Why do some HIV patients get side effects from efavirenz?
Most Ugandan patients starting the HIV drug efavirenz had neuropsychiatric side effects such as vivid dreams, and these were linked to higher blood levels of the drug, which in turn depended on a patient's CYP2B6 gene variant, while taking TB drugs at the same time made no difference.
Source
Influence of efavirenz pharmacokinetics and pharmacogenetics on neuropsychological disorders in Ugandan HIV-positive patients with or without tuberculosis: a prospective cohort study
Study at a glance
- Design
- Cohort — Prospective cohort: treatment-naive HIV patients started efavirenz 600 mg daily (plus zidovudine and lamivudine); TB co-infected patients also took rifampicin-based TB therapy. Mid-dose efavirenz levels were measured from day 3 to week 12, five drug-handling genes were genotyped, and neuropsychiatric symptoms were assessed at baseline, week 2 and week 12.
- N
- N=197 · 197 patients: 59 with HIV only on efavirenz alone and 138 with HIV-TB co-infection also receiving rifampicin; 89.9% were assessed at week 12.
- Population
- Newly diagnosed, antiretroviral-naive adults with HIV, with or without tuberculosis, at two national referral hospitals in Kampala, Uganda (2008-2009).
- Outcome
- Incidence and type of neuropsychiatric symptoms (sleep disorders, hallucinations, cognition on an adjusted MMSE) over 12 weeks, and their relation to plasma efavirenz concentration, rifampicin co-treatment and genotype.
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What they did
The researchers followed 197 newly diagnosed HIV patients in Kampala who started efavirenz-based treatment; 138 also had tuberculosis and were taking rifampicin, a drug known to speed up the breakdown of other medicines. They measured efavirenz blood levels repeatedly over the first 12 weeks, genotyped variants in CYP2B6, CYP3A5, CYP2A6, ABCB1 and NR1I3, and had a psychiatric nurse assess sleep problems, hallucinations and cognition at baseline, week 2 and week 12.
What they found
About 74% of patients developed at least one efavirenz-related neuropsychiatric symptom within 12 weeks, mostly sleep disturbances (60.5%, largely vivid dreams) and hallucinations (30.7%), nearly all starting in the first two weeks. Patients with symptoms had higher plasma efavirenz, and CYP2B6 genotype predicted drug levels at every time point; almost everyone with two copies of the slow-metabolising CYP2B6*6 variant had symptoms, though the direct genotype-symptom link was only a trend. Rifampicin lowered efavirenz levels only in the first week, and symptom rates were almost identical with and without it (74% versus 72%). Cognition actually improved on treatment, with severe cognitive impairment falling from 46 to 22 patients.
The limits
What it doesn't show
There was no comparison group of patients on a different HIV drug, so symptoms such as vivid dreams cannot be attributed to efavirenz with certainty, and assessment relied partly on patients' memory of sleep and hallucinations. The study was too small to confirm direct effects of less common gene variants, many results are described only as tendencies, and brain (cerebrospinal fluid) drug levels were not measured. Findings come from one Ugandan population and may not transfer to other African or non-African groups with different gene frequencies.
Key terms
- Pharmacogenetics
- The study of how inherited gene variants change the way individuals absorb, metabolise or respond to a drug.
- CYP2B6
- A liver enzyme that is the main route for breaking down efavirenz; the *6 variant slows this breakdown and raises blood levels.
- Enzyme induction
- When one drug (here rifampicin) increases production of metabolising enzymes, speeding up the clearance of another drug and potentially lowering its levels.
- Plasma concentration
- The amount of drug in the liquid part of the blood; for efavirenz, levels above about 4 mg/L are linked to more central nervous system side effects.
- Therapeutic drug monitoring
- Measuring drug levels in a patient's blood to adjust the dose so it is effective but not toxic.
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Quiz yourself
Which factor was most clearly associated with efavirenz neuropsychiatric symptoms?
Common questions
If rifampicin speeds up drug breakdown, why didn't it lower side effects?
In this population rifampicin reduced efavirenz levels only during the first week; after that levels were similar in both groups, so side-effect rates were also similar. Common slow-metabolising CYP2B6 variants may offset the induction effect.
Does having the CYP2B6*6 variant guarantee side effects?
Not proven here. Genotype strongly predicted drug levels, and nearly all *6/*6 carriers had symptoms, but the direct association between genotype and symptoms did not reach statistical significance in this sample.
Why did cognition get better after starting efavirenz?
Many patients had HIV-related cognitive problems before treatment; effective antiretroviral therapy can improve those, which outweighed any cognitive side effects of the drug.
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