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CATIE News - Will reduced-dose d4T be fat-friendly?Report from the 12th Conference on Retroviruses and Opportunistic Infections, February 22–25, 2005

Nucleoside analogues, or nukes, were the first class of drugs available for the treatment of HIV/AIDS. Today these medicines often form the backbone of anti-HIV therapy. Examples of nukes include the following:

* AZT (zidovudine, Retrovir)* 3TC (lamivudine, Epivir)* ABC (abacavir, Ziagen)* d4T (stavudine, Zerit)* ddI (didanosine, Videx)* FTC (emtricitabine, Emtriva—not yet available in Canada)

Although the drug tenofovir (Viread) is a nucleotide analogue, it is used as if it were a nuke.

Some nukes are combined in the same tablet (co-formulated), including the following:

* AZT + 3TC (Combivir)* AZT + 3TC + ABC (Trizivir)* ABC + 3TC (to be called Kivexa in Canada and the European Union—awaiting approval in Canada) * FTC + tenofovir (Truvada—not yet approved in Canada)

Although nukes play an important role in the treatment of HIV/AIDS, they can have side effects. Many of these occur because most nukes tend to affect the parts of a cell that produce energy—the mitochondria (Mt). When Mt become damaged, cells suffer a power shortage and can malfunction and die.

In general, damage to Mt may be responsible for a range of possible side effects including the following:

* peripheral neuropathy (pain or loss of sensation in the nerves of the feet, legs and hands)* lactic acidosis (higher-than-normal levels of lactic acid in the blood)* fatty liver* muscle wasting* damage to the bone marrow* weakened kidneys* pancreatitis (swollen pancreas gland)

Some nukes may also play a role in lipoatrophy (fat wasting). In particular, d4T has been associated with lipoatrophy in several studies. To a much lesser extent, AZT may be linked to a similar problem in some PHAs. Both of these drugs are called thymidine analogues. Thymidine is what the “T†in d4T and AZT represents.

Treatment guidelines in the United States and the United Kingdom discourage the use of d4T for the initial therapy of HIV/AIDS because of its side effects. However, d4T is still an important drug and avoiding its use may not be possible for all PHAs.

The currently recommended adult dose of d4T is as follows:

* PHAs who weigh 60 kg (132 lbs) or more—40 mg twice daily * PHAs who weigh less than 60 kg—30 mg twice daily

d4T may be taken with or without food, every 12 hours.

Researchers in Barcelona, Spain, theorize that reducing the adult dose of d4T by 25% may result in fewer side effects while preserving this drug’s anti-HIV activity. The research team performed a study whereby PHAs who were using d4T as part of combination therapy were randomly assigned to one of the following three groups—the only changes made to their regimens was their d4T dosing:

* continued d4T (40 mg twice daily)* reduced-dose d4T (30 mg twice daily)* replacing d4T with tenofovir (300 mg once daily)

After six months, in reduced-dose d4T and tenofovir users, researchers found improvements in measures of fat in the limbs as well as favourable changes in cholesterol and triglycerides in the blood. Further details appear below.

Study detailsResearchers recruited 58 PHAs who had been taking d4T for the previous six months at a dose of 40 mg twice daily and whose viral load was below the 200-copy mark. These PHAs were randomly assigned to one of three groups as noted above. The rest of their regimens remained the same.

At the start of the study, the average profile of participants was as follows:

* age – 45 years* CD4+ count – about 600 cells* viral load – below the 200-copy mark in all participants

Extensive blood tests and low-dose X-ray scans to assess changes in body composition were done at the start of the study and six months later.

Results—Changes in lipid levelsOverall, significantly reduced levels of total cholesterol, LDL-cholesterol (so-called “bad†cholesterol) and triglycerides were more likely to occur in tenofovir users compared to the group receiving 40 mg d4T. In the reduced-dose d4T group (30 mg), these lipids also decreased but not to a statistically significant degree.

Changes in levels of HDL-cholesterol (so-called “good†cholesterol) were not significant.

Results—Changes in lactate levelsRising levels of lactate in the blood can suggest increasing damage to Mt. This poses the risk of lactic acidosis, which can be fatal. Among participants in the 40 mg d4T group, lactate levels rose throughout the study, while in the 30 mg d4T group they remained stable. Among tenofovir users, lactate levels initially fell but then rose. By the end of the study, however, lactate levels in the tenofovir group were still below the pre-study levels.

Results—Viral load and CD4+ cell countsThese test results tended to remain stable throughout the study, although rising viral load was detected in two members of the 40 mg d4T group.

Results—Fat gain and lossOn average, fat in the limbs increased in tenofovir and reduced-dose d4T users, but only in the tenofovir group was the change statistically significant. Fat in the limbs decreased in the 40 mg d4T group. Assessments of total body fat found similar results.

This study highlights the possible benefits of reducing the recommended dose of d4T by 25% or switching from d4T to tenofovir. However, the researchers only released results from the first six months of a relatively small study. Much longer and more detailed results from a larger number of participants are needed before the safety and efficacy of reduced-dose d4T becomes clear.

— R. Hosein

REFERENCES1. British HIV Association guidelines for the treatment of HIV-infected adults with antiretroviral therapy. July 2003. Available at: http://www.bhiva.org/guidelines/2003/hiv/index.html

2. White AJ. Mitochondrial toxicity and HIV therapy. Sexually Transmitted Infections 2001;77(3):158-173.

3. Kakuda TN. Pharmacology of nucleoside and nucleotide reverse transcriptase inhibitor-induced mitochondrial toxicity. Clinical Therapeutics 2000;22(6):685-708.

4. Lonergan JT, Barber RE, Mathews WC. Safety and efficacy of switching to alternative nucleoside analogues following symptomatic hyperlactatemia and lactic acidosis. AIDS 2003;17(17):2495-9.

5. Velsor LW, Kovacevic M, Goldstein M, et al. Mitochondrial oxidative stress in human hepatoma cells exposed to stavudine. Toxicology and Applied Pharmacology 2004;199(1):10-19.

6. van der Valk M, Casula M, Weverlingz GJ, et al. Prevalence of lipoatrophy and mitochondrial DNA content of blood and subcutaneous fat in HIV-1-infected patients randomly allocated to zidovudine- or stavudine-based therapy. Antiviral Therapy 2004;9(3):385-393.

7. Nolan D, Hammond E, I, et al. Contribution of nucleoside-analogue reverse transcriptase inhibitor therapy to lipoatrophy from the population to the cellular level. Antiviral Therapy 2003;8(6):617-626.

8. Nolan D, Hammond E, A, et al. Mitochondrial DNA depletion and morphologic changes in adipocytes associated with nucleoside reverse transcriptase inhibitor therapy. AIDS 2003;17(9):1329-1338.

9. Milinkovic A, S, Vidal S, et al. A randomized open study comparing the effect of reducing stavudine dose vs. switching to tenofovir on mitochondrial function, metabolic parameters, and subcutaneous fat in HIV-infected patients receiving antiretroviral therapy containing stavudine. In: Program and abstracts of the 12th Conference on Retroviruses and Opportunistic Infections; February 22–25, 2005; Boston, U.S. Poster 857.

In health, VergelDirectorProgram for Wellness Restoration, PoWeRA 501 © 3 non profit national organizationpowerusa.orgsalvagetherapies.orgRemember that everyone you meet is afraid of something, loves something, and has lost something.DisclaimerThis information (and any accompanying printed material) is not intended to replace the attention or advice of a physician or other health care professional. Anyone who wishes to embark on any dietary, drug, exercise, or other lifestyle change intended to prevent or treat a specific disease or condition should first consult with and seek clearance from a qualified health care professional.

CATIE News - Will reduced-dose d4T be fat-friendly?Report from the 12th Conference on Retroviruses and Opportunistic Infections, February 22–25, 2005

Nucleoside analogues, or nukes, were the first class of drugs available for the treatment of HIV/AIDS. Today these medicines often form the backbone of anti-HIV therapy. Examples of nukes include the following:

* AZT (zidovudine, Retrovir)* 3TC (lamivudine, Epivir)* ABC (abacavir, Ziagen)* d4T (stavudine, Zerit)* ddI (didanosine, Videx)* FTC (emtricitabine, Emtriva—not yet available in Canada)

Although the drug tenofovir (Viread) is a nucleotide analogue, it is used as if it were a nuke.

Some nukes are combined in the same tablet (co-formulated), including the following:

* AZT + 3TC (Combivir)* AZT + 3TC + ABC (Trizivir)* ABC + 3TC (to be called Kivexa in Canada and the European Union—awaiting approval in Canada) * FTC + tenofovir (Truvada—not yet approved in Canada)

Although nukes play an important role in the treatment of HIV/AIDS, they can have side effects. Many of these occur because most nukes tend to affect the parts of a cell that produce energy—the mitochondria (Mt). When Mt become damaged, cells suffer a power shortage and can malfunction and die.

In general, damage to Mt may be responsible for a range of possible side effects including the following:

* peripheral neuropathy (pain or loss of sensation in the nerves of the feet, legs and hands)* lactic acidosis (higher-than-normal levels of lactic acid in the blood)* fatty liver* muscle wasting* damage to the bone marrow* weakened kidneys* pancreatitis (swollen pancreas gland)

Some nukes may also play a role in lipoatrophy (fat wasting). In particular, d4T has been associated with lipoatrophy in several studies. To a much lesser extent, AZT may be linked to a similar problem in some PHAs. Both of these drugs are called thymidine analogues. Thymidine is what the “T” in d4T and AZT represents.

Treatment guidelines in the United States and the United Kingdom discourage the use of d4T for the initial therapy of HIV/AIDS because of its side effects. However, d4T is still an important drug and avoiding its use may not be possible for all PHAs.

The currently recommended adult dose of d4T is as follows:

* PHAs who weigh 60 kg (132 lbs) or more—40 mg twice daily * PHAs who weigh less than 60 kg—30 mg twice daily

d4T may be taken with or without food, every 12 hours.

Researchers in Barcelona, Spain, theorize that reducing the adult dose of d4T by 25% may result in fewer side effects while preserving this drug’s anti-HIV activity. The research team performed a study whereby PHAs who were using d4T as part of combination therapy were randomly assigned to one of the following three groups—the only changes made to their regimens was their d4T dosing:

* continued d4T (40 mg twice daily)* reduced-dose d4T (30 mg twice daily)* replacing d4T with tenofovir (300 mg once daily)

After six months, in reduced-dose d4T and tenofovir users, researchers found improvements in measures of fat in the limbs as well as favourable changes in cholesterol and triglycerides in the blood. Further details appear below.

Study detailsResearchers recruited 58 PHAs who had been taking d4T for the previous six months at a dose of 40 mg twice daily and whose viral load was below the 200-copy mark. These PHAs were randomly assigned to one of three groups as noted above. The rest of their regimens remained the same.

At the start of the study, the average profile of participants was as follows:

* age – 45 years* CD4+ count – about 600 cells* viral load – below the 200-copy mark in all participants

Extensive blood tests and low-dose X-ray scans to assess changes in body composition were done at the start of the study and six months later.

Results—Changes in lipid levelsOverall, significantly reduced levels of total cholesterol, LDL-cholesterol (so-called “bad” cholesterol) and triglycerides were more likely to occur in tenofovir users compared to the group receiving 40 mg d4T. In the reduced-dose d4T group (30 mg), these lipids also decreased but not to a statistically significant degree.

Changes in levels of HDL-cholesterol (so-called “good” cholesterol) were not significant.

Results—Changes in lactate levelsRising levels of lactate in the blood can suggest increasing damage to Mt. This poses the risk of lactic acidosis, which can be fatal. Among participants in the 40 mg d4T group, lactate levels rose throughout the study, while in the 30 mg d4T group they remained stable. Among tenofovir users, lactate levels initially fell but then rose. By the end of the study, however, lactate levels in the tenofovir group were still below the pre-study levels.

Results—Viral load and CD4+ cell countsThese test results tended to remain stable throughout the study, although rising viral load was detected in two members of the 40 mg d4T group.

Results—Fat gain and lossOn average, fat in the limbs increased in tenofovir and reduced-dose d4T users, but only in the tenofovir group was the change statistically significant. Fat in the limbs decreased in the 40 mg d4T group. Assessments of total body fat found similar results.

This study highlights the possible benefits of reducing the recommended dose of d4T by 25% or switching from d4T to tenofovir. However, the researchers only released results from the first six months of a relatively small study. Much longer and more detailed results from a larger number of participants are needed before the safety and efficacy of reduced-dose d4T becomes clear.

— R. Hosein

REFERENCES1. British HIV Association guidelines for the treatment of HIV-infected adults with antiretroviral therapy. July 2003. Available at: http://www.bhiva.org/guidelines/2003/hiv/index.html

2. White AJ. Mitochondrial toxicity and HIV therapy. Sexually Transmitted Infections 2001;77(3):158-173.

3. Kakuda TN. Pharmacology of nucleoside and nucleotide reverse transcriptase inhibitor-induced mitochondrial toxicity. Clinical Therapeutics 2000;22(6):685-708.

4. Lonergan JT, Barber RE, Mathews WC. Safety and efficacy of switching to alternative nucleoside analogues following symptomatic hyperlactatemia and lactic acidosis. AIDS 2003;17(17):2495-9.

5. Velsor LW, Kovacevic M, Goldstein M, et al. Mitochondrial oxidative stress in human hepatoma cells exposed to stavudine. Toxicology and Applied Pharmacology 2004;199(1):10-19.

6. van der Valk M, Casula M, Weverlingz GJ, et al. Prevalence of lipoatrophy and mitochondrial DNA content of blood and subcutaneous fat in HIV-1-infected patients randomly allocated to zidovudine- or stavudine-based therapy. Antiviral Therapy 2004;9(3):385-393.

7. Nolan D, Hammond E, I, et al. Contribution of nucleoside-analogue reverse transcriptase inhibitor therapy to lipoatrophy from the population to the cellular level. Antiviral Therapy 2003;8(6):617-626.

8. Nolan D, Hammond E, A, et al. Mitochondrial DNA depletion and morphologic changes in adipocytes associated with nucleoside reverse transcriptase inhibitor therapy. AIDS 2003;17(9):1329-1338.

9. Milinkovic A, S, Vidal S, et al. A randomized open study comparing the effect of reducing stavudine dose vs. switching to tenofovir on mitochondrial function, metabolic parameters, and subcutaneous fat in HIV-infected patients receiving antiretroviral therapy containing stavudine. In: Program and abstracts of the 12th Conference on Retroviruses and Opportunistic Infections; February 22–25, 2005; Boston, U.S. Poster 857.

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