Tutorial 3B. ART and patient wellbeing

Side effect management

The risk of a serious side effect with modern ART is very low. Within a few weeks of starting their therapy most PLWH find that taking it is much easier than they had expected.

Individual drugs, as well as some classes of drugs, can cause side effects, which may be acute or develop gradually over time. Commonly experienced side effects are explored in more detail in this tutorial.

People who had no symptoms before they started therapy might feel that ART is doing them more harm than good initially, and can potentially lose motivation to keep taking their medication. It is important therefore to counsel patients and to explain that it is not inevitable that they will experience side effects, but that if they do they will be mild and can be alleviated, and in the majority of cases disappear after a couple of weeks.

Managing side effects requires:

• Honesty and a non-judgemental patient/clinician relationship
• Adequate consultation time and clinical resources
• An environment conducive to in-depth assessment
• A careful clinical history, baseline recordings and maintenance of patient self-report diaries (or similar)
• Clinician knowledge and expertise, including access to specialist practitioners
• Availability of specialist pharmacist advice
• Good record-keeping and continuity of care
• Effective MDT communication, consistency and reinforcement of advice

In the UK, both patients and healthcare professionals can report side effects directly to the Medicines and Healthcare products Regulatory Agency (MHRA), through the Yellow Card scheme. This contributes to an important safety database, especially for new and unexpected side effects. Side effects from new drugs often emerge after approval, and it is worth reporting something even if the PLWH is not certain that their symptom is due to the new medication. Side effects can be reported online with this scheme and through the Yellow Card app: www.yellowcard.mhra.gov.uk

Short term side effects – nausea and vomiting

Nausea is a distressing, non-specific and subjective symptom that can have a debilitating impact on daily life, and which has been associated with anorexia, malnutrition and wasting.

Acute and persistent nausea and vomiting can be very problematic, can lead to poor adherence and should be investigated. Switching to another antiviral drug should be considered if the symptoms persist for longer than 6 weeks. However, nowadays vomiting is a much less common side effect and is generally mild, as modern therapy has become much easier to tolerate. Symptoms usually disappear after only a few days. With older regimens, patients tended to be given anti-emetics prophylactically to help with nausea symptoms; however, modern regimens are more tolerable and not everyone will be required to take an anti-emetic.

Effective medications to combat nausea include domperidone 10–20mg every 4–6 hours, or metoclopramide, 10mg every 8 hours. If neither of these two are effective try prochlorperazine, 5–10mg every 8–12 hours. This drug can be given in buccal form to dissolve between the upper lip and the gum, and is beneficial for someone who is struggling to take any tablets due to sickness.

If a PLWH is taking abacavir and starts being sick, then they should contact the clinic straight away to rule out a hypersensitivity reaction.

Short-term side effects – diarrhoea

Diarrhoea is no longer a common side effect of ART, but can still be associated with PIs, and the booster drugs ritonavir and cobicistat. It can have a negative impact on sufferers (e.g. weight loss and dehydration) and cause significant psychological distress, such as anxiety, low self-esteem, sleep disruption and difficulty coping. Unfortunately, as a symptom it is often not treated properly because people find it difficult to discuss.

Imodium (loperamide) often brings relief and is usually adequate to reduce the frequency of bowel movements. Oatbran tablets help some people by adding bulk to the stool. Eating foods that are rich in high soluble fibre (e.g. rice, bread, starchy vegetables and fruits) can also help, and maintaining good hydration is also very important.

Persistent diarrhoea has a high risk of reducing treatment adherence, so it is important that it is managed properly and treatment reviewed and alternatives discussed if required. Moderate or severe diarrhoea can lead to dehydration, poor absorption of nutrients and drugs, weight loss and fatigue.

Often diarrhoea is temporary and may be due to starting or changing treatment. Symptoms often reduce within a few days or weeks as you get used to the HIV drugs. If HIV medications continue to cause this side effect, and are not improved by diet changes or simple treatments like Imodium, it is probably better to try another HIV drug.

Short term side effects – fatigue

People with HIV commonly experience fatigue. Whilst ART can cause fatigue, many other factors can have an impact, such as the virus itself (especially with high viral loads), illness, poor diet, stress, depression, anaemia, alcohol and recreational drugs, and sleep disruption.

Determining the cause of fatigue can be challenging as the symptom is subjective, difficult to measure and has so many possible influencing factors. Coordinating services of the multi-disciplinary team can help people with fatigue to:

• Develop coping strategies
• Access treatment for stress and/or depression
• Optimise calorie intake and ensure balanced nutrition
• Access alternative therapies, e.g. massage, acupuncture, reflexology
• Find the right balance of physical activity

Blood tests can check whether your fatigue is caused by anaemia (low red blood cells). This can be a side effect of AZT and can be treated easily with medication or with a blood transfusion in more serious cases.

Disturbed sleep

Certain ARTs have neurocognitive side-effects, e.g. efavirenz and rilpivirine, and may result in sleep disruption by causing vivid dreams or nightmares. Some of the newer integrase inhibitors, e.g. elvitegravir and dolutegravir, can also lead to an interrupted sleep pattern.

There are tools available, such as sleep wheels, which can record a person’s sleep pattern and keep a diary to record length of sleep, quality of sleep and other issues such as caffeine, drug and alcohol intake, time of last meal prior to going to bed, as well as their psychological wellbeing.

Ideally, a person struggling with sleep or fatigue should be referred to the mental health team for further assessment. They will suggest switching to another antiviral medication if they have ruled out other possible causes of poor sleep.

Insomnia is far more commonly related to depression than a side effect of HIV treatment. People with HIV are about twice as likely to be diagnosed with depression as matched controls in the general population [17]. Regular contact with a psychiatrist and a mental health nurse can be effective in helping to treat depression – prescribing anti-depressants may only be necessary for a short time.

Drug-specific side effects

1. CNS side effects – efavirenz and Atripla (contains efavirenz) can both cause CNS side-effects. Rilpivirine and those STRs containing rilpivirine, namely Eviplera and Odefsey can also lead to CNS side-effects, but to a lesser degree. Raltegravir and dolutegravir (also in Triumeq) have been linked to insomnia or mood changes, though more rarely.

Since 2016, UK guidelines [18] have stopped recommending efavirenz as the preferred choice for starting treatment. However, even in the UK it is still likely to be widely prescribed because generic efavirenz is now very inexpensive. Nearly everyone will get some of these symptoms but for most people they will be mild and easy to manage. This means that they might have some strange dreams, or find themselves daydreaming or getting more worried, or they might get more upset than usual. CNS side effects can occur after a few hours or after several days, and are more common over the first few weeks of treatment. They generally become easier to tolerate. Efavirenz is not recommended for people who are on shift work that alternates between days and nights. CNS side effects can lead to or worsen depression, including suicidal feelings and paranoia. BHIVA recommend that efavirenz-containing regimens be avoided in individuals with a current or past history of depression, psychosis, suicidal ideation or attempted suicide, or at risk of self-harm [19]. A high fat meal increases efavirenz drug levels by 60%, and this increases the chance of side effects, so it is better to take it on an empty stomach. Taking efavirenz a couple of hours before you go to sleep, rather than at bedtime, makes it more likely that you will be asleep when the drug levels are at their highest – about 4 hours after taking efavirenz.

2. Hypersensitivity reactions – mainly abacavir (also in Kivexa, Triumeq and Trizivir), and co-trimoxazole (Septrin). Hypersensitivity reactions can also occur with raltegravir, dolutegravir and nevirapine.

The main side effect of abacavir is a hypersensitivity reaction (HSR) that used to occur in around 5% of people. However, a screening test (called HLA-B*5701), reduces this risk to less than 1%. This test is recommended in the UK before using abacavir. If two or more of the following symptoms occur then the doctor should be contacted immediately: fever, rash, nausea, vomiting, diarrhoea, or stomach pain, or shortness of breath, cough or sore throat. A few people who test negative for B*5701 might still get HSR. Abacavir must never be restarted at any time in the future if a person has had the hypersensitivity reaction, as this can prove fatal.

3. Increased bilirubin, jaundice – atazanavir and Evotaz (atazanavir + cobicistat).

An increase in bilirubin (called hyperbilirubinaemia) is a common side effect of atazanavir. If levels get higher than five times normal, this is usually an indication to change or modify treatment.

4. Kidney health and renal side effects – drugs cleared by the kidney with potential for renal toxicity include AZT, 3TC, FTC, tenofovir DF, atazanavir and maraviroc. Many combination pills contain tenofovir DF. Kidney stones can also occur with atazanavir and efavirenz.

Kidney function (also called renal function) can be affected by HIV and other illnesses, including high blood pressure and diabetes. In someone who has reduced kidney function related to HIV (including HIVAN), this can be improved by starting HIV treatment. However, several HIV drugs can affect the kidneys and the use and monitoring of these drugs should be managed individually. Several HIV drugs are cleared by the kidney. These include tenofovir DF, 3TC, FTC and AZT. The dose for these medications might need to be changed depending on the eGFR level. Tenofovir DF (TDF) is a widely used HIV drug and it is mainly processed by the kidneys. Although serious kidney-related side effects (including Fanconi’s syndrome) were reported in studies, these were rare [20]. They were also often reversed when TDF was stopped. TDF also changes laboratory markers such as reducing creatinine clearance, low phosphate levels and increased protein levels in urine (called proteinuria). The importance of these changes in markers in the long term is unknown, but it is likely to be more important if a person has already started with reduced kidney function. Because TDF can also reduce eGFR compared to some other HIV drugs, it is not recommended in people who have eGFR below 75–80 mL/min if there are other HIV drugs to choose from. Similarly, if using TDF and the eGFR drops to this level, then switching to a different drug is recommended. A new version of TDF called tenofovir alafenamide (TAF) is available in several combination pills. TAF is less likely to cause kidney and bone side effects.

Kidney stones: atazanavir and efavirenz. Several reports of kidney stones that contained high levels of atazanavir or efavirenz, showed that this can be a rare side effect with these drugs. The side effect of kidney stones can be reduced by drinking an additional 1–2 litres of water daily.

5. Skin problems: rash – abacavir (also in Kivexa, Triumeq and Trizivir), emtricitabine (FTC), nevirapine, efavirenz, etravirine, atazanavir, darunavir, fosamprenavir, tipranavir, raltegravir and T20 (enfuvirtide). Although many drugs are linked to rash, the severity of the rash and how long it lasts vary widely. With some drugs, if a rash develops during the first few weeks of therapy, it must be reported immediately to a doctor. This is because it can sometimes lead to very serious reactions. Other rashes can be mild and disappear without treatment, or can be easily treated with antihistamine drugs such as cetirizine (Zirtek) or loratadine (Claritin). Atazanavir can cause a mild rash during the first 2 months in 10% of people but this disappears without additional treatment within a few weeks. Emtricitabine studies reported rash on the palms of the hands or feet in up to 10% of African Americans, but these have been reported less frequently. Although antihistamines are available over the counter, it is important that a doctor or pharmacist checks any potential interactions with HIV drugs. A rash can also occur as a reaction from exposure.

Nevirapine rash with liver toxicity: Nevirapine is linked to two different types of rash. One is the hypersensitivity-type reaction, known as Stevens–Johnson syndrome (SJS) and stopping treatment is essential. The second is a rash that is related to liver toxicity, and this is more likely to be caused by an immune-related problem, and from starting nevirapine at a high CD4 cell count. Up to 20% of people using nevirapine, efavirenz or etravirine can experience a mild to moderate rash in the first weeks of treatment. For most people this disappears over the next few weeks and they experience no further side effects. Less than 5% of people stop an NNRTI because of rash, and less than 1% people (0.1–0.5%) get a severe (grade 4) rash. This is why a rash needs to be seen by a doctor.

Other skin reactions include:

• Hyperpigmentation (usually seen on palms and soles of feet): AZT can darken nail and skin pigment in Africans and African-Americans, but this drug is now rarely used. Emtricitabine (Emtriva) has been reported to cause pigment changes, mainly to the palms of the hands or soles of the feet in African people.
• Hair loss: Changes in the thickness and quality of hair are rarely reported with HIV drugs. Balding patches of head hair, called alopecia, have also been reported, though rarely, with lamivudine.
• Dry skin: use of emollients (moisturisers) such as aqueous cream, diprobase, oilatum and balneum. Try to drink plenty of fluids as well.

6. Peripheral neuropathy – d4T, ddI, ddC, lamivudine.

Peripheral neuropathy (PN) is rare with modern HIV drugs. It only tends to be a problem in people who developed this side effect from using very early HIV d-drugs: ddC, ddI and d4T. Symptoms include increased sensitivity or numbness, or tingling in the hands and/ or feet. Painkillers are used to manage peripheral neuropathy but they do not repair the nerve damage. Amitriptyline, nortriptyline (tricyclic antidepressants) and gabapentin and pregabalin (antiepileptic drugs) are used to treat neuropathic pain. Capsaicin patches that contain chilli pepper are also available in the UK, but have had mixed success rates.