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Journal of NeuroVirology

, Volume 22, Issue 1, pp 104–113 | Cite as

Peripheral neuropathy in HIV patients in sub-Saharan Africa failing first-line therapy and the response to second-line ART in the EARNEST trial

  • Alejandro Arenas-Pinto
  • Jennifer Thompson
  • Godfrey Musoro
  • Hellen Musana
  • Abbas Lugemwa
  • Andrew Kambugu
  • Aggrey Mweemba
  • Dickens Atwongyeire
  • Margaret J. Thomason
  • A. Sarah Walker
  • Nicholas I. Paton
  • For the EARNEST Trial Team
Article

Abstract

Sensory peripheral neuropathy (PN) remains a common complication in HIV-positive patients despite effective combination anti-retroviral therapy (ART). Data on PN on second-line ART is scarce. We assessed PN using a standard tool in patients failing first-line ART and for 96 weeks following a switch to PI-based second-line ART in a large Randomised Clinical Trial in Sub-Saharan Africa. Factors associated with PN were investigated using logistic regression. Symptomatic PN (SPN) prevalence was 22 % at entry (N = 1,251) and was associated (p < 0.05) with older age (OR = 1.04 per year), female gender (OR = 1.64), Tuberculosis (TB; OR = 1.86), smoking (OR = 1.60), higher plasma creatinine (OR = 1.09 per 0.1 mg/dl increase), CD4 count (OR = 0.83 per doubling) and not consuming alcohol (OR = 0.55). SPN prevalence decreased to 17 % by week 96 (p = 0.0002) following similar trends in all study groups (p = 0.30). Asymptomatic PN (APN) increased over the same period from 21 to 29 % (p = 0.0002). Signs suggestive of PN (regardless of symptoms) returned to baseline levels by week 96. At weeks 48 and 96, after adjusting for time-updated associations above and baseline CD4 count and viral load, SPN was strongly associated with TB (p < 0.0001). In summary, SPN prevalence was significantly reduced with PI-based second-line therapy across all treatment groups, but we did not find any advantage to the NRTI-free regimens. The increase of APN and stability of PN-signs regardless of symptoms suggest an underlying trend of neuropathy progression that may be masked by reduction of symptoms accompanying general health improvement induced by second-line ART. SPN was strongly associated with isoniazid given for TB treatment.

Keywords

HIV Peripheral neuropathy Africa Second-line ART Tuberculosis 

Notes

Acknowledgments

We thank all the patients and staff from all the centres participating in the EARNEST trial. The EARNEST trial was funded by the European and Developing Countries Clinical Trials Partnership (EDCTP) with contributions from the Medical Research Council, UK, Institito de Salud Carlos III, Spain, Irish Aid, Ireland, Swedish International Development Cooperation Agency (SIDA), Sweden, Instituto Superiore di Sanita (ISS), Italy and Merck, USA. Substantive in-kind contributions were made by the Medical Research Council Clinical Trials Unit, UK, CINECA, Bologna, Italy, Janssen Diagnostics, Mechelen, Belgium; GSK, UK; Abbott Laboratories, USA. Trial medication was donated by AbbVie, Merck, Pfizer, GSK and Gilead

Conflict of interest

NIP was the EDCTP grant recipient for this trial. NIP, ASW, MT, JT and AAP are employed by the MRC-UK. NIP, ASW and AAP have received funding support for other studies from GSK or Janssen. AM, GM and HM have received support from the Research Councils-UK for research projects. NIP has received payments for lectures from Merck, Janssen and AbbVie. AAP has received payments for lectures from Janssen. Institutional payment has been received from Gilead Sciences because of a lecture given by ASW. ASW has been DSMB member—for studies sponsored by Tibotec.

Supplementary material

13365_2015_374_MOESM1_ESM.docx (86 kb)
ESM 1 (DOCX 85 kb)

References

  1. Arenas-Pinto A, Bhaskaran K, Dunn D, Weller IV (2008) The risk of developing peripheral neuropathy induced by nucleoside reverse transcriptase inhibitors decreases over time: evidence from the Delta trial. Antivir Ther 13(2):289–295PubMedGoogle Scholar
  2. Biraguma J, Rhoda A (2012) Peripheral neuropathy and quality of life of adults living with HIV/AIDS in the Rulindo district of Rwanda. SAHARA J 9(2):88–94PubMedGoogle Scholar
  3. Breen RA, Miller RF, Gorsuch T, Smith CJ, Schwenk A, Holmes W et al (2006) Adverse events and treatment interruption in tuberculosis patients with and without HIV co-infection. Thorax 61(9):791–794PubMedPubMedCentralCrossRefGoogle Scholar
  4. Cettomai D, Kwasa J, Kendi C, Birbeck GL, Price RW, Bukusi EA et al (2010) Utility of quantitative sensory testing and screening tools in identifying HIV-associated peripheral neuropathy in Western Kenya: pilot testing. PLoS One 5(12):e14256PubMedPubMedCentralCrossRefGoogle Scholar
  5. Chen H, Clifford DB, Deng L, Wu K, Lee AJ, Bosch RJ et al (2013) Peripheral neuropathy in ART-experienced patients: prevalence and risk factors. J Neurovirol 19(6):557–564PubMedPubMedCentralCrossRefGoogle Scholar
  6. Cherry CL, Affandi JS, Imran D, Yunihastuti E, Smyth K, Vanar S et al (2009) Age and height predict neuropathy risk in patients with HIV prescribed stavudine. Neurology 73(4):315–320PubMedCrossRefGoogle Scholar
  7. Childs EA, Lyles RH, Selnes OA, Chen B, Miller EN, Cohen BA et al (1999) Plasma viral load and CD4 lymphocytes predict HIV-associated dementia and sensory neuropathy. Neurology 52(3):607–613PubMedCrossRefGoogle Scholar
  8. Collins MA, Neafsey EJ, Zou JY (2000) HIV-I gpI20 neurotoxicity in brain cultures is prevented by moderate ethanol pretreatment. Neuroreport 11(6):1219–1222PubMedCrossRefGoogle Scholar
  9. Dean GL, Edwards SG, Ives NJ, Matthews G, Fox EF, Navaratne L et al (2002) Treatment of tuberculosis in HIV-infected persons in the era of highly active antiretroviral therapy. AIDS 16(1):75–83PubMedCrossRefGoogle Scholar
  10. Ellis RJ, Evans SR, Clifford DB, Moo LR, McArthur JC, Collier AC et al (2005) Clinical validation of the NeuroScreen. J Neurovirol 11(6):503–511PubMedCrossRefGoogle Scholar
  11. Ellis RJ, Marquie-Beck J, Delaney P, Alexander T, Clifford DB, McArthur JC et al (2008) Human immunodeficiency virus protease inhibitors and risk for peripheral neuropathy. Ann Neurol 64(5):566–572PubMedPubMedCentralCrossRefGoogle Scholar
  12. Ellis RJ, Rosario D, Clifford DB, McArthur JC, Simpson D, Alexander T et al (2010) Continued high prevalence and adverse clinical impact of human immunodeficiency virus-associated sensory neuropathy in the era of combination antiretroviral therapy: the CHARTER Study. Arch Neurol 67(5):552–558PubMedPubMedCentralCrossRefGoogle Scholar
  13. Evans SR, Ellis RJ, Chen H, Yeh TM, Lee AJ, Schifitto G et al (2011) Peripheral neuropathy in HIV: prevalence and risk factors. AIDS 25(7):919–928PubMedPubMedCentralCrossRefGoogle Scholar
  14. Evans D, Takuva S, Rassool M, Firnhaber C, Maskew M (2012) Prevalence of peripheral neuropathy in antiretroviral therapy naive HIV-positive patients and the impact on treatment outcomes—a retrospective study from a large urban cohort in Johannesburg, South Africa. J Neurovirol 18(3):162–171PubMedCrossRefGoogle Scholar
  15. Grant AD, Mngadi KT, van Halsema CL, Luttig MM, Fielding KL, Churchyard GJ (2010) Adverse events with isoniazid preventive therapy: experience from a large trial. AIDS 24(Suppl 5):S29–36PubMedCrossRefGoogle Scholar
  16. Kamerman PR, Wadley AL, Cherry CL (2012) HIV-associated sensory neuropathy: risk factors and genetics. Curr Pain Headache Rep 16(3):226–236PubMedCrossRefGoogle Scholar
  17. Kampira E, Kumwenda J, van Oosterhout JJ, Dandara C (2013) Mitochondrial DNA subhaplogroups L0a2 and L2a modify susceptibility to peripheral neuropathy in malawian adults on stavudine containing highly active antiretroviral therapy. J Acquir Immune Defic Syndr 63(5):647–652PubMedPubMedCentralCrossRefGoogle Scholar
  18. Lichtenstein KA, Armon C, Baron A, Moorman AC, Wood KC, Holmberg SD (2005) Modification of the incidence of drug-associated symmetrical peripheral neuropathy by host and disease factors in the HIV outpatient study cohort. Clin Infect Dis 40(1):148–157PubMedCrossRefGoogle Scholar
  19. Luma HN, Tchaleu BC, Doualla MS, Temfack E, Sopouassi VN, Mapoure YN et al (2012) HIV-associated sensory neuropathy in HIV-1 infected patients at the Douala General Hospital in Cameroon: a cross-sectional study. AIDS Res Ther 9(1):35PubMedPubMedCentralCrossRefGoogle Scholar
  20. Maritz J, Benatar M, Dave JA, Harrison TB, Badri M, Levitt NS et al (2010) HIV neuropathy in South Africans: frequency, characteristics, and risk factors. Muscle Nerve 41(5):599–606PubMedGoogle Scholar
  21. Marra CM, Boutin P, Collier AC (1998) Screening for distal sensory peripheral neuropathy in HIV-infected persons in research and clinical settings. Neurology 51(6):1678–1681PubMedCrossRefGoogle Scholar
  22. Mehta SA, Ahmed A, Laverty M, Holzman RS, Valentine F, Sivapalasingam S (2011) Sex differences in the incidence of peripheral neuropathy among Kenyans initiating antiretroviral therapy. Clin Infect Dis 53(5):490–496PubMedPubMedCentralCrossRefGoogle Scholar
  23. Nakamoto BK, McMurtray A, Davis J, Valcour V, Watters MR, Shiramizu B et al (2010) Incident neuropathy in HIV-infected patients on HAART. AIDS Res Hum Retrovir 26(7):759–765PubMedPubMedCentralCrossRefGoogle Scholar
  24. Paik IJ, Kotler DP (2011) The prevalence and pathogenesis of diabetes mellitus in treated HIV-infection. Best Pract Res Clin Endocrinol Metab 25(3):469–478PubMedCrossRefGoogle Scholar
  25. Paton NI, Kityo C, Hoppe A, Reid A, Kambugu A, Lugemwa A et al (2014) Assessment of second-line antiretroviral regimens for HIV therapy in Africa. N Engl J Med 371(3):234–247PubMedCrossRefGoogle Scholar
  26. Pettersen JA, Jones G, Worthington C, Krentz HB, Keppler OT, Hoke A et al (2006) Sensory neuropathy in human immunodeficiency virus/acquired immunodeficiency syndrome patients: protease inhibitor-mediated neurotoxicity. Ann Neurol 59(5):816–824PubMedCrossRefGoogle Scholar
  27. Shaikh A, Bentley A, Kamerman PR (2013) Symptomatology of peripheral neuropathy in an African language. PLoS One 8(5):e63986PubMedPubMedCentralCrossRefGoogle Scholar
  28. van Buuren S, Boshuizen HC, Knook DL (1999) Multiple imputation of missing blood pressure covariates in survival analysis. Stat Med 18(6):681–694PubMedCrossRefGoogle Scholar
  29. van der Watt JJ, Harrison TB, Benatar M, Heckmann JM (2011) Polyneuropathy, anti-tuberculosis treatment and the role of pyridoxine in the HIV/AIDS era: a systematic review. Int J Tuberc Lung Dis 15(6):722–728PubMedCrossRefGoogle Scholar
  30. van Oosterhout JJ, Mallewa J, Kaunda S, Chagoma N, Njalale Y, Kampira E et al (2012) Stavudine toxicity in adult longer-term ART patients in Blantyre, Malawi. PLoS One 7(7):e42029PubMedPubMedCentralCrossRefGoogle Scholar
  31. Wadley AL, Cherry CL, Price P, Kamerman PR (2011) HIV neuropathy risk factors and symptom characterization in stavudine-exposed South Africans. J Pain Symptom Manag 41(4):700–706CrossRefGoogle Scholar
  32. Westreich DJ, Sanne I, Maskew M, Malope-Kgokong B, Conradie F, Majuba P et al (2009) Tuberculosis treatment and risk of stavudine substitution in first-line antiretroviral therapy. Clin Infect Dis 48(11):1617–1623PubMedPubMedCentralCrossRefGoogle Scholar
  33. Wright E, Brew B, Arayawichanont A, Robertson K, Samintharapanya K, Kongsaengdao S et al (2008) Neurologic disorders are prevalent in HIV-positive outpatients in the Asia-Pacific region. Neurology 71(1):50–56PubMedCrossRefGoogle Scholar

Copyright information

© Journal of NeuroVirology, Inc. 2015

Authors and Affiliations

  • Alejandro Arenas-Pinto
    • 1
  • Jennifer Thompson
    • 1
  • Godfrey Musoro
    • 2
  • Hellen Musana
    • 3
  • Abbas Lugemwa
    • 4
  • Andrew Kambugu
    • 5
  • Aggrey Mweemba
    • 6
  • Dickens Atwongyeire
    • 7
  • Margaret J. Thomason
    • 1
  • A. Sarah Walker
    • 1
  • Nicholas I. Paton
    • 8
    • 1
  • For the EARNEST Trial Team
  1. 1.MRC Clinical Trials Unit at UCLInstitute of Clinical Trials & MethodologyLondonUK
  2. 2.University of Zimbabwe Clinical Research CentreHarareZimbabwe
  3. 3.Joint Clinical Research Centre (JCRC)KampalaUganda
  4. 4.Joint Clinical Research Centre (JCRC)MbararaUganda
  5. 5.Infectious Diseases InstituteMakerere UniversityKampalaUganda
  6. 6.University Teaching HospitalLusakaZambia
  7. 7.Joint Clinical Research Centre (JCRC)KakiraUganda
  8. 8.National University of SingaporeSingaporeSingapore

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