Types of side-effects

Toxic side-effects are those caused by the effects of a drug, rather than by the immune system’s reaction to the drug. Often the nature of the side-effect will depend on the part of the body adversely affected by the drug or the route of excretion from the body. One instance of this is drugs that damage the bone marrow cells responsible for producing new blood cells, leading to blood abnormalities such as anaemia or neutropenia. Nausea, malaise, diarrhoea, and drowsiness are other common side-effects resulting from toxicity.

Perhaps the organ most vulnerable to toxicity is the liver, the principal organ of drug metabolism. The liver has very high concentrations of most drug-metabolising enzyme systems, relative to other organs. Many drugs can cause liver toxicity, particularly if taken in excess.

Certain drugs can also produce a toxic response by increasing the amount of substances normally present in the body. In HIV treatment, the most common effect of this type is raised cholesterol or triglycerides (hyperlipidemia syndrome), which may be caused by protease inhibitors (PIs) and some of the nucleoside reverse transcriptase (NRTI) drugs. Glucose and bilirubin levels are also elevated by some drugs and may produce laboratory evidence as well as clinical symptoms. Other toxic side-effects include reduced bone density and fat redistribution among people on antiretroviral therapy; kidney failure associated with tenofovir (Viread); and pancreatic failure associated with ddI (didanosine/Videx).

Toxic side-effects are usually dose-related. The greater the amount of drug taken, the greater the risk is of a negative side-effect. Factors that can affect drug metabolism are age, nutrition status, gender, and individual variation.

Some people may be vulnerable to unusual or unpredictable side-effects because of inherited conditions. The most common case of this is among people whose genetic make-up results in very low production of certain enzymes. People lacking the enzyme glucose-6-phosphate dehydrogenase (G6PD) are more likely to suffer toxicities from antibiotics such as dapsone, because the body cannot process the drug and toxic accumulation result. At-risk groups can be tested for these genetic deficiencies.

Another common genetic variation (polymorphism) affecting drug biotransformation is variability of N-acetyltransferase (NAT). This is one of the earliest polymorphisms discovered and has both clinical and toxicological consequences.

Virtually every drug carries the risk of side-effects in a proportion of patients. Additionally, the more drugs an individual takes, the greater the chances are that additional or synergistic toxicity or undesired drug/drug interactions will occur. Side-effects are sometimes referred to as adverse drug reactions (ADRs) or adverse effects (AEs). Much of the information regarding ADRs is gathered when a new drug is being tested in large clinical trials. However, the emergence of metabolic and fat disorders associated with protease inhibitors demonstrates that some side-effects take months or years to be identified.

In the age of highly active antiretroviral therapy (HAART), drug side-effects are a common cause of ill health among people who have an undetectable viral load or asymptomatic HIV disease. Even mild or moderate side-effects can significantly affect the quality of life.

It is not always clear whether unwanted side-effects are a direct result of antiretroviral therapy or of a strengthened immune response to infections. For example, people with HIV and hepatitis C (HCV) who take anti-HIV drugs are more likely to experience liver toxicity than people who do not have HCV. An increased susceptibility to drug-related side-effects could be caused by HCV. Increased susceptibility might also be the result of an improved immune response to HCV leading to liver inflammation.

Additionally, people with HIV infection (or any other immunodeficiency) often have a higher susceptibility to drug side-effects than those with a healthy immune system. For example, cotrimoxazole causes side-effects in HIV-positive people about 30% of the time versus 10% of the time in those who are HIV-negative. People with advanced HIV infection also seem more prone to experience peripheral neuropathy, pancreatitis, and fat wasting from nucleoside analogue use.

Common allergic responses to a drug or its metabolites (substances produced by metabolism or a metabolic process) are rash, fever, hives, and swelling of tissues. The occurrence, severity, and timing of allergic reactions vary from person to person and even in the same person over time.

As with toxic side-effects, the amount of drug can dictate the severity of the reaction, although if someone is allergic to a drug, a response can be generated with a very small dose. The liver and the skin are the organs usually involved in hypersensitivity reactions and, at times, a systemic reaction in the form of fever or eosinophilia may occur.

The substance that triggers an allergic response is called an allergen and the bloodstream and most bodily fluids contain Immunoglobulin E (IgE) antibodies that capture provoking allergens that enter the body. Once IgE is produced, antibodies travel to mast cells, cells that are present in large amounts in the nose, eyes, gastrointestinal tract, and lungs.

In some cases, the immune system can be desensitised by starting a drug at a low dose and gradually building up over a period to the correct dose. This strategy has worked well with the antimicrobial co-trimoxazole, often used to prevent or treat opportunistic illnesses. In other cases, an allergic reaction may escalate upon repeated exposure and the drug needs to be stopped immediately.

Some hypersensitivity reactions can be life-threatening. In rare cases, nevirapine has caused serious liver damage and in several cases, led to Stevens-Johnson syndrome. Genetic factors can also predispose someone to a hypersensitivity reaction. Genotyping for the HLA-B*5701 allele (genetic variant) can reduce the incidence of hypersensitivity reactions to abacavir.¹

Most side-effects occur after a person has been taking a drug for one or two weeks, although there is no strict pattern to this. Some people will suffer problems after their first dose; others may find that side-effects lessen or disappear altogether after several weeks on a drug.

Side-effects such as nausea, vomiting, diarrhoea, bloating, abdominal discomfort, headache, and dizziness tend to be associated with the time at which drug levels reach their peak in the blood. This is why side-effects may occur regularly at certain times of day. It may be possible to minimise the inconvenience of these side-effects by adjusting the time of day at which particular medications are taken.

If intense side-effects occur in the first few days of treatment, these may become less pronounced after a steady-state plasma concentration of the drug is reached. If this is not the case, other treatments may need to be added to manage side-effects such as nausea or diarrhoea.

For a few drugs, the risk of side-effects depends on the cumulative dose taken over time. There may be few or no side-effects during the first weeks or months of treatment, but once the total amount of drug taken reaches a certain level, the risk of side-effects increases. This is the case with several cancer chemotherapy drugs such as bleomycin and doxorubicin.

Other side-effects associated with long-term antiretroviral use include lipodystrophy; wasting of the arms, legs and face; and metabolic abnormalities including high blood lipids, insulin resistance, and lactic acidosis.