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Nucleoside (NRTI) & Nucleotide (NtRTI) Reverse Transcriptase Inhibitors |
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Key Management Information |
| 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 |
| TDF/FTC/efavirenz | Atripla |
| Summary Information | |
| NRTI & NtRTI Summary Information | |
| Preferred NRTI & NtRTI Combinations | |
| NRTI Combinations to Avoid | |
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Red highlighting indicates a
recommendation
to avoid use if alternatives available |
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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. Atripla (efavirenz / emtricitabine / tenofovir) provides one pill per day dosing of a potent, highly effective NNRTI-based regimen. Obviously using co-formulated drugs lowers pill burden and accentuates adherence. However, considering the increasing prevalence of M184V mutations in both naive and experienced patients, these combinations are best used after a careful antiretroviral history and resistance testing (while on antiretroviral therapy if possible.) |
| 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) |
| 7 |
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.
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| 8 |
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. |
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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.
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| 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
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| 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 |
| 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. |
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NRTI Summary Information |
| NRTI & NtRTI Toxicity and Resistance Information Summary | ||||||||||
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Generic |
Pill Burden per day |
Bone Marrow |
Peripheral Neuropathy |
Pancreatitis | Lipo |
Mitochondrial Toxicity |
Other |
Active Against Hep B |
Hypersensitivity Associated With M184V |
High Level Resistance Mutations |
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zidovudine Retrovir AZT, ZDV |
2 | +++ | Rare | + | ++ | Nausea, headache |
Yes | Q151M, T215Y/F | ||
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lamivudine Epivir 3TC |
1-2 | Rare | + | Rare hair loss | Yes | M184V | ||||
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zalcitabine Hivid ddC |
3 | ++++ | + | ++ | +++ | Poor potency? Rare rash No longer available |
K65R, T69D/N/S/A/ins | |||
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didanosine Videx-EC ddI |
1 | ++ | ++ | ++ | ++ | Active in the
setting of multi-NRTI resistance? No longer recommended due to possible severe toxicity |
K65R, Q151M, L74V |
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abacavir Ziagen ABC |
2 | + | + | Hypersensitivity 5%, nausea, headache |
M184V, Q151M | |||||
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tenofovir Viread TDF |
1 | ? | + | Rare nephrotoxicity | Yes | Yes | K65R | |||
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emtricitabine Emtriva FTC |
1 | + | 3% skin hyperpigmentation | Yes | M184V | |||||
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stavudine Zerit d4T |
1-2 | + | ++++ | + | +++ | ++++ | No longer recommended due to possible severe toxicity | 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, HIVResistanceWeb.com or check the links section.
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Acceptable NRTI Combinations |
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Order of Preference |
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 |
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| 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 + 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 |
| 5 | 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]
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NRTI Combinations To Avoid |
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| 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 |
| Click HERE for detailed NNRTI Information or select a link below. |
| Links to Antiretroviral Sections |
| Nucleoside & Nucleotide Reverse Transcriptase Inhibitors (NRTI) |
| AZT | ddI | d4T | 3TC | ABC | FTC | TDF ||| Coformulation NRTI: Combivir | Trizivir | Epzicom | Truvada |
| Nonnucleoside Reverse Transcriptase Inhibitors (NNRTI) |
| efavirenz | nevirapine | delavirdine | etravirine | rilpivirine |
| Protease Inhibitors (PI) | Boosted Protease Inhibitors |
| saquinavir | indinavir | ritonavir | nelfinavir | lopinavir + ritonavir | atazanavir | fosamprenavir | tipranavir |
| Co-receptor Inhibitors |
| maraviroc |
| Fusion Inhibitors |
| enfuvirtide |
| Integrase Inhibitors |
| raltegravir | elvitegravir | dolutgravir |
| Antiretroviral Metabolic Inhibitors |
| cobicistat | ritonavir |
| Coformulations |
| Atripla (efavirenz/tenofovir/emtricitabine) | Complera (rilpivirine/tenofovir/emtricitabine) | Stribild (elvitegravir/cobicistat/tenofovir/emtricitabine) |
Updated 11710/2013