Nucleoside and nucleotide reverse transcriptase inhibitors

Just as HIV employs enzymes to copy its genetic material, so too do human cells and mitochondria. Nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs/NtRTIs) are defective versions of the building blocks that make up DNA. When HIV’s reverse transcriptase enzyme uses one of these defective links in a new DNA chain, real nucleotides cannot be added, and the replication process stops.

Much the same thing happens within the mitochondria. Mitochondrial replication requires an enzyme called polymerase-gamma. Like reverse transcriptase, this enzyme can add defective NRTI building blocks to new strands of genetic material. When this happens, the replication of mtDNA decreases, eventually leading to dysfunction and cell death.1 2

Some experts believe mitochondrial damage is the mechanism underlying many, if not all, side-effects associated with the NRTIs, from lactic acidosis to lipoatrophy (fat loss in the face, limbs, and buttocks). This theory is supported by the fact that similar symptoms are seen in people with inherited mitochondrial diseases.3

All approved NRTIs interfere with mtDNA replication, but some do so more than others. Test tube studies suggested that the likely ranking, from most to least mitotoxic, is:

  • ddC (zalcitabine, Hivid).
  • ddI (didanosine, Videx / VidexEC).
  • d4T (stavudine, Zerit).
  • AZT (zidovudine, Retrovir).
  • 3TC (lamivudine, Epivir)/FTC (emtricitabine, Emtriva).
  • Abacavir (Ziagen)/tenofovir (Viread).4 5

The first three,  the so-called 'd-drugs,' are significantly more mitotoxic than the rest, probably because they have a greater affinity for polymerase-gamma. Some data suggest that d4T may be more problematic than ddI, and the two drugs in combination are strongly linked to mitochondrial damage and its associated symptoms. In 2005, ddC was withdrawn from the market. Tenofovir can contribute to mitochondrial toxicity by boosting ddI levels. There are conflicting data about the relative mitotoxicity of AZT.6

Research in HIV-positive people supports the laboratory findings. Patients taking NRTIs have decreased levels of mtDNA in their mitochondria and lower numbers of mitochondria in their cells, compared with treatment-naive, HIV-positive individuals and HIV-negative controls.

In an Australian study, mtDNA declined by 60% or more within twelve months of starting treatment with d4T or AZT. A significant drop did not occur after starting abacavir or tenofovir.7 Other studies have failed to find evidence that NRTIs are associated with decreased mtDNA.8

References

  1. Kakuda TN. Pharmacology of nucleoside and nucleotide reverse transcriptase inhibitor-induced mitochondrial toxicity. Clin Ther 22: 685-708, 2000
  2. Lewis W et al. Antiretroviral nucleosides, deoxynucleotide carrier and mitochondrial DNA: evidence supporting the DNA pol gamma hypothesis. AIDS 20: 675-684, 2006
  3. Brinkman K et al. Mitochondrial toxicity induced by nucleoside-analogue reverse-transcriptase inhibitors is a key factor in the pathogenesis of antiretroviral-therapy-related lipodystrophy. Lancet 354: 1112-1115, 1999
  4. Birkus G et al. Assessment of mitochondrial toxicity in human cells treated with tenofovir: comparison with other nucleoside reverse transcriptase inhibitors. Antimicrob Agents Chemother 46: 716-723, 2002
  5. Lim SE et al. Differential incorporation and removal of antiviral deoxynucleotides by human DNA polymerase gamma. J Biol Chem 276: 23616-23623, 2001
  6. Johnson AA et al. Toxicity of antiviral nucleoside analogs and the human mitochondrial DNA polymerase. J Biol Chem 276: 40847-40857, 2001
  7. Hammond E et al. Reduction of mitochondrial DNA content and respiratory chain activity occurs in adipocytes with 6-12 months of commencing nucleoside reverse transcriptase inhibitor therapy. AIDS 18: 815-827, 2004
  8. McComsey G et al. Analysis of the mitochondrial DNA genome in the peripheral blood leukocytes of HIV-infected patients with or without lipoatrophy. AIDS 16: 513-518, 2002
Community Consensus Statement on Access to HIV Treatment and its Use for Prevention

Together, we can make it happen

We can end HIV soon if people have equal access to HIV drugs as treatment and as PrEP, and have free choice over whether to take them.

Launched today, the Community Consensus Statement is a basic set of principles aimed at making sure that happens.

The Community Consensus Statement is a joint initiative of AVAC, EATG, MSMGF, GNP+, HIV i-Base, the International HIV/AIDS Alliance, ITPC and NAM/aidsmap
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