Section 3: Introduction to ARVs

Transcription

1 Section : Introduction to ARVs Section : Introduction to ARVs.1 Introduction Section is about antiretroviral drugs (ARVs). It includes information about the medical approach to treatment as well as how to approach this if you are HIV positive. ART is more complicated than many other medical treatments. Everyone starting ART needs to understand the differences to have the best chance of long-term benefit..2 Aims for this section After completing section advocates will have a basic understanding of: How antiretroviral drugs work Treatment guidelines Using three or more drugs The importance of getting undetectable viral load The main drugs that are used Treatment choice and side effects Adherence and drug levels. This includes practical aspects (late doses, missed doses, being sick, tips etc) Resistance and treatment failure S: January 2016

2 Section : Introduction to ARVs. What is ART? Antiretroviral therapy (ART) is the term for treatment that uses three or more ARVs to treat HIV. ARV stands for antiretroviral. This is because HIV is a retrovirus. ART is also called: Combination therapy. ARV therapy. Triple therapy. cart (combination antiretroviral therapy). HAART (highly active antiretroviral therapy). In many ways HIV is difficult to treat. This is because the virus reproduces very quickly and in large quantities. If treatment is not strong enough or if doses of medication are missed, then drug resistance can easily develop. Combination treatment works because there are three (or more) different drugs actively fighting the virus. If some of your virus is resistant to one drug, the other drugs might still suppress it. If you miss doses or are late taking HIV drugs, then they may not work at all, or will only work for a few months. These are studies using a class of drugs called protease inhibitors (PIs). Some people use one protease inhibitor boosted by ritonavir (another PI) as combination therapy. Only some PIs can be used in this way. For some people this is almost as good as triple therapy combinations, but it is not quite as good. For this reason, boosted PI monotherapy is not recommended in most guidelines. In October 2015, very early results were reported from several studies using dolutegravir as single therapy, or as dual therapy with another ARV like lamivudine (TC). The link: i-base.info/htb/29154 These studies produced very surprising results. They showed that viral load stayed undetectable for up to 6 months. An important note is that these results were only in people who had never used integrase inhibitors (like dolutegravir). Further research in large studies is needed to understand why dolutegravir appears to be different to all other drugs. This has exciting implications for future treatment..4 Do the drugs really work? Yes. In every country that uses ART, the number of AIDS-related deaths and illnesses drop dramatically. Treatment works for women, men and children. It works no matter how you were infected with HIV whether this was sexually, through IV drug use, at birth or by blood transfusion. Taking HIV drugs, exactly as prescribed, will reduce the virus in your body to tiny amounts. This then lets your immune system recover and get stronger by itself. Now that HIV, treatment is so effective, it is especially important to know whether you are HIV positive. Many individual ARVs are also available in combination pills. Generic HIV drugs work just as well as brand-name drugs. S:4 January 2016

3 Section : Introduction to ARVs.5 How HIV drugs work main types of drugs Like every living thing, HIV can reproduce itself in order to survive. HIV does this inside CD4 cells and this involves many different stages. HIV drugs work by interfering with some of these stages. There are currently six classes of drugs: Entry inhibitors. This includes fusion inhibitors and CCR5 inhibitors Nucleoside and nucleotide reverse transcriptase inhibitors (nukes or NRTIs) Non-nucleoside reverse transcriptase inhibitors (non-nukes or NNRTIs) Integrase inhibitors (INIs) Protease inhibitors (PIs) Budding and maturation inhibitors (research stage only) Different drugs work at different stages of the HIV life cycle HIV uses CD4 cells as factories to make hundreds of copies of itself. Fig 1: HIV drugs work in different ways HIV virus work by stopping HIV entry inhibitors getting into the CD4 cell CD4 cell nukes & non-nukes both (NNRTIs) work by stopping one of the main ways that HIV reproduces inside the CD4 cell protease work by stopping inhibito any new HIV virus from leaving the CD4 cell HIV uses CD4 cells as factories to make hundreds of copies of itself. Different drugs work at different stages of the HIV life cycle. Entry inhibitors work by stopping HIV getting into the CD4 cell. Nukes and non-nukes work by stopping one of the main ways HIV reproduces inside the CD4 cell. Integrase inhibitors work by stopping HIV from being integrated into the CD4 cell s DNA (genetic material). Protease inhibitors work by stopping any new HIV from being cut into smaller, manageable proteins. Budding and maturation inhibitors will work by stopping new HIV from being able to infect other CD4 cells. None are currently approved. Further reading The 2015 i-base/tag pipeline report includes a chapter on antiretrovirals. This is a review of new drugs, combinations and drug classes in development. S:5 January 2016

4 Section : Introduction to ARVs.6 Treatment guidelines Most countries have guidelines about HIV treatment (ART). They main guidelines are for adult treatment. There are usually separate documents for treating children, treatment during pregnancy, for TB or hepatitis coinfection, for adherence, and for treating opportunistic infections. Guidelines generally use technical medical language and are written for doctors. They present consensus opinions of the most recent evidence. This includes, for example, on when to start ART, which drugs to use and how to manage side effects. There is sometimes a patient or community version in non-medical language. Guidelines need to be revised regularly to make them stay up-to-date. Always check the date of a guideline that you are using. Always check to see whether a more recent update is available. Guidelines on the Internet WHO guidelines Over 50 guidelines on all aspects of HIV diagnosis, monitoring, treatment and care. The 2015/16 guidelines cover both adult and children s care, for HIV treatment and prevention. US guidelines aidsinfo.nih.gov/guidelines Separate public US guidelines for adults, children, pregnancy, OIs, testing and prevention. Updated at least every year. UK guidelines Over 14 current guidelines on all aspects of HIV care. This includes treatment, pregnancy, coinfection with hepatitis and TB, malignancies, immunisations and organ transplants. UK guidelines for children European guidelines European guidelines on HIV treatment, non-infections co-morbidities and coinfection with hepatitis B/C. Selected international guidelines hivinsite.ucsf.edu/insite?page=cr S:6 January 2016

5 Section : Introduction to ARVs.7 When to start HIV treatment (ART) Most countries recommend ART for all HIV positive people. This is at any CD4 count, even when the count is strong and above 500. This change occurred in 2015 when several important studies (including START) showed the benefits of early ART. It is also related to other studies showing that ART dramatically reduces the risk of HIV transmission. www. Before starting treatment someone has to be ready to do so. All treatment guidelines state that someone needs to be prepared to take treatment before they start. Anyone with any HIV-related symptoms usually has a greater urgency to start ART. Everyone with or without symptoms is recommended to start before their CD4 count falls to below 50 cells/mm. Being ready to start treatment involves understanding that: Treatment will help your health. The best adherence means taking every dose and this is linked to the best chance of treatment success. Adherence means following any food recommendations. Side effects will usually be mild and can be managed. These non-medical aspects are very important: Someone has to be committed to treatment before they start. If adherence is not good, resistance will develop and treatment will fail. See Section 1.1 Use of CD4 count to start treatment.8 Why three or more drugs are used Current HIV drugs are not powerful enough to fight HIV on their own. But using several drugs in combination ART is strong enough. Using ART to bring viral load to undetectable levels prevents HIV replicating and controls HIV infection. When the first HIV drugs were developed (roughly 1987 to 199), each drug was used as single drug treatment. From 1994 to 1996 combinations of two drugs were used. In both cases the benefits only only lasted a few months or perhaps a year or two at the most. This was because HIV developed drug resistance to the drugs. Since 1996, ART has used three or more drugs together to treat HIV. This suppressed the virus to very low levels and the risk of drug resistance was dramatically reduced. Using three or more antiretroviral drugs together is called ART. Some drugs combine several drugs into the same pill. Sometimes a whole combination is fitted into a once-daily pill. In January 2016, there are now six full combinations in a single pill that are recommended in UK and US guidelines. There are several combinations of two-drug combinations to be used with other drugs. S:7 January 2016

6 Section : Introduction to ARVs Generic HIV drugs are also available in numerous single pill formulations. Some drug combinations are only available in generic formulations. Although some studies reported good results using only a boosted protease inhibitor (PI/b), the results are not as good as with three-drug combinations. In October 2015, several small studies reported results from using single therapy with the integrase inhibitor dolutegravir, or using dolutegravir plus lamivudine (TC). Although these studies produced exciting results, further research is still needed. Reducing viral load to less than 50 copies/ml (undetectable) If you reduce your viral load to under 50 copies/ml (called undetectable ) you are unlikely to develop drug resistance. You can then use the same drugs for many years. This does mean that you still need to take all the drugs on time. An undetectable viral load also dramatically reduces the risk of HIV transmission. In January 2016, approximately 95% of people starting ART who take their meds get an undetectable viral load. Although people start treatment to improve their health, and to stay healthy, the main goal of treatment in most guidelines is to reduce viral load to undetectable levels (less than 50 copies/ml). Viral load should go down by at least 90% (1 log) after 1 month of treatment, and get to below 50 copies/ml within -6 months..10 Treatment choice In all countries, more than 20 drugs and formulations are approved. However, only a few main combinations are recommended in treatment guidelines. Guidelines for high income countries usually include more treatment options than the WHO guidelines. This advocacy resource is mainly based on WHO guidelines which are developed for lowand middle-income countries (LMICs). WHO guidelines are for population based care. This means they are developed to tackle HIV on a population level usually because of the high numbers of people that need treatment with limited resources. This is a slightly different approach to high-income guidelines that emphasise individualised care. S:8 January 2016

7 Section : Introduction to ARVs First-line therapy in WHO guidelines Most guidelines recommend that first-line treatment is a combination of two nukes (NRTIs) plus a non-nuke (NNRTI). The next update of the WHO guidelines (2016) on which drugs to use were expected to be published by the end of December The main recommendations are included in a summary document released in November The recommendation for first-line therapy with a strong recommedation for fixed dose combinations is: tenofovir DF + TC (or FTC) + efavirenz If this combination is not available or cannot be used, one of the following options is recommended: AZT + TC + efavirenz 600mg (or nevirapine) tenofovir DF + TC (or FTC) + dolutegravir tenofovir DF + TC (or FTC) + efavirenz 400mg tenofovir DF + TC (or FTC) + nevirapine Fixed dose combinations (FDCs) are where the drugs in these combinations are supplied in 1 pill. Generic manufacturers produce FDCs but they are only available in some countries. Second-line therapy in WHO guidelines Most guidelines recommend changing to three new drugs for second-line therapy. This usually means that people who started on an NNRTI- or integrase-based combination with two nukes will change to a PI-based combination (usually with two nukes). The WHO 2016 guidelines recommend a boosted protease inhibitor (PI/r) plus two nucleoside analogues (nukes) for second-line therapy. It recommended atazanavir/r and lopinaivr/r are the preferred boosted PI s for second-line. The following sequence of second-line NRTI options is recommended for second-line ART: After failure on a tenofovir DF + TC (or FTC)-based first-line regimen, use AZT + TC. After failure on an AZT or d4t + TC-based first-line regimen, use tenofovir DF + TC (or FTC). Use of NRTI backbones as a fixed-dose combination is preferred. Heat-stable fixed-dose combinations of ATV/r and LPV/r are the preferred boosted PI options. In US, UK, European and other Western guidelines there are a wider choice of drugs and drug classes to use in second-line therapy. S:9 January 2016

8 Section : Introduction to ARVs.11 Side effects Modern HIV treatment (ART) has a low risk of serious side effects. Treatment is now more tolerable and easy to take than it has ever been. Most people on ART lead a normal life when taking medications. If side effects occur, it is important to change to an alternative combination. You should only put up with mild side effects that are easy to manage. Everyone is worried about side effects before they start treatment. Most side effects are usually mild. They can often be reduced with other medication that is easy to use. There is a small risk of more serious side effects. These need to be taken very seriously and should be picked up by routine monitoring from your doctor. But many people put up with side effects when they could change to another treatment and this is not good. This is why it is important to report any new symptoms or changes in your health to your doctor. If you are unlucky and get side effects, contact your doctor about this. You have to make sure that your doctor understands exactly how the side effects affect you. More serious side effects can usually be avoided by changing to alternative drugs. Before starting treatment, learn about the side effects that can occur with the drugs you are going to use. Ask your doctor, nurse, or HIV pharmacist about how likely they are to occur. Ask how many people stop treatment because of them (usually very few). Even rough estimates will give you a good idea of what is involved. Ask other people taking the drugs for their experience. This way you will know what to look out for. See Section 4 Side effects of ARVs Further reading i-base produce a detailed guide to side effects and long-term complications of HIV and treatment. This is a separate resource to the advocacy manual, and have been translated into other languages. S:40 January 2016

9 Section : Introduction to ARVs.12 Can I change treatment? In most cases, changing to an alternative treatment might be possible. If initial side effects have not improved after the first few weeks or months, it is easy to change or modify your treatment. This is as long as there is an alternative drug or combination that you can use. If this is your first combination, you have more choice. You should not put up with difficult side effects for months on end. Further reading i-base produce a detailed guide to changing treatment. This is a separate resource to the advocacy manual, and have been translated into other languages. Can I take a break in my treatment? Once you start HIV treatment (ART) it is best not to stop or take a break unless your doctor recommends this. If you have difficult side effects it is better to change treatment than to stop treatment. To get the best from ART you need to try to take every dose on time. The longer you stay on treatment the longer the benefit should continue. If you get a very good response to treatment and start to feel better, it is still important to continue taking all your meds on time. Stopping treatment for any short period is not recommended. Your viral load levels of HIV in your blood is likely to increase again very quickly if you stop ART. Viral load can increase from undetectable to several thousand within a week. Each interruption of treatment also carries a risk of developing drug resistance. This also makes you more infectious to your sexual partners. If you want to take a treatment break, it is essential to talk to your doctor first Some combinations include drugs that have to be stopped together, and others where individual drugs need to be stopped at different times. Nevirapine, efavirenz, TC and FTC all stay in the blood longer than AZT or boosted protease inhibitors. They are also easy drugs to develop resistance to. S:41 January 2016

10 Section : Introduction to ARVs.14 Recreational drugs, alcohol, vitamins, supplements and complementary therapy Some HIV drugs interact with recreational drugs, street drugs, methadone and complementary or traditional herbal therapies. Even over-the-counter medicine like antacids and multivitamins interact with some HIV medicines. The interactions can be complicated. Sometimes the interactions will increase the amount of recreational drugs found in blood to dangerous levels. Some recreational drugs can reduce the levels of HIV drugs. This increases the risk for drug resistance. Over-the-counter antacids can interact with atazanavir. Multivitamins can interact with integrase inhibitors. It is therefore very important that your doctor and pharmacist know about any other drugs or supplements that you use. Even if you use them rarely. Your doctor should treat this information in confidence. Alcohol does not interact with HIV medications. But, more heavy alcohol use, as with recreational drug use, may reduce adherence. It would help if your healthcare workers know about this. Several studies have shown a link between the amount of alcohol someone drinks and the chance of getting and maintaing an undetectable viral load. Further reading 1. Interactions between ARVs and street drugs Medical review from 200 on the available data on interactions between different street and recreational drugs and antiretrovirals Alcohol and HIV questions. Link to questions on alcohol and HIV shows a range of recent questions to i-base. pd4&cof=forid%a10&ie=utf-8&hq=-inurl%ahttps&q=alcohol&submit=search. Liverpool University drug interaction website. This resource lets you enter your HIV meds and pick the other drugs that might interact. It will then make an individualised PDF print-out of the potential interactions. S:42 January 2016

11 Section : Introduction to ARVs.15 Adherence and why it is so important What is adherence? Adherence means taking your drugs exactly as prescribed. This includes taking them at the right time. It also includes following any special diet restrictions. This will make sure that the level of each drug doesn t drop below the minimum needed to fight HIV. Drug levels need to stay above this minimum 24 hours a day, 7 days a week, 65 day a year... Every time that the levels of a drug fall below the minimum level, there is a risk that HIV develops resistance to your drugs. Getting into a good routine will help. ART involves a daily schedule. You may need some support to get used to the changes it makes in your life. Adherence can be difficult. Good adherence is the most important thing you have to think about when you start a new combination. Start ART when you can give yourself the extra time and space you may need to adjust. During the first few weeks, nothing else should take priority over getting your treatment right. Some HIV clinics have an adherence clinic or a nurse who can help. Although taking medication on time is very important, there is usually a window period of about an hour that is still okay. Some drugs, and some people, have a wider window period than others. Because of this variation, it is still better to aim for the same time each day. Whether your meds need to be taken with or without food is very important. Ignoring these can be like only taking half a dose. You will not absorb enough of the drug for it to work. Drug resistance is then more likely. How much adherence is enough? Many people want to know how exact they need to be for perfect adherence. Unfortunately, the answer is almost 100%, at least when starting ART... but there is some flexibility. Early studies showed that even missing one or two doses a week can have a big impact on the chances of successful treatment. One widely quoted study showed that even with 95% adherence only 81% people achieved undetectable viral load. (Paterson and others). That is only one in every 20 doses that was missed or late. S:4 January 2016

12 Section : Introduction to ARVs Table 1: Adherence rates and % of people undtectable 1 Adherence rates % of people undetectable over 95% 81% 90-95% 64% 80-90% 50% 70-80% 25% under 70% 6% This study was in the early days of ART, and modern treatments might have more flexibility. Adherence also directly impacts HIV-related mortality. In another study of 950 people starting treatment for the first time, for every 10% decrease in adherence there was a 16% increase in HIV-related death. 2 On the other hand, a US study of people in prison who took every dose showed much better results. Because these patients were in prison, every dose was supervised. All had viral loads below 400 copies/ml after a year and 85% were below 50 copies/ml. This result was more impressive than nearly every clinical trial. Most of these people had already failed previous treatments and so were even less likely to get a good result. The point is not that you need to be in prison. It is that if you find a way to take all your drugs as prescribed, you will get good results. Be strict with yourself in assessing how adherent you are through a regular week. If it s not looking so good, you need more support. You will need to ask. Talk to your doctor! Are some combinations more flexible? Whatever your combination and whatever your previous treatment history, it is common sense that the best adherence will give you the best chance of long term health. This is especially true when starting ART until viral load becomes undetectable. Once viral load is undetectable and has been this low for a few months, then occasionally missing one dose is unlikely to cause any harm. Most combinations allow you an hour or two either way when drug levels should still be ok. If your combination includes three drugs that are cleared more slowly from the body, this window period may be wider still. The only current combination that has shown this benefit in studies is the combination of efavirenz/tenofovir/ftc. This combination is also available in a single formulation called Atripla. In one study (called the FOTO study) people who had already had an undetectable viral load took Atripla from Monday to Friday but not at weekends. In this study of about 50 people followed for a year, viral load did not rebound and resistance did not develop. 4 This finding is specific to these three drugs. The study is more to show that an occasional missed dose may be okay. Even with these results daily adherence is recommended. Further reading See Learning support module: What happens when you take a drug See Learning support module: Drug levels, drug activity and side effects. S:44 January 2016

13 Section : Introduction to ARVs References: 1. Paterson DL et al. Adherence to protease inhibitor therapy and outcomes in patients with HIV infection. Ann Intern Med (2000). 2. Hogg RS et al. Non-adherence to triple combination therapy is predictive of AIDS and death in HIV-positive men and women. 7th CROI, Abstract 7.. Fischl M et al. Impact of Directly Observed Therapy (DOT) on outcomes in clinical trials. 7th CROI, Abstract Cohen C et al. The FOTO study. 5th IAS: The 48 week extension to assess durability of the strategy of taking efavirenz, tenofovir and emtricitabine five days on, two days off (FOTO) each week in virologically suppressed patients. (Poster abstract MoPeB06.) Paper presented at the Fifth IAS Conference on HIV Pathogenesis, Treatment, and Prevention, July 2009, Cape Town. South Africa. Tips to help adherence Before choosing treatment, gat all the information on what you will need to do before you start treatment: How many tablets? How big are they? How often do you need to take them? How exact do you have to be with timing? Are there food or storage restrictions? Can they be taken with any other medicines you need? Are there easier choices? Use a daily chart to plan your timetable and use it to get used to the routine. For the first few weeks mark off each dose and the time that you took it. Make sure that you contact your hospital or clinic if you have difficulties with side effects. They can prescribe additional medication to help. They can also change the treatment. Use a weekly pill box to count out your meds. Then you can always check if you think you have missed a dose. This is easy for once-daily ART, but larger pill boxes are available if you need to take more than one dose each day. Use a pill beeper or alarm watch for all doses. Take extra drugs if you go away for a few days. Keep a small supply where you may need them in an emergency. This can be in a cool place in your car, at work or at a friend s house. Ask friends to help you remember difficult dose times. Ask them to remind you when you are out at night. Ask friends who are already on ART what they do. Ask them how well they are managing. Ask your treatment centres if you can talk to someone who is already taking the same treatment if you think this will help. Before you start, ask your doctor for a supply of medications to control nausea and diarrhoea. These side effects are the most common when starting therapy. Most combinations are twice-daily regimens. This means taking them every 24 hours. Some drugs need to be taken twice a day. This means taking them every 12 hours. Completely missing a once-daily dose may be more serious than forgetting a dose from a twice-daily combination. Adherence is especially important with once day combinations. S:45 January 2016

14 Section : Introduction to ARVs.17 What if I forget to take my pills? The following information is a guide in case you missed a dose of meds. If you realise you have missed a dose, take it as soon as you remember. BUT, if you only realise when you re going to take your next dose, do not take a double dose. Almost everyone will forget or be late with their drugs at some time. But there is a difference between occasionally missing a dose, and regularly forgetting on a daily or weekly basis. You need to aim to take all your doses at approximately the right time. You may be regularly taking your meds late or missing doses. If you are missing doses each week it may be better to talk to your doctor about using meds that have less risk of resistance or in extreme cases stopping treatment. This would only be to help support you to get a more organised schedule. Stopping treatment is not recommended otherwise. This would limit your risk of resistance. You can restart treatment later when you are able to cope better. There may be an easier combination that you can use. Some people hate lots of pills. Some hate fatty foods or having to eat breakfast. Some people will always have trouble with taking medicine at work during the day. All these things are important in deciding which combination will suit you best. You have to follow your regimen everyday. This includes both during the weekend, and in the different situations involved in life. Taking days off is a risky way of using treatment. There are always things that can help you to avoid missing doses, whatever your lifestyle..18 Drug resistance to ARVs What is drug resistance? Drug resistance occurs when HIV makes tiny changes in its structure. These changes are called mutations. This can mean that the drugs no longer work as well or even at all. You can also be infected with a strain of HIV that is already resistant to some or all HIV drugs. How does drug resistance occur? Mutations that lead to drug resistance are usually produced only when you continue taking a treatment with a detectable viral load. Resistance can develop even at low viral load levels between 50 and 500 copies/ml. If your viral load is still above 50 copies/ml after 2- months, you may need to change your treatment. S:46 January 2016

15 Section : Introduction to ARVs Your doctor should look closely at why the results are not as good as they could be. They will want to discuss how you are managing adherence and side effects. If possible, they should also test for resistance and maybe drug levels. Most guidelines recommend you have a viral load test four weeks after starting or changing treatment. This should then be checked regularly when on treatment. Get the results when they are ready (usually two weeks after your blood was taken). Don t just wait until your next doctor s appointment. What is cross-resistance? Some drugs are cross-resistant to others. This means that if you become resistant to one drug you will also be resistant to other similar drugs, even if you have never taken them before. This is particularly true of drugs in the same class. There are also varying degrees of cross-resistance. Sometimes you may still get some benefit from the second drug but the response is less likely to be as strong or last as long. What are resistance tests Resistance tests can show if you have mutations that cause resistance. These tests are not available in every country. If resistance tests are recommended in your country and you are not given one, ask your doctor about this. In the UK resistance tests are recommended: When you are first diagnosed. Before starting treatment. When your viral load does not get below 50 copies/ml. When your viral load rebounds to higher than 200 copies/ml. Before changing treatment for drug failure. What if I can t get a resistance test? Some drugs are very vulnerable to resistance nevirapine, efavirenz, TC,FTC, raltegravir and elvitegravir. If resistance test are not available in your country, you can sometimes estimate whether you have resistance depending on your viral load and treatment history. If you have a detectable viral load on a combination that includes one of these drugs, or your viral load rebounds to levels above 2000 copies/ml, you would assume that you have developed resistance to one or more of these drugs in your combination. How do I avoid resistance? The best chance you have of stopping resistance involves reaching and maintaining an undetectable viral load. If possible this should be using a test that measures down to 50 copies/ml. Avoiding resistance is one of the most important conditions for using combination therapy. You need to use a combination that is potent enough to minimise the risk of getting resistance to any of the drugs you take. S:47 January 2016

16 Section : Introduction to ARVs You need to be careful to take your meds and not miss doses. Graph and refs to go in here..19 Treatment failure Treatment failure is defined in different ways. Sometimes this relates to the different treatments and monitoring tests that are available in a country. Virological failure If viral load never reaches undetectable, or rebounds and becomes detectable, this is called virological failure. This is when the drugs are not working to suppress the virus. With virological failure, you will not necessarily feel more ill in the short term. Clinical failure This is when you get symptoms (ie other illnesses). It means that the drugs are not stopping you from getting ill. This is called clinical failure. How to manage treatment failure depends on the choice of alternative drugs that are available in any country. Managing treatment failure Before making any decisions about changing treatment it is important to find out why treatment failed. It may be that you have not been taking treatment on time, or in the way prescribed. Or that you have stopped taking treatment altogether. It may be because of resistance. Or because the treatment was not potent enough. Or because the drugs were being poorly absorbed. Management of treatment failure is different depending on which country you live in. This is related to whether viral load tests are easily available. Virological failure is used to decide when to change ART in high-income countries. This is when there is access to viral load tests and/or there are several options for a new combination. Clinical failure is used to describe when to change treatment in many low- and middle-income countires (LMICs). This is when viral load tests are not available and/ or there are limited options for a new combination. When there are new treatment options, then changing all three drugs to a new combination is recommended. Blips do not count as treatment failure. S:48 January 2016

17 Virological failure ususally occurs first. It can sometimes take months for this to lead to clinical failure. Management of treatment failure is a specialised area, and approaches changes based on new research. Further reading i-base produce a detailed guide to changing treatment. This is a separate resource to the advocacy manual and is based on virological failure. It has been translated into other languages..20 Glossary: Section adherence DNA EI HAART the term to describe taking medication exactly as it is prescribed - both at the right time and following any special diet recommendations genetic material inside every living cell that contains the information and code for how that cell grows, functions and reproduces entry inhibitor - family of drugs that target HIV before it enters a cell Highly Active Anti-Retroviral Therapy - a term for HIV combination therapy using at least three drugs lactic acidosis life threatening side-effect, mainly associated with d4t when it is used in combination with ddi (didanosine) lipoatrophy side effect that reduces subcutaneous fat on the arms, legs or face lipodystrophy name for a set of side effects relating to the way your body processes fats and sugars. Symptoms include lipoatrophy, fat accumulation and increased blood cholesterol and triglycerides NRTI NNRTI PI peripheral neuropathy Nucleoside Reverse Transcriptase Inhibitor - family of anti-hiv drugs that work when HIV is in the cell, but before it is integrated into the cells DNA Non-Nucleoside Reverse Transcriptase Inhibitor - family of anti-hiv drugs, similar to NRTIs, that work when HIV is in the cell, but before it is integrated into the cells DNA Protease inhibitor - family of anti-hiv drugs that stop new viral material being cut into smaller sections. This prevents new assembled HIV from leaving the cell. this is a term for damage to the nerves in your hands and/or feet. Symptoms start gradually in your fingers and toes as tingling or numbness, or increased sensitivity. If allowed to continue it can become very painful and debilitating.it can be caused by HIV, and is also a common side effect of some ARVs. S:49 January 2016

18 .21 Questions: Section 1. What does ARV stand for? 2. How many drugs are usually used in ARV combination therapy?. Name four families of drugs 4. Which drug family is active before HIV enters a CD4 cell? 5. How many drugs are approved in the US to treat HIV? 6. How many combinations are recommended as first-line treatment by the WHO? 7. Name the individual drugs used in the WHO combinations 8. Give at least three reasons to delay starting treatment 9. What can affect the levels of ARVs in the blood? 10. What is adherence? 11. Give six examples of things that could help with adherence. 12. What is drug resistance? 1. What is clinical failure? 14. What is virological failure? 15. How low does viral load need to go to prevent resistance developing? 16. Write 500 words about adherence? S:50 January 2016

19 .22 Course evaluation for Section Please take a few minutes to complete this evaluation. Any comments are appreciated, including on the usefulness of the evaluation. Section : How much of the information was new? None All How useful was the source material? Very Not How much support time did you need in questions? Were you given enough support for this section? Did you find better internet sites for information, if so, which ones? Did the questions relate to the information you found yourself? What was your pass rate? Sit the test again in one week to see how much you remember. Did your pass rate improve? S:51 January 2016

20 S:52 January 2016