Side-effects

WHO is now recommending that national treatment programmes phase out the use of d4T in first-line treatment due to the high frequency of serious toxicity. The drug has been the mainstay of antiretroviral treatment scale-up in resource-limited settings due to its low cost and its availability in cheap, generic fixed dose combinations.

Instead, treatment programmes should use tenofovir or zidovudine (AZT). However, both these drugs are more expensive than d4T, and in the case of tenofovir, only available in three-drug fixed-dose combination with efavirenz, also more expensive than the other mainstay of treatment scale-up, nevirapine.

WHO acknowledged that implementation of the recommendations will depend on national circumstances, resources and priorities.The commonest side-effect of d4T (stavudine, Zerit) is peripheral neuropathy, nerve damage in the feet, legs, and hands, which can cause numbness, tingling, or pain in the extremities. The pain associated with neuropathy can be severe.

Peripheral neuropathy occurs in 15 to 21% of people on d4T, particularly in those on higher doses, with more advanced HIV disease, or who are also taking ddI (didanosine, Videx / VidexEC). If d4T is stopped, neuropathy usually gets better after about two weeks. If symptoms disappear, d4T can be restarted at half the recommended dose. Recent studies have also shown that halving or reducing the dose of d4T by 10mg has no effect on its efficacy but can reduce the incidence of peripheral neuropathy.1 2 3

Due to its tendency to make peripheral neuropathy worse, d4T is usually not recommended to people with pre-existing neuropathy.

Body fat changes known as lipodystrophy are also a major concern with d4T. Although the syndrome was originally linked with protease inhibitors, a number of studies have found an association between lipodystrophy and the nucleoside reverse transcriptase inhibitors, with the strongest association observed with d4T.4 5 6 7 8 This association is also found in children and adolescents.9 Consequently, the British HIV Association recommends that d4T should not be used in first-line therapy.

There is evidence that fat loss stops after the dose of d4T is reduced by 10mg or it is stopped altogether.10 11 12 13 Switching from d4T to abacavir (Ziagen) can also help to reverse fat loss.14 15

Risk factors for d4T-related fat loss include:

  • Being over 40 years old.
  • Having high baseline triglyceride levels (over 200mg/dl).
  • Using standard immediate-release d4T: although not yet routinely available, the new once daily extended-release (XR) version of the drug produces a slightly lower incidence of lipoatrophy over 48 weeks.16

Fat loss is thought to be due to damage to the mitochondria within fat cells, although d4T has been shown to reduce levels of mitochondrial DNA in fat cells long before fat loss is clinically apparent.17 18

Elevated lactate and other metabolic abnormalities have also been linked to d4T treatment. Lactic acidosis is a rare but serious side-effect of d4T causing symptoms such as nausea, malaise and liver pain, which can lead to eventual death if nucleoside reverse transcriptase inhibitor (NRTI) treatment is not stopped. Of all the NRTIs, d4T has been particularly associated with elevated lactate levels. It usually develops within the first few months of d4T treatment. Pregnant women taking d4T and ddI (didanosine, Videx / VidexEC) may be at increased risk of lactic acidosis, as may patients with hepatitis C who are taking interferon alfa (IntronA / Roferon-A / Viraferon) and ribavirin (Copegus / Rebetol / Virazole). Some experts believe that this is caused by d4T damaging the mitochondria, the subcellular compartments that provide energy for the cell, causing a range of side effects including fat loss and peripheral neuropathy. See Mitochondrial toxicity for more details.

Around 2% of people taking d4T develop pancreatitis, although the risk of this occurring is greater in patients who have had pancreatitis in the past. Elevated amylase levels are common, and can be a warning sign for increased risk of pancreatitis.

Other side-effects of d4T are most likely to occur during the early weeks of treatment. These include nausea, vomiting, listlessness, chills, fever, diarrhoea, constipation, headaches, abdominal pain and dehydration. Medicines to control nausea and diarrhoea can be prescribed before a patient starts d4T.

Other less common toxicities of d4T include elevated liver enzymes and fatty liver, particularly in people with hepatitis B or C co-infection.19 There have also been anecdotal reports of sleep disorders, mania and skin rashes, as well as elevations of urate levels in the blood, which can lead to gout and kidney problems.20

References

  1. Sanchez-Conde M et al. Dose reduction in stavudine from 40 to 30 mg bid provides similar virological and immunological benefit. 15th International AIDS Conference, Bangkok, abstract TuPeB4459, 2004
  2. Wolf E et al. Low dose stavudine: less side effects but as effective as standard dose. 15th International AIDS Conference, Bangkok, abstract WePeB5861, 2004
  3. Siangphoe U et al. Efficacy and safety of half dose compared to full dose stavudine (d4T) and zidovudine (AZT) in combination with didanosine (ddI) in Thai HIV-infected patients: 96 weeks results of ACTT002 / ARV065 study. 15th International AIDS Conference, Bangkok, abstract WePeB5952, 2004
  4. Garcia-Benayas T et al. Weight loss in HIV-infected patients. N Engl J Med 346: 1287-1288, 2002
  5. Gallant J et al. Favourable lipid and mitochondrial (mt) DNA profile for tenofovir disoproxil fumarate (TDF) compared to stavudine (d4T) in combination with lamivudine (3TC) and efavirenz (EFV) in antiretroviral therapy (ART) naïve patients: a 48 week interim analysis. 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy, San Diego, abstract LB-2, 2002
  6. Gerstoft J et al. Abacavir, didanosine and stavudine versus ritonavir, saquinavir, zidovudine and lamivudine or nelfinavir, nevirapine, zidovudine and lamivudine in antiretroviral naive HIV patients. 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy, San Diego, astract H-164, 2002
  7. Nolan D et al. Effect of stavudine, zidovudine and HIV protease inhibitor therapy on subcutaneous leg fat wasting in HIV-infected males. A longitudinal study. Fourth International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV, San Diego, abstract 28, 2002
  8. Staszewski S et al. Efficacy and safety of tenofovir DF (TDF) versus stavudine (d4T) when used in combination with lamivudine and efavirenz in antiretroviral naïve patients: 96-week preliminary interim results. Tenth Conference on Retroviruses and Opportunistic Infections, Boston, abstract 564b, 2003
  9. European Paediatric Lipodystrophy Group Antiretroviral therapy, fat redistribution and hyperlipidaemia in HIV-infected children in Europe. AIDS 18: 1443-1451, 2004
  10. Hanvanich M et al. Reduction of d4T dosage improves lipoatrophy without virologic failure. Antivir Ther 8: S392, 2003
  11. Thompson K et al. Improvements in body fat and mitochondrial DNA levels are accompanied by decreased adipose tissue cell apoptosis after replacement of stavudine therapy with either abacavir or zidovudine. Tenth Conference on Retroviruses and Opportunistic Infections, Boston, abstract P728, 2003
  12. Ribera E et al. A randomized study comparing the efficacy and tolerability of low-dose versus standard-dose stavudine in antiretroviral-naive patients (ETOX Study). Third International AIDS Society Conference on HIV Pathogenesis and Treatment, Rio de Janeiro, abstract TuPe2.4C10, 2005
  13. Milinkovic A et al. A randomized open label 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. Twelfth Conference on Retroviruses and Opportunistic Infections, Boston, abstract 857, 2005
  14. Martin A et al. Reversibility of lipoatrophy in HIV-infected patients 2 years after switching from a thymidine analogue to abacavir: the MITOX Extension Study. AIDS 18: 1029-1036, 2004
  15. John M et al. Randomized, controlled, 48 week study of switching stavudine and / or protease inhibitors to Combivir / abacavir to prevent or reverse lipoatrophy in HIV-infected patients. J Acquir Immune Defic Syndr 33: 29-33, 2003
  16. Noor et al. Baseline triglyceride levels predict the development of lipoatrophy in patients treated with stavudine extended-release / prolonged release capsules (XR / PRC) or stavudine immediate release (IR). Eleventh Conference on Retroviruses and Opportunistic Infections, San Francisco, abstract 722, 2004
  17. van der Valk M et al. Relation between use of nucleoside reverse transcriptase inhibitors, mitochondrial DNA depletion, and severity of lipoatrophy: results from a randomized trial comparing stavudine and zidovudine-based antiretroviral therapy. Tenth Conference on Retroviruses and Opportunistic Infections, Boston, abstract P739, 2003
  18. Nolan D et al. Differential effects of nucleoside reverse transciptase inhibitor (NRTI) regimens on adipocyte mitochondrial DNA depletion in HIV-infected patients. Antivir Ther 9: L11, 2004
  19. McGovern BH et al. Hepatic steatosis is associated with fibrosis, nucleoside analogue use, and hepatitis C virus genotype 3 infection in HIV-seropositive patients. Clin Infect Dis 43: 365-372, 2006
  20. Walker UA et al. High serum urate in HIV-infected persons: the choice of the antiretroviral drug matters. AIDS 20: 1556-1558, 2006
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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