4 Antiretroviral drugs

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Contents

• Objectives
• Introduction to anti­retroviral treatment
• Classes of antiretroviral drugs
• Standardised regimens for antiretroviral treatment
• Antiretroviral medication
• Side effects of antiretroviral drugs
• Case studies

Objectives

When you have completed this chapter you should be able to:

1. List the goals of antiretroviral treatment.
2. Describe the 3 classes of antiretroviral drugs commonly used.
3. Describe the actions of antiretroviral drugs.
4. Define multi-drug treatment of HIV.
5. Give the advantages of standardised regimens.
6. List the first- and second-line drug combinations.
7. Describe how antiretroviral drugs should be taken.
8. Recognise common and serious side effects of antiretroviral drugs.

Introduction to anti­retroviral treatment

4-1 What is antiretroviral treatment?

Antiretroviral treatment (ART) is the use of drugs (i.e. medicines) to treat patients with HIV infection.

For each generic drug there are 1 or more different trade names, depending on which company has made it. This makes it difficult to remember all the trade names. Therefore, it is best to remember the generic (common) names and only the trade names of the frequently used antiretroviral drugs (ARVs). If possible use the generic names rather than the trade names.

Note

In 1996 Dr David Ho of New York presented the results of a landmark study showing that multi-drug ART was successful in stopping viral replication and controlling the immune damage of HIV.


4-2 How does antiretroviral treatment work?

ARVs prevent HIV from multiplying (making copies of itself) in the CD4 lymphocytes. This reduces the number of viruses in the body and, thereby, allows the damaged immune system to recover. Antiretroviral treatment results in an improvement of the clinical disease.

Antiretroviral treatment stops HIV from multiplying in the body.

4-3 What are the goals of antiretroviral treatment?

The goals are to:

1. Prevent the multiplication (replication) of HIV and, thereby, suppress the viral load and keep it suppressed.
2. Prevent the further destruction of CD4 cells and allow the immune system to recover.
3. Improve the quality of life and general health by decreasing the clinical signs and symptoms of HIV infection.
4. Reduce the occurrence of HIV-associated infections and malignancies.
5. Reduce the risk of death due to AIDS.
6. Reduce transmission of HIV.
7. Do this with minimal antiretroviral side-effects.

The main goals of antiretroviral treatment are to improve the quality of life, reduce mortality due to AIDS and reduce HIV transmission.

4-4 At what sites in the CD4 lymphocytes do antiretroviral drugs act?

1. At the stage where the virus enters the cell.
2. At the stage where the virus gives instructions to produce new viruses.
3. At the stage where new viruses are manufactured and released into the body.

Classes of antiretroviral drugs

4-5 What are the classes of antiretroviral drugs?

The most commonly used drugs fall into 1 of 4 classes:

1. Integrase inhibitors (INSTIs): They block the incorporation of the HIV DNA into the host cell’s DNA. The integrase enzyme is blocked.
2. Nucleoside reverse transcriptase inhibitors (NRTIs) and nucleotide reverse transcriptase inhibitors (NtRTIs),: They are also known as ‘nucs’ (pronounced as ‘nukes’). They act at the stage where the virus infecting the CD4 lymphocyte gives instructions to these cells to produce new viruses.
3. Non-nucleoside reverse transcriptase inhibitors (NNRTIs): They are commonly called ‘non-nucs (pronounced as ‘non-nukes’)’. They also act at the stage where the virus gives instructions to the CD4 cells to produce new viruses, but the method of action is different from the ‘nucs’. Both ‘nucs’ and ‘non-nucs’ block the important reverse transcriptase enzyme.
4. Protease inhibitors (‘PIs’): They act at the final stage where the CD4 cell manufactures new viruses. The protease enzyme is blocked.

All 4 classes of ARVs block important enzymes need for the formation of new HIV.

The 4 classes of antiretrovirals are integrase inhibitors, nucleoside and nucleotide reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors and protase inhibitors.

4-6 What are common examples of nucs?

Common (generic) names of nucs are:

1. TDF – tenofovir
2. AZT – zidovudine
3. ABC – abacavir
4. 3TC – lamivudine
5. FTC – emtricitabine

d4T and ddI have serious side effects and should no longer be used.

Note

These are the common (generic) names of the drugs. For each generic drug there are 1 or more different trade names for the same drug manufactured by different companies. This makes it difficult to remember all the trade names. Therefore, it is best to remember the generic names and only the commonly used trade names of the frequently used ARVs. If possible, use the generic names rather than the trade names. Two older nucs, d4T (stavudine) and ddI (didanosine), have been phased out. No patient should still be receiving ddI. Serious side effects of ddI include pancreatitis, peripheral neuropathy and lactic acidosis are due to interference with mitochondrial metabolism. Some patients who started antiretroviral treatment a long time ago may still be receiving d4T. Initially d4T may be well tolerated but in the long term 20% of patients will have side effects. These may include serious complications such as peripheral neuropathy, pancreatitis, hepatitis, lipodystrophy and lactic acidosis due to mitochondrial DNA depletion. The risk of these side effects is particularly high with d4T, and further increased if the patient is a woman, obese or pregnant.

Note

NRTIs mimic (look like) natural nucleosides (DNA building blocks, e.g. thymidine) and thereby block the function of the reverse transcriptase enzyme. They act as false building blocks for HIV DNA and prevent the HIV instructions being inserted into the DNA of the CD4 cells.

4-7 What are common trade names for the ‘nucs’?

Examples of trade names for nucs are:

1. TDF – is sold as Viread, Ricovir, Zefin.
2. AZT – is sold as Retrovir, Dozra, Zidomat.
3. ABC – is sold as Ziagen, Invertron.
4. 3TC – is sold as 3TC, Legram, Lazena.
5. FTC – is only sold in combination tablet form.
6. d4T – is sold as Zerit.

Trade names are always spelled with a capital letter while generic names are spelled with a lower case letter.

4-8 Can different nucs be used together?

Nucs are generally used in pairs and form the back bone of current treatment regimens. Two nucs (often available as combination tablets) are used with a non-nuc, a PI or an integrase inhibitor to provide triple therapy.

4-9 What are examples of non-nucs?

Common non-nucs are:

1. EFV – efavirenz
2. NVP – nevirapine

Note

Other examples of non-nucs not commonly used are etravirine and rilpivirine.

Non-nucs are particularly powerful inhibitors of HIV multiplication. However, HIV rapidly becomes resistant to non-nucs if they are used alone (they have a low genetic resistance barrier). Therefore, they are usually used with a pair of nucs.

Note

NNRTIs directly inhibit the reverse transcriptase enzyme by binding to it and thereby prevent the formation of DNA containing the HIV genetic code in the CD4 lymphocytes.

4-10 What are common trade names for the non-nucs?

Common trade names for non-nucs are:

1. NVP – is sold as Viramune, Viropan.
2. EFV – is sold as Stocrin, Erige.

4-11 Can different non-nucs be used together?

Unlike nucs, non-nucs are not combined. Only 1 non-nuc is used in a treatment regimen.

4-12 What are examples of protease inhibitors?

Examples of protease inhibitors are:

1. RTV – Ritonavir
2. LPV – Lopinavir
3. ATV – Atazanavir
4. DRV – Darunavir

Lopinavir is only sold in combination with ritonavir. The abbreviation for this combination is LPV/r.

There are a large number of other PIs. They are easy to recognise as their generic names all end in ‘navir’ such as ritonavir. Be cautious not to confuse these with Integrase Inhibitors such as dolutegravir and raltegravir which end in ‘tegravir’.

4-13 What are common trade names for protease inhibitors?

Common trade names for protease inhibitors are:

1. RTV – is sold as Norvir
2. LPV/r – is sold as Aluvia
3. ATV – is sold as Reyataz
4. DRV – is sold as Prezista

4-14 Can different protease inhibitors be used together?

Yes. In fact, low dose ritonavir helps to boost the effect of the other protease inhibitors which means a lower dose of both can be used. This helps to reduce their side effects of the PI.

Lopinivir is only available in combination with ritonavir.

Atazanavir and darunavir are boosted with separate ritonavir capsules.

Other than the use of ritonavir, other PIs are not usually combined with each other. And ritonavir is not used alone.

4-15 What are examples of integrase inhibitors?

Integrase inhibitors (INSTIs) are a relatively new and exciting class of drug. They have recently been made available in the public sector in South Africa where they are available in a fixed dose combination tablet of TDF, 3TC and dolutegravir. The combination tablets is sometimes called TLD (TDF, lamivudine and DTG).

Examples are:

1. RAL – raltegravir
2. DTG – dolutegravir

4-16 What are common trade names for integrase inhibitors?

Common trade names for integrase inhibitors are:

1. RAL – is sold as Isentress
2. DTG – is sold as Tivicay

4-17 Can different integrase inhibitors be used together?

Integrase inhibitors are still a relatively new class of drug. At the moment, they are not used together. They are used in combination with ‘nucs’.

4-18 Can antiretroviral drugs be taken by mouth?

Yes. The common ARVs in all classes can be taken by mouth. It is very important that all ARVs are taken at approximately the same time every day. If a patient forgets a dose, they should be advised to take it as soon as they remember and then continue dosing as normal. All ARVs must be taken by mouth at approximately the same time every day.

4-19 Should a number of antiretroviral drugs be used together?

Yes. With antiretroviral treatment it is essential to use a number of drugs together. This is called multi-drug treatment. It is important to use multi-drug treatment as it is more effective and also reduces the chance of the HIV becoming resistant to the drugs. The same advantages of multi-drug therapy apply to the treatment of TB. Except for the prevention of mother-to-child transmission and post-exposure prophylaxis, single or double drug treatment of HIV infection should never be used.

Multi-drug treatment should be used to treat HIV.

Note

Multi-drug treatment of HIV infection in 1995 showed dramatic results following earlier disappointing results with single drug treatment.

4-20 What is HAART?

Highly active antiretroviral treatment (HAART) is another name for antiretroviral treatment (ART). It is the use of multiple drugs to treat HIV infection. Three or more drugs are always used together for ART.

Three or more antiretroviral drugs are always used together to provide antiretroviral treatment.

Note

Sometimes 1 drug (mono treatment) or 2 drugs (dual treatment) have been used in short-course prophylactic treatment to prevent the transmission of HIV from mother to child during pregnancy and delivery.

4-21 What combination of antiretroviral tablets are available?

There are more and more combination tablets becoming available in South Africa.

Examples of combination nuc tablets, and their trade names, are:

1. TDF + FTC = Truvada, Didivir
2. AZT + 3TC = Combivir, Lamzid, Duovir
3. ABC + 3TC = Kivexa, Epzicom

Non-nucs are not combined with each other, but are available in combination with nucs. This simplifies treatment regimens to 1 tablet taken either once or twice a day.

For example:

1. TDF + FTC + EFV = Odimune, Atripla, Tribuss, Atroiza
2. TDF + 3TC + EFV = Tenarenz
3. AZT + 3TC + NVP = Triplavar
4. D4T + 3TC + NVP = Triomune-30, Virtrium, LamNevStav

The most common protease inhibitor combination tablet is lopinavir/ritonavir.

The integrase inhibitor dolutegravir is available as:
TDF + 3TC + DTG = TLD (tenofovir, lamivudine, dolutegravir)

4-22 Can antiretroviral treatment cure HIV infection?

Unfortunately not. However, ART can dramatically improve the symptoms and clinical signs of HIV infection and allow the patient to remain healthy for many years. ART is the most important advance in the management of HIV infection. ART can change the outcome of HIV infection from a rapidly fatal disease into a manageable chronic illness.

Antiretroviral treatment is the most important advance in the management of HIV infection and has changed the course from a rapidly fatal disease into a manageable chronic illness.

Standardised regimens for antiretroviral treatment

4-23 What is a standardised regimen for treating HIV infection?

The choice of which ARVs to use can be based on either an individualised or a standardised approach. Initially an individualised approach was used where the most appropriate drugs were chosen to meet the needs of each patient. More recently a standardised approach has been used where all patients are started on the same combination, as is done with TB treatment.

4-24 What are the advantages of using a standardised regimen?

1. The standardised approach is safer, easier and simpler.
2. It is also affordable and effective.
3. Both healthcare workers and patients can learn how to use these drugs correctly and which side effects to be aware of. The education and training of healthcare workers and patients are much easier.
4. It limits the number of drugs that are used and makes it possible to monitor patterns of drug use and resistance. Monitoring for side effects is simplified.
5. It is easier to buy and distribute a limited range of drugs.
6. Fixed doses are used in the standardised approach.

The standardised approach to antiretroviral drugs is preferred.

A standardised regimen consists of a specific combination of ARVs where the risk of drug interactions and side effects are low. The drug combination should target at least 2 sites in the life cycle of HIV (i.e. important stages in the viral replication).

4-25 What are the disadvantages of an standardised approach?

Using combinations of ARVs is very complicated as each combination has its own risk of drug interactions. Some drugs counteract each other (block the function of the other drug). Other drug combinations have a high risk of serious side effects. Therefore, a wide knowledge and experience of these drugs is essential if the individual approach is to be used. This ability is usually only available at antiretroviral clinics where particularly difficult management problems are referred.

4-26 What is a first-line combination?

This is the combination of drugs which is routinely used when patients first start ART.

4-27 What is the first-line combination commonly used in South Africa?

Since 2014, South African guidelines have recommended the combination of TDF plus 3TC or FTC with efavirenz as first line treatment. But this has been changed replacing efivarenz with dolutegravir since 2019. Unless contraindicated, all patients, including pregnant women, should be started on this regimen which should preferably be prescribed as a once daily fixed dose combination tablet. Abacavir (ABC) can be used if there are contraindications to TDF and efivarenz, nevirapine or lopinavir/ritonavir can be prescribed if dolutegravir is contraindicated. Some old regimes still use d4T instead of TDF. However, d4T is being phased out and should be replaced by TDF, or AZT if TDF is contraindicated.

Note

The first line in South Africa has changed from TDF + FTC + EFV to TDF +FTC + DTG. This combination is commonly known as TLD Remember: patients should no longer be on d4t or ddI.

This combination of TDF, 3tc and DTG is chosen for its effectiveness and availability, few serious side effects and low cost.

In South Africa first line antiretroviral treatment is now with TDF, FTC and dolutegravir in a single fixed dose combination tablet taken once daily.

4-28 What is a second-line combination?

Patients who fail to respond to the first-line combination, despite good adherence, are changed to a second-line combination of ARVs.

4-29 What common second-line combination is used in South Africa?

Usually 2 nucs plus a boosted protease inhibitor. The common second-line combination in South Africa is AZT plus 3TC plus lopinivir boosted with ritonavir and lopinavir together. TDF can be used instead of AZT if the failed first-line combination included AZT or d4T.

The previous second-line combination of AZT, ddI and Aluvia is sometimes still used.

Therefore both the first- and second-line combinations include 2 nucs. However, only the first-line combination includes a non-nuc while usually only the second-line combination includes PIs.

In South Africa the standard new second-line combination is AZT plus 3TC plus lopinavir/ritonavir.

4-30 When are other combinations of antiretroviral drugs used?

Sometimes changes to the first- or second-line combinations are made when there are serious side effects to only 1 drug in a standardised regimen e.g.

1. Patients who experience severe psychological side effects to efavirenz may be switched to nevirapine. Nevirapine cannot be used in patients with a high CD4 count (women CD4 above 250 cells and men CD4 above 350 cells). In this case dolutegravir or lopinavir/ritonavir can be used as part of a first line regimen.
2. Patients who are intolerant to lopinavir and ritonavir (i.e. who have severe diarrhoea over a number of weeks or who have a total serum cholesterol above 6 mmol/l) may be switched to dolutegravir or atazanavir and ritonavir.
3. Patients who are on the old first line regimen of d4T, 3TC and efavirenz or nevirapine should be changed to a fixed-dose combination tablet of TDF, 3TC and DTG.
4. Patients who are hepatitis B positive and fail a first line regimen containing TDF should remain on TDF in addition to 2 nucs and dolutegravir or a protese inhibitor in their second line regimen (for example, TDF + AZT + 3TC + DTG or lopinivir/ritonavir).

Changes (swaps) should only be made by an experienced clinician at an antiretroviral clinic and care should be taken to ensure that the patient has a suppressed viral load at the time of a 1 drug switch. Using individualised combinations reduces the future options of treatment.

Note

Patients who have failed to respond to both first- and second-line combinations, despite proven good adherence (e.g. pill count), may be offered third-line treatment if resistance testing shows resistance to protease inhibitors. If the patient is treated in the public sector, an expert panel will review the patient’s history and resistance results and will recommend a third-line regimen which may contain darunavir–ritonavir together with the integrase inhibitor, raltegravir and an NNRTI, etravirine.

The most common reason for failing to respond, especially to second line, is poor adherence.

Antiretroviral medication

4-31 What are the practical implications of taking antiretroviral treatment?

The following questions must be considered:

1. Which medications are taken?
2. How many tablets or capsules are taken at a time?
3. When and how often is the medication taken?
4. Should the medication be taken with or without food?
5. Can all the drugs be taken together at the same time?

4-32 How should tenofovir be taken?

TDF is taken once a day, usually at night, with or without food. TDF may cause renal impairment, noted by an increase in serum creatinine concentration in the first few months of treatment.

4-33 How should AZT be taken?

AZT is taken twice daily (12-hourly). Tablets can be taken with or without food. However, nausea may be less if taken with food. AZT has many short term minor side effects such as fatigue, nausea and vomiting, headache, muscle pains and altered taste. These are common at the start of treatment and are worse with higher doses. However, they become less after a few weeks. AZT may also discolour the nails.

The most important side effect of AZT is anaemia. This usually occurs in the first few months of treatment.

AZT may cause anaemia.

Note

Serious complications of AZT are anaemia, neutropenia and lactic acidosis.

Table 4-1: Details of antiretroviral drugs

Drug	Drug class	Generic	Trade	Dose	Frequency*
TDF	Nuc	tenofovir	Viread	300 mg	Daily
AZT	Nuc	zidovudine	Retrovit	300 mg	Twice daily
ABC	Nuc	abacavir	Viagen	600 mg	Daily
ABC**	Nuc	abacavir	Viagen	300 mg	Twice daily
3TC	Nuc	lamivudine	3TC	300 mg	Daily
3TC**	Nuc	lamivudine	3TC	150 mg	Twice daily
FTC	Nuc	emtracitibine	Truvada (with TDF)	200 mg	Daily
NVP	Non-nuc	nevirapine	Viramune	200 mg	Twice daily***
EFV****	Non-nuc	efavirenz	Stocrin	600 mg	Daily
LPV/r	PI	lopinavir/ritonavir	Aluvia	400 mg/100 mg	Twice daily
Atazanavir/ritonavir	PI	atazanavir/ritonavir	Reyataz/Novir	300 mg/100 mg	Daily
d4T	Nuc	stavudine	Zerit	30 mg	Twice daily
DTG	INSTI	dolutegravir	Tivicay	50 mg	Daily

* Twice daily doses are best taken 12 hours apart e.g. 7 am and 7 pm.
** 3TC and abacavir can be taken daily or twice daily, depending on whether the rest of the regimen is daily or twice daily.
*** Only 1 tablet of nevirapine daily at night for the first 2 weeks of treatment.
**** Efavirenz is best taken on an empty stomach for the first few weeks.

4-34 How should abacavir be taken?

ABC 300 mg (1 tablet) should be taken every 12 hours if taken twice a day. ABC can also be taken as 2 tablets once a day. ABC is usually used if a patient cannot take TDF. ABC is well-tolerated though there is a small risk of a severe initial hypersensitivity reaction.

Note

Up to 3% of people taking ABC will have an initial reaction which can be severe and even fatal if treatment is not stopped.

4-35 How should 3TC or FTC be taken?

3TC can be taken as a 150 mg twice a day (12-hourly) or as 300 mg (one 300 mg tablet or two 150 mg tablets) once a day, with or without food. 3TC is well tolerated and has very few side effects. Mild nausea, headache and diarrhoea may occur.

FTC is very similar to 3TC in terms of function and side effect profile. It is only available in combination with TDF so dosing should be as for TDF.

3TC and FTC are well tolerated with few side effects

4-36 How should efavirenz be taken?

Efavirenz is usually taken at night. Efavirenz has the advantage of the patient only needing a single dose a day.

A rash may occur. However this side effect is less common and not always as severe as with nevirapine. Efavirenz commonly causes mild emotional symptoms for the first few weeks (mood changes, abnormal dreams, insomnia and dizziness). It can also cause drowsiness. These are reduced if efavirenz is taken on an empty stomach in the evening. When side effects have cleared efavirenz should be taken with meals.

Note

The absorption of efavirenz is greater if it is taken with meals. This may make side effects worse during the first weeks of treatment and so patients can then choose to take their dose on an empty stomach for the first few weeks. Patients who work at night and are on efavirenz can take their ART in the morning, before they go to sleep, but should try to take it at approximately the same time every day.

4-37 How should nevirapine be taken?

Nevirapine is very similar to efavirenz.

One nevirapine 200 mg tablet is taken at night to start with. After 14 days the dosage is increased to 1 tablet twice daily (12-hourly). If there is a mild rash or raised liver enzymes, do not increase the dose to twice a day until the liver enzymes have dropped and the rash has cleared.

A mild rash is common, usually during the first 6 weeks of treatment. A severe rash may also occur with nevirapine. The drugs must be stopped immediately if a severe rash appears.

Note

Serious complications of nevirapine include blistering rash with mucosal involvement, hepatitis and fever due to a hypersensitivity reaction. This is more common if NVP is started in patients with a high CD4 count (women above 250 cells, men above 400 cells).

Nevirapine may cause early, serious side effects.

4-38 Is efavirenz safe for pregnant women?

Initially, efavirenz was avoided during the first trimester of pregnancy, as it was thought to cause fetal abnormalities (birth defects). Subsequent data has shown no increase in fetal abnormalities with efavirenz and current guidelines recommend the use of efavirenz throughout pregnancy.

TDF, AZT, ABC, FTC, 3TC, NVP and Aluvia are all considered safe in pregnancy, too.

Efavirenz is safe in women who want to fall pregnant or who are already pregnant.

4-39 How should protease inhibitors be taken?

Lopinavir is only available as a combination tablet with ritonavir. This combination of Lopinavir 400 mg and ritonavir 100 mg (LPV/r) is called Aluvia. Two tablets of Aluvia are taken twice a day (12-hourly) with or without food. Nausea and diarrhoea are common for the first few weeks. These side effects can be reduced if the drug is taken with food. Metoclopramide (Maxalon) and loperamide (Imodium) can be used to try to counter the side effects of Aluvia. Due to drug interactions, the dosages of many drugs have to be altered if they are used together with lopinavir and ritonavir.

Atazanavir 300 mg is usually taken with ritonavir 100 mg, both once a day. Atazanavir is usually better tolerated than lopinavir. Patients may present with jaundice, due to an increase in unconjugated bilirubin. Liver functions will be normal. This jaundice is harmless and the atazanavir can be continued.

Note

Protease inhibitors may be associated with insulin resistance and hyperlipidaemia. Protease inhibitors may also affect the metabolism and breakdown of many drugs (ritonavir inhibits cytochrome P450 and thereby increases the blood level of lopinavir and a wide range of other drugs). A small dose of ritonavir therefore boosts the effect of lopinavir. 
 The dose of lopinavir/ritonavir must be increased if used with efavirenz or rifampicin. Atazanavir/ritonavir cannot be used with rifampicin.

4-40 How should dolutegravir be taken?

Dolutegravir is taken as a 50mg tablet, once daily. It may be taken with or without food.

The most common side effects are insomnia and headaches in the first few weeks. Drug induced liver injury is uncommon but has been documented, much more rarely when compared to efivarenz and nevirapine.

In patients on TB treatment with rifampicin, the dolutegravir dose needs to be doubled. The WHO cautions the use of dolutegravir in women of child bearing age who plan to be pregnant, further analysis of risk is still ongoing.

4-41 Which antiretroviral drugs are best be taken with a meal?

Only Aluvia capsules and atazanivir are best taken with a meal.

AZT works best on an empty stomach, but nausea is less if it is taken with a fatty meal.

The side effects of EFV are less if taken on an empty stomach in the first few weeks.

Most other ART can be taken with or without food.

Most antiretrovirals can be taken with or without food. Not having food is not a reason to miss a dose.

4-42 Which drugs must be kept cool?

Only LPV/r capsules should be kept in the fridge, although they are stable at room temperature for 30 days. LPV/r tablets do not need to be refrigerated.

Side effects of antiretroviral drugs

4-43 Do all antiretroviral drugs have side effects?

Side effects to ARVs are common and usually mild, but they can sometimes be severe. Remember that drugs used to treat HIV-associated infections also cause side effects, which may be similar to the clinical symptoms and signs of HIV infection. Most side effects can be easily managed.

Side effects can be graded into mild (grade 1), moderate (grade 2), severe (grade 3) and potentially life threatening (grade 4).

All drugs, including antiretroviral drugs, may have side effects.

4-44 Should patients be warned about side effects?

It is very important that patients know the common side effects of the ARVs that they are taking. Educating patients about side effects is an important part of care. It is important that patients are able to monitor themselves for side effects and know which side effects to look out for and which can be serious.

Patients should be educated about side effects.

4-45 What should patients do if they are concerned they may have side effects?

Whenever a patient is concerned about side effects, they should report to the clinic. If side effects are mild, ARVs should not be stopped. Sometimes other medication can be taken to help relieve symptoms (paracetamol for headache and anti-emetics for nausea and vomiting). Taking antiretroviral treatment with food often helps reduce side effects. Antiretroviral treatment may need to be stopped if side effects are severe. Fortunately, most side effects are mild. The majority of patients will not experience any side effects.

4-46 When do most side effects occur?

Most side effects occur in the first 6 weeks of starting antiretroviral treatment. They usually get better on their own after 1 to 2 months. However, some serious side effects may occur at any time that ARVs are taken even years later, and the longer a patient takes antiretroviral treatment, the more late-occurring side effects we will learn about.

4-47 Which side effects occur during early treatment?

Minor side effects are common, e.g. nausea, vomiting, diarrhoea, headaches, muscle pains, sleeplessness, minor rashes. However, serious side effects such as serious rashes and hepatitis may also occur early and need to be looked out for.

Most minor side effects during the initiation of ART get better over time without any treatment.

Peripheral neuropathy may also occur early in treatment.

4-48 Which side effects occur during later treatment?

Side effects which occur late in treatment include:

• Lipodystrophy and fat wasting
• Lactic acidosis
• Peripheral neuropathy

Note

Some other metabolic disorders can occur later in treatment (with or without lipodystrophy) including high cholesterol and glucose levels.

4-49 What are the common but less serious side effects of antiretroviral drugs?

Tiredness, nausea and vomiting, headaches and diarrhoea are common and may be caused by all classes of ARVs. These side effects are not serious and usually settle after the first few days or weeks.

Most patients experience no side effects.

Note

Severe vomiting or diarrhoea may cause dehydration as well as reduce absorption of medication.

4-50 What are the serious but less common side effects may occur with antiretroviral drugs?

1. Rash
2. Hepatitis
3. Anaemia
4. Peripheral neuropathy
5. Renal failure
6. Wasting and accumulation of fat (lipodystrophy)
7. Pancreatitis
8. Severe vomiting or diarrhoea

Table 4-2: Summary of side effects of antiretrovirals drugs

Drug	Common side effects	Serious side effects
NRTIs (Nucs)
TDF	Nausea, diarrhoea, vomiting, renal impairment	Rash Severe acute exacerbations of Hepatitis B on withdrawal of TDF**
AZT	Nausea and vomiting, anaemia, neutropenia	Hyperlactataemia, hepatic steathosis (fatty liver)
ABC	Generally well tolerated	Potentially life threatening hypersensitivity reaction*
3TC and FTC	Generally well tolerated
d4T	Peripheral neuropathy, lipodystrophy	Pancreatitis, lactic acidosis
ddI	Peripheral neuropathy, lipodystrophy	Pancreatitis, lactic acidosis
NNRTIs (Non-nucs)
Nevirapine	Rash, abnormal liver function tests, clinical hepatitis	Potentially life threatening hypersensitivity reaction*
Efavirenz	Abnormal dreams, headache, impaired concentration, dizziness, insomnia, fatigue, rash, gynaecomastia.	Severe rash Severe depression and psychotic-like symptoms
Protease Inhibitors (PIs)
Ritonavir	Nausea, vomiting, diarrhoea, hyperglycaemia, new onset diabetes, worsening of existing diabetes Lipodystrophy	Hypersensitivity reaction including anaphylaxis
Lopinavir/ritonavir	Diarrhoea, hyperglycaemia, new onset diabetes, worsening of existing diabetes Lipodystrophy
Atazanivir	Nausea, jaundice (unconjugated hyperbilirubinaemia), better tolerated than LPV/r	Hypersensitivity reaction
Integrase Inhibitors
Dolutegravir	Hypersensitivity reaction and hepatotoxicity (liver problems)	Insomnia, fatigue and headache

* Usually in first 6 weeks of treatment
** This may occur on withdrawal of TDF. Patients failing first line should be tested for Hepatitis B surface antigen, and if they are positive should remain on TDF in addition to the standard third line regimen.

4-51 What rashes occur commonly with antiretroviral drugs?

1. Mild rashes are common and include a localised or generalised erythematous (pink), maculopapular (measles-like) or urticarial rash with no other symptoms.
2. Severe rashes include any rash with blistering, peeling or involvement of the mucous membranes of the mouth and conjunctivae. A severe rash may also present together with fever, a fast pulse or abdominal pain (due to hepatitis). Severe rashes are due to a hyper­sensitivity reaction and can be fatal.

Rashes are common with antiretroviral treatment and usually are caused by non‑nucs, especially nevirapine. TDF and ABC may also cause a rash. These rashes almost always occur in the first 6 weeks of treatment. The rashes from NVP and ABC may be part of a systemic hypersensitivity reaction and can be life threatening.

Antiretroviral treatment commonly causes skin rashes. The rashes from NVP and ABC hypersensitivity can be life threatening.

Remember that HIV infection itself and drugs used to treat HIV-associated infections (especially co-trimoxazole) also commonly causes rashes. Therefore the rash may not be due to the ARVs.

Note

Severe rashes due to a hypersensitivity reaction may result in Stevens-Johnson syndrome and toxic epidermal necrolysis (TEN). Always look for mucous membrane involvement. Constitutional symptoms such as fever are also present and warn of a dangerous side effect. Always look for hepatitis with severe drug rashes.

4-52 How should skin rashes be managed?

Nevirapine must always be started at half doses (i.e. 200 mg once daily) for the first 14 days as this reduces the risk of a rash. Continue treatment if the rash is mild. Do not increase the dose of nevirapine until any rash has settled.

All patients with a severe rash must be referred to an experienced clinician urgently. If this cannot be done on the same day, stop all 3 ARVs immediately and send the patient to an antiretroviral clinic as soon as possible. Usually nevirapine is swapped for a protease inhibitor. Patients who develop a severe rash or hypersensitity reaction on NVP or EFV must never be given a non-nuc again (i.e. neither nevirapine nor efavirenz should ever be prescribed again). Patients who develop a severe rash or hypersensitivity on ABC must never get ABC again.

Note

Severe side effects with nevirapine are more common if antiretroviral treatment is started in patients who have a high CD4 count, above 250 cells/µl in women and above 400 cells/µl in men. Nevirapine should not be substituted by efivarenz if a patient has a serious rash from nevirapine, this is because there’s usually cross reaction between nevirapine and efivarenz.

All antiretroviral drugs must be stopped immediately if a severe rash occurs.

Note

Steroids and antihistamines do not help most sensitivity rashes caused by nevirapine.

4-53 Which antiretroviral drugs cause hepatitis?

All classes of ARVs can cause hepatitis. However, nevirapine is the drug which is usually associated with hepatitis. Efavirenz can also cause hepatitis but less commonly, with dolutegravir hepatitis is even less common.

Hepatitis due to nevirapine is most common in patients, especially women, who have a high CD4 count before the start of treatment.

Liver function tests (ALT, i.e. alanine amino transferase) should be done on all patients when nevirapine is started and also should be checked if a patient on efavirenz or nevirapine develops a rash or symptoms of hepatitis. Total bilirubin should be done in addition to ALT if symptoms of hepatitis appear.

Hepatitis is usually caused by nevirapine.

Note

Nevirapine causes asymptomatic hepatitis in 10% and clinical hepatitis in 1% of patients. Nevirapine plus TB treatment increases the risk of severe rash and hepatitis. Co-trimoxazole may also cause hepatitis with raised enzymes. Nucleoside reverse transcriptase inhibitors may cause a fatty liver (steatosis).

4-54 What are the clinical signs of hepatitis?

Hepatitis may be clinical (nausea, loss of appetite, jaundice, enlarged liver, itching and abdominal pain) or asymptomatic (when it is diagnosed by finding raised liver enzymes in the blood without any clinical signs of hepatitis). An ALT level above 3 times normal (normal below 40 iu/l) indicates an increased risk of hepatitis.

Note

Liver damage can be severe and permanent, but rarely fatal.

4-55 What is the management of a patient with hepatitis?

Patients with asymptomatic hepatitis and only mildly raised liver enzymes (up to 5 times normal) can be followed clinically without stopping the drugs. The hepatitis usually resolves. Using a low dose of nevirapine (200 mg daily) for the first 2 weeks lowers the risk of hepatitis (and rash).

Patients with clinical hepatitis or asymptomatic hepatitis with markedly raised liver enzymes should be urgently referred to an antiretroviral clinic where stopping all treatment may be considered.

4-56 Is anaemia a common problem with antiretroviral drugs?

Anaemia (Hb below 10 g/dl) is seen in few patients receiving AZT. These patients may appear pale and feel weak and dizzy. Anaemia is usually mild and the AZT need not be stopped.

A haemoglobin level or full blood count should be done when AZT is started and should be repeated at months 3 and 6 and then every 12 months. Patients with a haemoglobin level below 8 g/dl due to AZT should have the AZT dose reduced or should swap the AZT for another NRTI.

Anaemia is a side effect of AZT. HIV can also cause anaemia so a baseline Hb is important.

Note

With severe anaemia (haemoglobin less than 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 should be closely followed. The AZT dose can be reduced to 200 mg twice daily. AZT also causes neutropenia but does not lower the platelet count.

4-57 What is peripheral neuropathy and can anything be done to treat it?

This is a problem which affects the peripheral nerves, especially in the legs. It presents with burning pain, numbness and abnormal sensation in a ‘glove and stocking’ distribution. Most patients with peripheral neuropathy present with painful feet at night.

Peripheral neuropathy is usually caused by nucs which have a ‘d’ in their names, e.g. ddI and d4T. Since these drugs were previously commonly used, patients who have been on ART for a long time may have residual symptoms of peripheral neuropathy and so it is important to know how to manage it. The symptoms of peripheral neuropathy may slowly improve after the drugs have been stopped. Other drugs, such as INH and alcohol may also cause peripheral neuropathy.

d4T and ddI are associated with peripheral neuropathy and should not be used together. Patients who have been on antiretroviral treatment for a long time may have residual symptoms.

This is neuropathic pain and usually responds well to amitriptyline at night.

4-58 Do any antiretroviral drugs cause renal damage?

TDF can cause renal damage, which presents as a drop in creatinine clearance. Therefore creatinine clearance should be monitored at 1 month, 3 or 4 months, 6 months and then 12-monthly thereafter, when the drug is used. Do not use TDF if the creatinine clearance is less than 50 ml/min.

Note

TDF may also cause a rash and, on rare occasions, decrease phosphate levels, resulting in bone fractures.


TDF can cause kidney damage.

4-59 What is lipodystrophy and what can be done about it?

Lipodystrophy is an abnormal distribution of subcutaneous fat resulting in a change in body shape (fat redistribution syndrome). Fat is lost (lipoatrophy) from the face and limbs and gained (accumulated) over the abdomen, back of the neck and breasts. Unfortunately lipodystrophy is not usually corrected when the ARVs are changed. Many patients gain weight when antiretroviral treatment is started. Lipodystrophy is usually caused by the older nucs (ddI, d4T) efavirenz, AZT and the protease inhibitors.

A lot of fat accumulation can resolve with weight loss. Plastic surgery remains an option for disfiguring fat accumulation such as buffalo hump.

Lipodystrophy is a redistribution in body fat and is usually worse with AZT, and the proteas inhibitors.

Note

Lipodystrophy with central obesity and peripheral wasting may be associated with insulin resistance and fasting hyperlipidaemia with a raised plasma cholesterol and triglyceride concentration (the lipodystrophy syndrome). Marked hypertriglyceridaemia can cause pancreatitis while a raised serum cholesterol increases the risk of coronary heart disease.

4-60 Which drugs may cause lactic acidosis?

Lactic acidosis is a rare but serious and potentially fatal side effect of nucs, particularly d4T and ddI. Lactic acidosis has become a rare side effect of ART since the introduction of TDF in first line treatment instead of d4T, but one should be aware of it due to its serious consequences. It usually only occurs more than 6 months into treatment when patients have responded well and are clinically improving with good adherence. It is most common in women who are overweight or pregnant. Patients with lactic acidosis present with a gradual onset of tiredness, weight loss and abdominal complaints (nausea, vomiting, abdominal pain or discomfort). Always suspect lactic acidosis if patients, who have been well and gaining weight for months, start to lose weight.

Lactic acidosis is a rare but serious side effect of nucs and occurs after months of good response to treatment.

Patients with suspected lactic acidosis must be immediately taken off all treatment and urgently referred to hospital for investigation and management.

Note

Hyperlactataemia (serum lactate above 2 mmol/l) and lactic acidosis often with hepatic steatosis (fatty liver), liver failure, pancreatitis or peripheral neuropathy, are due to mitochondrial damage as nucs also interfere with the replication of mitochondrial DNA. Asymptomatic hyperlactataemia (without acidosis) is common (up to 20%) while symptomatic hyperlactataemia (without acidosis) occurs in 1% and hyperlactataemia with lactic acidosis in 0.1% of patients on nucs. The risk is lower with AZT than d4T. TDF, ABC and 3TC are relatively safe and can be started once the lactate has returned to normal.

4-61 Which drugs cause pancreatitis?

Pancreatitis (inflammation of the pancreas) is another severe complication of d4T and ddI, especially when they are used together. Again, with the phasing out of these drugs, pancreatitis due to ART should be rare. Alcohol abuse may increase the risk of pancreatitis.

Pancreatitis presents with vomiting, abdominal pain and tenderness. The drugs must be stopped immediately and the patient urgently referred.

Abdominal pain or discomfort is an important symptom in patients on ART as it may be due to hepatitis, lactic acidosis or pancreatitis.

Note

The serum amylase and lipase levels are raised in pancreatitis.

4-62 What is the management of severe vomiting or diarrhoea?

Some ARVs cause nausea and 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 Aluvia). This can lead to dehydration. Taking medicine with food and anti-nausea medication may help reduce vomiting. Efavirenz should be taken without food if it causes vomiting.

Oral rehydration solution will help prevent or correct dehydration. Patients with signs of severe dehydration should be urgently referred to hospital.

4-63 Should antiretroviral drugs rather not be used because of their side effects?

No. ARVs are a very important part in the treatment of HIV infection and the only way of managing AIDS. Like most other drugs, they have side effects. Usually side effects are mild and the ARVs need not be stopped. Most patients have no or only mild side effects. However, both patients and health workers should know the symptoms and signs of severe side effects. If these appear the drugs must be stopped immediately and the patient referred urgently to an antiretroviral clinic for assessment.

Patients should be encouraged to return to the clinic before their given date if the side effects are making them not want to take their antiretroviral treatment so that the clinician can help reassure, manage the side effects or find an alternative drug.

The advantages of antiretroviral drugs far outweigh the side effects.

4-64 Do patients lose weight on antiretroviral treatment?

Normally patients feel better and gain weight when ART is started. Therefore weight loss on ART is an important danger sign. It may be due to common early side effects such as nausea, vomiting or diarrhoea. However, weight loss in patients who have previously been well may also indicate the development of lactic acidosis or TB.

Many patients on ART complain of hunger once their immune system starts to recover. This may be a problem in poor people who cannot afford to buy more food.

Patients who have been doing well on antiretroviral treatment who start to lose weight should have the cause investigated.

4-65 Should one drug be stopped if side effects are severe?

It may be necessary to stop an ARV if severe side effects occur, e.g. severe rash or clinical hepatitis. If this is done, all drugs must be stopped together. Stopping 1 drug will lead to resistance of the remaining 2 drugs. The drug combination must be carefully examined as the problem drug may have to be swapped or a different combination may be needed. Changing drugs must always be done at an antiretroviral clinic by an HIV expert. HIV infection must never be treated with only 1 or 2 drugs. A full combination of 3 drugs is always needed.

If necessary, stop all antiretroviral drugs and not just 1 drug.

Case study 1

A patient with HIV infection, who has been treated with AZT alone for 2 weeks by a general practitioner, is referred to an HIV clinic. The patient complains of headache, nausea and feeling generally unwell since the treatment was started.

1. Do you agree with AZT alone as acceptable treatment for AIDS?

No. One or 2 drugs alone should never be used to treat HIV. Three drugs are always used together (multi-drug therapy), e.g. AZT, 3TC and lopinavir/ritonavir.

2. What is the advantage of using multiple drugs?

There is a higher rate of successful treatment with less drug resistance.

3. Why is this patient complaining of headache, nausea and feeling unwell?

These are common side effects of AZT. Mild side effects of ART usually settle on their own after a few weeks. Unless the side effects are serious, treatment should not be stopped. Mild side effects can be treated symptomatically.

4. What is an important side effect of AZT?

Anaemia. Therefore the haemoglobin concentration should be monitored in patients receiving ART which includes AZT.

5. What class of drug is AZT?

TDF, AZT, 3TC, d4T, ABC and ddI are nucs. They all block an important enzyme and thereby prevent HIV from infecting CD4 lymphocytes. Nucs are used in most multi-drug regimens to treat HIV.

6. What are the main goals of antiretroviral treatment?

To suppress the replication of HIV. This will allow the immune system to recover (increased CD4 count), improve the patient’s clinical condition and decrease the risk of death, while at the same time reducing HIV transmission risk.

Case study 2

A young woman who has HIV infection presents at an HIV clinic with the hope of being cured. She wants to start a family as soon as she is well again.

1. Can antiretroviral treatment cure HIV infection?

Unfortunately not. However, it can markedly improve the patient’s health and make HIV infection a chronic but manageable disease.

2. What treatment should she receive?

She should be given a standardised regimen. Once she has been prepared for treatment, a first-line combination of TDF, FTC and efavirenz will be started. EFV instead of dolutegravir as she is wanting to start a family.

3. What is a standardised regimen?

This is a fixed combination of ARVs. There are many advantages to a standardised regimen over an individualised regimen. With an individualised regimen each patient is given their own specific combination of ARVs.

4. What are the advantages of a standardised regimen?

It is simpler, safer and cheaper to use with fewer side effects and drug interactions. The education and training of both patients and staff is much easier. Tuberculosis is also treated with a standardised fixed combination of drugs.

5. What first-line regimens are used in South Africa?

The first line regimen of choice is TDF plus FTC and dolutegravir as a once daily combination tablet (TLD).

Other first line regimens are:

1. TDF, FTC and efivarenz if dolutegravir is contra-indicated.
2. Abacavir, 3TC and efavirenz if there is a contraindication to TDF
3. TDF, 3TC and nevirapine or Aluvia if there is a contraindication to efavirenz or dolutegravir.

6. Which non-nuc would you choose for this woman?

Efavirenz is the non-nuc of choice, particularly if her CD4 count is above 250 cells/µl as people with high CD4 cell counts have an increased risk of hepatitis when starting nevirapine.

Case study 3

A patient has recently started on a first-line regimen with nevirapine. Three weeks after starting ART he develops a fever and feels ill with a generalised blistering skin rash which also involves his mouth.

1. Are skin rashes common with nevirapine?

Yes. They are usually mild and the patient does not feel generally unwell. With continued ART most mild skin rashes caused by nevirapine will disappear.

2. Would you be concerned about this patient’s skin rash?

Yes, because this is a serious rash and the patient is ill with a fever. Any blistering skin rash, especially if it involves the mouth, is potentially life threatening. All drugs must be stopped immediately and the patient should be referred urgently to hospital. Nevirapine will have to be replaced (swapped) with a protease inhibitors such as Aluvia.

Nevirapine should not be substituted by efivarenz if patient has a serious rash from nevirapine because there’s usually cross reaction between nevirapine and efivarenz.

3. Should this patient be given efavirenz instead of nevirapine?

No. This patient must never again be given a non-nuc (either nevirapine or efavirenz) as the severe reaction is likely to recur.

4. What other serious side effect may be caused by nevirapine?

Hepatitis. Clinical hepatitis presents with nausea and vomiting, abdominal pain and jaundice. A rash and hepatitis may occur together. Patients with any signs of hepatitis must be urgently referred to hospital. Severe hepatitis can be fatal.

5. How can the risk of side effects with nevirapine be reduced?

By starting with a smaller dose for the first 2 weeks of treatment (1 tablet at night only).

6. Should patients be warned about side effects?

It is very important that patients be well educated about the symptoms and signs of the common side effects before ART starts. They should immediately report any side effects to the clinician, which means they should be educated to come to the clinic before their next scheduled appointment if they have any side effects that they are concerned about.

Case study 4

During preparation for ART a group of patients is fully informed about the drugs they are going to take. One patient is afraid of starting treatment when he learns about the possible side effects. A friend of his developed very painful legs after ART was started.

1. What information about the anti­retroviral drugs should patients be given?

They should know the names and appearances of the drugs in the first-line combination. They must know how many drugs to take and when they should be taken.

2. How many times a day are antiretroviral drugs taken?

Some drugs (e.g. AZT and 3TC) are taken twice a day (12-hourly) while TDF and Efavirenz are taken once a day. Some formulations of 3TC also allow once daily dosing. Nevirapine is taken once a day to start, but later is also taken twice a day. In general, first line is taken once a day and second line is taken twice a day.

3. Should antiretroviral drugs be taken with meals?

Most ARVs can be taken with or without meals. Efavirenz can be taken on an empty stomach initially to reduce side effects. Nausea from AZT can be reduced by taking it with a meal.

4. Should patients who are afraid of the side effects rather not take antiretroviral drugs?

No. ARVs are the only way to effectively treat patients with HIV. Without antiretroviral treatment they will die. Most patients have no or only mild side effects. Side effects can be managed symptomatically, or a drug switch can be made if necessary, if the clinician is made aware of the side effects.

5. Which antiretroviral drugs cause painful legs?

Pain and numbness of the hands and feet are due to peripheral neuropathy. This is usually caused by d4T or ddI but can also be seen with AZT. Other drugs such as INH and alcohol may also cause peripheral neuropathy. It is important to know about this because, even though most patients won’t be on these drugs anymore, they may have residual peripheral neuropathy from taking these drugs in the past.

Case study 5

After failing treatment with the first-line combination of ART, a patient is started on the second-line combination. She feels much better on the new treatment. However, after a few months she notices that her face is becoming wasted and she is gaining weight around her abdomen.

1. What antiretroviral drugs are used in the second-line combination?

This depends on the first line regimen but the usual combination is AZT and 3TC plus lopinavir/ritonavir.

2. What class of drugs are these?

AZT and 3TC are nucs. As with the first-line combination, nucs are an important part of the multi-drug regimen. Aluvia is a combination of 2 protease inhibitors (ritonavir and lopinavir). The second-line combination therefore includes protease inhibitors but not non-nucs.

3. How should lopinavir/ritonavir be taken?

Twice a day with or without meals.

4. What are common minor side effects with lopinavir/ritonavir?

Nausea and loose stools. These are less troublesome if the medication is taken with meals. Metoclopramide and loperamide can also help with these symptoms.

5. Why is this patient developing wasting of the face?

Unfortunately peripheral wasting of the face and limbs and central fat accumulation over the stomach and back of the neck may occur with AZT and the protease inhibitors. This change of body shape due to the redistribution of fat does not always resolve if these drugs are stopped.

6. What is the name of this condition?

Lipodystrophy.