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Nucleoside (NRTI) & Nucleotide (NtRTI)

Reverse Transcriptase Inhibitors
November 2005



Direct Links to N(t)RTI Info
Principles of NRTI / NtRTI Use
Major toxicities of NRTI use
Generic Brand
zidovudine Retrovir
zalcitabine Hivid
didanosine Videx, Videx EC
stavudine Zerit, Zerit-XR
lamivudine Epivir
abacavir Ziagen
emtricitabine Emtriva
tenofovir Viread
Combination NRTIs
AZT/3TC Combivir
AZT/3TC/ABC Trizivir
ABC/3TC Epzicom
TDF/FTC Truvada
Summary Information
NRTI & NtRTI Summary Information
Preferred NRTI & NtRTI Combinations
NRTI Combinations to Avoid



Key Principles of NRTI / NtRTI Usage


NRTIs serve as the backbone for antiretroviral combination therapy in most situations. Side effects vary greatly, are usually mild, but may be severe rarely. Monitor with laboratory and clinical follow-up frequently at least initially.
1 Consider use of fixed dose combinations such as abacavir / zidovudine / lamivudine (Trizivir) or zidovudine / lamivudine (Combivir) when possible.  (see point 3 below)  Newly approved fixed-dose combinations of abacavir / lamivudine (Epzicom) and tenofovir / entricitabine (Truvada) offer single daily dosing of two potent and well-tolerated NRTIs in one pill each.   Obviously using co-formulated drugs lowers pill burden and accentuates adherence.
2 Consider once-a-day NRTIs for first line (naive) therapy: tenofovir, didanosine-EC, emtricitabine, lamivudine-qd,
3 Use 2-3 active NRTIs in combination with either a nonnucleoside reverse transcriptase inhibitor or a protease inhibitor in most regimens for optimal potency.
4 Avoid triple NRTI regimens that do not include a NNRTI or PI.  Abacavir/zidovudine/lamivudine (ABC/ZDV/3TC, Trizivir) and abacavir/tenofovir/lamivudine (ABC/TDF/3TC) have shown fairly definitive inferiority to PI or NNRTI-based regimens in several studies.
5 Avoid the use of NRTIs with overlapping or additive toxicities, e.g. two with potent mitochondrial toxicity (see below)
6 Avoid NRTIs that have not shown additive or synergistic actions (d4T-AZT, FTC-3TC, etc.) (see below)

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



Mitochondrial toxicity due to inhibition of mitochondrial DNA-polymerase by NRTIs
Pancreatitis Usually associated with ddI (~10%), rare with d4T, ddC, 3TC

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 This condition is frequently asymptomatic, yet potentially fatal rarely and has been associated with nearly all NRTIs

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


Peripheral neuropathy ddC > d4T > ddI

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)


Lipoatrophy and hyperlipidemia
(metabolic syndrome)

This is probably another effect of the mitochondrial toxicity of this class of agents.  Fat cell mitochondria are inhibited by drugs with known mitochondrial toxicity.  Generally stavudine = zalcitabine > didanosine > zidovudine are thought to display more of this type of toxicity than the remaining drugs.  Lipoatrophy is the effect on the body shape produced by loss of subcutaneous fat in the face and extremities.  Type 2 diabetes may also be seen.



Bone marrow suppression
Mainly AZT but other NRTIs may cause bone marrow suppression with a much lower frequency.
Leukopenia is frequent whereas granulocytopenia is infrequent.
Anemia is infrequent. No thrombocytopenia is usually seen with NRTIs.
Recombinant human erythropoietin and/or granulocyte colony stimulating factor (G-CSF) may be useful if less toxic NRTI substitutes are not practical



Abacavir hypersensitivity
5% incidence usually in the first 6 weeks of therapy but the syndrome is possible later.
The syndrome consists of two or more symptoms: fever, rash, progressive nausea, diarrhea, cough, dyspnea. 
If present, the syndrome progresses somewhat with each dose of abacavir.
Once symptoms compatible with hypersensitivity develop, monitor the patient closely for progression of the syndrome over 24-48hrs.
Close monitoring is necessary as the primary syndrome may rarely progress to severe morbidity or mortality.
If the syndrome clearly progresses on a dose by dose basis, discontinue abacavir and DO NOT RESTART IT.
Abacavir rechallenge of persons with abacavir hypersensitivity usually results in fairly rapid death of the patient.



NRTI Summary Information



NRTI & NtRTI Toxicity and Resistance Information Summary


Pill Burden
per day
Pancreatitis Lipo Mitochondrial
Other Active
With M184V
High Level
Resistance Mutations


2 +++ Rare   + ++ Nausea,
  Yes Q151M, T215Y/F
1-2     Rare   + Rare hair loss Yes   M184V
3   ++++ + ++ +++ Poor potency?
Rare rash
    K65R, T69D/N/S/A/ins
1   ++ ++ ++ ++ Active in the setting of multi-NRTI resistance?     K65R, Q151M,
2       + + Hypersensitivity 5%,
nausea, headache
    M184V, Q151M
1       ? + Rare nephrotoxicity Yes Yes K65R
1         + 3% skin hyperpigmentation Yes   M184V
1-2 + ++++ + +++ ++++     Yes Q151M


Lipo = potential for fat cell mitochondrial toxicity and clinical syndrome of fat redistribution, hyperlipidemia, Type 2 diabetes


For detailed NRTI & NtRTI Mutation information, please consult with the Antiretroviral Resistance section of this site, or check the links section.



Acceptable NRTI Combinations
[should be combined with PI or NNRTI in almost all instances]

Regimen Rationale
1 abacavir + zidovudine + lamivudine (Trizivir) Pro: 3 drugs combined in one pill with twice a day dosing and good tolerance
Con: 3 drugs may be unnecessary
2 zidovudine + lamivudine (Combivir) Pro: 2 drugs combined in one pill with twice a day dosing and excellent tolerance
Con: slow onset of mitochondrial toxicity (lipoatrophy) and rapid onset of myelopsuppression and anemia possible
  tenofovir + emtricitabine (Truvada) 1 pill per day with excellent potency and tolerance
  abacavir + lamivudine (Epzicom) Pro: 1 pill per day with excellent potency and very good tolerance
Con: abacavir hypersensitivity possible
3 abacavir + tenofovir Pro: low mitochondrial toxicity and high potency; probably can be taken as 3 pills once a day
Con: abacavir hypersensitivity possible
4 tenofovir + didanosine-EC Pro: 2 pills with excellent potency, tolerance, and once-a-day dosing (adjust didanosine for interaction with tenofovir)
Con:  tenofovir and didanosine combination may limit CD4-lymphocyte response to virologic suppression; pancreatitis possible with didanosine
5 didanosine-EC + (emtricitabine or lamivudine-daily) Pro: 2 drug in 2-3 pills with excellent potency, tolerability once-a-day
Con: pancreatitis possible with didanosine
6 tenofovir + Combivir Pro: 3 drugs in 3 pills per day with excellent potency, good tolerance and twice a day dosing
Con: 3 NRTI drugs may be unnecessary, toxic, and expensive
7 abacavir + emtricitabine Pro: 2 drugs in 3 pills per day with excellent potency, excellent tolerance, and twice a day dosing
Con: abacavir hypersensitivity possible; abacavir and lamivudine co-formulated and therefore will reduce pill burden


lamivudine-daily = 300 mg lamivudine as a single daily dose of one or two pills

stavudine-daily = once-a-day stavudine extended-release form [not yet available May 2005]



NRTI Combinations To Avoid

AZT + d4T In vitro and in vivo antagonism
3TC + ddC In vitro antagonism
ddI + ddC Increased mitochondrial toxicity especially peripheral neuropathy
ddC + d4T Increased mitochondrial toxicity especially peripheral neuropathy
ddC + 3TC Poor potency?
ddC + ddI Increased mitochondrial toxicity especially peripheral neuropathy
ABC + TDF + 3TC Unclear interaction, but probably decreased ABC at cellular level; especially avoid single daily dosing of ABC in this combination without a PI or NNRTI; high failure rate and high rate of development of K65R and M184V mutations.  Although the high rate of failure has been seen in the setting of non-PI and non-NNRTI based regimens, it is probably prudent to avoid this combination even when used with other classes of antiretroviral therapy.
FTC + 3TC Identical mechanism of action and resistance; unlikely to increase the activity of each other; equivalent to monotherapy with FTC or 3TC
ddI + d4T Increased mitochondrial toxicity which may be severe





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Links to Antiretroviral Sections
Nucleoside & Nucleotide Reverse Transcriptase Inhibitors (NRTI)
AZT  |  ddC  |  ddI  |  d4T  |  3TC  |  ABC  |  FTC  |  TDF  |  Combivir  |  Trizivir  |  Truvada  |  Epzicom
Nonnucleoside Reverse Transcriptase Inhibitors (NNRTI)
efavirenz  |  nevirapine  |  delavirdine
Protease Inhibitors (PI) |  Boosted Protease Inhibitors
saquinavir  indinavir  |  ritonavir  |  nelfinavir  |  amprenavir  |  lopinavir + ritonavir  |  atazanavir  |  fosamprenavir
Fusion Inhibitors



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Updated 10.25.2005