Section 4: Side effects of ARVs. 4.1 Introduction. 4.2 Aims for this section

Transcription

1 Section : Side effects of ARVs Section : Side effects of ARVs Regular blood tests will check for some side effects. If you have any difficulties make sure your doctor takes these seriously... Nausea and fatigue can be very serious....1 Introduction This section provides information about side effects from ARVs, and how to avoid and manage them. Treatment can be an easy, routine part of life as long as any side effects are well managed. Modern ART should not be difficult to take. Options include treatment for the side effect, changing to alternnative drugs, and sometimes dose adjustments. A few side effects can be extremely serious. It is important to know which drugs can cause which side effects..2 Aims for this section After reading section, advocates will have a basic understanding of: overview of risk of side effects difference between major and minor side effects how to reduce side effects, including switching treatment main side effects linked to common combinations S:53 January 2016

2 Section : Side effects of ARVs.3 Side effects overview Drugs are generally developed to treat specific illnesses. When they affect the body in other ways, these are called side effects. Many of the symptoms of side effects are similar to symptoms of illnesses. Different treatment is needed when these symptoms relate to illnesses. Side effects are also called adverse events (AEs) or drug toxicity. Why do side effects occur? Although drugs are designed to work against specific illnesses, they sometimes interfere with other ways that your body works. It is difficult enough to develop a drug that works well against HIV. Any approved drug has already undergone a lot of research to minimise toxicity. Often, very promising drugs have their development stopped because of toxicity. The aim is always to develop safer and more tolerable, as well as better drugs. Most people people living with HIV, doctors and researchers recognise that the current drugs are significantly better and easier to take than earlier drugs. Although current drugs are not perfect, newer drugs in the future might be even easier to take. Do all drugs have side effects? Most drugs have side effects for some people. In the majority of cases these side effects are mild and easy to manage. Some side effects are so mild that they are unnoticed, or only picked up by a special test. Some only affect a small proportion of people that use that drug. Some rare side effects only become apparent after the drugs have beenn licenced and approved. This is after many more people use them over a much longer period than the original studies. All drugs have side effects, but not all people taking drugs will experience the same effects and to the same extent. Summary of Product Characteristics The leaflet included in the packaging with a drug is called the Summary of Product Characteristics or SPC. This leaflet lists all the reported range of possible side effects associated with each drug. It also includes other useful information, including how the drug needs to be taken and interactions with other medicines. How are side effects reported? When drugs are first studied, every symptom that occurs in the study is recorded. This is even if it only affects a few people, and even if it cannot be directly linked to the drug being studied. This means that if you look at the SPC leaflet you usually find a long and daunting list of potential side effects. It does not mean you are going to get all these side effects. S:5 January 2016

3 Section : Side effects of ARVs Side effects that are serious or occur most frequently are also usually discussed in more detail. If side effects only become apparent after the drug has been approved, the SPC may not list it. It usually takes time for this to be included in a new leaflet. Starting ART for the first time Risk of side effects can be a big worry if you are about to start ART for the first time. It helps to know what to expect from each drug before choosing your combination. Ask for information about each of the drugs you might take, including the likelihood of side effects occurring. For example, what percentage of people had side effects related to those drugs and how serious they were? You may be asked to consider entering a study looking at side effects in different combinations and these studies are important to define the extent of side effects in different combinations. Can I change drugs easily? If starting ART for the first time, you will have more options to choose from. You will have more options to change drugs until you find a combination that works and is easy to take. There are already over 30 approved ARV drugs and formulations. While you can t quite mix and match them all, you have a lot of choice. If one or more of the drugs in your combination are difficult to tolerate, you can change it for another. Often people are not given a choice when starting treatment. However, the fewer drugs you have used previously, the more choice you have if you need to change. If you change a drug because of side effects, you can usually use it again later if you need to. Just because you used a drug once, doesn t mean you have used up your option of using it again in the future. The only drug you cannot use again is abacavir. If you have a hypersensitivity reaction to abacavir you must never take it again. Some side effects improve after the first few weeks or months, but some don t. You do not have to continue with a drug to prove anything to yourself or to please your doctor. If something is wrong, ask your doctor to change it to something else. Some drugs are just not for everyone. Can I predict the side effects I may get? Generally you cannot predict how difficult or easy you will find it to take any particular drug. Sometimes, if you already have similar symptoms related to the side effects, these may make the risk of side effects greater. For example: If you have raised liver enzymes, these may increase higher still if you use nevirapine. If you have high cholesterol or triglycerides before treatment, these are more likely to increase if you use some protease inhibitors. S:55 January 2016

4 Section : Side effects of ARVs Are side effects different in men and women? Many trials in the past enrolled far too few women to study gender differences properly. Sometimes differences in side effects between men and women are reported later. Women have shown higher rates of side effects in some nevirapine studies (both liver toxicity and rash), which highlights the importance of careful monitoring. With lipodystrophy (fat loss in your arms, legs or face; or fat gain in abdomen, breasts, and shoulders), women are more likely to report symptoms of fat accumulation rather than fat loss. What about side effects and adherence? Whether you are starting your first treatment or have been using HIV drugs for a long time, your doctor should have talked to you about the importance of adherence. Adherence means taking the meds in your combination exactly as they are prescribed on time and following any diet advice. Getting your doctor to do something There can be a big difference between what is actually going on and what a doctor thinks is going on and this is why side effects are often ignored. Unfortunately: Some doctors think that their patients overestimate side effects. Most patients underestimate side effects. Doctors generally think that their patients exaggerate side effects, and that they are not really as bad as their patients say. Patients generally say that side effects are less difficult than they really are, or often forget to mention them at all. Regular blood tests will check for some side effects. If you have any side effects make sure your doctor takes these seriously... What happens if side effects persist? If the first treatment you are given to help with a side effect does not work, there are usually others that you can use. In this manual we have listed a range of options, including alternative treatments, for each of the main side effects. If one doesn t work try the other options. Changing or stopping treatment are important options that you can discuss with your doctor. S:56 January 2016

5 Section : Side effects of ARVs. Common side effets: feeling sick, diarrhoea and tiredness Feeling sick (nausea), diarrhoea and tiredness used to be common general side effects of HIV drugs. In 2016, even these side efects are more rare. If these side effects do occur, they usually become easier within the first few weeks. But because nausea and tiredness can be serious symptoms of other infections, you should tell your doctor of any problems. If your doctor thinks this is a side effect, anti-nausea and diarrhoea medications can help. If these medications aren t effective, ask your clinic for stronger or more effective drugs. If this still doesn t help you may be able to change to a different drug. Further reading Information about nausea from the i-base guide to side effetcs and other complications. Information about diarrhoea from the i-base guide to side efects and other complications. Information about tiredness from the i-base guide to side efects and other complications. Liver toxicity and rash Liver toxicity Although most HIV meds are filtered by the liver, it is rare for modern HIV drugs to cause liver problems. When liver complications occur, they are nearly always related to coinfections of HIV and viral hepatitis (hep A, B or C). Routine monitoring for liver enzymes (ALT or AST) is likely to identify early problems. However, some NNRTIs have a low risk of serious liver toxicity. These drugs include nevirapine and efavirenz. Less than 5% of people have to change treatment for this reason. Although both these NNRTIs are now used more rarely, they are both included in fixed dose combinations (FDCs) recommended by the WHO, so it is very important to know about these symptoms. If you have a rash with nevirapine, it is important that you have a blood test to check whether your liver is being affected. These tests are usually for levels of liver enzymes called ALT or AST. If this is not available, other symptoms include: Feeling sick (nausea) or being sick (vomiting) Poor appetite If your eyes or skin looks more yellow (jaundice) Light coloured stool or dark coloured urine Tenderness or swelling in your liver your liver is just under your ribs, on the right If you have any of these symptoms, you should contact your doctor straight away. S:57 January 2016

6 Section : Side effects of ARVs Liver toxicity usually occurs in the first 6 weeks of treatment, but can also occur later. If you are co-infected with hepatitis then the risk of liver toxicity is much higher, and another choice of drug would be more appropriate. Rash 10-15% people who use nevirapine or efavirenz get a low level rash that is not serious. Rash can also occur with other HIVdrugs. About 1 in 20 people discontinue efavirenz or nevirapine because of rash. 2-3% people can be at risk of a much more serious rash, especially using nevirapine. Nevirapine should be dosed at 200mg once-daily for the first two weeks. If there in no rash at the end of these two weeks then the dose increases to 200mg every 12 hours (00 mg a day). The staggered does is just as important with fixed dose combinations, but sometimes in practice it is ignored. The nevirapine dose should never be increased if you still have a rash. If the rash covers more than 10% of your body or breaks the skin at all, you must see your doctor immediately. In these rare cases, nevirapine has to be stopped very quickly to reduce the risk of a severe reaction that can be fatal. This is something you should check and ask your doctor about. Differences in men and women Women have shown higher rates of side effets in some nevirapine studies (both liver toxicity and rash). This highlights the importance of careful monitoring. Women with CD counts of 250 cells/mm 3 or higher before treatment should not start nevirapine. Men with CD counts of 00 cells/mm 3 or higher before treatment should not start nevirapine. Further reading For information about liver related side effects from the i-base guide to side effects and other complications see these links: Peripheral neuropathy: dt, ddi, rarely 3TC Peripheral neuropathy (PN) is not a side effect of modern HIV treatment (ART). PN is the medical term for nerve damage in your hands or feet. Sometimes this starts as a mild tingling or numbness. If it is allowed to develop it can become very painful, more extensive and permanent. PN is sometimes caused by HIV, especially if you have a very low CD count. But PN can also be a side effect from some early HIV drugs. These drugs are now rarely used. This means that you have to be very aware of any tingling or pain in your hands or feet and report this to your doctor. S:58 January 2016

7 Section : Side effects of ARVs Peripheral neuropathy caused by ARVs is usually bilateral (both sides). The main drugs linked to neuropathy are dt, ddi, ddc and possibly 3TC. In the last few years dt has been replaced bt tenofovir DF. dt is one of the drugs in Triomune, and it is still used in some countries, even though it is no longer recommended in WHO guidelines. Because there is no cure for neuropathy, the best choice is to stop using dt and change it to another drug. This usually involves switching to tenofovir or AZT. Symptoms may be helped by using a reduced the dose of just the dt part of the combination. Triomune for example comes with a dose of either 30mg or 0mg of dt. If you can get each drug prescribed separately, then you may be able to reduce the dose even further to 20mg twice a day. Reducing the dose of dt can sometimes be enough to stop further nerve damage, especially if this is done early while symptoms are mild. If neuropathy continues and there are no other treatment choices, then it may be better to stop your treatment for a period. You can only do this if you are doing well now and your lowest ever CD count never dropped much below 200 cells/mm 3. You could restart treatment later if you need it again or when an alternative ARV becomes available. If your combination includes the boosted protease inhibitor lopinavir/r (Kaletra/ Aluvia), then stopping dt and continuing Kaletra plus another nuke may also be possible. Neuropathy can reverse by itself when you stop the drug that is causing it, but only if you stop the drug before serious damage has been caused. Further reading For information about neuropathy from the i-base guide to side effects and other complications see these links: neuropathy Lipodystrophy (fat changes) Lipodystrophy refers to changes in fat cells and the distribution of body fat. It can also be linked to changes in blood fat and blood sugar levels. Lipodystrophy can result in losing fat from your arms, legs and face or gaining fat in your abdomen, breasts or shoulders. We do not know what causes lipodystrophy. Different drugs may be responsible for fat gain and fat loss. Similar symptoms only occur rarely in HIV-positive people who are not on treatment. Lipodystrophy usually, but not always, develops slowly over many months or years. Early symptoms may reverse if you switch to different HIV drugs. Exercise and dietary changes can also help. Careful body measurements by a dietician, by DEXA scan, or photographs can monitor changes. Blood tests can monitor changes in blood fats and blood sugar levels. S:59 January 2016

8 Section : Side effects of ARVs Fat gain Fat gain to the stomach or breasts and/or across the shoulders, has been more linked to protease inhibitors and nonnukes. Fat loss is also called lipoatrophy and it occurs from arms, legs, face and buttocks. Fat loss was nearly always caused by an oild HIV drug called dt. Fat loss can also occur with AZT. Neither dt and AZT are recommended as first-line therapy in the WHO guidelines. Changes to blood fats Raised levels of blood fats (lipids) has been mainly linked to protease inhibitors. Raised blood fats increase the risk of heart disease. There are two kinds of blood fat: cholesterols and triglycerides. Cholesterol is often categorised as good or bad. High density cholesterol (HDL) is good and low density cholesterol (LDL) is generally bad. The relationship of HDL to total cholesterol (TC) called the HDL:TC ration is often used as a more important clinical test for monitoring. Changes to blood sugars High blood sugar levels are directly related to some protease inhibitors and possibly indirectly related to nukes through their effect on fat distribution. High blood sugar is related to many long-term health problems, including type 2 diabetes (low sensitivity to insulin). Changes to blood sugar levels and low insulin sensitivity are closely related to other symptoms of lipodystrophy. This complication of HIV therapy often gets little recognition. Differences in men and women Women are more likely to report symptoms of fat gain than fat loss according to several studies. Other studies tell us that for people who start off thin, fat loss appears worse, and people who start off larger are more likely to report accumulation. Further reading For information about lipodystrophy and metabolic complications from the i-base guide to side effects and other complications see these links: Information about fat loss (lipoatrophy) Information about fat accumulation Information about cholesterol and triglycerides Information about blood sugar and T2 diabetes diabetes S:60 January 2016

9 Section : Side effects of ARVs.8 Mood changes, strange dreams, anxiety: efavirenz Efavirenz (Sustiva, Stocrin) has side effects that are different to other HIV drugs. This is because it can affect your mood and feelings. Efavirenz is one of the drugs in Atripla. Efavirenz can make you feel disorientated or anxious. This includes vivid or disturbing dreams. This is a side effect of this drug. Most people get some side effects when they first start to take efavirenz, so mild symptoms are normal. These usually reduce after the first few weeks and become easier to manage. Some people get very serious problems including severe depression and anxiety. In this case, contact the doctor in case it is important to switch to another drug. Efavirenz can make existing worries or depression more serious. You need to be aware of this if you start a combination that includes this drug. Further reading For information about efavirenz side effects from the i-base guide to side effects and other complications see these links: Anaemia: AZT and lactic acidosis Anaemia Anaemia is a shortage of oxygen-carrying red blood cells. The main symptom is extreme tiredness. AZT can cause anaemia by its effect on bone marrow. AZT is no longer recommended as a preferred drug for people starting treatment. It is still recommended in WHO guidelines for second-line treatment. Lower doses of AZT may be just as effective against HIV, but this is not possible when using the current fixed dose combinations. If you are using AZT and become extremely tired or weak, you need to see your doctor who should perform a blood test or change this treatment. Lactic acidosis Lactic acidosis is a term for a dangerous build up of lactate in the blood. Lactate is a waste product produced when sugar is turned into energy by the body. The symptoms include feeling sick and/or very tired and muscle weakness. If you have these symptoms, it is essential to contact your doctor. The risk of lactic acidosis with modern drugs is very low close to zero. It was nearly always linked to the use of older HIV drugs called dt and ddi. Neither of these drugs are recommended in WHO treatment guidelines. Further reading For information about lactic acidosis from the i-base guide to side effects and other complications see: S:61 January 2016

10 Section : Side effects of ARVs.10 Other side effects This manual concentrates on side effects that have historically caused problems. This is because they are often the side effects that people worry about before starting HIV treatment (ART). Luckily, wherever in the world you live, modern ART has a low risk of side effects. Many of the side effects were linked to the use of dt, which is now largely replaced by tenofovir DF in most countries. The following side effects are related to currently used drugs: Fatigue feeling tired: most ARVs but generally mild. Hypersensitivity reactions: abacavir (also Trizivir, Epzicom, Kivexa). Kidney toxicity including kidney stones: tenofovir, Truvada, atazanavir. Increased bilirubin and jaundice: atazanavir. Increased cholesterol and triglycerides: some NNRTIs, most protease inhibitors. Increased blood sugar and risk of type 2 diabetes: protease inhibitors. If ARVs make you feel unwell even if it s not serious you should tell your doctor. Finding information on drugs and side effects The internet provides information about the drugs and side effects. Sites with good information (in English) on drugs and side effects include: The i-base Guide to HIV and Quality of Life includes an online review of these and other side effects. i-base also has online information on each drug with links to the full prescribing information. An excellent and inpressive set of basic factsheets on every drug are online in English and Spanish at AIDS infonet Test Positive Aware Network (TPAN) is a US community organisation that includes an online review of each HIV drug. How to report side effects It is not good for anyone if side effects are allowed to continue. Often this is because the doctor doesn t understand the problem. If you want your doctor to help, you need to clearly describe your side effects and how they affect you. Your doctor will need to check for all causes. For example, diarrhoea might be caused by food poisoning. Or a low sex drive might be related to low testosterone levels. S:62 January 2016

11 Section : Side effects of ARVs Recording side effects The best way to record side effects is to keep a side effects diary. Be as detailed as you can. Try to do this for several weeks and take the diary when you next see your doctor. Include information about the following: How often? frequency: How often do you get symptoms? Once or twice a week? Once every day, or 5 10 times a day etc? Do they occur at night as well as during the day? How long? duration: How long do the symptoms last? If you feel sick or get headaches, do they last for 20 minutes or for 3 hours, or for different times? Is there a pattern to when they occur? Is this when you take your medications or at a regular time afterwards? How bad? severity: How bad are the symptoms? Often it helps to rate them on a scale (from 1 for very minor to 10 for very severe). A scale is a useful tool for describing anything that involves pain. Recording how severe side effects are when they occur is better than recording them later. Have you noticed anything that helps to reduce or stop them? All this information can really help your doctor understand how difficult the side effects are..12 How side effects are graded Each side effect is reported slightly differently. But all side effects are graded from 1 to. Grade 1 is very mild. Grade is very serious life threatening or requiring hospital. Side effect grades GRADE 1 (Mild): Transient (goes away after a short time) or mild discomfort. No limitation in activity. No medical intervention required. GRADE 2 (Moderate): Your daily activity is affected mild to moderately. You need some assistance. No or only minimal medical intervention is needed. GRADE 3 (Severe): Your daily activity is markedly reduced. Some assistance is usually needed. Medical intervention is needed. Hospitalisation or hospice care possible. GRADE (Potentially life threatening): Extreme limitation to daily activity. Significant assistance required. Significant medical intervention, hospital or hospice care very likely. S:63 January 2016

12 Section : Side effects of ARVs Side effect Grade 1 Grade 2 Grade 3 Grade Diarrhoea 3 loose 5 7 loose stools Bloody diarrhoea or Hospitalisation stools a day or a day or diarrhoea over 7 loose stools required mild diarrhoea lasting more than a day or needing IV (possible also lasting less than one week treatment or feeling for grade 3) one week dizzy when standing Fatigue Normal activity Normal activity Normal activity Unable to care reduced by reduced by 25 50% for yourself by less than 25% Cannot work Liver toxicity AST or ALT AST or ALT AST or ALT AST or ALT levels to 5.0 ULN 5.0+ to 7.5 ULN 7.5+ ULN Upper Limit Normal (ULN) Mood Mild anxiety, Moderate anxiety/ Severe mood changes Acute psychosis able to disturbance requiring medical suicidal continue daily interferring with treatment. thoughts tasks ability to work, etc Unable to work Nausea Mild or transient Moderate discomfort Severe discomfort or Hospitalisation reasonable food or intake decreased intake decreased for required intake for less than 3 days minimal food intake for more than 3 days Rash Redness or itchy Rash that breaks skin, Blistering, open ulcers, Severe rash, skin on part or hard or soft pimples wet peeling, serious Stevens whole body light peeling/scaling rash over large areas Johnson syndrome. Severe broken skin, etc Vomiting 2 3 episodes a 5 episodes a day Severe vomiting of all Hospitalisation day or mild or mild vomiting for food and fluids over for IV treatment vomiting for more than one week 2 hours or needing (possibly also less than one IV treatment or feeling for Grade 3) week dizzy when standing Discussion Most information about the risk of side effects comes from the original studies when the drugs were first being developed. This is why it is very important to report to your doctor all side effects if you take part in any trials. These studies collect information about frequency and severity of all side effects. However, studies for new HIV drugs generally only use small groups of people for relatively short periods of time. Some side effects only become apparent after the drugs have been approved. This is because it might need thousands more people to report over a longer period of time. S:6 January 2016

13 Section : Side effects of ARVs Find out the risk of side effects are for any particular drug. What percentage of people get the side effects? This can help make informed decisions about which drugs to choose. Knowing what percentage of people needed to change therapy because of a side effect is useful too. Accurate information on how many people get side effects may be provided by your doctor, or from a community treatment organisation. It is usually also included in the information that you should get with all HIV drugs. Side effects record sheet: Take this diary with you when you see your doctor at your next appointment..9 Side Effects Diary Use this page to record any changes in your health that could be related to side effects as this will help you describe them to your doctor. Some of the most common side effects are listed below but include others even if they are not listed here. 1 Tingling or pain in hands/feet 2 Pain in hands/feet 3 Nausea/vomiting Headache 5 Feeling tired 6 Dry skin 7 Rash 8 Diarrhoea 9 Stomach pains 10 Hair loss 11 Body shape changes 12 Weight gain 13 Weight loss 1 Changes in taste or appetite 15 Injection reactions (T-20) 16 Disturbed sleep / vivid dreams 17 Sexual problems 18 Feeling anxious/nervous 19 Visual changes 20 Other(s) specify Side effect symptom Day Time(s) Scale: 1= very mild 5 = very bad Other comments and questions to ask your doctor: S:65 January 2016

14 Section : Side effects of ARVs.10 Glossary: Section anaemia ALT AST low or reduced red blood cells - this reduces the amount of oxygen distributed to the body alanine transaminase - a liver enzyme which, if raised, can be an indication of liver disease or liver toxicity aspartate transaminase - a liver enzyme which, if raised, can be an indication of liver disease or liver toxicity CNS Central Nervous System. Consists of the brain and the spinal cord - the parts of the body that process and conduct sensory information DEXA scan liver toxicity side effects SPC Stevens Johnson syndrome (SJS) toxicity ULN Dual Energy X-ray Absorptiometry, is a type of X-ray that can measures the proportion of fat, muscle and bone in a body and can also measure bone mineral density side effects that damage the liver or reduce liver function secondary effect of a drug other than the reason it is prescibed. Side effects are usually related to negative effects. Some side effects can be positive and lead to new uses for that drug Summary of Product Characteristics - the leaflet included in the packaging with your drugs Severe life-threatening skin reaction harmful effects of a substance Upper Limit of Normal S:66 January 2016

15 Section : Side effects of ARVs S:67 January 2016