AIDS Treatment Update, Issue 41, May 1996
Edward King

Side-effects are sometimes referred to as adverse drug reactions (ADRs), adverse effects (AEs) or simply toxicities. The side-effects of most drugs are well established. Information on toxicities is gathered during clinical trials and from reports from doctors who prescribe the drugs once they are approved.

However, many drugs used by people with HIV are relatively new, and the urgent need for effective medications has meant that many anti-HIV drugs have been released onto the market after only a relatively small number of people have taken them for a relatively short period of time. This means that the information on side-effects and drug interactions is likely to be less complete than with other drugs.

In addition, people with HIV infection may be more likely to experience side-effects from a drug than uninfected people. For example, co-trimoxazole (Septrin) causes side-effects in about 30% of HIV-positive people, but in only about 10% of those who are HIV-negative. People with advanced HIV infection are more likely to experience side-effects from a given drug than healthier people with HIV. The risk of side-effects from a given drug may also be altered if you are taking several other drugs too.

* Types of side-effects

Side-effects can be divided into two main types: allergic side-effects and side-effects due to the direct effects of the drug. Allergic side-effects occur when the immune system reacts to a drug or its metabolites (the chemicals into which a drug is broken down in the body) by causing symptoms such as a rash or fever. This is unpredictable - some people can take a drug without developing an allergy, while others suffer severe reactions to it. Sometimes allergies do not occur when a person first takes a drug, but take time to develop.

If you are allergic to a drug, you will probably experience the reactions no matter what dose you take. Often they become more severe each time you encounter the reaction. However, in some cases it is possible to desensitise the immune system to the allergic reactions by starting to take the drug at a very low dose, then gradually building up to the correct dose over time. This strategy has worked well for many people who are allergic to co-trimoxazole (often known by the brand-names Septrin or Bactrim), the commonest form of PCP prophylaxis, but must always be done under medical supervision.

Allergic reactions can sometimes be so serious that they are life-threatening. One of the most serious drug allergies is called Stevens-Johnson syndrome, and is characterised by a blistering rash and ulcers in the mouth, eyes and/or genitals. To reduce the risk of such serious problems, people who develop severe allergic reactions are advised never to take the drug in question again.

Other side-effects may be caused directly by unwanted effects of the drug itself, rather than by the immune system's response. Often the nature of the side-effects will depend on the part of the body which is adversely affected by the drug, or the route by which it is excreted from the body. For example, some drugs damage the cells in the bone marrow which are responsible for producing new blood cells, so may lead to blood abnormalities such as anaemia or neutropenia. Some drugs produce generalised discomfort, such as those that cause nausea, malaise or drowsiness.

Toxic side-effects are usually dose-related; the more drug that is taken, the greater the risk and/or the severity of the side-effects. So a drug may cause side-effects in only a small proportion of people who take the usual dose, but in a larger proportion of people when it is given at a higher dose.

Some people may be vulnerable to unusual or unpredictable side-effects because of inherited conditions. The most common cases are among people whose genetic make-up means that they produce unusually low levels of certain enzymes. For example, people who are lacking the enzyme glucose-6-phosphate dehydrogenase (G6PD) are more likely to suffer blood toxicities from antibiotics such as dapsone, because the lack of this enzyme allows toxic by-products of the drug to accumulate in the body. At-risk groups can be tested for these genetic deficiencies.

* Timing of side-effects

Most side-effects occur after a person has been taking the drug for one or two weeks, although there is no strict pattern to this, and some people will suffer problems after their first dose.

Some side-effects are worst for the first month or two of taking a drug, but may then lessen or disappear altogether. This is often the case with the nausea, vomiting and headaches that can affect people starting AZT. It is now also being reported in the USA among people starting to take the protease inhibitor ritonavir; at first it causes unpleasant side-effects, but these tend to subside after a month or so as your body adjusts to the medication.

If you have decided that it is worth taking a particular treatment, this is an important reason to persevere for a few weeks (as long as your doctor feels that this is safe) even if at first the side-effects seem unacceptable. During this period you may need to take other treatments to deal with the side-effects, such as anti-nausea or anti-diarrhoea medicines.

For a few drugs, the risk of side-effects depends on the cumulative dose you have taken. In other words, you may experience few or no side-effects during the first weeks or months of treatment, but once the total amount of drug you have taken passes a certain level, the risk of side-effects increases. This is the case with several cancer chemotherapy drugs such as bleomycin and doxorubicin.

* Drug interactions

Drug interactions are usually divided into four groups: antagonism, synergism, potentiation and interaction with metabolism.

Antagonism means that one drug reduces or blocks the effect of another. There are various ways in which this can happen; for instance, drugs can interfere with each other's absorption in the gut, circulation in the blood or uptake by cells. An example in HIV therapy is the interaction between the anti-HIV drug ddI and the anti-fungal drug ketoconazole: the antacid in ddI tablets reduces the acidity of the gut, which in turn limits the absorption of ketoconazole.

Synergism means that two or more drugs work together against one target, producing an effect that is greater that the individual effects of the drug added together (like combining two plus two and getting five). Synergistic interactions can be beneficial, and treatments may be deliberately chosen for this effect; for example, many anti-HIV drug combinations seem to be synergistic in their effects against the virus.

Potentiation means that drug A boosts the effects of drug B, often by increasing the levels of drug B in the blood. Like synergism, this may be useful in cases in which the beneficial effects of drug B are enhanced. However, the toxicities of drug B may also be potentiated, leading to an increased level of side-effects.

A significant proportion of drug interactions depend on the way the drugs are processed in the body. Many drugs are processed in the liver, where the metabolism of one drug may interfere with the metabolism of others. This is the main cause of interactions between drugs such as the protease inhibitors, anti-mycobacterial drugs for TB and MAI, anti-histamines (for allergies), anti-fungals and anti-depressants.

If you are taking several different drugs, check with your doctor whether there are interactions that affect how you take them - for example, it can be important to leave a couple of hours between taking certain drugs. Combining drugs that can cause similar side-effects, such as two drugs that cause peripheral neuropathy, for example, should only be done with caution.

The main interactions for the most common treatments used by people with HIV are listed in the table on pages 4 to 9; however, this list is not exhaustive.

Bear in mind that it is not only prescribed medicines that can interact. Food in the stomach can also increase or decrease the absorption of drugs. There may also be interactions between prescribed medicines and recreational drugs, although these are often poorly researched.

* Coping with side-effects

The risk of side-effects is something to be considered when deciding whether or not to take a certain treatment. If you are ill, your need for the treatment may be clear-cut. But for preventive drugs intended to reduce your risk of developing an infection, such as PCP prophylaxis, you need to weigh up the potential benefit of avoiding a life-threatening infection against the potential drawback of side-effects when you are otherwise well.

If you have decided it is worthwhile taking certain medications but you do experience side-effects, it is important to try to establish which medication is causing which problem. This can be quite tricky among people who are taking many drugs that may cause similar side-effects or which may be interacting in complex ways.

One approach is to reduce the dose or stop taking each drug in turn, to see if the symptoms go away. Another common method is to stop all drugs then start them again one-by-one, beginning with the most essential ones. This is called a 'staged re-challenge'. When the problematic drug(s) has been identified, it may be possible to use less toxic alternatives.

Starting and stopping treatments in this way should only be done with your doctor's knowledge and advice. For instance, it may be unwise to stop certain drugs if you are receiving treatment for an acute infection, as stopping treatment may hinder your recovery. Likewise, reducing the dose of protease inhibitors may encourage the development of resistance which may prevent you from benefiting further from the drug.

If you can identify the drug that is causing side-effects, there may be practical strategies to minimise the chances of side-effects. Some tips on taking the commonest anti-HIV drugs are given in the table. There may be additional medications that can help to control the side-effects. Alternatively, your doctor may be able to offer alternatives, or suggest a new dose, or may recommend that you discontinue the treatment. If you do stop taking a drug because of side-effects and there are no good alternative treatments, it may still be worth re-trying the drug at a later date, as it is not inevitable that the problems will recur.

* Table of drug side-effects and interactions

This table listing 40 drugs used in the treatment of people with HIV, their side-effects, interactions and tips on taking them, is provided as a separate file in Microsoft Word for Windows 6 format (TABLE.DOC).

* Credits

In addition to our medical advisory panel, we gratefully acknowledge the following for providing information on drug side-effects and interactions: Rachel Heylen of Middlesex Hospital Pharmacy; Liz Randall of St Bartholomew's Hospital Pharmacy; The HIV Drug Book (Project Inform, 1995)

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