Adult HIV: Antiretroviral drugs
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Adult HIV: Antiretroviral drugs

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Adult HIV was developed by doctors and nurses with wide experience in the care of adults with HIV, under the auspices of the Desmond Tutu HIV Foundation at the University of Cape Town. It covers: ...

Adult HIV was developed by doctors and nurses with wide experience in the care of adults with HIV, under the auspices of the Desmond Tutu HIV Foundation at the University of Cape Town. It covers: introduction to HIV infection, management of HIV-infected adults at primary-care clinics, preparing patients for antiretroviral (ARV) treatment, ARV drugs, starting and maintaining patients on ARV treatment, opportunistic infection. The aim of the book is to enable healthcare workers at primary-care clinics to manage all aspects of HIV-related patient care.

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    Adult HIV: Antiretroviral drugs Adult HIV: Antiretroviral drugs Document Transcript

    • 4 Antiretroviral drugsBefore you begin this unit, please take the NOTE In 1996 Dr David Ho of New York presentedcorresponding test at the end of the book to the results of a landmark study showingassess your knowledge of the subject matter. You that multi-drug antiretroviral treatment wasshould redo the test after you’ve worked through successful in stopping viral replication and controlling the immune damage of HIV.the unit, to evaluate what you have learned. 4-2 How does antiretroviral treatment work? Objectives Antiretroviral drugs prevent HIV from multiplying (making copies of itself) in the When you have completed this unit you CD4 lymphocytes. This reduces the number should be able to: of viruses in the body and, thereby, allows • List the goals of antiretroviral treatment. the damaged immune system to recover. • Describe the three classes of Antiretroviral treatment results in an antiretroviral drugs. improvement of the clinical disease. • Describe the actions of antiretroviral drugs. • Define multi-drug treatment of HIV. Antiretroviral treatment stops HIV from • Give the advantages of standardised multiplying in the body. regimens. • List the first- and second-line drug 4-3 What are the goals of combinations. antiretroviral treatment? • Describe how antiretroviral drugs should be taken. The goals are to: • Recognise common and serious side 1. Prevent the multiplication (replication) of effects of antiretroviral drugs. HIV and, thereby, suppress the viral load and keep it suppressed. 2. Prevent the further destruction of CD4 cellsINTRODUCTION TO ANTI- and allow the immune function to recover. 3. Improve the quality of life and generalRETROVIRAL TREATMENT health by decreasing the clinical signs and symptoms of HIV infection. 4. Manage the side effects of antiretroviral4-1 What is antiretroviral treatment? treatment.Antiretroviral treatment (ART) is the use of 5. Reduce the occurrence of HIV-associateddrugs (i.e. medicines) to treat patients with infections.HIV infection. 6. Reduce the risk of death due to AIDS.
    • 56 ADULT HIV 4-6 What are common examples of ‘nucs’? The main goals of antiretroviral treatment are to improve the quality of life and reduce mortality 1. AZT (zidovudine) due to AIDS. 2. 3TC (lamivudine) 3. FTC (emtricitabine) 4. d4T (stavudine)4-4 At what sites in the CD4 lymphocytes 5. ddI (didanosine)do antiretroviral drugs act? 6. TDF (tenofovir)1. At the stage where the virus gives These are the generic (common) names of the instructions to produce new viruses. drugs. For each generic drug there are one2. At the stage where new viruses are or more different trade names for the same manufactured and released into the body. drug manufactured by different companies. This makes it difficult to remember all theCLASSES OF ANTI- trade names. Therefore, it is best to remember the generic names and only the commonlyRETROVIRAL DRUGS used trade names of the frequently used antiretroviral drugs. If possible, use the generic names rather than the trade names.4-5 What are the classes ofantiretroviral drugs? NOTE NRTIs mimic (look like) natural nucleosides (DNA building blocks, e.g. thymidine) and therebyMost drugs used fall into one of three clases: block the function of the reverse transcriptase1. Nucleoside reverse transcriptase inhibitors enzyme. They act as false building blocks for and nucleotide reverse transcriptase HIV DNA and prevent the HIV instructions inhibitors, are also known as ‘nucs’ being inserted into the DNA of the CD4 cells. (pronounced as ‘nukes’). They act at . the stage where the virus infects CD4 4-7 Can different ‘nucs’ be used together? lymphocyte and gives instructions to these ‘Nucs’ are generally used in pairs, e.g. d4T cells to produce new viruses. and 3TC or AZT and ddI. However, AZT2. Non-nucleoside reverse transcriptase and d4T should not be used together as they inhibitors are commonly called ‘non- compete with each other. AZT and 3TC can be nucs’. They also act at the stage where the combined as Combivir. TDF is usually given virus gives instructions to the CD4 cells with 3TC or FTC. to produce new viruses but the method of action is different from the ‘nucs’.3. Protease inhibitors (‘PIs’). They act AZT and d4T should never be used together as at the final stage where the CD4 cell they compete with one another. manufactures new viruses. NOTE Nucleoside reverse transcriptase inhibitors 4-8 What are common trade (NRTIs) and nucleotide reverse transcriptase names for the ‘nucs’? inhibitors (NtRTIs) are also known as nucleoside Common ‘nucs’ are: and nucleotide reverse transcriptase antagonists. Two new classes of antiretrovirals (intergrase 1. AZT is sold as Retrovir. inhibitors and entry inhibitors) may be available 2. 3TC is simply called 3TC. in the next few years. NRTIs were the first 3. d4T is sold as Zerit. group of antiretroviral drugs available. 4. ddl is sold as Videx. 5. TDF is sold as Viread. NOTE TDF together with FTC is sold as Truvada.
    • ANTIRETROVIRAL DRUGS 574-9 What are examples of ‘non-nucs’? All antiretroviral drugs must be taken by mouthCommon ‘non-nucs’ are: at the same time every day.1. Nevirapine2. Efavirenz 4-13 Should a number of antiretroviral drugs be used together?‘Non-nucs’ are particularly powerful inhibitorsof HIV multiplication. However, HIV rapidly Yes. With antiretroviral treatment it is essentialbecomes resistant to ‘non-nucs’ if they are to use a number of drugs together. This is calledused alone. Therefore, they are usually used multi-drug treatment. It is important to usewith a pair of ‘nucs’. multi-drug treatment as it is more effective and also reduces the chance of the HIV becoming NOTE NRTIs directly inhibit the reverse resistant to the drugs. The same advantages transcriptase enzyme by binding to it and of multi-drug therapy apply to the treatment thereby prevent the formation of DNA containing of TB. Except for the prevention of mother- the HIV genetic code in the CD4 lymphocytes. to-child transmission and post-exposure prophylaxis, single or double drug treatment of4-10 What are common trade HIV infection should never be used.names for the ‘non-nucs’?• Nevirapine is called Viramune. Multi-drug treatment should be used to treat HIV.• Efavirenz is called Stocrin. NOTE Multi-drug treatment of HIV infection in4-11 What are examples of ‘PIs’? 1995 showed dramatic results following earlier disappointing results with single drug treatment.1. Ritonavir2. Lopinavir 4-14 What is HAART?The common trade name for ritonaviris Norvir. Sometimes two ‘PIs’ (protease Highly active antiretroviral treatment (HAART)inhibitors) are put together in a single is another name for antiretroviral treatmentpreparation such as Aluvia (a trade name for (ART). It is the use of multiple drugs to treatlopinavir combined with ritonavir). Using two HIV infection. Three or more drugs are always‘PIs’ together allow a lower dose of both with used together for antiretroviral treatment.fewer side effects.There are a large number of other ‘PIs’. They Three or more antiretroviral drugs are alwaysare easy to recognise as their generic names all used to provide antiretroviral treatment.end in ‘avir’ such as ritonavir. NOTE Sometimes one drug (monotreatment) NOTE A low dose of ritonavir is used or two drugs (dual treatment) are used in to boost the effect of lopinavir. short-course prophylactic treatment to prevent the transmission of HIV from mother to child4-12 Can antiretroviral drugs during pregnancy and delivery. One or twobe taken by mouth? drugs are only appropriate in HIV prophylaxis.Yes. The common antiretroviral drugs in all 4-15 Can antiretroviral treatmentclasses can be taken by mouth. cure HIV infection?It is very important that all antiretroviral drugs Unfortunately not. However, antiretroviralare taken at the same time every day. treatment can dramatically improve the symptoms and clinical signs of HIV infection and allow the patient to remain healthy for
    • 58 ADULT HIVmany years. Antiretroviral treatment is the most of drug use and resistance. Monitoring forimportant advance in the management of HIV side effects is simplified.infection. Antiretroviral treatment can change 5. It is easier to buy and distribute a limitedthe outcome of HIV infection from a rapidly range of drugs.fatal disease into a manageable chronic illness. 6. Fixed doses are used in the standardised approach. Antiretroviral treatment is the most important advance in the management of HIV infection The standardised approach to antiretroviral drugs and has changed the course from a rapidly fatal is preferred. disease into a manageable chronic illness. A standardised regimen consists of a specific NOTE In November 2003 the South African combination of antiretroviral drugs where government agreed to the widespread the risk of drug interactions and side effects introduction of antiretroviral treatment in the are low. The drug combination should target management of patients with HIV infection. at least two sites in the lifecycle of HIV (i.e. important stages in the viral replication).STANDARDISED REGIMENS 4-18 What are the disadvantagesFOR ANTIRETROVIRAL of an individualised approach?TREATMENT Using combinations of antiretroviral drugs is very complicated as each combination has its own risk of drug interactions. Some drugs4-16 What is a standardised regimen counteract each other (block the function offor treating HIV infection? the other drug). Other drug combinations have a high risk of serious side effects. Therefore,The choice of which antiretroviral drugs to a wide knowledge and experience of theseuse can be based on either an individualised drugs is essential if the individual approach isor a standardised approach. Initially an to be used. This ability is usually only availableindividualised approach was used where the at antiretroviral clinics where particularlymost appropriate drugs were chosen to meet difficult management problems are referred.the needs of each patient. More recently astandardised approach has been used where all 4-19 What is a first-line combination?patients are started on the same combination,as is done with TB treatment. This is the combination of drugs which is routinely used when patients first start4-17 What are the advantages of antiretroviral treatment.using a standardised regimen? 4-20 What is the first-line combination1. The standardised approach is safer, easier commonly used in South Africa? and simpler.2. It is also affordable and effective. When treating adults with HIV infection in3. Both healthcare workers and patients can South Africa, the first-line combination is learn how to use these drugs correctly usually two ‘nucs’ together with a ‘non-nuc’. and which side effects to be aware of. The currently recommended South The education and training of healthcare African combination is TDF plus 3TC workers and patients are much easier. plus either efavirenz or nevirapine. Unless4. It limits the number of drugs that are used contraindicated, all patients should be started and makes it possible to monitor patterns on this regimen. AZT can be used if there are
    • ANTIRETROVIRAL DRUGS 59contraindications to TDF. Some old regimes 4-23 When are other combinationsstill use d4T instead of TDF. of antiretroviral drugs used? NOTE Sometimes TDF is combined with Sometimes changes to the first- or second-line FTC. The combination is called Truvada. combinations are made: 1. When there are serious side effects to only In South Africa antiretroviral treatment is usually one drug in a standardised regimen. 2. In patients who have previously been started with TDF and 3TC or FTC plus either exposed to one or more antiretroviral efavirenz or nevirapine. drugs, e.g. nevirapine in labour.This combination is chosen for its effectiveness These changes (swaps) should only be madeand availability, few serious side effects and by an experienced doctor at an antiretrovirallow cost. clinic. Using individualised combinations reduce the future options of treatment.4-21 What is a second-line combination? NOTE Patients who have failed to respond toPatients who fail to respond to the first-line both first- and second-line combinations,combination, despite good adherence, are despite good adherence, may be offeredchanged to a second-line combination of ‘salvage treatment’ with new drugs.antiretroviral drugs. NOTE Unfortunately there is no standardised ANTIRETROVIRAL third-line combination of drugs available in the public sector in South Africa. This will change MEDICATION when new drugs are introduced in the future. 4-24 What are the practical implications4-22 What common second-line of taking antiretroviral treatment?combination is used in South Africa? The following questions must be considered:Usually two ‘nucs’ plus a combination of two‘PIs’. The common second-line combination in 1. Which medications are taken?South Africa is AZT plus 3TC plus ritonavir 2. How many tablets or capsules are taken atand lopinavir together. TDF can be used if the a time?failed first-line combination included AZT. 3. When and how often is the medication taken?The previous second-line combination is 4. Should the medication be taken with orsometimes still used. without food?Therefore both the first- and second-line 5. Can all the drugs be taken together at thecombinations include two ‘nucs’. However, same time?only the first-line combination includesa ‘non-nuc’ while only the second-line 4-25 How should tenofovir be taken?combination includes ‘PIs’. TDF (generic name tenofovir) is a ‘nuc’ (trade name is Viread). One TDF 300 mg In South Africa the new second-line tablet is taken daily, usually at night, with or combination is AZT plus 3TC plus ritonavir and without food. lopinavir together. Some patients on an older regime may still receive d4T (generic name stavudine). D4T is also a ‘nuc’ (trade name is Zerit). One 30 mg capsule is taken twice a day (12-hourly).
    • 60 ADULT HIVCapsules can be taken with or without food. NOTESerious complications of AZT areHowever, taking d4T with food reduces nausea. anaemia, neutropenia and lactic acidosis.More recent guidelines do not include d4T. 4-28 How should ddI be taken? NOTE Initially d4T may be well tolerated but in the long term 20% of patients will have side ddI (generic name didanosine) is a ‘nuc’ (trade effects. These may include serious complications name is Videx). Usually four tablets (100 mg such as peripheral neuropathy, pancreatitis, each) are taken once a day on waking, giving hepatitis, lipodystrophy and lactic acidosis due to a total dose of 400 mg. All four tablets are mitochondrial DNA depletion. The risk of these dissolved in water (about 30 ml) and taken side effects is particularly high with d4T, and immediately. Only water or clear apple juice further increased if d4T is taken together with ddI must be used to dissolve the tablets. Unlike or if the patient is a woman, obese or pregnant. other antiretroviral drugs, ddI tablets should not be taken with meals as food reduces d4T must not be given with ddI. absorption of the drug. ddI should be taken at least an hour before a meal or not less than two hours after a meal. The more recent South4-26 How should 3TC be taken? African guidelines minimise the use of ddI.3TC is also a ‘nuc’ (generic name is lamivudinewhile trade name is also 3TC). One 150 mg NOTE The most common side effects oftablet is taken twice a day (12-hourly) with or ddI are gastrointestinal symptoms. Seriouswithout food. However, 300 mg 3TC is taken side effects include pancreatitis, peripheral neuropathy and lactic acidosis due toas a once-daily dose. 3TC is well tolerated interference with mitochondrial metabolism.and has very few side effects. Mild nausea, If d4T is still being used, these side effectsheadache and diarrhoea may occur. may be worsened if ddI is given with d4T. 3TC is well tolerated with few side effects. ddI tablets must be dissolved in water.4-27 How should AZT be taken? 4-29 How should nevirapine be taken?AZT (generic name zidovudine) is a ‘nuc’ Nevirapine is a ‘non-nuc’. One nevirapine(trade name is Retrovir). One 300 mg tablet is 200 mg tablet (trade name is Viramune) istaken twice daily (12-hourly). Tablets can be taken at night to start with. After 14 daystaken with or without food. However, nausea the dosage is increased to one tablet twicemay be less if taken with food. AZT has many daily (12-hourly). If there is a mild rash orshort term minor side effects such as fatigue, raised liver enzymes, do not increase the dosenausea and vomiting, headache, muscle pains to twice a day until the liver enzymes haveand altered taste. These are common at the dropped and the rash has cleared.start of treatment and are worse with higherdoses. However, they become less after a few A mild rash is common, usually during theweeks. AZT may also discolour the nails. first six weeks of treatment. A severe rash may also occur with nevirapine. The drugs must beThe most important side effect of AZT is stopped immediately if a severe rash appears.anaemia. This usually occurs in the first fewmonths of treatment. NOTE Serious complications of nevirapine include blistering rash with mucosal involvement, hepatitis and fever due to a hypersensitivity reaction. AZT may cause anaemia. Nevirapine may cause early, serious side effects.
    • ANTIRETROVIRAL DRUGS 614-30 How should efavirenz be taken? dosages of many drugs have to be altered if they are used together with lopinavir and ritonavir.Efavirenz is also a ‘non-nuc’ and is very similarto nevirapine. NOTE Protease inhibitors may cause lipodystrophyOne efavirenz 600 mg capsule (trade name with abnormal fat distribution. LipodystrophyStocrin) is taken at night. Efavirenz has the may be associated with insulin resistance and hyperlipidaemia. Protease inhibitors may alsoadvantage of the patient only needing a single affect the metabolism and breakdown of manydose a day. drugs (ritonavir inhibits cytochrome P450 andA rash may occur. However this side effect thereby increases the blood level of lopinaviris less common and not as severe as with and a wide range of other drugs). A small dose of ritonavir therefore boosts the effect of lopinavir.nevirapine. Efavirenz commonly causes mildemotional symptoms for the first few weeks The dose of lopinavir/ritonavir must be(mood changes, abnormal dreams, insomnia increased if used with efavirenz or rifampicin.and dizziness). These are reduced if efavirenz Expert advice should be asked for.is taken on an empty stomach in the evening.When side effects have cleared efavirenz 4-33 Which antiretroviral drugsshould be taken with meals. should not be taken with a meal? NOTE The absorption of efavirenz is greater if it It is important that ddI is taken on an empty is taken with meals. This may make side effects stomach as food decreases the absorption of the worse during the first weeks of treatment. drug. In addition, the side effects of efavirenz are less if the drug is taken on an empty4-31 Who should not take efavirenz? stomach in the evenings. Therefore it is best if efavirenz is taken without food for the firstEfavirenz must not be taken during the few weeks. However, most other antiretroviralfirst trimester of pregnancy, if pregnancy is drugs can be taken twice a day with meals.planned or if reliable contraception is notbeing used as it may cause fetal abnormalities(birth defects). People who cannot use ddI must be taken on an empty stomach.contraception reliably should take nevirapinerather than efavirenz. Injectable contraception With the first-line combination all three drugsplus condoms are recommended. can be taken with meals, except efavirenz for the first few weeks. Efavirenz should not be used in a woman who is If the previous second-line combination is at risk of falling pregnant. used, AZT and lopinavir/ritonavir are best taken with meals, but ddI must be taken on an empty stomach. Take ddI at least an hour4-32 How should ‘PIs’ be taken? before or two hours after a meal.Usually lopinavir 400 mg and ritonavir 100 mg(LPV/r) are taken in combination as Kaletraor Aluvia (trade names). Three capsules of It is important to know which drugs should beKaletra are taken twice daily (12-hourly) with taken with meals and which drugs must be takenfood (i.e. a total of six capsules a day) or two on an empty stomach.tablets of Aluvia twice a day (12-hourly) withor without food. Nausea and diarrhoea are 4-34 Which drugs must be kept cool?common for the first few weeks, especially withKaletra. These side effects can be reduced if the Kaletra should be kept in a fridge if possible. Ifdrug is taken with food. Unlike Kaletra, Aluvia a fridge is not available, keep Kaletra in a coolneed not be kept in a fridge or cool place. The place (less than 25 °C).
    • 62 ADULT HIVTable 4-1: Details of antiretroviral drugs Drug Generic Trade Dose Frequency# With Meals TDF tenofovir Viread 1 tablet Daily No AZT zidovudine Retrovir 1 tablet Twice daily Yes 3TC lamivudine 3TC 1 tablet Twice daily Yes d4T stavudine Zerit 1 capsule Twice daily Yes ddI didanosine Videx 4 tablets Daily No NVP nevirapine Viramune 1 tablet Twice daily* Yes EFV efavirenz Stocrin 1 capsule Daily Yes** LPV/r lopinavir/ Aluvia 3 capsules Twice daily Yes ritonavir# Twice daily doses are best taken 12 hours apart e.g. 7 am and 7 pm* Only one tablet of nevirapine daily at night for the first two weeks of treatment** Efavirenz is best taken on an empty stomach for the first few weeksSIDE EFFECTS OF that patients know which side effects to look out for and which can be serious. If sideANTIRETROVIRAL DRUGS effects are mild, patients should not stop the antiretroviral drugs. With severe side effects they should report immediately to the4-35 Do all antiretroviral clinic. Educating patients about side effectsdrugs have side effects? is an important part of care. All patientsSide effects to antiretroviral drugs are common on antiretroviral treatment must be able toand usually mild, but they can sometimes be monitor themselves for side effects.severe. Remember that drugs used to treatHIV-associated infections also cause side Patients should be educated about side effects.effects, which may be similar to the clinicalsymptoms and signs of HIV infection. Mostside effects can be easily managed. 4-37 What are the common side effects of antiretroviral drugs?Side effects can be graded into mild (grade 1),moderate (grade 2), severe (grade 3) and Tiredness, nausea and vomiting, headachespotentially life threatening (grade 4). and diarrhoea are common and may be caused by all classes of antiretroviral drugs. These side effects are not serious and usually settle All antiretroviral drugs may have side effects. after the first few days or weeks. It is important that patients continue with their antiretroviral4-36 Should patients be warned drugs in spite of mild side effects. Sometimesabout side effects? other medication can be taken to help relieve these symptoms (paracetamol for headacheIt is very important that patients know the and antiemetics for nausea and vomiting).common side effects of the antiretroviral Taking antiretroviral treatment with food oftendrugs that they are taking. It is also important helps reduce side effects. Side effects, no matter
    • ANTIRETROVIRAL DRUGS 63how mild, must always be reported to the staff. especially nevirapine. These rashes almostFortunately, most side effects are mild. Most always occur in the first six weeks of treatment.patients will not experience side effects. Nevirapine commonly causes skin rashes. Most patients have no side effects. Remember that HIV infection itself and NOTE Severe vomiting or diarrhoea drugs used to treat HIV-associated infections may cause dehydration as well as (especially co-trimoxazole) also commonly reduce absorption of medication. causes rashes. Therefore the rash may not be due to the antiretroviral drugs.4-38 When do most side effects occur? NOTE Severe rashes due to a hypersensitivityMost side effects occur in the first six weeks of reaction may result in Stevens-Johnsonstarting antiretroviral treatment. They usually syndrome and toxic epidermal necrolysis (TEN).get better on their own after one to two months. Constitutional symptoms such as fever are alsoHowever, some serious side effects may occur at present and warn of a dangerous side effect.any time that antiretroviral drugs are taken. Always look for hepatitis with severe drug rashes.4-39 What serious side effects may 4-41 How should skin rashes be managed?occur with antiretroviral drugs? Nevirapine must always be started at half doses1. Rash (i.e. 200 mg once daily) for the first 14 days2. Hepatitis as this reduces the risk of a rash. Continue3. Anaemia treatment if the rash is mild. Do not increase4. Peripheral neuropathy the dose of nevirapine until any rash has settled.5. Renal failure All patients with a severe rash must be referred6. Wasting and accumulation of fat to an antiretroviral clinic urgently. If this (lipodystrophy) cannot be done on the same day, stop all three7. Pancreatitis antiretroviral drugs immediately and send8. Lactic (metabolic) acidosis the patient to an antiretroviral clinic as soon9. Severe vomiting or diarrhoea as possible. Usually nevirapine is swapped for a ‘PI’. These patients must never be given4-40 What rashes occur commonly a ‘non-nuc’ again (i.e. neither nevirapine norwith antiretroviral drugs? efavirenz should ever be prescribed again).1. Mild rashes are common and include a localised or generalised erythematous All antiretroviral drugs must be stopped (pink), maculopapular (measles-like) or immediately if a severe rash occurs. urticarial rash with no other symptoms.2. Severe rashes include any rash with NOTESteroids and antihistamines do not help blistering, peeling or involvement of the most sensitivity rashes caused by nevirapine. mucous membranes of the mouth and conjunctivae. A severe rash may also present together with fever, a fast pulse 4-42 Which antiretroviral or abdominal pain (due to hepatitis). drugs cause hepatitis? Severe rashes are due to a hypersensitivity All classes of antiretroviral drugs can cause reaction and can be fatal. hepatitis. However, nevirapine is the drug whichRashes are common with antiretroviral is usually associated with hepatitis. Efavirenztreatment and usually are caused by ‘non-nucs’, can also cause hepatitis but less commonly.
    • 64 ADULT HIVHepatitis due to nevirapine is most common 4-45 Is anaemia a common problemin patients, especially women, who have a high with antiretroviral drugs?CD4 count before the start of treatment. Anaemia (Hb below 10 g/dl) is seen in fewLiver function tests (ALT, i.e. alanine amino patients receiving AZT. These patients maytransferase) should be done on all patients appear pale and feel weak and dizzy. Anaemia iswhen nevirapine is started and then repeated usually mild and the AZT need not be stopped.after two weeks, four weeks and eight weeks A full blood count should be done when AZTof treatment as hepatitis usually occurs during is started and then be repeated at four weeks,the first weeks of treatment. eight weeks, 12 weeks and 24 weeks. Patients with a haemoglobin concentration (Hb) below Hepatitis is usually caused by nevirapine. 8 g/dl due to AZT should be referred to an antiretroviral clinic. It is important to monitor NOTE Nevirapine causes asymptomatic hepatitis the Hb in patients receiving AZT. in 10% and clinical hepatitis in 1% of patients. Nevirapine plus TB treatment increases the risk of severe rash and hepatitis. d4T and co- Anaemia is a side effect of AZT. trimoxazole may also cause hepatitis with raised enzymes. Nucleoside reverse transcriptase NOTE With severe anaemia (haemoglobin less than inhibitors may cause a fatty liver (steatosis). 6.5 g/dl) it is important to stop AZT and replace with TDF. A blood transfusion may be needed. Patients with an Hb between 6.5 and 8 g/dl should4-43 What are the clinical signs of hepatitis? be closely followed. AZT also causes neutropeniaHepatitis may be clinical (nausea, loss of but does not lower the platelet count.appetite, jaundice, enlarged liver, itchingand abdominal pain) or asymptomatic 4-46 What is peripheral neuropathy?(when it is diagnosed by finding raised liverenzymes in the blood without any clinical This is a problem which affects the peripheralsigns of hepatitis). An ALT level above three nerves, especially in the legs. It presents withtimes normal (normal< 40 iu/l) indicates an pain, numbness and abnormal sensation in aincreased risk of hepatitis. ‘glove and stocking’ distribution. Most patients with peripheral neuropathy present with NOTE Liver damage can be severe painful feet at night. and permanent, but rarely fatal. Peripheral neuropathy is usually caused by ‘nucs’ which have a ‘d’ in their names, e.g.4-44 What is the management ddI and d4T. These drugs should not be usedof a patient with hepatitis? together as this increases the risk of peripheralPatients with asymptomatic hepatitis and only neuropathy. Depending on the severity of themildly raised liver enzymes (up to five times neuropathy, the drugs may have to be changed,normal) can be followed clinically without after consultation with an HIV clinic, as thestopping the drugs. The hepatitis usually peripheral neuropathy can become worseresolves. Using a low dose of nevirapine if the drug is continued. The symptoms of(200 mg daily) for the first two weeks lowers peripheral neuropathy usually slowly improvethe risk of hepatitis (and rash). after the drugs have been stopped. Other drugs, such as INH and alcohol may also causePatients with clinical hepatitis or peripheral neuropathy.asymptomatic hepatitis with markedly raisedliver enzymes should be urgently referredto an antiretroviral clinic where stopping all d4T and ddI are associated with peripheraltreatment may be considered. neuropathy and should not be used together.
    • ANTIRETROVIRAL DRUGS 65 NOTE d4T is the commonest cause of peripheral neuropathy. It may need to be swapped for TDF. Lactic acidosis is a rare but serious side effect of ‘nucs’ and occurs after months of good response4-47 What is lipodystrophy? to treatment.This is an abnormal distribution of Patients with suspected lactic acidosis mustsubcutaneous fat resulting in a change in be immediately taken off all treatment andbody shape. Fat is lost (fat atrophy) from the urgently referred to an HIV treatment centreface and limbs and gained (accumulated) for investigation and management.over the abdomen, back of the neck andbreasts. Unfortunately lipodystrophy is not NOTE Hyperlactataemia (serum lactate aboveusually corrected when the antiretroviral 2 mmol/l) and lactic acidosis often withdrugs are changed. Many patients gain weight hepatic steatosis (fatty liver), liver failure,when antiretroviral treatment is started. pancreatitis or peripheral neuropathy, areLipodystrophy is usually caused by the ‘PIs’, due to mitochondrial damage as ‘nucs’ alsobut also by ddI, d4T and efavirenz. interfere with the replication of mitochondrial DNA. Asymptomatic hyperlactaemia (without acidosis) is common (up to 20%) while Lipodystrophy is a redistribution in body fat and symptomatic hyperlactaemia (without acidosis) occurs in 1% and hyperlactataemia with lactic is usually associated with ‘PIs’. acidosis in 0.1% of patients on ‘nucs’. The risk is lower with TDF and AZT than d4T. TDF and NOTE Lipodystrophy with central obesity and 3TC are relatively safe and can be started peripheral wasting may be associated with once the lactate has returned to normal. insulin resistance and fasting hyperlipidaemia with a raised plasma cholesterol and triglyceride concentration (the lipodystrophy syndrome). 4-49 Which drugs cause pancreatitis? Marked hypertriglyceridaemia can cause Pancreatitis (inflammation of the pancreas) is pancreatitis while a raised serum cholesterol another severe complication of d4T and ddI, increases the risk of coronary heart disease. especially when they are used together. Alcohol abuse may increase the risk of pancreatitis.4-48 Which drugs may cause lactic acidosis? Pancreatitis presents with vomiting, abdominalLactic acidosis is a rare but serious and pain and tenderness. The drugs must be stoppedpotentially fatal side effect of ‘nucs’, immediately and the patient urgently referred.particularly d4T and ddI. Therefore thesedrugs must never be used together. It usually Abdominal pain or discomfort is an importantonly occurs more than six months into symptom in patients on antiretroviral treatmenttreatment when patients have responded as it may be due to hepatitis, lactic acidosis orwell and are clinically improving with good pancreatitis.adherence. It is most common in women NOTE The serum amylase and lipasewho are overweight or pregnant. Patients levels are raised in pancreatitis.with lactic acidosis present with a gradualonset of tiredness, weight loss and abdominalcomplaints (nausea, vomiting, abdominal pain 4-50 What is the management ofor discomfort). Always suspect lactic acidosis severe vomiting or diarrhoea?if patients, who have been well and gaining Some antiretroviral drugs cause nausea andweight for months, start to lose weight. vomiting or diarrhoea. The problem is usually mild and settles after a few weeks. However, vomiting may be severe (especially with AZT) while diarrhoea may also be severe (especially with d4T). This can lead to dehydration. Taking
    • 66 ADULT HIVmedicine with food and anti-nausea medication a while. Most minor side effects during themay help reduce vomiting. Efavirenz should be initiation of antiretroviral treatment get bettertaken without food if it causes vomiting. over time without any treatment.Oral rehydration solution will help prevent Peripheral neuropathy may also occur early inor correct dehydration. Patients with signs treatment.of severe dehydration should be urgentlyreferred to hospital. The sudden onset of 4-54 Which side effects occursevere vomiting after weeks of treatment may during later treatment?indicate lactic acidosis. 1. Lipodystrophy and fat wasting 2. Lactic acidosis4-51 Should antiretroviral drugs rather 3. Peripheral neuropathynot be used because of their side effects?No. Antiretroviral drugs are a very important NOTE Some other metabolic disorders can occurpart in the treatment of HIV infection and later in treatment (with or without lipodystrophy)the only way of managing AIDS. Like most including high cholesterol and glucose levels.other drugs, they have side effects. Usuallyside effects are mild and the antiretroviral 4-55 Do patients lose weight ondrugs need not be stopped. Most patients have antiretroviral treatment?no or only mild side effects. However, both Normally patients feel better and gain weightpatients and health workers should know the when antiretroviral treatment is started.symptoms and signs of severe side effects. Therefore weight loss on antiretroviralIf these appear the drugs must be stopped treatment is an important danger sign. It mayimmediately and the patient referred urgently be due to common early side effects suchto an antiretroviral clinic for assessment. as nausea, vomiting or diarrhoea. However, weight loss in patients who have previously The advantages of antiretroviral drugs far been well may also indicate the development outweigh the side effects. of lactic acidosis. Many patients on antiretroviral treatment4-52 When do side effects occur? complain of hunger once their immune system starts to recover. This may be a problem in poor1. They may occur early during the initiation people who cannot afford to buy more food. of treatment (the first few weeks or months of treatment). 4-56 Should one drug be stopped2. They may occur later when treatment is if side effects are severe? stabilised (after many months). It may be necessary to stop an antiretroviral4-53 Which side effects occur drug if severe side effects occur, e.g. severeduring early treatment? rash or clinical hepatitis. If this is done, allMinor side effects are common, e.g. nausea, drugs must be stopped together. Stopping onevomiting, diarrhoea, headaches, muscle drug will lead to resistance of the remainingpains, sleeplessness, minor rashes. However, two drugs. The drug combination must beserious side effects such as serious rashes and carefully examined as the problem drug mayhepatitis may also occur early and need to be have to be swapped or a different combinationlooked out for. may be needed. Changing drugs must always be done at an antiretroviral clinic by anTo reduce early side effects, some drugs (e.g. HIV expert. HIV infection must never benevirapine) are started at half doses. The doses treated with only one or two drugs. A fullof other drugs may have to be reduced for combination of three drugs is always needed.
    • ANTIRETROVIRAL DRUGS 67Table 4-2: Summary of side effects of antiretroviral drugs. Name of drug Major side effects ‘Nucs’ TDF Renal failure, rash, fractures 3TC Few side effects AZT Nausea and vomiting, anaemia, neutropenia d4T Peripheral neuropathy, pancreatitis, lactic acidosis, lipodystrophy ddI Peripheral neuropathy, pancreatitis, lactic acidosis, lipodystrophy ‘Non-nucs’ Nevirapine Severe rash, hepatitis Efavirenz Emotional or psychiatric symptoms, rash ‘PIs’ Ritonavir Lipodystrophy Lopinavir/ritonavir Diarrhoea, lipodystrophy If necessary, stop all antiretroviral drugs and not TDF can cause kidney damage. just one drug.4-57 Which antiretroviral drug should CASE STUDY 1not be used during pregnancy? A patient with HIV infection, who has beenEfavirenz should not be used during pregnancy treated with AZT alone for two weeks by a(especially during the first trimester) as it general practitioner, is referred to an HIVmay cause congenital malformations (birth clinic. The patient complains of headache,defects). It is usually swapped for nevirapine or nausea and feeling generally unwell since thelopinavir/ritonavir. treatment was started.4-58 Do any antiretroviral drugs 1. Do you agree with AZT alone ascause renal damage? acceptable treatment for AIDS?TDF can cause renal damage, which presents One or two drugs alone should never be usedas a drop in creatinine clearance. Therefore to treat HIV. Three drugs are always usedcreatine clearance should be monitored at one together (multi-drug therapy), e.g. AZT, 3TCmonth, three months, six months and then 12- and lopinavir/ritonavir.monthly thereafter, when the drug is used. Donot use TDF if the creatinine clearance is lessthan 50 ml/min. 2. What is the advantage of using multiple drugs? NOTE TDF may also cause a rash and, There is a higher rate of successful treatment on rare occasions, decrease phosphate levels, resulting in bone fractures. with less drug resistance.
    • 68 ADULT HIV3. Why is this patient complaining of 2. What treatment should she receive?headache, nausea and feeling unwell? She should be given a standardised regimen.These are common side effects of AZT. Mild Once she has been prepared for treatment, aside effects of antiretroviral treatment usually first-line combination using nevirapine willsettle on their own after a few weeks. Unless be started.the side effects are serious, treatment shouldnot be stopped. Mild side effects can be treated 3. What is a standardised regimen?symptomatically. This is a fixed combination of antiretroviral drugs. There are many advantages to a4. What is an important side effect of AZT? standardised regimen over an individualisedAnaemia. Therefore the haemoglobin regimen. With an individualised regimen eachconcentration should be monitored in patient is given their own combination ofpatients receiving antiretroviral treatment antiretroviral drugs.which includes AZT. 4. What are the advantages of5. What class of drug is AZT? a standardised regimen?TDF, AZT, 3TC, d4T and ddI are ‘nucs’. It is simpler, safer and cheaper to use withThey all block an important enzyme and fewer side effects and drug interactions. Thethereby prevent HIV from infecting CD4 education and training of both patients andlymphocytes. ‘Nucs’ are used in most multi- staff is much easier. Tuberculosis is also treateddrug regimens to treat HIV. with a standardised fixed combination of drugs.6. What are the main goals of 5. What first-line regimen isantiretroviral treatment? used in South Africa?To suppress the multiplication of HIV. This will TDF or AZT plus 3TC (‘nucs’) plus eitherallow the immune system to recover (increased efavirenz or nevirapine (‘non-nucs’).CD4 count), improve the patient’s clinicalcondition and decrease the risk of death. 6. Which ‘non-nuc’ would you choose for this woman?CASE STUDY 2 Nevirapine, as she plans to start her family when she is well. Efavirenz has fewer serious side effects than nevirapine, but may causeA young woman who has HIV infection congenital abnormalities in the unborn infant.presents at an HIV clinic with the hope of Efavirenz should only be used in women whobeing cured. She wants to start a family as are on reliable contraception, and thereforesoon as she is well again. unlikely to fall pregnant, and men.1. Can antiretroviral treatmentcure HIV infection? CASE STUDY 3Unfortunately not. However, it can markedlyimprove the patient’s health and make HIV A patient has recently started on a first-lineinfection a chronic but manageable disease. regimen with nevirapine. Three weeks after starting antiretroviral treatment he develops a fever and feels ill with a generalised blistering skin rash which also involves his mouth.
    • ANTIRETROVIRAL DRUGS 691. Are skin rashes common CASE STUDY 4with nevirapine?Yes. They are usually mild and the patient During preparation for antiretroviral treatmentdoes not feel generally unwell. With continued a group of patients is fully informed aboutantiretroviral treatment most mild skin rashes the drugs they are gong to take. One patientcaused by nevirapine will disappear. is afraid of starting treatment when he learns about the possible side effects. A friend of his2. Would you be concerned about developed very painful legs after antiretroviralthis patient’s skin rash? treatment was started.Yes, because this is a serious rash and the 1. What information about the anti-patient is ill with a fever. Any blistering skin retroviral drugs should patients be given?rash, especially if it involves the mouth,is serious. All drugs must be stopped They must know the names and appearancesimmediately and the patient should be referred of the drugs in the first-line combination. Theyurgently to hospital. Nevirapine will have to be must know how many drugs to take and whenreplaced (swapped) with a ‘PI’ such as Aluvia. they should be taken.3. Should this patient be given 2. How many times a day areefavirenz instead of nevirapine? antiretroviral drugs taken?No. This patient must never again be given a Some drugs in the first-line combination (AZT‘non-nuc’ (either nevirapine or efavirenz) as and 3TC) are taken twice a day (12-hourly)the severe reaction is likely to recur. while TDF and Efavirenz are taken once a day. Nevirapine is taken once a day to start, but4. What other serious side effect later is also taken twice a day. 300 mg 3TC canmay be caused by nevirapine? also be taken once a day.Hepatitis. Clinical hepatitis presents with 3. Should antiretroviral drugsnausea and vomiting, abdominal pain and be taken with meals?jaundice. A rash and hepatitis may occurtogether. Patients with any signs of hepatitis Most antiretroviral drugs in the first-linemust be urgently referred to hospital. Severe combination should be taken with meals as thishepatitis can be fatal. reduces the risk of side effects. For the first few weeks efavirenz should be taken on an empty5. How can the risk of side effects stomach. Second-line drugs are also taken withwith nevirapine be reduced? meals, except ddI which must be dissolved with water and taken on an empty stomach, oneBy starting with a smaller dose for the first two hour before a meal or two hours after a meal.weeks of treatment (one tablet at night only). 4. Should patients who are afraid of the side6. Should patients be warned effects rather not take antiretroviral drugs.about side effects? No. Antiretroviral drugs are the only way toIt is very important that patients be well effectively treat patients with HIV. Withouteducated about the symptoms and signs of antiretroviral treatment they will die. Mostthe common side effects before antiretroviral patients have no or only mild side effects.treatment starts. They should immediatelyreport any side effects.
    • 70 ADULT HIV5. Which antiretroviral drugs multi-drug regimen. Kaletra and Aluvia (tradecause painful legs? names) are a combination of two ‘PIs’ (ritonavir and lopinavir). The second-line combinationPain and numbness of the hands and feet are therefore includes ‘PIs’ but not ‘non-nucs’.due to peripheral neuropathy. This is usuallycaused by d4T or ddI. Therefore, these twodrugs should never be used together as this 3. How should lopinavir/ritonavir be taken?increases the risk of peripheral neuropathy. Twice a day with meals.Other drugs such as INH and alcohol may alsocause peripheral neuropathy. 4. What are common minor side effects with lopinavir/rinonavir?CASE STUDY 5 Nausea and loose stools. These are less troublesome if the medication is taken with meals.After failing treatment with the first-linecombination of antiretroviral treatmenta patient is started on the second-line 5. Why is this patient developingcombination. She feels much better on the new wasting of the face?treatment. However, after a few months she Unfortunately peripheral wasting of the facenotices that her face is becoming wasted and and limbs and central fat accumulation overshe is gaining weight around her abdomen. the stomach and back of the neck may occur with ‘PIs’. This change of body shape due to the1. What antiretroviral drugs are used redistribution of fat does not always resolvein the second-line combination? when the ‘PIs’ are stopped.Usually AZT and 3TC plus lopinavir/ritonavir. 6. What is the name of this condition?2. What class of drugs are these? Lipodystrophy.AZT and 3TC are ‘nucs’. As with the first-linecombination, ‘nucs’ are an important part of the