An Introduction To Anti Retro Viral Therapy

An Introduction to Antiretroviral Therapy

Drug Adherence - A Key to Treatment SUCCESS

Special Preventive Programme

Centre for Health Protection Department of Health

Content Preface

3

The Human Immunodeficiency Virus (HIV) life cycle

4

What is antiretroviral therapy?

5

Effects of antiretroviral therapy

6

What kinds of antiretroviral therapy are available in Hong Kong?

7

When to consider using antiretroviral therapy?

9

Special attention while taking antiretroviral drugs

10

Nine tips on successful drug taking

11

How to control over antiretroviral therapy?

12

How to know whether treatment is working?

12

What is meant by "undetectable" viral load?

13

The importance of drug adherence

14

Degree of drug adherence

14

Non-adherence can lead to drug resistance

15

Signs of treatment failure

17

Side effects of antiretroviral therapy

18

Managing side effects

20

The use of antiretroviral agents for prophylaxis

26

Conclusion

27

Appendix I. Classes of antiretroviral drugs

28

Progress sheet

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Useful telephone numbers and websites

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II . III.

PREFACE The use of antiretroviral therapy can effectively control HIV and its disease progress. Successful treatment depends on how you know about and get the most from your medicine over a long period of time. Stay on your medication and work together with your health care providers is a smart way to reach the goal. This booklet aims to promote your understanding about how antiretroviral therapy can help you live a longer and healthier life. If you have further questions after reading this booklet, please be sure to talk to your doctor and / or other health care providers to obtain the feedback.

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1 The Human Immunodeficiency Virus (HIV) life cycle

HIV enters a healthy CD4 cell. Once inside the cell, HIV coverts its own genetic material RNA into DNA using the enzyme reverse transcriptase. This new DNA acts as a blueprint directing the infected cell to make new virus particles. Mature viral cores are produced through action of viral protease after budding. The new virus is then released and can infect other healthy cells. Thus, the function of immune system will be progressively destroyed.

Human DNA HIV DNA

HIV RNA

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HIV DNA

2 What is antiretroviral therapy (ART) ?

The antiretroviral agents attack HIV at different stages of its life cycle to inhibit HIV replication and thus bring the viral load down. Combination therapy of two or more drug components has become the standard of treatment of HIV disease. "Cocktail" is a colloquial term for HIV combination therapy.

Highly active anti-retroviral therapy (HAART) HAART refers to very potent regimen in which almost invariably inhibits viral replication to an undetectable level in the blood. An example of HAART is the use of triple therapy comprises 2 Nucleoside Reverse Transcriptase Inhibitors (NRTI) and 1 Protease Inhibitors (PI).

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3 Effects of antiretroviral therapy Restore health and defense function Decline in AIDS morbidity, hospitalization and mortality Improve well-being Improve the quality of life Prolong survival of the patients with AIDS

Goals of Therapy Suppression of viral replication to an undetectable level is the goal of HAART. Effectiveness of the treatment is readily demonstrable by a precipitous fall in plasma viral load and often a rise in CD4 count.

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4 What kinds of antiretroviral therapy are available in Hong Kong?

(I)

(NRTI)

1

There are three classes of antiretroviral drugs available in Hong Kong (Appendix I):

(I) Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NRTI) Action: HIV's enzyme called reverse transcriptase convert RNA to DNA. NRTI block reverse transcription by providing faulty building blocks that interrupt the process.

Currently available drugs in this class are: 1. Zidovudine 2. Didanosine 3. Didanosine EC 4. Lamivudine 5. Zalcitabine 6. Stavudine 7. Combivir 8. Abacavir 9. Tenofovir 10. Trizivir

(AZT) (ddI) (ddIEC) (3TC) (ddC) (d4T) (CBV) (ABC) (TDF) (ABC+AZT+3TC)

(Retrovir) (Videx) (Videx EC) (Epivir) (Hivid) (Zerit) (Ziagen) (Viread)

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(II)

(NNRTI)

2

(II) Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTI)

Action: NNRTI stop HIV production by binding directly onto reverse transcriptase and prevent the enzyme from converting RNA to DNA.

Currently available drugs in this class are:

3 1. Efavirenz 2. Nevirapine

(III)

(EFZ) (NVP)

(Sustiva) (Viramune)

(PI)

(III) Protease Inhibitors (PI)

Action : PI block the action of an enzyme, called Protease that cuts HIV protein chains into specific proteins needed to assemble a new copy of HIV. Therefore, PI prevent the cell from producing new HIV.

Currently available drugs in this class are: 1. Indinavir 2. Saquinavir 3. Ritonavir 4. Nelfinavir 5. Kaletra

8

(IDV) (SQV) (RTV) (NFV) (LPV+RTV)

(Crixivan) (Hard gel-Invirase, Soft gel-Fortovase) (Norvir) (Viracept)

5 When to consider using antiretroviral therapy?

The doctor will consider using antiretroviral therapy when the infected individual has suffered clinically or immunologically from the virus or has at a heightened risk of disease progression. The following are the indicators for treatment: Low CD4 count High viral load level Signs of opportunistic infection Psychologically well prepared to comply with this long-term treatment in order to achieve the goal of therapy

? ?

? ?? ? ??? ?

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6 Special attention while taking antiretroviral drugs

Different drugs would have different precautions, e.g.: Some drugs work best when they are taken with food while some should be taken on an empty stomach. May need to increase water intake. Some kinds of food, drugs, Chinese medicines or alcohol should be avoided to prevent adverse reaction. Some drugs need to be stored in a refrigerator or special container.

Thus, the infected individual should follow the instruction of health care providers when taking antiretroviral drugs.

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7 Nine tips on successful drug taking Commit to drug taking strongly Fit the drug regimen into your daily activities Keep drugs in the places you usually go Know well your drug regimen in terms of the right dosage, frequency and ways of drug taking Bring along a bottle of water for drug taking Make use of an alarm clock, a pager or chart to remind yourself the time of drug taking Use a pill box to contain one-day medication to remind yourself of the correct dosage Seek help from health care providers to work out a drug schedule that suit you most Seek support from significant others

this ! o d n a c u o y Drug Adherence - A key to treatment success

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8 How to control over antiretroviral therapy? Make a personal commitment to your therapy Keep in close touch with your health care providers Attend regular follow-up

9 How to know whether treatment is working?

Health monitoring blood test: CD4 count reflect how strong immune system is Viral load measurement measure level of HIV in blood In general, treatment is considered to be working if the viral load is falling or remains low, and the CD4 count level is rising or remains stable.

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10 What is meant by "undetectable" viral load?

Undetectable viral load means that HIV level is too low to be picked up by the viral load test. HIV are still in the body and can transmit to others through sexual and blood contact. Therefore, it is essential to continue treatment and take precautions against its spread e.g. safer sex.

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11 The importance of drug adherence

The most important element in the success of your anti-HIV treatment is to strictly adhere to the drug regimen. Good drug adherence can prevent treatment failure and the emergence of resistance. Poor drug adherence will lead to the development of drug resistance, limiting the effectiveness of therapy. Thus, the most important thing you can do to stay healthy is always to take your drugs in the right way and at the right time.

12 Degree of drug adherence The nurse counsellor usually calculates your degree of drug adherence by:

No. of doses of ART taken

14

No. of prescribed doses of ART

100%

13 Non-adherence can lead to drug resistance

Drug resistance means the reduction of a drug's ability to work against HIV. Resistance is thought to occur when its target mutates, changing its structure so that the drug can no longer bind to work as well as it used to. Missing doses or taking even short "drug holidays" give the virus change its form and multiply. When you start taking your drugs again, they may not work as well. Thus, non-adherence to drug regimen can lead to drug resistance.

Cross-resistance: The mechanism by which HIV that has developed resistance to one drug may also be resistant to other similar drugs.

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DRUG RESISTANCE Taking drugs regularly helps you control the virus: Drug concentration

Virus replication is inhibited, mutation is unlikely to occur. Level that inhibits viral replication

Taking your drugs on time, every time is essential and has its reward: Lower or undetectable viral load result higher CD4 count, increase/maintain immune function.

Non-adherence enables the virus to gain control again: Drug concentration

Virus will replicate!

Mutations are more frequent during active replication. Some mutated virus are resistant to drugs. Missed dose!! TREATMENT FAILURE

The best way to avoid resistance is to adhere to the regimenEVERYDAY, EVERY TIME

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14 Signs of treatment failure

Increase viral load Decrease CD4 count Increase risk of disease progression Increase hospitalization and risk of death

Missing doses or taking the wrong doses can lead to drug resistance. You can quickly become resistant to antiretroviral drugs if you do not take them at the right time, in the right way and in the right dose. If drug failure is evident in terms of clinical, immunological, or virological deterioration, change of antiretroviral regimen is indicated.

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15 Side effects of antiretroviral therapy Many side effects are temporary. If you encounter unpleasant side effects, do not discontinue the drugs or alter the dosage by yourself. You should discuss your problem with the health care providers to understand the alternatives of the way and time of drug taking, so that a more appropriate drug taking plan could be developed.

Transient side effects: Nausea/ vomiting Diarrhoea Allergy Headache Fatigue Fever Central Nervous System (CNS) symptoms (e.g. dizziness, insomnia, drowsiness, nightmares, inability to concentrate, etc.) Potential long term side effects: Anaemia (low red blood cell count) Kidney stones Deranged liver function Peripheral neuropathy Pancreatitis Redistribution of fat (lipodystrophy) Metabolic problems (e.g. increase blood fats/ blood sugar) Neutropenia (an abnormal decrease in the number of neutrophils in the blood)

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16 Managing side effects Side effects to antiretroviral drugs are common during the first few weeks of treatment. However, these symptoms will often pass as your body gets used to the drugs. You should report any unusual symptoms to your doctor/health care providers. If necessary, your doctor will prescribe medications to help you get over the initial period. The following is a quick reference for managing side effects of antiretroviral drugs. Managing side effects: A quick reference chart Diarrhoea Self management:

Eat white rice, toast, oatmeal, apple sauce, or bananas Avoid spicy foods, fatty foods, and foods that promote gas, e.g. peanuts, onion Avoid high fibre food, such as brown rice or whole grain bread Drink a lot of liquid to replace fluids lost Consult your doctor:

Check for signs of infections Prescribe medications for diarrhoea Upset Stomach (Nausea, Vomiting, Poor Appetite) Self management:

Eat dry foods like crackers, toast, and dry cereal Sip clear liquids like ginger ale or juice mixed with water Eat foods that appeal to you even when you are not hungry Eat small and frequent meals Avoid eating very sweet , spicy or fatty food Avoid lying down directly after a meal Avoid drinking fluids immediately before, with or after meals Consult your doctor:

Prescribe medications for upset stomach Prescribe medications to improve your appetite Clarify with your doctor about your drug taking pattern and the suitable timing of meals to avoid gastric upset

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Feeling Tired (Fatigue) Self management:

Take a balance diet and exercise regularly Get adequate rest Ask for help with work so as to save energy for important tasks Consult your doctor:

Check for signs of anaemia Dizziness, Confusion, and Sleeping Problems Self management:

Take medications at the best time of day to reduce side effects, e.g. Efavirenz is best taken at bedtime Stay in bed if possible Consult your doctor:

Consider other causes, leading to the side effect e.g. depression Enquire about the change of drugs or time of drug taking Prescribe medications for discomfort Headache Self management:

Take adequate rest Do relaxation exercise Listen to light music Consult your doctor:

Prescribe medications for headache Fat Problems (Lipodystrophy) Self management:

Get regular exercise and eat a healthy diet. This may not reduce lipodystrophy, but it will keep your weight and overall body fat at a healthier level Consult your doctor:

Enquire about experimental treatments to be used for repairing facial fat changes

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Nerve Problems, Tingling Hands and Feet (Neuropathy) Self management:

Avoid walking or standing for a long period of time Soak your feet in cool water Massage hands and feet Avoid wearing tight socks or shoes Consult your doctor:

Enquire the possibility of change of drugs Refer to see a neurologist Prescribe medications for neuropathy Liver Problems Self management:

Quit or reduce alcohol drinking Consult your doctor:

Monitor liver enzyme blood tests regularly Enquire about changing of drugs or alternative therapy Metabolic Problems Self management:

Exercise on a regular basis if possible Quit or reduce smoking Consult your doctor:

Monitor cholesterol, triglycerides, and glucose tests (the blood tests that measure fats and sugar in your blood) regularly Bone Problems Self management:

Get enough calcium and vitamin D from food, such as fortified soy, rice milk Do weight-bearing exercise like walking or weight lifting Consult your doctor:

Prescribe medications for discomfort

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17 The use of antiretroviral agents for prophylaxis

Effectiveness of antiretroviral drugs is already well-proven as prophylaxis to reduce the risk of HIV transmission in two specific health care settings: Perinatal infection (mother to child transmission) Post occupational exposure prophylaxis

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18 Conclusion

By using antiretroviral therapy and adopting good drug adherence practice, you can stay a healthy life. Be relax, take nutritious food, do regular exercise, join a support group and develop a hobby are some smart ways to maintain good health and improve your quality of life.

qua lity of life Drug Adherence - A key to treatment success

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I (NRTI)

1 Zidovudine (AZT) Retrovir

2 Didanosine (ddI) Videx

3 Didanosine EC (ddIEC) Videx EC

4 Lamivudine (3TC) Epivir

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APPENDIX

I Classes of antiretroviral drugs (A)Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NRTI) Drug Drug

Potential side effects

Remarks

200mg 3 times/day or 300mg 2 times/day

Anaemia Neutropenia G I intolerance Headache Insomnia Asthenia Lactic acidosis with hepatic steatosis (rare): fatigue, severe vomiting, dyspnoea

If nausea, take after meal

2 Didanosine 125mg or (ddI) 200mg Videx 2 times/day 25mg/tab 100mg/tab

Peripheral neuropathy Pancreatitis Nausea Diarrhoea Lactic acidosis with hepatic steatosis (rare): fatigue, severe vomiting, dyspnoea

Chewed/crushed/ dissolved Take on empty stomach Take with IDV at least 1 hr apart

3 Didanosine 250mg or EC 400mg (ddIEC) daily Videx EC 250mg/tab 400mg/tab

Peripheral neuropathy Pancreatitis Nausea Diarrhoea Lactic acidosis with hepatic steatosis (rare): fatigue, severe vomiting, dyspnoea

Take on empty stomach Take with IDV at least 1 hr apart Take with meal if take TDF together

4 Lamivudine 150mg (3TC) 2 times/day Epivir 150mg/tab

Minimal toxicity Lactic acidosis with hepatic steatosis (rare): fatigue, severe vomiting, dyspnoea

Rapid emergence of resistant strains if non-adherent

1 Zidovudine (AZT) Retrovir 100mg/cap

Dosage

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5 Zalcitabine (ddC) Hivid

6 Stavudine (d4T) Zerit

7 Combivir (CBV)

8 Abacavir (ABC) Ziagen

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APPENDIX Drug

Dosage

Potential side effects

5 Zalcitabine 0.75 mg (ddC) 3 times/day Hivid 0.75mg/tab

Peripheral neuropathy Stomatitis Pancreatitis Lactic acidosis with hepatic steatosis (rare): fatigue, severe vomiting, dyspnoea

6 Stavudine (d4T) Zerit 30mg/cap 40mg/cap

30mg or 40mg 2 times/day

Peripheral neuropathy Lipodystrophy Lactic acidosis with hepatic steatosis (rare): fatigue, severe vomiting, dyspnoea Pancreatitis Rapidly progressive ascending neuromuscular weakness (rare)

7 Combivir (CBV) =150mg 3TC + 300mg AZT/tab

1 tab 2 times/day

Anaemia Neutropenia Headache G I intolerance Insomnia Asthenia Lactic acidosis with hepatic steatosis (rare): fatigue, severe vomiting, dyspnoea

8 Abacavir (ABC) Ziagen 300mg/tab

300mg 2 times/day

Hypersensitivity reaction (5% of people) symptoms may include fever, rash, nausea, vomiting, malaise, fatigue or loss of appetite, respiratory symptoms such as sore throat, cough, shortness of breath

Remarks

If there is fever, rash, report to health care workers at once

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9 Tenofovir (TDF) Viread

10 Trizivir (ABC + AZT + 3TC)

(NNRTI)

1 Efavirenz (EFZ) Stocrin, Sustiva

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APPENDIX Drug Drug

9 Tenofovir (TDF) Viread 300mg/tab

Dosage

Potential side effects

300mg daily Asthenia Headache G I intolerance Flatulence Lactic acidosis with hepatic steatosis (rare): fatigue, severe vomiting, dyspnoea Rare report of renal insufficiency

1 tab 10 Trizivir (ABC + 2 times/day AZT + 3TC)

Anaemia Neutropenia G I intolerance Headache Insomnia Asthenia Lactic acidosis with hepatic steatosis: fatigue, severe vomiting, dyspnoea Hypersensitivity reaction

Remarks

Take with meal Dosage adjustment in renal insufficiency

If there is any flu like symptom fever, rash, report to health care workers at once

(B)Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTI) Drug

Dosage

600mg daily 1 Efavirenz (preferably (EFZ) at bed time) Stocrin, Sustiva 200mg/cap 600mg/tab

Potential side effects

Remarks

Rash CNS symptoms: dizziness, somnolence, insomnia, drowsiness, nightmares, hallucinations, poor concentration (usually subside in 2-4 weeks if really appear) Increased transaminase levels

Decrease CNS symptoms if take at bed time Pregnancy is contraindicated

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2 Nevirapine (NVP) Viramune

(PI)

1 Indinavir (IDV) Crixivan

2 Saquinavir (SQV) Invirase ( ) Fortovase ( )

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APPENDIX Drug Drug

2 Nevirapine (NVP) Viramune 200mg/tab

Dosage

200mg daily for 2 weeks, then 200mg 2 times/day

Potential side effects

Remarks

Rash Symptomatic hepatitis

Anti-TB drugs and oral contraceptive pills should be used with caution Rapid emergence of resistant strains if non-adherent

(C)Protease Inhibitors (PI) Potential side effects

Remarks

1 Indinavir 800mg Q8h (IDV) 3 times/day Crixivan 200mg/cap 400mg/cap

Drug

Dosage

Nephrolithiasis G I intolerance Increased indirect bilirubinemia Misc.: headache, asthenia, blurred vision, dizziness, rash, metallic taste, thrombocytopenia, alopecia, and hemolytic anaemia Fat redistribution Lipid abnormalities Hyperglycemia

Take with empty stomach Drink water 1.5 litre/day Avoid grapefruit juice

2 Saquinavir (SQV) Invirase (hard gel) 200mg/cap Fortovase (soft gel) 200mg/cap

Headache G I intolerance Elevated transaminase enzymes Hyperglycemia Fat redistribution Lipid abnormalities Possible increased bleeding episodes in patients with hemophilia

Take after meal, preferably fatty to increase absorption Rifampicin & Rifabutin are contraindicated with SQV Fortovase (soft gel) should be refrigerated or stored at room temperature 25 C (up to 3 months)

Invirase 600mg 3 times/day Fortovase 1200mg 3 times/day

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3 Ritonavir (RTV) Norvir

4 Nelfinavir (NFV) Viracept

5 Kaletra = Lopinavir (LPV) 133.3mg + Ritonavir (RTV)

Reference: Department of Health, Guidelines for the Use of Antiretroviral Agents in HIV-I-Infected Adults and Adolescents. convened by DHHS. March, 2004. P.59-64

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APPENDIX Drug

Dosage

Potential side effects

Remarks

3 Ritonavir 600mg (RTV) 2 times/day Norvir 100mg/cap syrup 80mg/ml

Headache G I intolerance Paresthesias - circumoral and extremities Hepatitis Pancreatitis Asthenia Taste perversion Lab.: Triglycerides increase >200%, transaminase elevation, elevated CPK and uric acid Hyperglycemia Fat redistribution Lipid abnormalities Possible increased bleeding episodes in patients with hemophilia

Capsules should be refrigerated. If stored at room temperature 25 C, it is stable for 30 days Take after meal to improve tolerance Need dosage adjustment if take with SQV Avoid self-prescribe drugs because of drug interaction

4 Nelfinavir (NFV) Viracept 250mg/tab

750mg 3 times/day or 1250mg 2 times/day

Diarrhoea Hyperglycemia Fat redistribution Lipid abnormalities Serum transaminase elevation Possible increased bleeding episodes in patients with hemophilia

Take with meal

5 Kaletra 3 capsules = Lopinavir 2 times/day (LPV) 133.3mg + Ritonavir (RTV) 33.3mg/cap

Diarrhoea G I intolerance Asthenia Elevated serum transaminases Hyperglycemia Fat redistribution Lipid abnormalities Possible increased bleeding episodes in patients with hemophilia

Take with meal Use additional type of contraception since Kaletra may reduce the effectiveness of oral contraceptives Should be refrigerated. If stored at room temperature 25 C, it is stable for 2 months

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II

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APPENDIX

II Progress Sheet Date

CD4 Count

Viral Load

Remarks

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III

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APPENDIX

III Useful telephone numbers and websites: Government Organizations: Kowloon Bay Integrated Treatment Centre Tel: 2117 0333 Red Ribbon Centre Tel: 2304 6268

http://www.rrc-hk.com

AIDS Hotline Tel: 2780 2211

http://www.27802211.com

Harm Reduction Hotline Tel: 2112 9977

http://www.harmreduction-hk.com

AIDS Non-governmental Organizations & Drug related Organizations: Hong Kong AIDS Foundation Tel: 2560 8528 http://www.aids.org.hk

Hotline: 2513 0513 AIDS Concern Hotline Tel: 2898 4422

http://www.aidsconcern.org.hk

The Society for AIDS Care Tel: 2559 2006

http://www.aidscare.com.hk/cindex.htm

Teen AIDS Tel: 2554 3399

http://www.teenaids.org.hk

The Society for the AIDS and Rehabilitation of Drug Abusers (SARDA) Hotline Tel: 2574 3300 Overseas Internet / Website for more information about HIV Treatment: http://www.aidsmap.com http://www.hivatis.org http://www.hivresources.com http://www.iasusa.org http://www.medscape.com http://www.treathiv.com http://www.unaids.org

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11 / 2004 Production of Integrated Treatment Centre B O K / A A 5 / 0 4 - 1 0 ( B ) H I V- E D U