Nucleoside (NRTI) & Nucleotide (NtRTI)

Reverse Transcriptase Inhibitors
November 2005

Key Principles of NRTI / NtRTI Usage

Resistance to NRTIs is simplistically cross-reactive.  Certain mutations are unique to certain drugs (K56R to tenofovir) while other mutations convey resistance to a range of NRTIs (215, 184) and may be induced as a result of exposure to any of multiple NRTIs.

Lamivudine and emtricitabine: complete resistance is mediated by M184V.  This mutation uniquely confers hypersensitivity to certain other NRTIs such as zidovudine, but the clinical significance of this is uncertain.

Q151M and T215Y/F seem to convey NRTI-class cross-resistance.

Lamivudine, emtricitabine, and tenofovir possess significant activity against hepatitis B virus.  These NRTIs especially tenofovir should be strongly considered for persons with chronic hepatitis B co-infection.  Sudden cessation of these NRTIs or immune reconstitution may result in a flare of hepatitis B which may be severe. 

Major Toxicities Associated With NRTI / NtRTI Usage

Pancreatitis is probably due to mitochondrial toxicity of NRTIs on pancreatic cells

It is important to encourage zero or minimal alcohol intake in patients taking didanosine

Pancreatitis usually occurs in setting of advanced disease

ddI is contraindicated with any prior history of pancreatitis

Consider obtaining a pretherapy serum lipase, fractionated amylase (nonfractionated amylase testing is not recommended due to low specificity), or p-amylase

Watch serum triglycerides especially with PI-based regime

Pancreatitis is rarely fatal

Check serum lipase for any episodes of abdominal pain, nausea and vomiting

The utility of routine lipase monitoring while on therapy is unclear.

Lactic acidosis is usually associated with hepatic steatosis and/or other liver disease including hepatitis C

Presents as vague but troubling symptoms of a progressive or chronic nature including nausea, achiness, profound fatigue

Syndrome may progress toward pancreatitis, renal failure, and hepatic failure in fatal variant

Check serum lactic acid level (avoid venipuncture with tourniquet) in setting of anion gap acidosis and vague nonspecific symptoms such as those listed above.

Routine monitoring of lactic acid levels is not useful.

Avoid two d-drugs (especially d4T in combination with ddI if possible.) especially in the setting of liver disease

Small studies have indicated that restarting NRTIs such as abacavir and tenofovir after resolution of the syndrome may be safe if close monitoring is assured.

Treatment of lactic acidosis

Remove antiretrovirals and provide supportive care

Riboflavin therapy is investigational

Rapid onset distal sensory polyneuropathy, usually on the soles of the feet with proximal extension over time.

Avoid two of these NRTIs together, except under VERY close surveillance [ddC should not be combined at all with other d-drugs]

Avoid hydroxyurea with d4t AND ddI especially in boderline renal insufficiency, lower BMIs, and pre-existing peripheral neuropathy except under very close supervision.

Watch concommitant neurotoxins carefully: dapsone, isoniazid, antineoplastic chemotherapy

Check serum B12, serum folate, TSH, RPR

Treatment of peripheral neuropathy
Remove offending agent.  Worsening of the symptoms may continue for 6-12 weeks after discontinuation ("coasting phenomenon")
Begin acetyl-L-carnitine 1500 mg bid (see Updates section HERE)
Palliative care: transdermal lidocaine patches applied to ankles for 12 hours each day, gabapentin titrated up to 5600 mg per day in 3 divided doses (or other suitable anticonvulsant), and opiate analgesics if necessary (although neuropathic pain is typically difficult to control with opiates)
 

NRTI Summary Information

Generic
Brand
Nomenclature

AZT, ZDV

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