Nucleoside and Nucleotide Reverse  Transcriptase Inhibitors

Agents: tenofovir (TDF), emtricitabine (FTC), lamivudine (3TC), zidovudine (ZDV, AZT), abacavir (ABC), stavudine (d4T), didanosine (ddI)

Combinations: emtricitabine/tenofovir  (Truvada), abacavir/lamividune (Epzicom), lamivudine/zidovudine (Combivir), abacavir/lamivudine/zidovudine (Trizivir)

The nucleoside reverse transcriptase inhibitors  (NRTIs) are the oldest class of antiretrovirals  (tenofovir is technically a nucleotide but is grouped with these agents). A combination of two of these drugs typically forms the “backbone” of most anti-HIV regimens.

Spectrum

In addition to being used to treat the HIV virus, several of these drugs (tenofovir, emtricitabine, lamivudine) have clinically useful activity against hepatitis B virus (HBV).

Adverse Effects

Extremities:  Peripheral neuropathy is seen as a delayed, slowly progressive adverse effect in some patients taking didanosine or stavudine  (and especially in combination).

Gastrointestinal: NRTIs tend to have less GI toxicity (nausea, vomiting, diarrhea) than many antiretrovirals, but zidovudine and didanosine may be problematic.

Hematologic:  Bone marrow suppression (anemia,  neutropenia) occurs frequently with zidovudine,  and rarely with other NRTIs.

Hypersensitivity: In a minority of patients, abacavir use is associated with a hypersensitivity reaction manifesting with fever, rash, and flulike symptoms days to weeks after starting therapy. Continuation of or rechallenge with abacavir in patients experiencing this syndrome can be fatal. Patients at highest risk for this toxicity can be identified by a genetic test for the HLA B*5701 allele before starting therapy; patients testing positive should not be offered abacavir.

Metabolic: Lactic acidosis, hepatic steatosis, and pancreatitis are part of a complex of toxicities suspected to be of mitochondrial origin that are a class wide adverse effect of NRTIs. Mortality can be high if symptoms are not recognized early—which is a problem because symptoms are typically delayed (for months) in onset and may be nonspecific in initial presentation.  Agents with a higher propensity for this toxicity include stavudine, didanosine, and zidovudine.  Didanosine and zidovudine may also contribute to hyperlipidemia, insulin resistance, and lipoatrophy (loss of fat causing changes in appearance, primarily in the face and buttocks).

Renal: Nephrotoxicity, evidenced by increased  serum creatinine and renal electrolyte and pro-tein wasting, is a well-documented adverse effect of tenofovir and requires regular monitoring of renal function.

Important Facts

• Most of the NRTIs require dosage adjustment in renal dysfunction. This may require avoiding the fixed-dose combination preparations to give more dose flexibility.

• NRTIs have minimal metabolic drug interactions compared with the other antiretroviral drug classes. Tenofovir has interactions with didanosine and atazanavir that require dosage adjustment.

• Didanosine, stavudine, and zidovudine tend to have the most toxicity and are now mostly used as second-line treatment for resistant cases.

• Various patterns of cross-resistance among the NRTIs occur. Expert interpretation of antiviral susceptibility is required, and in some cases NRTIs may confer a therapeutic benefit even for resistant viruses.

What They’re Good For

NRTIs are used as components of a combination antiretroviral regimen for HIV. For treatment-naive patients, two NRTIs are typically combined with a drug from another class. For treatment-experienced patients, three or more NRTIs may be part of a salvage regimen. As noted, certain NRTIs are also used to manage HBV infections. Use of these drugs in management of HIV/HBV co-infected patients requires accounting for the overlap in activity between the viruses to ensure that resistance doesn’t emerge because of suboptimal activity against one of the viruses.

Don’t Forget!

If there aren’t two NRTIs (taking into account com-bination preparations as well) as part of a patient’s anti-HIV regimen, something is weird. The patient may be on an unusual salvage regimen (hopefully under the care of an HIV expert), but it’s best to check to make sure something didn’t get left out.

References

Gallagher ,J.C. and MacDougall ,c. (2012). Antibiotics Simplified. Second Edition. Jones & Bartlett Learning, LLC.