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This page is intended as a basic introduction to the use of antiretroviral drugs for the treatment of HIV/AIDS in adults and adolescents in resource poor and/or highly affected communities. For more detailed information, and for information regarding treatment for specific groups such as pregnant women, children, and people with TB, other documents should also be consulted, and in particular the WHO document "Scaling Up of Antiretroviral Therapy In Resource Limited Settings".I Also, this page should not be used as a guide to treatment for an individual, when a physician or similar health care professional should be consulted. What is HIV antiretroviral drug treatment?It is the main type of treatment for HIV or AIDS. It is not a cure, but it can stop people from becoming ill for many years. The treatment consists of drugs that have to be taken every day for the rest of someone's life. HIV is a virus and when it is in a cell in the body it produces new copies of itself. With these new copies, HIV can go and infect other previously healthy cells. So HIV can quickly spread through the billions of cells in the body, if it is not stopped from reproducing or producing new copies of itself. Antiretroviral treatment (ART) for HIV infection consists of drugs which work by slowing down the reproduction of HIV in the body. The drugs are often referred as:
Do you take more than one drug at the time?You need to take at least two and preferably three drugs at the same time. The reason for this is that if you only take one drug, it will just be a short time before the drug will stop working. This is referred to as becoming "resistant" to the drug. If you take several drugs together, and if the drugs are from more than one group, then it generally takes longer before you become resistant. How do you decide which drugs to take?The decision about which drugs to take, and indeed which drugs should be made available in a particular country or area, depends on a number of different factors. These include the availability and price of drugs, the numbers of pills, the side-effects of the drugs, the laboratory monitoring requirements and whether there are co-blister packs or fixed dose combinations available. What are co-blister packs & fixed dose combinations (FDC)?A co-blister pack is when two or more pills, capsules or tablets are packaged together in one unit of use of a plastic or aluminium blister pack. In contrast, a fixed dose combination (FDC) is when two or more drugs are combined together in one pill, capsule or tablet. FDCs reduce the number of pills or tablets to be taken. Also the person taking the pills cannot leave out one of their drugs by not taking some of the pills. This improves the ability of people to take the drugs correctly (known as adherence) and it limits the emergence of resistance. Co-blister packs help people to take the pills at the correct time by packaging them together, but the drugs can still be separated, and co-blister packs do not reduce the number of pills or tablets to be taken. Using standard regimesThe World Health Organisation (WHO) recommends that if HIV/AIDS antiretroviral (ARV) drug treatment is to be made available to a large number of people in a resource poor, or developing country, then it is advisable that the provision of treatment is standardised. WHO recommends that a particular combination of drugs is chosen to be provided for everyone to take when they start treatment. This is sometimes called the "first line regimen". For those people who need to later change from this first choice of drugs, there should have been a second choice of drugs selected which is known as the "second line regimen". WHO recommends that if someone needs to change from the second line regimen, they should then be referred to a specialist physician for individualised care. What drug combinations are recommended by WHO for a first line regimen?There is a need in any combination to have drugs from more than one group. And in general the drugs from the protease inhibitor (PI) group are the least suitable for a number of reasons including cost, the number of pills which need to be taken, and the particular side effects that occur with the protease drugs. So WHO recommends that generally a first line regime should consist of two drugs from the nucleoside (NRTI) group and one from the non nucleoside (NNRTI) group. More specifically they recommend just four possible combinations which are listed below. WHO Recommendations for a First Line Regimen in Adults and Adolescents
d4T (NRTI) alternative name Stavudine 3TC is recommended for inclusion in all instances, because it is a potent drug, and WHO considers that it has an excellent record of efficacy, safety and tolerability. It can be taken either once or twice daily, and it has been incorporated into a number of fixed dose combinations. With regard to making a choice between d4T and ZDV, d4T is initially better tolerated than ZDV but among the NRTIs, it has been most consistently associated with certain metabolic abnormalities, and it can also cause peripheral neuropathy and pancreatitis. ZDV can also cause metabolic abnormalities, but it would seem to a lesser extent. However, ZDV can cause severe anaemia and neutropenia, and this requires that haemoglobin is monitored both prior to and during treatment with ZDV. WHO recommends that in any country a choice is made between d4T and ZDV at country level, based on local considerations, but it advises that both drugs are made available. So it is likely that in any country five different drugs will need to be available to allow switching between NVP and EFZ and between AZT and d4T. With regard to a choice between NVP and EFZ, there are a number of different issues that need to be considered which particularly include the side effects of the different drugs, and the complication of people with HIV having other infections such as TB. NVP has a higher incidence of rash and a greater risk of hepatotoxicity (damage to the liver) both of which can be life threatening. This makes the drug less suitable for treating patients who may be on other hepatotoxic medications, or that can cause rash, such as rifampicin (used for TB treatment). But EFV also has some major toxicities which are central nervous system (CNS) related, teratogenicity and rash. The CNS symptoms will often abate after ten to fourteen days. Also, what should be considered is that NVP is available as three drug FDC, whereas EFZ is not. How available are FDCs?The antiretroviral drugs used in more developed countries, are manufactured by a number of different companies. There have been difficulties with these companies working sufficiently together to produce, in one tablet or pill, drugs made by different companies. In addition, some of these drugs, the protease inhibitors in particular, cannot easily be combined with other drugs, as the dose needed can vary from person to person, and is generally too large to go in one capsule. Similarly, there are chemical reasons why ddI (an NRTI) in particular, cannot easily be combined with other drugs. So apart from one drug combination produced by GlaxoSmithKline (a combination of AZT, 3TC & abacavir known as Trizivir) and which is not suitable for widespread use, all the FDCs are only available as generics from generic manufacturers. What are generic drugs? Are they safe?A generic drug is a non-branded copy of a branded drug, and is supposed to be an identical, or ‘bio-equivalent’ copy. It is allowed to be produced and marketed after the brand name drug's patent has expired, or in circumstances where the drug patent does not apply, or has been waived by the patent-holder. If the generic drug is a bio-equivalent copy, then it is as safe as the branded drug. What generic FDCs are available?Drug combinations such as AZT+3TC+NVP, and d4T+3TC+NVP are available from a number of different manufacturers which include Cipla, Imunus Aurobindo, Ranbaxy Laboratories and Hetero Genix Pharma. The number of different manufacturers is increasing rapidly, and there are also rapid changes taking place in the price of these drugs. AVERT.org has more about generic drugs and the issues surrounding their use. When do you start treatment?WHO recommends that before anyone starts treatment in a resource-limited setting, a basic clinical assessment should be carried out. This should include: documentation of past medical history, identification of current and past HIV-related illnesses, identification of other medical conditions that might influence the timing and choice of ART, and current symptoms and physical signs of other medical conditions such as TB or pregnancy. Once this assessment has been carried out, it will be known which stage of HIV disease the person has. WHO has a method of describing people with HIV as being at different stages of HIV infection, according to the different clinical symptoms they may have. This is known as the WHO staging system for HIV infection and disease, and further details are given at the end of this page. WHO accepts that their HIV staging system is several years old, and has consequent limitations as a result of which adaptations may be necessary. However, they still consider it to be a useful tool in deciding when therapy should be started in resource limited settings. WHO recommends that all people who have WHO stage IV disease, should start treatment. But making a decision about whether other people should start depends on what laboratory tests are available and in particular whether the person's CD4 cell count is known. What is a CD4 cell count?A CD4 test measures the number of CD4 or T-helper cells in a person's blood. The more CD4 cells there are per millimetre, the stronger is the immune system. The stronger the immune system, the better the body can fight illnesses. So when should people start if they have a CD4 test result?A person who has WHO Stage IV disease they should start whatever the result of their CD4 test. And they should also start if they have stage I or stage II disease and a CD4 count of less than 200. If the person has stage III disease, then whether they should start depends on their clinical symptoms, and it should also be taken into account whether they have a CD4 cell count of less than or equal to 350. Starting Treatment Summary
If a CD4 test result is not available, when should people start treatment?As has been previously stated, if a person has WHO Stage IV disease, then WHO recommends that they start treatment. They should also start if they have Stage III disease. If no CD4 test is available, then the person should not start therapy if they have Stage I disease. If the person has Stage II disease, then the total lymphocyte (a type of white blood cell) count (TLC) for the person is needed to help assess whether the person should start treatment. If the person has Stage II disease and a TLC of less than or equal to 1200, then WHO recommends that they start treatment. Starting Treatment Summary
Clinical Assessments After Starting TreatmentOnce therapy has begun, there should be additional clinical assessments which should include:
Laboratory MonitoringIn addition to clinical assessments at baseline (pre-ART) and whilst on treatment, some laboratory monitoring is also desirable at these two different stages, although the specific requirements depend on the regime as shown below.
Changing antiretroviral therapyThere are two main reasons why ARV treatment needs to be changed. Side EffectsFirstly the drug combinations often cause side-effects. A side-effect is when a drug affects the body in ways other than those that are intended. Some people only experience mild side-effects and find them easily manageable. But for some people the side-effects are so severe that they have to consider alternative drugs. If it is possible to identify the drug that is causing the side-effects then it may be possible to replace it with another drug that does not have the same side-effects. (For example, replacing ZDV with d4T if the side effect is anaemia, or replacing EFZ with NVP if the side effect is central nervous system effects). Given the limited number of ARV combination options in resource limited settings, it is important to try to use drug substitutions where possible so that early switching to a completely new regimen is minimised. Treatment FailureThe second reason for changing treatment is treatment failure. This is when the drugs have failed to work and are not slowing down the reproduction of the virus in the body. What is the definition of treatment failure?The WHO definition of treatment failure again depends on whether a CD4 test is available. If a CD4 test is available, then treatment failure has occurred if the CD4 count has returned to the level that is was before treatment was started, or if there has been a fall of more than 50% of the count whilst the person has been on therapy, unless there has been some other infection to explain this decrease. If a CD4 test is not available, then treatment failure is defined firstly as the occurrence of new opportunistic infections, or a new malignancy, signifying clinically the progression of disease. This must however be differentiated from the immune reconstitution syndrome which can occur in the first three months following the initiation of ART. Treatment failure can also be indicated by the onset or recurrence of WHO Stage III conditions. Changing to a second line therapyIf treatment failure has occurred then WHO recommends that the entire drug combination is changed from a first to a second line regime. The new second line regime will ideally include at least three new drugs, with one from at least one new class, in order to increase the likelihood of treatment success and minimize the risk of cross resistance. Sometimes a version of HIV is resistant to more than one drug. When this happens, the drugs are called "cross-resistant". Cross-resistance is important when medications are changed and drugs need to be chosen that are not cross resistant to drugs that have already been taken. For example, cross resistance exists between d4T and ZDV, so if treatment failure has occurred when taking d4T, then the second line regime should not include ZDV. So what are suitable second line regimes?If the first line regime is one of the four first line regimes recommended by WHO, then WHO recommends that a second line regime could be as shown below:
TDF, alternative name Tenofovir, is in a fourth group called nucleotide analogues, but it has limited availability and relatively high cost. ABC (NRTI) alternative name Abacavir LPV/r is LPV enhanced by Ritonavir (PI) and SQV/r is Saquinavir enhanced by Ritonavir There are a number of issues regarding all of these choices. For example, there is an issue of drug hypersensitivity with ABC, and both LPV/r and SQV/r require a cold chain. (A cold chain means that the drugs have to be kept at a reduced temperature throughout distribution, storage and use.) The difficulty in choosing suitable second line regimes in resource poor settings, emphasises the need for great attention to be paid to adherence in order to reduce the likelihood of resistance occurring, and to ensure the long term success of ARV therapy. What is meant by adherence?The term adherence means taking the drugs exactly as prescribed. It also means taking the drugs on time and following any dietary restrictions. What makes adherence work?There are a number of different aspects with regard to making adherence successful. Firstly, there is a need for education, which is needed before the patient starts taking the medication. The person needs to know basic information about HIV and its manifestations, the benefits and side effects of ARV medications, how the medications should be taken (and this needs to ensure that taking the ARVs is fitted into the person's lifestyle) and the importance of not missing any doses. There is also a need for ongoing support to ensure that adherence is maintained. This should involve adherence assessments at every health center visit, reinforcement of adherence principles to the patient by treatment supporters and the continuous involvement of relatives, friends and/or community support personnel. Other things that can be done to help with adherence include minimizing the number of pills that need to be taken and also the frequency of dosing, avoiding dietary restrictions, and providing the medication free of charge for those who cannot afford treatment. There can be additional issues and difficulties with ensuring that adherence can be maintained at a high level in certain groups of people, such as pregnant women. WHO disease staging system for HIV Infection and Disease in Adults and AdolescentsIn resource-poor countries and communities, sometimes medical facilities and testing is unavailable, and it isn’t possible to decide the appropriate time to begin treatment on the basis of test results. The World Health Organization has developed a disease staging system for HIV infection which is not dependent on testing. Clinical Stage I:1. Asymptomatic Performance scale 1: asymptomatic, normal activity Clinical Stage II:3. Weight loss, 10% of body weight And/or performance scale 2: symptomatic, normal activity Clinical Stage III:7. Weight loss, > 10% of body weight And/or performance scale 3: bedridden 50% of the day during last month Clinical Stage IV:14. HIV wasting syndromei And/or performance scale 4: bedridden > 50% of the day during last month Footnotes:
This page was written and edited by Annabel Kanabus. Main source:
For more information see our web pages HIV/AIDS treatment and care in resource poor communities and HIV/AIDS related opportunistic infections, prevention, treatment and care in resource poor communities. Last updated January 19, 2005 |