OUTCOME OF STAVUDINE INDUCED PERIPHERAL NEUROPATHY IN HIV-1 POSITIVE PATIENTS SWITCHED OR SUBSTITUTED TO A NON-STAVUDINE- BASED REGIMEN Dr P Gorejena-Chidawanyika Co-Authors : Prof James Hakim and Dr Andrew Reid

BACKGROUND Stavudine is used in combination with other antiretroviral agents for the treatment of HIV-1infection. ¹ Causes a potentially crippling peripheral neuropathy. ² No longer an appropriate drug of choice. A study to assess the prevalence as well as the outcome of Stavudine induced peripheral neuropathy in individuals who are no longer on the drug has not been previously described in this setting.

OBJECTIVES PRIMARY OBJECTIVE: To determine the outcome of Stavudine induced peripheral neuropathy following Stavudine discontinuation. SECONDARY OBJECTIVES: To determine the factors that contribute to the persistence of peripheral neuropathy in patients with ongoing symptoms. To assess the rate of discontinuation of drugs for treatment of peripheral neuropathy.

STUDY DESIGN: A cross-sectional study of 385 participants performed over 10 months at Parirenyatwa Hospital Opportunistic Infections Clinic in Harare, Zimbabwe. SUBJECTS: Consenting adults aged 18 years and above, who were on a Stavudine-based regimen for at least one month prior to switch to a non-Stavudine- based regimen.

INCLUSION CRITERIA HIV positive patients with symptoms of peripheral neuropathy at time of switch who were previously on a Stavudine containing regimen for at least one month prior to commencement of 2 nd line therapy or switch to alternative non-Stavudine based regimen. Participants had to be 18 years or older. They were required to provide written informed consent

EXCLUSION CRITERIA Patients who experienced symptoms of peripheral neuropathy i.e. pain, paraesthesiae or numbness prior to commencing a Stavudine based therapy.

PRIMARY OUTCOME MEASURES: The proportion of patients with persistent peripheral neuropathy following cessation of Stavudine as determined by the ACTG Brief Peripheral Neuropathy Score (BPNS). SECONDARY OUTCOME MEASURES: Demographic and clinical factors associated with persistence of symptoms of Stavudine induced peripheral neuropathy following cessation.

Subjective gradeBPNS severity symptom score Grade 00 – (absent ) Grade 11-2 Grade 23-5 Grade 36-7 Grade Objective BPNS gradeVibration perception scoreAnkle reflexes score Grade 0Felt >10 secs (normal )Absent despite reinforcement Grade 1Felt 6-10 secs (mild loss)Reduced contraction Grade 2Felt < 5 secs (moderate loss)Normal Grade 3Not felt (severe loss)Hyperactive Grade 4 Clonus Grade 8Unable or did not assess BPNS TOOL (AT LEAST ONE SUBJECTIVE PLUS AT LEAST ONE OBJECTIVE SIGN)

RESULTS 385 participants were recruited into the study. (256) 66.5% were female. The mean age, weight and height were 42.7+\-11.7 yrs, 69.3+\ kg and \ cm respectively. The median duration on Stavudine was 39 months (IQR ). The median duration off Stavudine was 23 months (IQR ).

Variable PN N=174 No PN N=211 OR (95%CI)P value Age (34.44) 118 (65.56) 94 (45.85) 111 (54.15) 1.61 ( ) Sex Male Female 71 (39.44) 109 (60.56) 58 (28.29) 147 (71.71) 0.63 ( ) Height 1.70 m 141 (78.33) 39 (21.67) 173 (84.39) 32 (15.61) 1.50 ( ) Weight 60kg 48 (26.67) 132 (73.33) 64 (31.22) 141 (68.78) 1.25 ( ) RESULTS

Variable PN N=174 No PN N=211 OR (95%CI)P value CD4+ count (85.56) 26 (14.44) 141 (68.78) 64 (31.22) 2.69 ( ) Hypertension Yes No 42 (23.33) 138 (76.67) 19 (9.27) 186 (90.73) 2.98 (1.66 – 5.35) Diabetes Mellitus Yes No 8 (4.44) 172 (95.56) 5 (2.44) 200 (97.56) 1.86 (0.60 – 5.79) TB treatment Yes No 6 (3.33) 174 (96.67) 1 (0.49) 204 (99.51) 7.03 (0.84 – 58.99) Alcohol intake Yes No 43 (23.89) 137 (76.11) 34 (16.59) 171 (83.41) 1.58 (0.95 – 2.61) Duration of Stavudine therapy 24 months 73 (40.56) 107 (59.44) 55 (26.83) 150 (73.17) 0.54 (0.35 – 0.82) Duration off Stavudine 24 months 91 (50.56) 89 (49.44) 105 (51.22) 100 (48.78) 1.03 (0.69 – 1.53) 0.897

Variable Adjusted odds ratio (AOR) 95% CIP value Concurrent TB treatment – Low CD4+ count – Hypertension – RESULTS After adjusting for age, sex and alcohol consumption – a low CD4+ count and hypertension were associated with a greater risk of persistent Stavudine induced peripheral neuropathy.

RESULTS Out of those that did not report symptoms 24.6% had abnormal ankle jerks, 11.3% had diminished vibration sense. Conversely 24.5% with a normal vibration sense, and 24.2% with normal ankle jerks had subjective symptoms of neuropathy.

RESULTS Out of the total number of participants, 45.2% had ongoing Stavudine induced peripheral neuropathy. Stavudine induced peripheral neuropathy was strongly associated with a low CD4+ count, concurrent hypertension as well as tuberculosis therapy (OR [95% CI ;p=0.0001],2.98-[95% CI ;p=0.0002] and 7.03-[95%CI ;p=0.037]) respectively. Individuals exposed to Stavudine for longer than 24 months were 46% less likely to develop peripheral neuropathy. (OR [ ;p=0.004]) 29.6% of patients were on Amitriptyline for the treatment of peripheral neuropathy, 7.3% were on over-the-counter analgesia, 1.3% were on Carbamazepine and less than 1% were on Gabapentin.

LIMITATIONS The Brief Peripheral Neuropathy Score (BPNS) may give an underestimate of the true number of participants with peripheral neuropathy Convenience sampling method introduces selection bias No objective screening test done at the onset of the study to ascertain that the peripheral neuropathy was attributed to Stavudine. Cross – sectional study not the most appropriate to establish a temporal association between the various variables and progressive Stavudine induced peripheral neuropathy.

CONCLUSION Stavudine induced peripheral neuropathy persists in a significant subgroup of patients after cessation of use. Its continued use as part of any antiretroviral regimen should therefore be discouraged. Identification of such patients following cessation of therapy with a simple screening tool will allow targeted early treatment to prevent further progression of peripheral neuropathy.

REFERENCES 1. Moyle G J. Stavudine: pharmacology, clinical use and future role. Expert Opinion Investigating Drugs 1997; 6: World Health Organisation. Antiretroviral therapy for HIV infection in adults and adolescents. Recommendations for a public health approach 2010 revision. Available at (accessed June 2011)

ACKNOWLEDGEMENTS Participants Prof J Hakim and Dr A Reid Faculty of the Department of Medicine This work was supported by Grant number 2U2RTW from the Forgarty International Centre, National Institutes of Health (NIH, USA) through the International Clinical, Operational and Health Services Research and Training Award for TB/HIV (ICOHRTA).