Abacavir can cause a potentially lethal, multisystem hypersensitivity reaction within six weeks of starting treatment.4 Patients who have the HLA-B*5701 genotype are especially susceptible, so genotypic screening is needed before prescribing abacavir.
Abacavir has been associated with an increased risk of ischaemic cardiovascular events in some cohort studies.5-8 However, other studies and meta-analyses concluded that abacavir does not confer a higher risk of cardiovascular events compared to regimens without abacavir.9 While the data remain conflicting and no plausible biological mechanism explains the increased risk, most experts and international guidelines recommend avoiding abacavir in patients with cardiovascular risk factors.10-12
Tenofovir disoproxil fumarate is primarily eliminated by the kidneys. It has been associated with renal toxicity, including Fanconi syndrome manifesting as type 2 renal tubular acidosis and phosphate wasting.13-15 The drug is not recommended for patients with an estimated glomerular filtration rate (eGFR) below 60 mL/minute. Monitoring of renal function is essential and includes the eGFR, urinalysis for glucose and protein, and the protein:creatinine ratio. Renal monitoring (six-monthly eGFR) is also recommended in PrEP users, although the risk of toxicity in this group is much lower than in people living with HIV.16-18 Reduced bone mineral density has been reported so tenofovir disoproxil fumarate should be avoided in patients with osteoporosis.19-20
Renal and bone effects occur to a lesser extent with tenofovir alafenamide as serum drug concentrations are lower, however this formulation should be avoided in patients with an eGFR below 30 mL/minute. Tenofovir alafenamide has previously been reported to cause greater weight gain, especially when combined with dolutegravir, compared to tenofovir disoproxil fumarate. Whether this is an effect of weight gain with tenofovir alafenamide, weight loss with tenofovir disoproxil, or simply represents better gastrointestinal tolerability and improved health is uncertain.21-22
Tenofovir disoproxil fumarate and tenofovir alafenamide are first-line drugs for hepatitis B management. In patients co-infected with HIV and hepatitis B, dual therapy with tenofovir disoproxil fumarate or tenofovir alafenamide in combination with either lamivudine or emtricitabine is used to avoid the development of hepatitis B virus drug resistance. These patients also require a third drug with activity against HIV, for example bictegravir/tenofovir alafenamide/emtricitabine. Patients with hepatitis B should be advised on the importance of adherence as stopping their hepatitis B antiviral therapy can result in a flare of hepatitis.
Integrase strand inhibitors
Integrase strand inhibitors are highly effective with few adverse effects and are recommended for most patients in combination with nucleotide reverse transcriptase inhibitors. Possible adverse effects include headache, nausea and diarrhoea. Several studies have concluded that integrase strand inhibitors, particularly dolutegravir, lead to greater weight gain than other classes of antiretroviral therapy, but the mechanism and clinical significance are unclear.23-26
Bictegravir, dolutegravir and raltegravir can increase serum creatine kinase and there are case reports of rhabdomyolysis with raltegravir.27-29 Serum creatine kinase should be checked in those presenting with myalgia and specialist advice sought as the patient may require switching to a different regimen.
Bictegravir, dolutegravir and certain other drugs (e.g. rilpivirine, cobicistat) inhibit creatinine excretion in the proximal renal tubule. This causes a physiological, but clinically unimportant 10–20% increase in serum creatinine within the first eight weeks of treatment. Aside from measuring serum creatinine to establish a new baseline when starting therapy, no further action is required.
Integrase inhibitors have rarely been associated with central nervous system effects, such as insomnia and headache. A meta-analysis reported no significant effect of dolutegravir on the risk of suicide-related adverse events.30
Non-nucleoside and non-nucleotide reverse transcriptase inhibitors
The most prescribed drug in this class is rilpivirine which is generally well tolerated, however it needs to be taken with a meal to facilitate its absorption. An important adverse effect is prolongation of the QT interval on the ECG which also has implications for drug–drug interactions. Rilpivirine may also exacerbate existing psychiatric conditions, but has fewer neuropsychiatric adverse effects than efavirenz.
Efavirenz, although rarely used nowadays, can cause dizziness and vivid dreams. Taking it at bedtime on an empty stomach reduces insomnia and dizziness. It can also cause or worsen depression and increase the risk of suicidal ideation.31
Gastrointestinal adverse effects may occur with any antiretroviral therapy, but are most common with protease inhibitors, especially when in combination with a booster drug (cobicistat or ritonavir). Troublesome diarrhoea may be managed with loperamide after exclusion of other causes.
Hyperlipidaemia is a common adverse effect of protease inhibitors, especially ritonavir-boosted regimens. This may require drug treatment in addition to optimising diet and exercise.32 Simvastatin is contraindicated with boosted regimens as there is an increased risk of rhabdomyolysis. Atorvastatin, rosuvastatin and pravastatin should be started at low doses with careful dose titration to the lowest effective dose with measurement of creatine kinase if indicated. The maximum dose of these statins is reduced when they are taken with boosted regimens.
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