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

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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.

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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.

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Authors and Affiliations

  1. MRC Clinical Trials Unit at UCL, Institute of Clinical Trials & Methodology, Aviation House, 125 Kingsway, London, WC2B 6NH, UK

    Alejandro Arenas-Pinto, Jennifer Thompson, Margaret J. Thomason, A. Sarah Walker & Nicholas I. Paton

  2. University of Zimbabwe Clinical Research Centre, Harare, Zimbabwe

    Godfrey Musoro

  3. Joint Clinical Research Centre (JCRC), Kampala, Uganda

    Hellen Musana

  4. Joint Clinical Research Centre (JCRC), Mbarara, Uganda

    Abbas Lugemwa

  5. Infectious Diseases Institute, Makerere University, Kampala, Uganda

    Andrew Kambugu

  6. University Teaching Hospital, Lusaka, Zambia

    Aggrey Mweemba

  7. Joint Clinical Research Centre (JCRC), Kakira, Uganda

    Dickens Atwongyeire

  8. National University of Singapore, Singapore, Singapore

    Nicholas I. Paton

Authors
  1. Alejandro Arenas-Pinto
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  2. Jennifer Thompson
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  3. Godfrey Musoro
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  4. Hellen Musana
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  5. Abbas Lugemwa
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  6. Andrew Kambugu
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  7. Aggrey Mweemba
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  8. Dickens Atwongyeire
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  9. Margaret J. Thomason
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  10. A. Sarah Walker
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  11. Nicholas I. Paton
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Consortia

For the EARNEST Trial Team

Corresponding author

Correspondence to Alejandro Arenas-Pinto.

Additional information

Members of the Europe Africa Research Network for Evaluation of Second-line Therapy (EARNEST) Trial Team are listed in the Appendix

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The EARNEST Trial Team are:

The EARNEST Trial Team are:

Participating Sites

Uganda:

JCRC Kampala (African trial co-ordinating centre; 231) E Agweng, P Awio, G Bakeinyaga, C Isabirye, U Kabuga, S Kasuswa, M Katuramu, C Kityo, F Kiweewa, H Kyomugisha, E Lutalo, P Mugyenyi, D Mulima, H Musana, G Musitwa, V Musiime, M Ndigendawan, H Namata, J Nkalubo, P Ocitti Labejja, P Okello, P Olal, G Pimundu, P Segonga, F Ssali, Z Tamale, D Tumukunde, W Namala, R Byaruhanga, J Kayiwa, J Tukamushaba.

IDI, Kampala (216): G Bihabwa, E Buluma, P Easterbrook, A Elbireer, A Kambugu, D Kamya, M Katwere, R Kiggundu, C Komujuni, E Laker, E Lubwama, I Mambule, J Matovu, A Nakajubi, J Nakku, R Nalumenya, L Namuyimbwa, F Semitala, B Wandera, J Wanyama

JCRC, Mbarara (97): H Mugerwa, A Lugemwa, E Ninsiima, T Ssenkindu, S Mwebe, L Atwine, H William, C Katemba, S Abunyang, M Acaku, P Ssebutinde, H Kitizo, J Kukundakwe, M Naluguza, K Ssegawa, Namayanja, F Nsibuka, P Tuhirirwe, M Fortunate

JCRC Fort Portal (66): J Acen, J Achidri, A Amone, M. Chamai, J Ditai, M Kemigisa, M Kiconco, C Matama, D Mbanza, F Nambaziira, M Owor Odoi, A Rweyora, G. Tumwebaze

San Raphael of St Francis Hospital, Nsambya (48): H Kalanzi, J Katabaazi , A Kiyingi, M Mbidde, M. Mugenyi, R Mwebaze, P Okong, I Senoga

JCRC Mbale (47): M Abwola, D Baliruno, J Bwomezi, A Kasede, M Mudoola, R Namisi, F Ssennono, S Tuhirwe

JCRC Gulu (43): G Abongomera, G Amone, J Abach, I Aciro, B Arach, P Kidega, J Omongin, E Ocung, W Odong, A Philliam

JCRC Kabale (33): H Alima, B Ahimbisibwe, E Atuhaire, F Atukunda, G Bekusike, A Bulegyeya, D. Kahatano, S Kamukama, J Kyoshabire, A Nassali, A Mbonye, T M Naturinda, Ndukukire, A Nshabohurira, H. Ntawiha, A Rogers, M Tibyasa;

JCRC Kakira (31): S. Kiirya, D. Atwongeire, A. Nankya, C. Draleku, D. Nakiboneka, D. Odoch, L. Lakidi, R. Ruganda, R. Abiriga, M. Mulindwa, F. Balmoi, S. Kafuma, E. Moriku

Zimbabwe

University of Zimbabwe Clinical Research Centre, Harare (265): J Hakim, A Reid, E Chidziva, GMusoro,

C Warambwa, G Tinago, S Mutsai, M Phiri, S Mudzingwa, T Bafana, V Masore, C Moyo, R Nhema, S Chitongo.

Malawi

College of Medicine, University of Malawi, Blanytre (92): Rob Heyderman, Lucky Kabanga, Symon Kaunda, Aubrey Kudzala, Linly Lifa, Jane Mallewa, Mike Moore, Chrissie Mtali, George Musowa, Grace Mwimaniwa, Rosemary Sikwese, Joep van Oosterhout, Milton Ziwoya

Mzuzu Central Hospital, Mzuzu (19): H Chimbaka. B Chitete, S Kamanga, T Kayinga E Makwakwa, R Mbiya, M Mlenga, T Mphande, C Mtika, G Mushani, O Ndhlovu, M Ngonga, I Nkhana, R Nyirenda

Kenya

Moi Teaching and Referral Hospital (52): P Cheruiyot, C Kwobah, W Lokitala Ekiru, M Mokaya, A Mudogo, A Nzioka, A Siika, M Tanui, S Wachira, K Wools-Kaloustian

Zambia

University Teaching Hospital (37): P Alipalli, E Chikatula, J Kipaila, I Kunda, S Lakhi, J Malama, W Mufwambi, L Mulenga, P Mwaba, E Mwamba, A Mweemba, M Namfukwe

The Aids Support Organisation (TASO), Uganda: E Kerukadho, B Ngwatu, J Birungi

MRC Clinical Trials Unit: N Paton, J Boles, A Burke, L Castle, S Ghuman, L Kendall, A Hoppe, S Tebbs, M Thomason, J Thompson, S Walker, J Whittle, H Wilkes, N Young

Monitors: C Kapuya, F Kyomuhendo, D Kyakundi, N Mkandawire, S Mulambo, S Senyonjo

Clinical Expert Review Committee: B Angus, A Arenas-Pinto, A Palfreeman, F Post, D Ishola

European Collaborators: J Arribas, B Colebunders, M Floridia, M Giuliano, P Mallon, P Walsh, M De Rosa, E Rinaldi

Trial Steering Committee: I Weller (Chair), C Gilks, J Hakim, A Kangewende, S Lakhi, E Luyirika, F Miiro, P Mwamba, P Mugyenyi, S Ojoo, N Paton, S Phiri, J van Oosterhout, A Siika, S Walker, A Wapakabulo,

Data Monitoring Committee: T Peto (Chair), N French, J Matenga

Pharmaceutical companies: G Cloherty, J van Wyk, M Norton, S Lehrman, P Lamba, K Malik, J Rooney, W Snowden, J Villacian

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Arenas-Pinto, A., Thompson, J., Musoro, G. et al. Peripheral neuropathy in HIV patients in sub-Saharan Africa failing first-line therapy and the response to second-line ART in the EARNEST trial. J. Neurovirol. 22, 104–113 (2016). https://doi.org/10.1007/s13365-015-0374-7

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