Skip to main content
NCBI home page
Current Therapeutic Research, Clinical and Experimental logoLink to Current Therapeutic Research, Clinical and Experimental
. 2005 Mar;66(2):117–129. doi: 10.1016/j.curtheres.2005.04.002

Treatment-limiting toxicities associated withnucleoside analogue reverse transcriptase inhibitor therapy: A prospective, observational study**

Rosario Palacios 1, Jesús Santos 1, Xavier Camino 2, Piedad Arazo 3, Rafael Torres Perea 4, Santiago Echevarrfa 5, Esteban Ribera 6, Rainel Sánchez de la Rosa 7, Santiago Moreno Guillen 8,***; Recover Study Group*
PMCID: PMC3964549  PMID: 24672118

Abstract

Background:

The Recover Study is an ongoing, prospective study designed 10 to assess toxicity associated with the use of nucleoside analogue reverse transcriptase inhibitors (NRTIs) (stavudine, zidovudine, lamivudine, didanosine, abacavir) in HIV-1-infected patients receiving highly active antiretroviral therapy (HAART) in routine clinical practice. This project is being conducted at 120 HIV units at teaching hospitals across Spain.

Objective:

The aim of this study was to identify the most common treatment-limiting 10 moderate to severe clinical and laboratory adverse effects (AEs), and the individual NRTIs involved in the development of these effects, in HIV-1-infected patients receiving HAART who discontinued use of an NRTI in the Recover Study.

Methods:

Patients eligible for participation in the Recover Study are aged10 ≥18 years; have virologically documented HIV-1 infection; have sustained viral suppression (viral load <200 cells/mL or stable, heavily experienced [ie, have received ≥3 antiretroviral regimens] patients with viral load <5000 cells/mL) for ≥6 months; are receiving HAART; are undergoing active follow-up; and have developed 2:1 NRTI-associated AE that, in the opinion of a study investigator and under the conditions of routine clinical practice, justified discontinuation of treatment with the offending drug (principal AE/offending NRTI). The present study included patients recruited for the Recover Study between September 2002 and May 2003.

Results:

A total of 1391 patients were enrolled (966 men, 425 women; mean 1 age, 42 years [range, 18–67 years]). Five hundred six patients (36.4%) had been diagnosed with AIDS. The mean duration of treatment with the offending NRTI was 74 months (range, 6–156 months). Seven hundred nine patients (51.0%) were receiving fourth-line (or more) therapy. Eight hundred twenty-one patients (59.0%) were receiving nonnucleoside analogues, and 552 patients (39.7%), protease inhibitors, as components of their HAART regimens. The NRTIs with the highest discontinuation rates were stavudine (914 patients [65.7%]) and zidovudine (177 [12.7%]). The most frequent NRTI-related AEs were lipoatrophy (550 patients [39.5%]) and peripheral neuropathy (170 [12.2%]). Lipoatrophy was most commonly associated with stavudine (480/550 cases [87.3%]); periph eral neuropathy, with stavudine and didanosine (107/170 [62.9%] and 48/170 [28.2%] cases, respectively); and anemia, with zidovudine (70/77 cases [90.9%]).

Conclusions:

The results of this study in patients with HIV-1 recruited in the10 Recover Study and undergoing HAART suggest that long-term treatment with NRTIs is associated with AEs (lipoatrophy, peripheral neuropathy, and lipodystrophy), with morphologic disorders (lipoatrophy, lipodystrophy) being the most common AEs leading to discontinuation. Minimizing these AEs by switching to an NRTI not associated with these AEs (eg, tenofovir) would contribute to adherence and hence efficacy of long-term HAART.

Key words: nucleoside analogue reverse transcriptase inhibitor toxicity, stavudine, zidovudine, lamivudine, didanosine, abacavir, tenofovir, HIV-1 infection, AIDS, highly active antiretroviral therapy

Full Text

The Full Text of this article is available as a PDF (712.4 KB).

Footnotes

**

This work was published in abstract form in: Program and abstracts of the 9th European AIDS Conference; October 25–29, 2003; Warsaw,Poland. Abstract 9.1/4.

References

  • 1.Dieterich D.T. Long-term complications of nucleoside reverse transcriptase inhibitor therapy. AIDS Read. 2003;13:176–184. [PubMed] [Google Scholar]; Dieterich D.T. Long-term complications of nucleoside reverse transcriptase inhibitor therapy. AIDS Read. 2003;13:187. [PubMed] [Google Scholar]
  • 2.Palella F.J., Jr, Delaney K.M., Moorman A.C., HIV Outpatient Study Investigators Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. N Engl J Med. 1998;338:853–860. doi: 10.1056/NEJM199803263381301. [DOI] [PubMed] [Google Scholar]
  • 3.Carr A., Cooper D.A. Adverse effects of antiretroviral therapy. Lancet. 2000;356:1423–1430. doi: 10.1016/S0140-6736(00)02854-3. [DOI] [PubMed] [Google Scholar]
  • 4.Carr A., Samaras K., Burton S. A syndrome of peripheral lipodystrophy, hyperlipidaemia and insulin resistance in patients receiving HIV protease inhibitors. AIDS. 1998;12:F51–F58. doi: 10.1097/00002030-199807000-00003. [DOI] [PubMed] [Google Scholar]
  • 5.Safrin S., Grunfeld C. Fat distribution and metabolic changes in patients with HIV infection. AIDS. 1999;13:2493–2505. doi: 10.1097/00002030-199912240-00002. [DOI] [PubMed] [Google Scholar]
  • 6.Ammassari A., Antinori A., Cozzi-Lepri A., AdlCoNA Study Group. LipolCoNA Study Group Relationship between HAART adherence and adipose tissue alterations. J Acquir Inmune Defic Syndr. 2002;31(Suppl 3):S140–S144. doi: 10.1097/00126334-200212153-00011. [DOI] [PubMed] [Google Scholar]
  • 7.Viraben R., Aquilina C. Indinavir-associated lipodystrophy. AIDS. 1998;12:F37–F39. doi: 10.1097/00002030-199806000-00001. [DOI] [PubMed] [Google Scholar]
  • 8.Carr A., Samaras K., Chisholm D.J., Cooper D.A. Pathogenesis of HIV-1-protease inhibitor-associated peripheral lipodystrophy, hyperlipidaemia, and insulin resistance. Lancet. 1998;351:1881–1883. doi: 10.1016/S0140-6736(98)03391-1. [DOI] [PubMed] [Google Scholar]
  • 9.Saint-Marc T., Partisani M., Poizot-Martin I. A syndrome of peripheral fat wasting (lipodystrophy) in patients receiving long-term nucleoside analogue therapy. AIDS. 1999;13:1659–1667. doi: 10.1097/00002030-199909100-00009. [DOI] [PubMed] [Google Scholar]
  • 10.Mallal S.A., John M., Moore C.B. Contribution of nucleoside analogue reverse transcriptase inhibitors to subcutaneous fat wasting in patients with HIV infection. AIDS. 2000;14:1309–1316. doi: 10.1097/00002030-200007070-00002. [DOI] [PubMed] [Google Scholar]
  • 11.Brinkman K., Smeitink J.A., Romijn J.A., Reiss P. Mitochondrial toxicity induced by nucleoside-analogue reverse-transcriptase inhibitors is a key factor in the pathogenesis ofantiretroviral-therapy-related lipodystrophy. Lancet. 1999;354:1112–1115. doi: 10.1016/S0140-6736(99)06102-4. [DOI] [PubMed] [Google Scholar]
  • 12.Brinkman K. Editorial response: Hyperlactatemia and hepatic steatosis as features of mitochondrial toxicity of nucleoside analogue reverse transcriptase inhibitors. Clin Infect Dis. 2000;31:167–169. doi: 10.1086/313921. [DOI] [PubMed] [Google Scholar]
  • 13.Walker U.A., Setzer B., Venhoff N. Increased long-term mitochondrial toxicity in combinations of nucleoside analogue reverse-transcriptase inhibitors. AIDS. 2002;16:2165–2173. doi: 10.1097/00002030-200211080-00009. [DOI] [PubMed] [Google Scholar]
  • 14.Drechsler H., Powderly W.G. Switching effective antiretroviral therapy: A review. Clin Infect Dis. 2002;35:1219–1230. doi: 10.1086/343050. [DOI] [PubMed] [Google Scholar]
  • 15.Castro K.G., Ward J.W., Slutsker L., Centers for Disease Control and Prevention, National Center for Infectious Diseases Division of HIV/AIDS Revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. MMWR Morb Mortal Wkly Rep. 1993;18:RR–17. 1992. [Google Scholar]
  • 16.Gerschenson M. Mitochondria and lipodystrophy: Where are we now? Antivir Ther. 2003;8:261–263. [PubMed] [Google Scholar]
  • 17.Carr A., Workman C., Smith D.E., Mitochondrial Toxicity (MITOX) Study Group Abacavir substitution for nucleoside analogs in patients with HIV lipoatrophy: A randomized trial. JAMA. 2002;288:207–215. doi: 10.1001/jama.288.2.207. [DOI] [PubMed] [Google Scholar]
  • 18.Carr A., Samaras K., Thorisdottir A. Diagnosis, prediction, and natural course of HIV-1 protease-inhibitor-associated lipodystrophy, hyperlipidaemia, and diabetes mellitus: A cohort study. Lancet. 1999;353:2093–2099. doi: 10.1016/S0140-6736(98)08468-2. [DOI] [PubMed] [Google Scholar]
  • 19.Lewis W. Mitochondrial dysfunction and nucleoside reverse transcriptase inhibitor therapy: Experimental clarifications and persistent clinical questions. Antiviral Res. 2003;58:189–197. doi: 10.1016/s0166-3542(03)00069-x. [DOI] [PubMed] [Google Scholar]
  • 20.Moyle G., Carr A. HIV-associated lipodystrophy, metabolic complications, and antiretroviral toxicities. HIV Clin Trials. 2002;3:89–98. [PubMed] [Google Scholar]
  • 21.Martinez E., Arnaiz J.A., Podzamczer D., Nevirapine Efavirenz, and Abacavir (NEFA) Study Team Substitution of nevirapine, efavirenz, or abacavir for protease inhibitors in patients with human immunodeficiency virus infection. N Engl J Med. 2003;349:1036–1046. doi: 10.1056/NEJMoa021589. [DOI] [PubMed] [Google Scholar]
  • 22.Martin A., Smith D.E., Carr A., Mitochondrial Toxicity Study Group Reversibility of lipoatrophy in HIV-infected patients 2 years after switching from a thymidine analogue to abacavir: The MITOX Extension Study. AIDS. 2004;18:1029–1036. doi: 10.1097/00002030-200404300-00011. [DOI] [PubMed] [Google Scholar]
  • 23.Moyle G., Sabin C., Cartledge J. 12th Conference on Retroviruses and Opportunistic Infections. 2005. A 48-week, randomized, open-label comparative study of tenofovir DF vs. abacavir as substitutes for a thymidine analog in persons with lipoatrophy and sustained virological suppression on HAART. Presented at. Boston, Mass. Late Breaker 44. Boston, Mass. Late Breaker 44. [Google Scholar]
  • 24.Ribera E., Paradineiro J., Sauleda S. 12th Conference on Retroviruses and Opportunistic Infections. 2005. Improvement of subcutaneous fat, lipid profile and parameters of mitochondrial toxicity in patients with peripheral lipoatrophy when stavudine isswitched to tenofovir: The Lipotest Study. Poster presented at. Boston, Mass. Poster 860. Boston, Mass. Poster 860. [DOI] [PubMed] [Google Scholar]
  • 25.Milinkovic A., Lopez S., Vidal S. 12th Conference on Retroviruses and Opportunistic Infections. 2005. A randomized open study comparing the impact of reducing stavudine dose vs switching to tenofovir on mitochondrial function, metabolic parameters, and subcutaneous fat in HIV-infected patients receiving anti retroviral therapy containing stavudine. Poster presented at. Boston, Mass. Poster 857. Boston, Mass. Poster 857. [Google Scholar]
  • 26.Domingo P., Labarga P., Palacios R., Recover Study Group Improvement of dyslipidemia in patients switching from stavudine to tenofovir: Preliminary results. AIDS. 2004;18:1475–1478. doi: 10.1097/01.aids.0000131343.53419.04. [DOI] [PubMed] [Google Scholar]

Articles from Current Therapeutic Research, Clinical and Experimental are provided here courtesy of Elsevier

RESOURCES