotrimoxazole, oral:Grimwade K, Swingler, G. Cotrimoxazole prophylaxis for opportunistic infections in adults with HIV. Cochrane Database Syst Rev. 2003;(3):CD003108. http://www.ncbi.nlm.nih.gov/pubmed/12917946 xxixFluconazole (CD4 < 100 cells/mm3): Meya DB, Manabe YC, Castelnuovo B, Cook BA, Elbireer AM, Kambugu A, Kamya MR, Bohjanen PR, Boulware DR. Cost-effectiveness of serum cryptococcal antigen screening to prevent deaths among HIV-infected persons with a CD4+ cell count < or = 100 cells/microL who start HIV therapy in resource-limited settings. Clin Infect Dis. 2010 Aug 15;51(4):448-55. http://www.ncbi.nlm.nih.gov/pubmed/20597693 xxx Fluconazole, oral (cryptococcosis): WHO. Guidelines for the diagnosis, prevention and management of cryptococcal disease in HIV-infected adults, adolescents and children supplement to the 2016 consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection, March 2018. https://www.who.int/hiv/pub/guidelines/cryptococcal-disease/en/ Fluconazole, oral (cryptococcosis): Govender NP, Meintjes G (Chairpersons), Bicanic T, Dawood H, Harrison TS, Jarvis JN, Karstaedt AS, Maartens G, McCarthy KM, Rabie H, Variava E, Venter WDF(Expert panel members), 2019 10.36 CHAPTER10 HIV AND AIDS Boulware DR, Chiller T, Meya DB, Scriven J (Reviewers). Guideline for the prevention, diagnosis and management of cryptococcal meningitis among HIV-infected persons: 2013 update. S Afr J HIV Med 2013;14(2):76-86. http://www.sajhivmed.org.za/index.php/hivmed/article/view/82/128 Fluconazole, oral (cryptococcosis): NICD data on file xxxiFluconazole, oral (cryptococcosis): WHO. Guidelines for the diagnosis, prevention and management of cryptococcal disease in HIV-infected adults, adolescents and children supplement to the 2016 consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection, March 2018. https://www.who.int/hiv/pub/guidelines/cryptococcal-disease/en/ Fluconazole, oral (cryptococcosis): Govender NP, Meintjes G (Chairpersons), Bicanic T, Dawood H, Harrison TS, Jarvis JN, Karstaedt AS, Maartens G, McCarthy KM, Rabie H, Variava E, Venter WDF(Expert panel members), Boulware DR, Chiller T, Meya DB, Scriven J (Reviewers). Guideline for the prevention, diagnosis and management of cryptococcal meningitis among HIV-infected persons: 2013 update. S Afr J HIV Med 2013;14(2):76-86. http://www.sajhivmed.org.za/index.php/hivmed/article/view/82/128 Fluconazole, oral (cryptococcosis): NICD data on file. xxxii ART: Makadzange AT, Ndhlovu CE, Takarinda K, Reid M, Kurangwa M, Gona P, Hakim JG. Early versus delayed initiation of antiretroviral therapy for concurrent HIV infection and cryptococcal meningitis in sub-saharan Africa. Clin Infect Dis. 2010 Jun 1;50(11):1532-8.http://www.ncbi.nlm.nih.gov/pubmed/20415574 ART: WHO. Guidelines for the diagnosis, prevention and management of cryptococcal disease in HIV-infected adults, adolescents and children supplement to the 2016 consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection, March 2018. https://www.who.int/hiv/pub/guidelines/cryptococcal- disease/en/ ART: Govender NP, Meintjes G (Chairpersons), Bicanic T, Dawood H, Harrison TS, Jarvis JN, Karstaedt AS, Maartens G, McCarthy KM, Rabie H, Variava E, Venter WDF(Expert panel members), Boulware DR, Chiller T, Meya DB, Scriven J (Reviewers). Guideline for the prevention, diagnosis and management of cryptococcal meningitis among HIV-infected persons: 2013 update. S Afr J HIV Med 2013;14(2):76-86. http://www.sajhivmed.org.za/index.php/hivmed/article/view/82/128 xxxiii Fluconazole, oral (pregnancy): Mølgaard-Nielsen D, Pasternak B, Hviid A. Use of oral fluconazole during pregnancy and the risk of birth defects. N Engl J Med. 2013 Aug 29;369(9):830-9. http://www.ncbi.nlm.nih.gov/pubmed/23984730 Fluconazole, oral (pregnancy): Mølgaard-Nielsen D, Svanström H, Melbye M, Hviid A, Pasternak B. Association Between Use of Oral Fluconazole During Pregnancy and Risk of Spontaneous Abortion and Stillbirth. JAMA. 2016 Jan 5;315(1):58-67. http://www.ncbi.nlm.nih.gov/pubmed/26746458 Fluconazole, oral (pregnancy): Govender NP, Meintjes G (Chairpersons), Bicanic T, Dawood H, Harrison TS, Jarvis JN, Karstaedt AS, Maartens G, McCarthy KM, Rabie H, Variava E, Venter WDF(Expert panel members), Boulware DR, Chiller T, Meya DB, Scriven J (Reviewers). Guideline for the prevention, diagnosis and management of cryptococcal meningitis among HIV-infected persons: 2013 update. S Afr J HIV Med 2013;14(2):76-86. http://www.sajhivmed.org.za/index.php/hivmed/article/view/82/128 xxxiv Fluconazole, oral (breastfeeding): South African Medicines Formulary. 12th Edition. Division of Clinical Pharmacology. University of Cape Town, 2016. Fluconazole, oral (breastfeeding): Govender NP, Meintjes G (Chairpersons), Bicanic T, Dawood H, Harrison TS, Jarvis JN, Karstaedt AS, Maartens G, McCarthy KM, Rabie H, Variava E, Venter WDF(Expert panel members), Boulware DR, Chiller T, Meya DB, Scriven J (Reviewers). Guideline for the prevention, diagnosis and management of cryptococcal meningitis among HIV-infected persons: 2013 update. S Afr J HIV Med 2013;14(2):76-86. http://www.sajhivmed.org.za/index.php/hivmed/article/view/82/128 xxxvFluconazole, oral (cryptococcosis): WHO. Guidelines for the diagnosis, prevention and management of cryptococcal disease in HIV-infected adults, adolescents and children supplement to the 2016 consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection, March 2018. https://www.who.int/hiv/pub/guidelines/cryptococcal-disease/en/ Fluconazole, oral (cryptococcosis): Govender NP, Meintjes G (Chairpersons), Bicanic T, Dawood H, Harrison TS, Jarvis JN, Karstaedt AS, Maartens G, McCarthy KM, Rabie H, Variava E, Venter WDF(Expert panel members), Boulware DR, Chiller T, Meya DB, Scriven J (Reviewers). Guideline for the prevention, diagnosis and management of cryptococcal meningitis among HIV-infected persons: 2013 update. S Afr J HIV Med 2013;14(2):76-86. http://www.sajhivmed.org.za/index.php/hivmed/article/view/82/128 Fluconazole, oral (cryptococcosis): NICD data on file. xxxviFluconazole, oral (cryptococcosis): WHO. Guidelines for the diagnosis, prevention and management of cryptococcal disease in HIV-infected adults, adolescents and children supplement to the 2016 consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection, March 2018. https://www.who.int/hiv/pub/guidelines/cryptococcal-disease/en/ Fluconazole, oral (cryptococcosis): Govender NP, Meintjes G (Chairpersons), Bicanic T, Dawood H, Harrison TS, Jarvis JN, Karstaedt AS, Maartens G, McCarthy KM, Rabie H, Variava E, Venter WDF(Expert panel members), Boulware DR, Chiller T, Meya DB, Scriven J (Reviewers). Guideline for the prevention, diagnosis and management of cryptococcal meningitis among HIV-infected persons: 2013 update. S Afr J HIV Med 2013;14(2):76-86. http://www.sajhivmed.org.za/index.php/hivmed/article/view/82/128 Fluconazole, oral (cryptococcosis): NICD data on file. xxxvii ART: Makadzange AT, Ndhlovu CE, Takarinda K, Reid M, Kurangwa M, Gona P, Hakim JG. Early versus delayed initiation of antiretroviral therapy for concurrent HIV infection and cryptococcal meningitis in sub-saharan Africa. Clin Infect Dis. 2010 Jun 1;50(11):1532-8.http://www.ncbi.nlm.nih.gov/pubmed/20415574 ART: WHO. Guidelines for the diagnosis, prevention and management of cryptococcal disease in HIV-infected adults, adolescents and children supplement to the 2016 consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection, March 2018. https://www.who.int/hiv/pub/guidelines/cryptococcal- disease/en/ 2019 10.37 CHAPTER10 HIV AND AIDS ART: Govender NP, Meintjes G (Chairpersons), Bicanic T, Dawood H, Harrison TS, Jarvis JN, Karstaedt AS, Maartens G, McCarthy KM, Rabie H, Variava E, Venter WDF(Expert panel members), Boulware DR, Chiller T, Meya DB, Scriven J (Reviewers). Guideline for the prevention, diagnosis and management of cryptococcal meningitis among HIV-infected persons: 2013 update. S Afr J HIV Med 2013;14(2):76-86. http://www.sajhivmed.org.za/index.php/hivmed/article/view/82/128 xxxviiiSteroids and HIV-associated Cryptococcal Meningitis Treatment: Beardsley J, Wolbers M, Kibengo FM, Ggayi AB, Kamali A, Cuc NT, et al. Adjunctive dexamethasone in HIV-associated cryptococcal meningitis. N Engl J Med 2016;374:542-54. https://www.ncbi.nlm.nih.gov/pubmed/26863355 xxxixValganciclovir, oral: 1. Martin DF, Sierra-Madero J, Walmsley S, Wolitz RA, Macey K, Georgiou P, Robinson CA, Stempien MJ; Valganciclovir Study Group. A controlled trial of valganciclovir as induction therapy for cytomegalovirus retinitis. N Engl J Med. 2002 Apr 11;346(15):1119-26. http://www.ncbi.nlm.nih.gov/pubmed/11948271 Valganciclovir, oral:Brown F, Banken L, Saywell K, Arum I. Pharmacokinetics of valganciclovir and ganciclovir following multiple oral dosages of valganciclovir in HIV- and CMV-seropositive volunteers. Clin Pharmacokinet. 1999 Aug;37(2):167-76. http://www.ncbi.nlm.nih.gov/pubmed/10496303 xlAzithromycin: Dunne M, Fessel J, Kumar P, Dickenson G, Keiser P, Boulos M, Mogyros M, White Jr AC, Cahn P, O'Connor M, Lewi D, Green S, Tilles J, Hicks C, Bissett J, Schneider MM, Benner R. A randomized, double-blind trial comparing azithromycin and clarithromycin in the treatment of disseminated Mycobacterium avium infection in patients with human immunodeficiency virus. Clin Infect Dis. 2000 Nov;31(5):1245-52. Erratum in: Clin Infect Dis 2001 May 1;32(9):1386. http://www.ncbi.nlm.nih.gov/pubmed/11073759 Azithromycin: Ward TT, Rimland D, Kauffman C, Huycke M, Evans TG, Heifets L. Randomized, open-label trial of azithromycin plus ethambutol vs. clarithromycin plus ethambutol as therapy for Mycobacterium avium complex bacteremia in patients with human immunodeficiency virus infection. Veterans Affairs HIV Research Consortium. Clin Infect Dis. 1998 Nov;27(5):1278-85. http://www.ncbi.nlm.nih.gov/pubmed/9827282 xli Dolutegravir-based PEP regimen: Ford N, Shubber Z, Calmy A, Irvine C, Rapparini C, Ajose O, et al. Choice of antiretroviral drugs for postexposure prophylaxis for adults and adolescents: A systematic review. Clinical Infectious Diseases. 2015;60 Suppl 3:S170–6. https://www.ncbi.nlm.nih.gov/pubmed/25972499 Dolutegravir-based PEP regimen: McAllister JW, Towns JM, McNulty A, Pierce AB, Foster R, Richardson R, et al. Dolutegravir with tenofovir disoproxil fumarate-emtricitabine as HIV postexposure prophylaxis in gay and bisexual men. AIDS. 2017;31(9):1291–5. https://www.ncbi.nlm.nih.gov/pubmed/28301425 Dolutegravir-based PEP regimen: Goldschmidt RH. CDC Releases Updated Guidelines for Postexposure Prophylaxis After Sexual, Injection Drug, or Other Nonoccupational Exposures to HIV. Am Fam Physician. 2016 Sep 1;94(5):392-3. https://www.ncbi.nlm.nih.gov/pubmed/27583430 Dolutegravir-based PEP regimen: Canadian guideline on HIV pre-exposure prophylaxis and nonoccupational postexposure prophylaxis. CMAJ. 2018 Jun 25;190(25):E782. https://www.ncbi.nlm.nih.gov/pubmed/29941442 xliiProtease-inhibitor- based PEP regimen: Ford N, Shubber Z, Calmy A, Irvine C, Rapparini C, Ajose O, et al. Choice of antiretroviral drugs for postexposure prophylaxis for adults and adolescents: A systematic review. Clinical Infectious Diseases. 2015;60 Suppl 3:S170–6. https://www.ncbi.nlm.nih.gov/pubmed/25972499 Protease-inhibitor- based PEP regimen: Zash R, Holmes L, Diseko M, Jacobson DL, Brummel S, Mayondi G, Isaacson A, Davey S, Mabuta J, Mmalane M, Gaolathe T, Essex M, Lockman S, Makhema J, Shapiro RL. Neural- Tube Defects and Antiretroviral Treatment Regimens in Botswana. N Engl J Med. 2019 Aug 29;381(9):827-840. https://www.ncbi.nlm.nih.gov/pubmed/31329379 Protease-inhibitor- based PEP regimen: Goldschmidt RH. CDC Releases Updated Guidelines for Postexposure Prophylaxis After Sexual, Injection Drug, or Other Nonoccupational Exposures to HIV. Am Fam Physician. 2016 Sep 1;94(5):392-3. https://www.ncbi.nlm.nih.gov/pubmed/27583430 Protease-inhibitor- based PEP regimen: Canadian guideline on HIV pre-exposure prophylaxis and nonoccupational postexposure prophylaxis. CMAJ. 2018 Jun 25;190(25):E782. https://www.ncbi.nlm.nih.gov/pubmed/29941442 xliiiLevonorgestrel 1.5 mg: National Department of Health, Essential Drugs Programme: Primary Health Care STGs and EML, 2018. http://www.health.gov.za/ xliv Levonorgesterol, oral - emergency contraception (double dose): Carten ML, Kiser JJ, Kwara A, Mawhinney S, Cu-Uvin S. Pharmacokinetic interactions between the hormonal emergency contraception, levonorgestrel (Plan B), and Efavirenz. Infect Dis Obstet Gynecol. 2012;2012:137192. http://www.ncbi.nlm.nih.gov/pubmed/22536010 Levonorgesterol, oral - emergency contraception (double dose): Tittle V, Bull L, Boffito M, Nwokolo N. Pharmacokinetic and pharmacodynamic drug interactions between antiretrovirals and oral contraceptives. ClinPharmacokinet. 2015 Jan;54(1):23-34. http://www.ncbi.nlm.nih.gov/pubmed/25331712 Levonorgesterol, oral - emergency contraception (double dose): Jatlaoui TC and Curtis KM. Safety and effectiveness data for emergency contraceptive pills among women with obesity: a systematic review. Contraception 94 (2016) 605–611. https://www.ncbi.nlm.nih.gov/pubmed/27234874 xlv Metoclopramide, oral: National Department of Health, Essential Drugs Programme: Primary Health Care STGs and EML, 2018. http://www.health.gov.za/ xlviSTI prophylaxis:National Department of Health, Essential Drugs Programme: Primary Health Care STGs and EML, 2018. http://www.health.gov.za/ xlviiNon-occupational PEP: South African HIV Clinician Society. Post-exposure prophylaxis guidelines. The S A Jr of HIV Med, Winter 2008.[Online] Available at:http://www.sahivsoc.org/upload/documents/guidelines_nov_2008.pdf 2019 10.38  CHAPTER 11 SURGICAL ANTIBIOTIC PROPHYLAXIS GENERAL PRINCIPLES » Prophylactic antibiotic therapy reduces the risk of surgical site infection. » The need for surgical antibiotic prophylaxis depends on the nature of the expected wound from the procedure. » Wounds that are expected to be clean (defined as no inflammation encountered; and the respiratory, alimentary, genital, or uninfected urinary tracts were not entered) generally do not require antibiotic prophylaxis, except where the consequences of surgical site infection could be severe (e.g. joint replacement in orthopaedic surgery). » Antibiotic prophylaxis is indicated for procedures with clean-contaminated wounds (defined as entering the respiratory, alimentary, genital, or urinary tracts under controlled conditions; and without unusual contamination). LoE:IIIi » A course of antibiotic treatment, not antibiotic prophylaxis, is required for procedures with contaminated wounds (defined as fresh open accidental wounds, or operations with major breaks in sterile technique), or dirty or infected wounds (defined as old traumatic wounds with retained devitalized tissue; and those that involve existing clinical infection or perforated viscera). LoE:IIIii (See chapter 20: Emergencies and injuries for antibiotic treatment). » The antibiotic of choice should be active against Gram positive organisms, notably Staphylococcus aureus, which is the commonest cause of surgical site infections, with additional cover for other common pathogens according to the surgical site (e.g. anaerobic bacteria for GIT surgery). » Give prophylaxis at induction. LoE:IIIiii » If a tourniquet is used at the site of surgery, administer the entire antibiotic dose before the tourniquet is inflated. LoE:IIIiv » Implement perioperative glycaemic control and use blood glucose target levels less than 11.1 mmol/L in patients with and without diabetes. LoE:IIIv » Maintain perioperative normothermia. vi » Antibiotic prophylaxis should be used in conjunction with LoE:III good pre-, intra-, and post-operative infection prevention strategies. » Advise patient to shower or bathe with soap or antiseptic agent on at least the night before the procedure. LoE:IIIvii 2019 11.1 CHAPTER 11 SURGICAL ANTIBIOTIC PROPHYLAXIS » Do not remove hair preoperatively unless the hair at or around the incision site will interfere with the operation. If hair removal is necessary, remove immediately before the operation, with clippers. LoE:Iviii DOSAGE RECOMMENDATIONS:  Cefazolin, IV. o 35: 3g LoE:IIIix Pregnant women: o 100 kg: 3g LoE:IIIx  Metronidazole, IV, 500 mg.  Azithromycin, IV, 500 mg.  Gentamicin, IV, 6 mg/kg (See Appendix II, for guidance on prescribing).  Clindamycin, IV, 600 mg. In most instances a single antibiotic dose prior to the procedure is sufficient for prophylaxis. Postoperative antimicrobial administration is not recommended for most surgeries as this selects for antimicrobial resistance. LoE:Ixi » Additional intra-operative doses should be administered in circumstances of significant blood loss (>1500 mL) in order to ensure an adequate antimicrobial level until wound closure. LoE:IIIxii » With prolonged procedures, antibiotics are required to be re-dosed (i.e. >4 hours for cefazolin; >8 hours for metronidazole; > 6 hours for clindamycin and gentamicin). LoE:IIIxiii 2019 11.2 CHAPTER 11 SURGICAL ANTIBIOTIC PROPHYLAXIS ANTIBIOTIC PROPHYLAXIS TYPE OF SURGERY ANTIBIOTIC RECOMMENDED  Cefazolin, IV  Cefazolin, IV PLUS Orthopaedic surgery Primary total hip/ total knee replacement; internal fixation of hip; spinal procedures; open reduction and internal fixation of fractures; insertion of prostheses, screws, plates, lower limb amputation, etc. Gastrointestinal surgery Gastric/ duodenal/ Biliary, colorectal, oesophageal hernia manipulation of viscera, repair. appendicectomy, division of adhesions, exploratory laparotomy: ADD  Metronidazole, IV. Thoracic Pneumonectomy/ surgery(specialist) lobectomy: ADD  Metronidazole, IV. Cardiac surgery Coronary artery bypass (specialist) surgery/ routine cardiac valve surgery (continue cefazolin, IV, 8 hourly for 24 hours); cardiac device insertion (pacemaker implantation). Vascular surgery Vascular Lower limb amputation: (specialist) reconstruction: ADD (Prophylaxis is not abdominal aorta, groin  Metronidazole, IV. recommended for other incision (continue 8 clean procedures). hourly for 24 hours); AV fistula formation; and ligation of varicose veins. Urology Clean procedures Clean-contaminated procedures: ADD  Metronidazole, IV. 2019 11.3 CHAPTER 11 SURGICAL ANTIBIOTIC PROPHYLAXIS Plastic and Craniotomy reconstructive surgery procedures. (Prophylaxis is not recommended for clean bone or soft tissue surgery). Otorhinolaryngology/ No incision through the With incision through the head and neck surgery oropharyngeal oropharyngeal mucosa: (Prophylaxisis not mucosa. ADD recommended for other  Metronidazole, IV. procedures such as tonsillectomy, sinus procedures, etc.). Hysterectomy, Obstetrics/ laparotomy procedures, gynaecology vaginal repair: (Prophylaxis is not ADD recommended for early  Metronidazole, IV. suction termination). Caesarean delivery: ADD  Azithromycin, IV. Neurosurgery Craniotomy; CSF (Prophylaxis is not shunt/drain; recommended for other laminectomy. minor clean procedures). Endoscopic Percutaneous gastrointestinal endoscopic procedures gastrostomy (Prophylaxis is not insertion/revision. recommended for all other procedures, with or without biopsy). General Surgery Clean contaminated (Prophylaxis is not procedures recommended for (mastectomy, node uncomplicated clean biopsy, etc.), procedures or clean splenectomy. excision procedures i.e. wound revision, excision of scar tissue, etc.). LoE:Ixiv Beta lactam allergies: Avoid beta-lactam antimicrobials in patients with a history of anaphylaxis, bronchospasm, urticaria, or angioedema after exposure to one of these agents. 2019 11.4 CHAPTER 11 SURGICAL ANTIBIOTIC PROPHYLAXIS  Clindamycin, IV. ADD  Gentamicin, IV for the procedures listed below: (See Appendix II, for guidance on prescribing). » Gastrointestinal surgery, urology procedures (clean-contaminated), and obstetric/gynaecological surgery (hysterectomy, laparotomy procedures, vaginal repair). Note: Clindamycin has good coverage against Gram positive organisms and anaerobes, so the addition of metronidazole is unnecessary. LoE:IIIxv Ophthalmic surgery:  Chloramphenicol 0.5% ophthalmic drops, instil 1 drop 2–4 hourly for 24 hours prior to surgery. SPECIAL CONSIDERATIONS » Elective splenectomy patients should be vaccinated at least 14 days prior to surgery. If splenectomy was urgent, or if vaccination was omitted before elective splenectomy, vaccinate at least 14 days post-splenectomy. » The following vaccines should be administered: LoE:IIxvi VACCINE SCHEDULE  Polyvalent pneumococcal vaccine, 0.5 o PCV13, SC, 2 weeks before sur