Although porphyria cutanea tarda has been associated with HIV infection and antiretroviral therapy (ART) [1–3], acute porphyria precipitated by antiretrovirals has not previously been reported. We describe, for the first time, acute porphyria manifesting with unexplained abdominal pain and seizures, precipitated by nevirapine. A 28-year-old HIV-infected woman with WHO stage 2 disease by virtue of vulval warts was started on stavudine, lamivudine, and nevirapine when her CD4 cell count nadir was of 129 cells/μl. One month pre-ART, co-trimoxazole primary prophylaxis was stopped due to a persistent itch, without rash, which resolved on drug withdrawal. One week after starting ART, she developed abdominal pain, nausea and anorexia, and presented 1 week later with worsening symptoms, generalized abdominal tenderness, an isolated rise in alanine transaminase 76 IU/l, a normal lipase and total white cell count and a C-reactive protein of 12 mg/l. Abdominal ultrasound was normal but upper gastrointestinal tract endoscopy revealed a Helicobacter pylori-negative erosive fundal gastritis. She was discharged on a proton pump inhibitor. One week later, she re-presented with continued abdominal pain and new onset generalized tonic–clonic seizure. Contrast-enhanced computed tomography scan of her brain was normal, blood tests remained unchanged and subsequent exploratory laparoscopy was normal. A urine sample was sent for porphyria screen in view of unexplained abdominal pain and neurological symptoms. Increased excretion of urinary 5-aminolevulinate (ALA) and porphobilinogen (PBG) was found, indicating a diagnosis of acute porphyria (Table 1). Although porphyric skin lesions were absent, the urine porphyrin pattern was suggestive of variegate porphyria as opposed to acute intermittent porphyria (AIP). Further support for variegate porphyria was found in the stool porphyrin profile and a plasma porphyrin peak of 625 nm. However, she was negative for the typical R59W mutation of South African variegate porphyria. This is not unexpected given her black ethnicity and a search for her mutation is ongoing.Table 1: Porphyrin analysis.ART and the proton pump inhibitor were stopped with resolution of symptoms within 72 h. One week later, stavudine and lamivudine were restarted with unboosted atazanavir as the 3rd drug. Six months later, she remained asymptomatic, her CD4 cell count had increased to 288 cells/μl and her HIV viral load was undetectable. Follow-up urine analysis showed a reduction in urinary porphyrin levels, but the level remained elevated despite her asymptomatic state. Although usually in keeping with AIP, this may reflect an inductive drug effect [4]. Twenty-one months after her acute presentation, urinary porphyrin levels had normalized, although urinary PBG remained slightly elevated. The acute porphyrias, AIP, variegate porphyria, hereditary coproporphyria and ALA dehydratase deficiency porphyria are inherited disorders associated with enzyme defects in the haem biosynthetic pathway. The rate-limiting enzyme in this pathway is 5-aminolevulinate synthase (ALAS), which is negatively regulated by haem. Acute attacks occur when a trigger, often a drug, directly or indirectly induces ALAS transcription through perturbation of this negative feedback regulation. This may result in overproduction and accumulation in ALA and PBG, possibly leading to acute symptoms via a neurotoxic mechanism which remains to be fully elucidated [4]. Cytochrome P450 proteins (CYP), which are important in antiretroviral drug metabolism, are haemoproteins that require haem as a prosthetic group and activate ALAS transcription with resultant flux down the haem biosynthesis pathway [5,6]. Certain CYP subclasses cause greater haem ‘depletion’ and consequent ALAS transcription. CYPs 3A4 and 2C9 have the strongest effect, and thus theoretically higher ‘porphyrinogenicity’ [6]. Nevirapine, efavirenz and ritonavir are all inducers of CYP 3A4 and may induce other CYP subclasses [7,8]. Furthermore, ritonavir may also deplete haem by its inhibitory effect on CYP 3A4. Reports of cases such as ours are vital in developing the growing list of porphyrinogenic drugs. Antiretrovirals least likely to be porphyrinogenic are tenofovir, lamivudine, abacavir and didanosine, whereas ritonavir and indinavir should be avoided where possible [7]. We reasoned that although using an unboosted protease inhibitor-based regimen was potentially suboptimal for viral suppression, it would give the least chance of precipitating an acute attack. Therefore, we elected for unboosted atazanavir in combination with her previous nucleoside analogue backbone. At the time our patient presented, we did not have tenofovir or abacavir available in the state sector in South Africa. The fact that zidovudine may depress hepatic regulatory haem, thereby increasing haem synthesis [7], meant that stavudine coupled with lamivudine was the optimal backbone available to us. With good adherence, she has achieved and sustained viral suppression. Acute porphyria is an important differential diagnosis of unexplained abdominal pain. This report adds to the list of porphyrinogenic drugs and should alert clinicians to the potential effect of nevirapine and other non-nucleoside reverse transcriptase inhibitors in this regard.
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Oct 4, 2024
Karol M Córdoba + 29
Open Access