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Treatment of Specific Disorders in Porphyria

Management of HIV in Patients with Porphyria

See also Summary: Drugs used in the management of HIV. This is a table summarising the safety of drugs used in antiretroviral therapy and for the management of opportunistic infections.

Introduction

Patients with the acute porphyrias, including those with variegate porphyria (VP) and acute intermittent porphyria (AIP) may develop severe acute attacks in response to drugs. It is important to note that patients with porphyria cutanea tarda (PCT) do not develop acute attacks and are not sensitive to medication: all medication may safely be used in these patients.

Patients with porphyria differ markedly in their sensitivity to drugs. Indeed, there are many instances where people with porphyria have received even the most dangerous medication without ill effects. As a general rule however, patients who meet the following criteria are most likely to experience problems:

  • Patients with acute intermittent porphyria tend to be more sensitive than those with variegate porphyria
  • Exposure to multiple potentially dangerous drugs sequentially or simultaneously is more dangerous than exposure to a single potentially dangerous drug.

Management of porphyria patients who are HIV-positive requires particular caution because of the frequent need to expose patients with HIV to regimens containing multiple drugs. In particular, commonly used drugs for the prevention or treatment of pneumocystis pneumonia, fungal infections and tuberculosis are potentially hazardous in porphyria.

Antiretroviral therapy for HIV-positive patients should begin while patients still have a relatively well preserved immune function, when the CD4 count is 200 to 350 - higher than the count used in the general population. This is to reduce the likelihood of the patient developing one of these infections, and therefore requiring hazardous adjunctive therapies such as cotrimoxazole, fluconazole or antituberculous therapy.

Where patients receiving treatment for tuberculosis require antiretroviral therapy, this should not be started until the patient is stable on an antituberculous regimen without evidence of porphyria induction. Antiretroviral therapy may then be cautiously started, using the safest of the regimens described below. In the event that there is an aggravation of porphyria, it may be appropriate to defer antiretroviral therapy until after the completion of antituberculous therapy, and the options should be discussed with us.

There is as yet little experience with antiretroviral therapy in patients with porphyria. However, we believe that most patients should tolerate at least one of the regimens described below. The chances for successful tolerance can be improved by avoiding simultaneous exposure to other drugs, including alcohol, cigarettes and oral contraception.

It is also essential that patients received the benefit of triple antiretroviral therapy from the start. It is inappropriate to stagger the introduction of therapy in order to test the effects of individual drugs on the patient's porphyria. Exposure to mono- or dual therapy may severely compromise the patient's prospects by accelerating the onset of drug resistance without actually increasing drug safety.

Since there is as yet little clinical experience with antiretroviral therapy in patients with porphyria, the safety recommendations used here are based largely on an appraisal of the metabolic processes by which the drugs are handled in the body. All clinical experience, both positive and negative, should be reported to us so that this advice can be refined.

Where Should Treatment Be Started?​​

Treatment should preferably be started in a tertiary centre, and the patient transferred to the clinic once stable on an antiretroviral regimen. However, it would be acceptable for patients to commence therapy at district hospital or clinic level provided that:

1. The patient has had a recent porphyrin analysis, with full results to hand and available for discussion with an expert. (Experience has taught us not to accept the patient's assurances that he/she has porphyria at face value; furthermore, testing of urine porphyrins and precursors allows an estimate of the activity of the porphyria, which is helpful in predicting the likelihood of adverse outcomes.)

2. The case has been discussed with a porphyria expert or an HIV expert with experience in porphyria at a tertiary centre.

3. Both patient and clinician are aware of the risks of an exacerbation of porphyria, know how to recognise early symptoms of the acute attack, are aware of the contents of these guidelines, and have planned in advance how they will respond to a possible acute attack in terms of diagnostic confirmation, transfer of the patient or access to haem arginate therapy.

Disclaimer​​

Note that the safety of the drugs recommended here cannot be guaranteed. Many are newer drugs and there is still minimal actual clinical experienceof their use in porphyria. The responsibility for a decision to use any drug in porphyria is that of the doctor and his or her patient.


CHOICE OF REGIMEN: PRINCIPLES

The choice of nucleoside reverse transcriptase inhibitor (NRTI) in porphyria is uncomplicated, since most are unlikely to give trouble. Zidovudine may on theoretical grounds be less safe than the others since it is associated in vitro with marked haem depletion.

The major difficulty rests with the non-nucleoside reverse transcriptase inhibitor (NNRTI) or protease inhibitor (PI) component: here the safest regimen on theoretical grounds is the saquinavir/low-dose ritonavir combination, followed by lopinavir/low-dose ritonavir combination, efavirenz and nevirapine.

An assessment of their metabolism suggests that they be used in that order, though the information on which this is based is weak.

Recommended Regimens​​

The safety of antiretrovirals and of drugs used to treat opportunistic infections are summarised in table-form on a separate page: Summary: Drugs used in the management of HIV.

First-line therapy for HIV in porphyria

These are listed in descending order of safety, with 1 being, on theoretical grounds, the most desirable, and 4 the least desirable.

1. Stavudine (d4T)+ lamivudine (3TC)+ saquinavir/low-dose ritonavir 
2. Stavudine (d4T)+ lamivudine (3TC)+ lopinavir/low-dose ritonavir (Kaletra )
3. Stavudine (d4T)+ lamivudine (3TC)+ efavirenz*
4. Stavudine (d4T)+ lamivudine (3TC)+ nevirapine*

Substitution of zidovudine for stavudine as allowed by WHO should be avoided if possible.

Second-line therapy for HIV in porphyria, for treatment failure

These are listed in descending order of safety, with 1 being, on theoretical grounds, the safest, and 3 the least safe.

1. Abacavir, didanosine and saquinavir/low-dose ritonavir combination
2. Abacavir, didanosine and lopinavir/low-dose ritonavir combination
3. Substitution of zidovudine for the abacavir*

Note that tenofovir is not recommended in combination with didanosine as there is enhanced toxicity and less efficacy.

In the Event of a Suspected Attack

Stopping therapy

Ideally one would stop all antiretrovirals immediately. However: NNRTIs (nevirapine and efavirenz) have very long half-lives. If all drugs are stopped abruptly, then there is a real risk of NNRTI resistance developing in response to de facto monotherapy (the NNRTI remains active because of its long half-life, whereas the NRTI disappears rapidly form the system following drug withdrawal). Therefore, we recommend wherever possible that the NNRTI (which is on balance of probability the most likely offending) agent is stopped immediately but that the patient continues on dual NRTI therapy for a further 2 weeks. It would be wise to discuss this on a case-by-case basis with us.

As a matter of extreme urgency, confirm that an acute exacerbation of porphyria is indeed present by demonstrating the presence of elevated urine precursors (ALA and PBG) in the laboratory.

Treating the attack

Treat the acute attack appropriately, prescribing haem arginate if necessary. (See Management of the acute attack.)

Reintroduction of therapy

Following complete recovery, recommence antiretroviral therapy. If the patient had been receiving any but the safest regimens (those listed first under the headings first-line therapy and second-line therapy above), then recommence using one of these two regimens. This should be done in consultation with us. Under all other circumstances, a very careful consideration of the circumstances will be necessary with an individually tailored approach to therapy which must take cognisance of the rules regarding successful antiretroviral therapy as well as safety in porphyria.

Under some circumstances it may be necessary to challenge the patient sequentially with different drugs to determine which are tolerated.

  • For the purposes of the rechallenge, it is permissible to prescribe the protease inhibitors as effective monotherapy for the 2-4 week trial period necessary to establish patient tolerance.
     
  • Nucleoside reverse transcriptase inhibitors (NRTIs) other than lamivudine may also be used alone or in a 2-drug combination for trial purposes not exceeding 3-4 weeks.
     
  • Lamivudine should not be used on its own if resistance is to be avoided.
     
  • Non-nucleoside reverse transcriptase inhibitors (NNRTIs) -- efavirenz and nevirapine -- must never be used in any regimen other than full triple therapy.

Treatment of Opportunistic Infections

Pneumocystis pneumonia

Wherever possible, antiretroviral therapy should be commenced before immunosuppression reaches the state where pneumocystis pneumonia is likely. Cotrimoxazole, dapsone, trimethoprim and clindamycin are all potentially hazardous in porphyria. Where needed for prophylaxis or treatment, atovaquone(750 mg 8 hourly for 21 days followed by 1,500 mg daily for suppressive treatment) is recommended, but note that atovaquone is less effective than cotrimoxazole. Pentamidine is an alternative for severe PCP, but is unfortunately unavailable in SA and can only be obtained with permission from the Medicines Control Council.

Antifungal Therapy

All the systemic azoles are potentially hazardous and should be avoided. Mild oral candidiasis should be treated with topical antifungals. Intravenous amphotericin B should be used for more serious infections.

For cryptococcal meningitis, a suitable regimen is amphotericin B 0.7 mg/kg daily continued until fungal culture on CSF is negative, or for a maximum of 6 weeks. This should then be followed with a course of weekly amphotericin B until the CD4 count rises to above 100 on antiretroviral therapy.

Oesophageal candidiasis can be treated with amphotericin B 0.7 mg/kg weekly for 7-14 days.

Tuberculosis and Other Mycobacterial Infections​

Consult the page Treatment of tuberculosis in patients with porphyria.

Acknowledgements

We acknowledge the assistance of Prof Gary Maartens and Dr Eulah Mothibe, and also the drug database of the Norwegian Porphyria Centre (NAPOS).