mmed dissertation - university of zimbabwe
TRANSCRIPT
MMed DISSERTATION
Outcome of Stavudine induced peripheral neuropathy in HIV – 1
positive patients switched or substituted to a non-Stavudine-
based regimen.
By
Dr Pamela Gorejena - Chidawanyika
Thesis Submitted in Partial Fulfillment of the Degree of
Masters in Medicine (Medicine), University of Zimbabwe.
Faculty of Medicine
College of Health Sciences
June 2014
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ABSTRACT
A study to assess the outcome of Stavudine induced peripheral neuropathy in HIV – 1 positive patients switched or
substituted to a non-Stavudine-based regimen.
Background : Stavudine is used in combination with other antiretroviral agents for the treatment of HIV- 1 infection .
Among several serious complications it can cause a potentially crippling peripheral neuropathy. It is for this reason
that it is no longer considered an appropriate drug of choice in any antiretroviral regimen in developed and more
recently developing countries. 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.
Objective : To determine the outcome of Stavudine induced peripheral neuropathy following its discontinuation.
Methodology : Peripheral neuropathy was defined using the ACTG Brief Peripheral Neuropathy Score which requires
the presence of at least one symptom of peripheral neuropathy plus one objective abnormal examination finding.
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 yrs and above , who were on a Stavudine-based regimen for at least one month
prior to switch to a non-Stavudine-based regimen.
Primary outcome measures : The proportion of patients with persistent peripheral neuropathy following cessation
of Stavudine as determined by the ACTG Brief Peripheral Neuropathy Score.
Secondary outcome measures : Demographic and clinical factors associated with persistence of symptoms of
Stavudine induced peripheral neuropathy following cessation.
Results : A total of 385 participants were recruited into the study. Out of these (256)66.5% were female. The mean
age, weight and height were 42.7 11.7 yrs, 69.3 14.8 kg and 163.7 8.83 cm respectively. The median duration
on Stavudine was 39 months (IQR 19.5-63). The median duration off Stavudine was 23 months (IQR 12.5-36.5). Out
of the total number of participants, 45.19% 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 -2.69-[95% CI 1.61-4.48;p=0.0001],2.98-[95% CI 1.66-5.35;p=0.0002] and 7.03-[95%CI 0.84-
58.99;p=0.037]) respectively. Individuals exposed to Stavudine for longer than 24 months were 46% less likely to
develop peripheral neuropathy. (OR - 0.54-[0.35-0.82;p=0.004])
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.
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ACKNOWLEDGEMENTS
I wish to express my profound gratitude to my supervisors Prof James Hakim and Dr Andrew Reid for their
invaluable support in the designing and execution of this study.
I would also like to thank Dr Gift Ngwende and Prof Margaret Borok for their most helpful advice.
The research methodology training and financial support by the Biomedical Research and Training Institute
through the International Clinical, Operational and Health Services Research and Training Award for TB/HIV
was invaluable in moulding me into a competent young researcher.
To Prof Rusakaniko, for his assistance with the statistical aspects of the study.
Lastly, to my dear husband Ennocent for his patience and for urging me on during these last four years.
This work was supported by Grant number 2U2RTW007367 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).
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TABLE OF CONTENTS PAGE
1. Introduction and problem statement 1
2. Background and Literature review 3
3. Materials and methods 18
4. Statistical Analysis 25
5. Ethical Considerations 26
6. Results 27
7. Discussion 37
8. Conclusion 41
9. References 42
10. Appendix 51
Tables and Figures
Table 1: Prevalence of Stavudine induced peripheral neuropathy (SIPN) 8
Table 2 : Grading of peripheral neuropathy 13
Table 3 : Subjective symptoms of Peripheral Neuropathy 22
Table 4 : Objective symptoms of Peripheral Neuropathy 23
Table 5 : Demographic characteristics of participants 27
Table 6: Categorized demographic characteristics of participants 27
Table 7: Clinical characteristics of participants 29
Table 8 : Categorized clinical characteristics of participants 29
Table 9: Clinical History and Drug History of participants 31
Table 10: Prevalence of peripheral neuropathy and signs and symptoms
consistent with SIPN 33
Table 11 : Demographic factors associated with SIPN 34
Table 12 : Clinical factors associated with SIPN 35
Table 13: Multivariate analysis of associated factors 36
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LIST OF ABBREVIATIONS AND ACRONYMS
WHO World Health Organisation
UNAIDS Joint United Nations Programme on HIV/AIDS
UNICEF United Nation International Children’s Fund
HIV Human Immunodeficiency Virus
AIDS Acquired Immune Deficiency Syndrome
NRTI Nucleoside Reverse Transcriptase Inhibitor
PI Protease Inhibitor
ART Anti-Retroviral Therapy
ARV Anti-Retroviral Drugs
MOHCC Ministry of Health and Child Care
DNA Deoxyribonucleic Acid
HIV-SN HIV associated sensory neuropathy
SIPN Stavudine Induced Peripheral Neuropathy
BPNS Brief Peripheral Neuropathy Score
NCIC National Cancer Institute of Canada
ACTG AIDS Clinical Trial Group
FDA Food and Drug Administration
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Introduction and Problem statement
Stavudine is a Nucleoside Reverse Transcriptase Inhibitor (NRTI) often used in combination with other
antiretroviral agents for the treatment of HIV- 1. Among its major side effects are lipodystrophy, a
potentially fatal lactic acidosis and peripheral neuropathy which can be crippling in some individuals. It is
for this reason that it is no longer considered an appropriate drug of choice in any antiretroviral (ARV)
regimen in developed and more recently developing countries. ¹
Previous studies reveal that 21% of participants on a Stavudine-based regimen developed peripheral
neuropathy.² The incidence rose significantly in participants with longer exposure to Stavudine. In addition,
the risk was approximately doubled with each year of exposure. In a study in Kenya, 55% of 1286
participants on a Stavudine-based regimen followed up for two years had their antiretroviral therapy (ART)
regimen switched. Peripheral neuropathy was the reason for switching to a non-Stavudine regimen in 21%
of the total number of partipants. ³
In a study done in Uganda, 38% of 102 treatment naïve participants developed numbness of the feet six
months following commencement of Stavudine containing ART. These participants had no symptoms at
baseline.´ Studies have shown that symptoms of Stavudine induced peripheral neuropathy can regress
after discontinuation of the drug, with improvement more likely to be seen in those with a baseline CD4+
count of more than 200cells/uL.µ˒¶ . In addition, in participants who developed mitochondrial dysfunction,
such as that caused by Stavudine induced peripheral neuropathy, replacement of Stavudine with less toxic
agents eg. Tenofovir was associated with improvement in mitochondrial morphology and DNA content.·
However, this does not translate to an improvement in symptoms. Regenerative capacity of the peripheral
nerves is slow and the neuropathy may be permanent, especially when there has been prolonged exposure
to the drug and in those with severe forms of neuropathy at onset.
At the beginning of the ART rollout program in Zimbabwe the first-line ART combination was known as
STALANEV, a combination of Stavudine, Lamivudine and Nevirapine. ¸A large number of HIV positive
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patients have to date been exposed to this ART combination. Phasing out of this first-line combination
started in 2010 although there are still a significant number of patients on this combination. There has
been little information published on the prevalence of peripheral neuropathy among patients on this
treatment. Moreover no information is available on the progress of peripheral neuropathy in those
patients in whom it was discontinued.
A study assessing the outcome of the progression of peripheral neuropathy in participants switched from a
Stavudine based regimen could potentially yield important information given the large number of
participants who have been exposed to this regimen in this country. Furthermore, this could yield
knowledge on the possible factors contributing to the severity and ultimate outcome of Stavudine induced
peripheral neuropathy. The wide variability of incidence and prevalence of peripheral neuropathy from
studies in various sub-Saharan African countries dictates that a country specific study is necessary to get
accurate information related to this condition in Zimbabwe.
Despite the fact that Stavudine is being phased out as one of the first line ART drugs, its side effects persist
in a significant subgroup of HIV positive patients. Prompt diagnosis in patients at particular risk with
discontinuation of treatment can potentially prevent its progression.
This study will give an estimate of the burden of persistent Stavudine induced peripheral neuropathy and
identify patients at risk of developing persistent symptoms despite cessation of the drug. In addition, the
results of this study may also be useful in providing a platform for designing a longitudinal study that
actually assesses the evolution of symptoms of Stavudine induced peripheral neuropathy in susceptible
patients.
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Background and Literature Review
WHO/UNAIDS/UNICEF statistics at the end of 2011 showed that approximately 34 million people were
estimated to be living with HIV. Sub Saharan Africa being the worst affected with 23.5 million people living
with the virus.¹
Access of antiretroviral therapy to even the poorest regions of the world is one of the most important
successes of contemporary medicine. Antiretroviral therapy not only reduces mortality and morbidity from
HIV related illnesses but it also improves the quality of life of patients on treatment. In addition,
antiretroviral access also improves a nation’s social and political stability. However, the choice of
antiretroviral drugs for national ARV programmes in resource-limited countries is highly dependent on
external funding especially from the United States President’s Emergency Plan for AIDS Relief (PEPFAR) and
the Global Fund to Fight AIDS Tuberculosis and Malaria which procure antiretroviral drugs at negotiated
prices.¹⁰
Stavudine is a Nucleoside Reverse Transcriptase Inhibitor previously very popular in combination therapy
for the treatment of HIV-1 infection. The United States Food and Drug Administration (FDA) approved
Stavudine in 1994 for adult use and in 1996 for Paediatric use.¹¹ In 2003, WHO proposed that Stavudine or
Zidovudine in combination with Lamivudine and a Non Nucleoside Reverse Transcriptase inhibitor such as
Nevirapine would be the most appropriate first line regimen in resource poor settings.¹² The choice
between Stavudine or Zidovudine would be made at country level.
A study done by Muazu M et al under the Presidential Emergency Plan for AIDS Relief in Nigeria proved
that Stavudine in combination with Lamivudine and Nevirapine was an effective regimen in treating ART
naïve participants in resource limited settings. Out of 100 participants under study 74 % developed an
undetectable viral load six months after initiation of therapy. During the same period CD4+ count rose
from 135cells/ L to >350 cells/ L in 52% of participants.¹³ Similar findings were observed in another trial
by Laurent et al ,demonstrating the efficacy of the same regimen in multiple centres in Cameroon. Out of
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the 60 participants under study, 80% had a VL below 200 copies/mL after 24 weeks from initiation of
therapy.¹´
Evidence of the efficacy of a Stavudine based regimen ( i.e.sustained increase in CD4+ cell counts and
suppression of HIV-1 viral loads) led to the approval of its use in many resource limited countries including
Zimbabwe. The FDA therefore granted generic formulations of Stavudine "tentative approval" status for
purchase and use only as part of the President's Emergency Plan for AIDS Relief (PEPFAR) in resource-poor
countries.¹⁰
The Ministry of Health and Child Care (MOHCC) in Zimbabwe developed and disseminated its own
guidelines for antiretroviral (ARV) therapy in Zimbabwe in December 2003. Approach to HIV and AIDS
treatment was standardized and aligned to the 2003 WHO recommendations promoting rational use of
ARVs in Zimbabwe. Stavudine, Lamivudine and Nevirapine triple combination therapy was recommended
as one of the first line regimens for the treatment of HIV in Zimbabwe.¹µ
In addition, Varichem (a licensed pharmaceutical company in Zimbabwe) was granted authority to
manufacture anti-retroviral drugs and other HIV and AIDS-related drugs after the November 2001 World
Trade Organisation Ministerial conference held in Doha. ¹¶ Despite its efficacy in reducing viral load,
Stavudine was noted to have associated side effects.
Initially WHO recommended a higher dose of Stavudine of 40mg for participants weighing 60kg or more
and a smaller dose of 30mg for those weighing less than 60kg.¹· Studies were carried out to compare the
efficacy and side effect profile of these differing doses. Of particular note is a study performed in Kenya by
Karara et al which compared the efficacy and tolerability of Stavudine at 30mg and 40mg dose levels in
participants attending a clinic in Kenya.¹¸ Fewer Stavudine related adverse effects were seen in participants
who weighed more than 60 kg treated with 30 mg Stavudine compared to those who received 40 mg (4.2
% vs 16.7%, p < 0.001). Participants weighing less than 60 kg were more likely to experience drug toxicity
than those weighing more than 60 kg when given 30 mg Stavudine (12.8 vs 4.2%, p < 0.001). Of note was
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that peripheral neuropathy was the most frequent serious adverse drug event occurring in 20.5% of
participants on Stavudine. Therefore, in 2006, WHO recommended decreasing the dose of Stavudine from
40mg to 30mg for those participants with a weight above 60kg to reduce the incidence of toxicities,
including peripheral neuropathy (PN), while maintaining viral efficacy.¹¹
Following this reduction in dose, a study by Hoffman et al discovered that the 30mg lower dose of
Stavudine had just as much antiviral efficacy as the higher dose with evidence of some lower rates of
peripheral neuropathy and lipodystrophy.²⁰ Mashew et al showed that the lower dose of Stavudine had
fewer side effects and fewer rates of discontinuation compared to the higher dose.²¹
A comparative study conducted in Kwazulu Natal, South Africa by Pahuja M et al showed that participants
on the 30mg group had a much lower incidence of peripheral neuropathy compared to those taking a
40mg dose.²² However, lowering the dose did not decrease the incidence of severe peripheral neuropathy
or the time to developing severe peripheral neuropathy. The incidence of severe peripheral neuropathy
remained unacceptably high despite the lowering of the dose.
As a result, in 2010 WHO released a new set of guidelines emphasising the avoidance of ART regimens
containing Stavudine and Didanosine because of treatment-limiting side effects.²³ Furthermore, the
guidelines also recommended that if Stavudine were to be used, it should be dosed at 30mg twice daily for
all individuals irrespective of body weight.
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Stavudine induced peripheral neuropathy
Stavudine (2’,3’-didehydro-2’,3’-dideoxythymidine), is a nucleoside reverse transcriptase inhibitor active
against HIV. It requires intracellular phosphorylation before exerting its effects. It inhibits the activity of
HIV reverse transcriptase by competing with the natural substrate, thymidine triphosphate. Stavudine is
metabolised by the same enzymes that phosphorylate thymidine. The major toxicity of Stavudine is dose
related peripheral neuropathy particularly affecting sensory nerves. ²´
Peripheral neuropathy is a clinical syndrome that arises when there is damage to the nerves of the
peripheral nervous system. ²µ The peripheral nervous system is comprised of connections from the brain
and spinal cord to the peripheral organs, muscles, skin and glandular structures. It is divided into 4 major
classes :
1. distal sensory neuropathy (HIV sensory neuropathy – HIV-SN)
2. inflammatory demyelinating polyneuropathy
3. mononeuritis multiplex
4. polyradiculopathy ²·˒²¸
Distal sensory neuropathy (HIV-SN) is the most common neuropathic disorder in HIV positive individuals. It
can arise as a consequence of HIV itself or it can be a complication of NRTI use (ARV toxic neuropathy).²¸
ARV toxic neuropathy usually results from exposure to the “d” drugs - d4T (Stavudine), ddl (Didanosine)
and ddC (Zalcitabine). ³⁰ Studies have shown that drug-induced and HIV sensory neuropathy are
indistinguishable clinically. ³¹
The effects of these drugs on the nervous system have not been clearly elucidated. Various mechanisms
have been proposed.
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1. The drugs’ effect on oxidative metabolism can lead to a decrease in levels of acetyl carnitine
production.
2. The presence of the virus has been associated with low levels of vitamin B12 levels in the serum.
3. The drugs may have an inhibitory effect on nerve growth factor.²·
Up to 50% of HIV positive patients have HIV associated peripheral neuropathy and the symptoms tend to
progress as the disease progresses. People with CD4+ counts of less than 200 are more likely to develop
this. ³¹
The effect of HIV on the peripheral nervous system is not well defined. Much of what is known about the
mechanism was derived from animal studies and models. Some studies propose that HIV gp120 initiates
an inflammatory response that results in cytokine production and subsequent nerve damage.²·
In both HIV associated and Stavudine induced peripheral neuropathy, the mechanism of damage is length
dependant axonal degeneration. Initially, the small unmyelinated fibres are damaged and subsequently the
large myelinated fibres are also involved. Regeneration of these injured fibres is rare.³²
Symptoms of Stavudine induced peripheral neuropathy
Patients may complain of a tingling sensation, burning sensation or pain in the lower extremities especially
at night.³³ Symptoms usually begin within three weeks of commencement and resolve within one to nine
weeks after the drug is discontinued. Sixty three percent of participants within a pivotal study on Stavudine
had grade 1-2 peripheral neuropathy that resolved after discontinuation within a median time of
seventeen days.³´
Those with persistent symptoms despite discontinuation of treatment were more likely to have lower
CD4+ counts (i.e. <100) and a higher grade of toxicity at baseline.³µ It is unclear whether the persistence of
symptoms was due to permanent damage from Stavudine or due to direct damage from the virus. There
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have also been reports of temporary worsening of symptoms upon discontinuation. This phenomenon is
described as the “coasting effect” of the drug . It usually lasts for two to three weeks, but there have been
longer intervals described. ³¶
Epidemiology
The following studies show the prevalence of Stavudine induced peripheral neuropathy in regional and
international studies.
Table 1 :Prevalence of Stavudine induced peripheral neuropathy
Author, Site, Year Prevalence
Cherry CL et al, Melbourne (Australia) 2009³⁷ 42%
Cherry CL et al, Kuala Lumpur (Malaysia) 2009³⁷ 19%
Cherry CL et al, Jakarta (Indonesia) 2009³⁷ 34%
Maritz J et al, Johannesburg (SA) 2010³⁸ 57%
Beadles et al, Lilongwe (Malawi) 2009³⁹ 13%
Hawkins C et al, Meru Hospital (Kenya) 2007⁴⁰ 23%
Canestri et al, Senegal, 2006⁴¹ 37.5%
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Risk factors for Stavudine induced peripheral neuropathy
Various risk factors have been shown in the literature to be associated with the development of Stavudine
induced peripheral neuropathy.
Age
A study by Cherry CL et al in 2009 showed that the prevalence of Stavudine induced peripheral neuropathy
increases with age. The results showed that participants above the age of 40 years were more likely to
develop neuropathy. ³·
Height
The same trial by Cherry CL et al, also showed that height could also be used as a risk assessment for
peripheral neuropathy. The risk of Stavudine-induced neuropathy was higher in taller i.e. those above
170cm than shorter participants. ³· This study showed that the risk of neuropathy following Stavudine was
20% in younger, shorter participants, compared with 66% in older, taller individuals.
Weight
Karara et al carried out a study to compare the tolerability and efficacy of Stavudine 30mg vs 40mg in
participants on ARV therapy in Kenya.¹¸ Not only did the results show a greater incidence of peripheral
neuropathy in those on the higher dose but they also revealed that in participants treated with 30 mg
Stavudine, those weighing less than 60 kg had a higher incidence of adverse events (including neuropathy)
than those weighing more than 60 kg (12.8 vs 4.2%, p < 0.001).
Isoniazid exposure
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Isoniazid exposure at baseline was shown to be associated with a worse outcome in participants with
Stavudine induced peripheral neuropathy in a study done in Tororo, Uganda (odds ratio = 0.36, 95% CI
0.12-1.0).´² In contrast, Isoniazid exposure (present in 56% of participants) in a trial in Jakarta in 2009 did
not show any significant risk for Stavudine induced peripheral neuropathy. Of note is that all participants in
this cohort had received Pyridoxine co-administration.³·
Combination therapy with Didanosine
The combination of Stavudine and Didanosine has been associated with overlapping toxicities and results
in severe peripheral neuropathy, severe pancreatitis, lactic acidosis or hepatic steatosis. In 2000, Moore et
al showed that the incidence of peripheral neuropathy on Stavudine alone was 9.8%. However the
incidence doubled when Stavudine was used in combination with Didanosine to 17.5%. ´³
In contrast, a similar study performed in 2001 by Reliquet et al disputed these findings. All participants in
the study were put on a Stavudine and Didanosine based triple regimen. 11.8 % of participants developed
neuropathy within a median time of 24 weeks. In all participants peripheral neuropathy resolved following
cessation of Stavudine and the Stavudine/Didanosine combination did not seem to increase the incidence
of peripheral neuropathy.´´
Duration of Stavudine exposure
Participants with a longer duration of exposure to Stavudine are more likely to develop peripheral
neuropathy than those who take it for a shorter duration. A trial performed by Scarsella et al showed that
the incidence of peripheral neuropathy was higher in participants with longer exposure to Stavudine (29%
with exposure of more than 24 months vs 13% with exposure of less than 24 months).² Participants on a
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Stavudine based regimen in a study done in Kenya for ≥ 25 months were more likely to develop peripheral
neuropathy than those who had been on the drug for a shorter period. OR = 2.37, 95% CI - 1.08-5.18 ´µ
Dose of Stavudine
The incidence of sensory peripheral neuropathy is dose-related; the highest frequency is associated with
dosages of 4–8 mg/kg/day, which are much higher than the recommended dosage of about 1 mg/kg/day.
In 2006, WHO recommended decreasing the dose of Stavudine from 40mg to 30mg to alleviate toxicities
associated with the drug. ¹¹
In Durban South Africa, Pahuja et al showed that decreasing the dose of Stavudine reduced the incidence
of peripheral neuropathy significantly.´¶ The incidence of peripheral neuropathy was 78/100 person years
(95% CI 66-91) in the 40mg cohort versus 43/100 person years (95% CI 35-53) in the 30mg cohort (RR 0.56,
p < 0.0001). However, there was no difference in the number of severe peripheral neuropathy cases
between the cohorts. A Kenyan study also showed that participants weighing more than 60 kg treated with
30 mg Stavudine experienced fewer adverse effects compared to those treated with 40 mg Stavudine in
the same weight category (4.2 vs 16.7%, p < 0.001).´⁰
WHO clinical stage and CD4+ count
A Uganda based trial by Gerald et al , assessed the outcome of Stavudine associated peripheral
neuropathy. Results from the study showed that a baseline CD4+ count of 200cells/ L or higher was
associated with improvement of peripheral neuropathy following substitution of Stavudine with
Zidovudine.¶ In addition , a trial done in Kenya by Karara et al in 2010, showed that occurrence of any
adverse drug reaction, including peripheral neuropathy was significantly associated with severe
immunosuppression i.e WHO clinical stage 3 and 4 disease. (HR =1.45, CI: 0.86 - 2.45, p < 0.001)¹¸ Another
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trial carried out the same year in Kenya by Thuranira also showed that those with CD4 counts less than 130
cells/mm3 were more likely to develop peripheral neuropathy (OR=2.43, 95% CI, 1.29-4.57).´µ
Alcohol consumption
Results from the trial by Gerald et al also showed that alcohol consumption reduced improvement from
Stavudine neuropathy following substitution with Zidovudine.¶
Vitamin B12 Deficiency
A trial by Moyle et al showed that participants with nutritional deficiencies such as vitamin B12 deficiency
had a greater likelihood of developing neuropathy from nucleoside analogues such as Stavudine,
Zalcitabine or Didanosine. One of the conclusions from that study was that participants with vitamin B12
deficiency should avoid this class of antiretrovirals. ´¹
Grading of peripheral neuropathy pain or neuropathic pain
Assessment of a patient with symptoms of peripheral neuropathy is often subjective and can be both
inaccurate and difficult. This is the reason why many grading systems have emerged to cater for the
potential imprecisions that may arise when one is assessing symptoms like peripheral neuropathy or pain.
The following grading systems have been validated in the assessment of peripheral neuropathy or
neuropathic pain.
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Table 2: Grading of peripheral neuropathy
*ADL-activities of daily living
Table 2 above illustrates two commonly used tools for the assessment of peripheral neuropathy. The
World Health Organisation screening tool is a subjective tool to assess the presence of peripheral
neuropathy. The National Cancer Institute of Canada Common Toxicity Criteria is a purely objective
measure of peripheral neuropathy.
Name of tool Grade 0 Grade 1 Grade 2 Grade 3 Grade 4
1. WHO Toxicity Criteria ´·
None Paraesthesias and/or decreased deep tendon reflexes
Severe paraesthesias and/or mild weakness
Intolerable paraesthesias and/or motor loss
Paralysis
2. NCIC Common Toxicity Criteria ´¸
Sensory neuropathy Motor neuropathy
None None
Loss of deep tendon reflexes or paraesthesia but not interfering with function. Subjective weakness but no objective findings
Objective sensory loss or paraesthesia interfering with function but not ADL.* Objective mild weakness, interfering with function but not with ADL*
Sensory loss or paraesthesia interfering with ADL.* Severe paraesthesia, moderate objective abnormality, severe functional abnormality
Permanent sensory loss that interferes with function Paralysis
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3. The ACTG Brief Peripheral Neuropathy Scale (BPNS)
This is a screening tool that has been validated for scaling the degree of peripheral neuropathy. It is a
simple tool to administer. It can be administered in as little as 10 minutes and assesses both subjective and
objective clinical findings of peripheral neuropathy. A study to evaluate the accuracy of this brief clinical
neuropathy screening tool in detecting peripheral neuropathy by Cherry et al showed that the BPNS was as
effective as objective measures to assess the presence of peripheral neuropathy in HIV-1 infected
participants.´¹ Participants presenting with symptoms of peripheral neuropathy and abnormal ankle jerks
or vibration sensation were more likely to have abnormal sensory thresholds and reduced epidermal nerve
fibre densities. The conclusion following the results of this study was that the BPNS with its chosen
definition of neuropathy was a suitable tool to use in resource limited settings in the context of HIV related
neuropathy.
Simpson et al showed that when compared to the Total Neuropathy Score (an objective measure of
peripheral neuropathy), the BPNS had a specificity of 89.5% vs 90% and a sensitivity of 34.9% vs 49% for
detecting distal sensory peripheral neuropathy secondary to HIV, with a positive predictive value of 72%. µ⁰
A study done in Mombasa Kenya, to assess the feasibility of this tool in a resource-limited setting showed
that despite adding another five minutes to the clinic visit, the BPNS was an easy tool to administer and
was found to be an extremely useful clinical tool by the trained providers who administered the tool. µ¹
The diagnosis of peripheral neuropathy can be made when an individual experiences one or more
symptoms specified in the BPNS which are :
Pain
Paraesthesia
Numbness
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and one of the following :
Diminished ankle reflexes
Reduced vibration sense of the big toe´¹
The basis for this limited sensory examination is that distal sensory loss has a temporal progression. Loss of
vibration sense occurs first, followed by loss of temperature sensation and lastly pain sensation.
Findings are usually bilateral and symmetrical. In the presence of asymmetry, an alternative diagnosis
should be sought. ³³
This tool has limitations however. There is a subgroup of patients that are not accounted for when utilising
this tool. The BPNS excludes patients who report symptoms of peripheral neuropathy but have subclinical
evidence of neuropathy on clinical examination. Conversely, there are those patients who do not report
symptoms but may have clinical evidence of neuropathic damage. A more objective assessment of
peripheral neuropathy such as electrophysiologic studies may be useful in this scenario to overcome this
discrepancy. This investigation is however not readily available in resource limited settings.´¹
Treatment of Stavudine induced peripheral neuropathy
Treatment of peripheral neuropathy can be difficult and frustrating for both the physician and the patient.
Various modalities have been used.
1. Antidepressants
Tricyclic antidepressants for instance amitryptiline, desipramine or nortriptyline are the first line of
treatment for peripheral neuropathy and have shown efficacy in previous studies. These drugs block the
reuptake of noradrenaline and serotonin and relieve pain by inhibition of the sodium channel.
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Selective Serotonin Reuptake Inhibitors selectively inhibit reuptake of serotonin only. Studies have shown
these groups of drugs to be less efficacious than the tricyclic antidepressants.µ²
2. Anticonvulsants
Carbamazepine
Data on this drug’s efficacy in treating distal sensory neuropathy is limited. It has been shown in a study by
Simpson et al to be quite useful in the treatment of diabetic neuropathy and trigeminal neuralgia.µ³
Phenytoin
It is rarely used as first line therapy for neuropathic pain. Simpson et al also reported reduction in
symptoms from neuropathies of differing aetiologies following intravenous administration of phenytoin.µ³
Gabapentin
Clinical trials have demonstrated pain relief in participants with diabetic neuropathy. Gabapentin
monotherapy was shown to be effective in the treatment of insomnia and pain associated with diabetic
peripheral neuropathy in a study by Backonja et al. Its efficacy has also been shown to be equal to that of
amitryptiline. µ´
Lamotrigine
In a study by Simpson et al, Lamotrigine was shown to be useful at a dose of 400 – 600 mg and provided
moderate pain relief in participants with HIV neuropathy and diabetic neuropathy.µ³
3. Topical agents
Topical Capsaicin has been shown to be useful in participants with diabetic neuropathy, but did not show
much benefit in participants with HIV neuropathy or distal sensory painful neuropathy. µµ
4. Alternative therapies
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Recombinant nerve growth factor has been shown in a study by McAurthur et al to provide reduction of
symptoms in participants with HIV associated peripheral neuropathy. µ¶
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MATERIALS AND METHODS
General objective
Determine the outcome of Stavudine induced peripheral neuropathy following cessation of the drug.
Research Question
What is the outcome of Stavudine induced peripheral neuropathy in HIV positive participants switched to
an alternative regimen following discontinuation of Stavudine?
Specific objectives
Primary Objective
1. To determine the outcome of Stavudine induced peripheral neuropathy following Stavudine
discontinuation.
Secondary Objectives
1. To determine the factors that contribute to the persistence of peripheral neuropathy in participants
with ongoing symptoms.
The factors under investigation are :
Age
Sex
Weight
Height
Duration of Stavudine therapy
Duration off Stavudine therapy
CD4 count at initiation of Stavudine (or first CD4 count from time of initiation)
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Viral load at time of recruitment (after Stavudine discontinuation)
Concomitant TB treatment at time of recruitment (after Stavudine discontinuation)
Concomitant diagnosis of Vitamin B12 deficiency at recruitment
Concomitant diagnosis of Hypertension
Concomitant Diabetes mellitus
Concomitant intake of potentially neurotoxic drugs (i.e. didanosine, alcohol intake,
chemotherapy). Alcohol intake is defined as the consumption of more than 14 units per
week in women and more than 21 units per week in men.
Concurrent therapy for peripheral neuropathy (i.e. amitriptyline, carbamazepine, over-the-
counter analgesia, herbal medicines, pyridoxine and gabapentin)
2. To assess the rate of discontinuation of drugs for treatment of peripheral neuropathy.
Hypothesis
Stavudine induced peripheral neuropathy persists for over a month in at least 50% of HIV positive
participants despite its discontinuation.
Study design
Cross-sectional study
Reference population
HIV positive participants switched or substituted to a non-Stavudine based combination from a Stavudine-
based regimen.
Sampling
20
The sampling frame was all participants who attended the Opportunistic Infections (OI) outpatients clinic
at Parirenyatwa Hospital who were on a Stavudine based regimen for at least one month prior to switch to
a non-Stavudine based regimen. A non-probability purposive sampling method was employed. Participants
who met the criteria for recruitment and who provided voluntary informed consent were recruited into
the study.
Sample size
The sample size n was derived from the equation
n =
p =prevalence of the outcome of interest in the target group of population – obtained from previous
literature. (Prevalence of peripheral neuropathy in a South African study)³¸
Ƶ = standard normal value which depends on the level of confidence (= 1.96df- 95% confidence level)
d = precision of our estimate (5%)
n =
n = 377 (This represents the minimum number of participants required for analysis)
Recruitment
Study subjects were recruited into the study over a period of 10 months between August 2013 and March
2014.
Inclusion criteria
21
1. HIV positive participants 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 2nd
line therapy or switch to alternative non-Stavudine based regimen.
2. Participants had to be 18 years or older.
3. 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.
Methods
Eligible participants were recruited from Parirenyatwa Opportunistic Infections (OI) Clinic between August
2013 and March 2014 as they attended their prescheduled visits. Written informed consent was sought
from all enrolled participants. With the aid of an administered written questionnaire, information
pertaining to relevant demographic features, co-morbidity history, relevant clinical variables and
antiretroviral therapy (ART) history were collected.
Thereafter the ACTG- Brief Peripheral Neuropathy Scale (BPNS) was used to evaluate the presence and
assess the severity of peripheral neuropathy. This is a validated screening tool for assessing the degree of
peripheral neuropathy which includes both subjective and objective information.
If a participant reported at least one of the symptoms of peripheral neuropathy (i.e. pain, numbness or
paraethesiae), the participant was then required to give a subjective assessment of the severity of the
symptom (or symptoms) by ranking their symptom (or symptoms) on a scale from 0 to 10, where 0 implies
22
the absence of symptoms and 10 corresponds to the maximum severity. This ranking was illustrated to the
participant using a table from a section on the questionnaire (see appendix – section B). The final
subjective sensory score for each participant was rated from the highest severity rating out of 10 and was
assigned a grade as follows:
Table 3: Subjective symptoms of peripheral neuropathy
Subjective grade BPNS severity symptom score
Grade 0 0 – (absent )
Grade 1 1-2
Grade 2 3-5
Grade 3 6-7
Grade 4 8-10
Thereafter the researcher performed a targeted neurological examination to evaluate the participant’s
vibration perception sense in both lower limbs with a 128Hz tuning fork. The researcher counted the
number of seconds the participant felt the vibrations of a 128Hz tuning fork when applied to the Distal
interphalangeal joint (DIP) of the first big toe. Thereafter, bilateral ankle reflexes were assessed with the
aid of a patella hammer.
The participants were assigned grades depending on the clinical findings as follows:
23
Table 4: Objective symptoms of peripheral neuropathy
Objective BPNS grade Vibration perception score Ankle reflexes score
Grade 0 Felt >10 secs (normal ) Absent despite reinforcement
Grade 1 Felt 6-10 secs (mild loss) Reduced contraction
Grade 2 Felt < 5 secs (moderate loss) Normal
Grade 3 Not felt (severe loss) Hyperactive
Grade 4 Clonus
Grade 8 Unable or did not assess Unable or did not assess
The diagnosis of Stavudine-induced peripheral neuropathy was made when a participant exhibited ≥1 of
the neuropathy symptoms specified in the BPNS (i.e. grade 1, 2,3 or 4 [see table 3]) which are:
Pain – described as burning, aching or stabbing
Paraesthesia – often described as ‘pins and needles’ sensation
Numbness – loss of feeling
And one of the following: [see table 4]
diminished ankle reflexes (grades 0 or 1)
reduced vibration sense at the first toe (grades 1, 2 or 3)
Study variables:
The study variables were:
Age -
Sex
24
BMI
CD4+ - categorised into CD4+ count of 200 and above and below.
Viral load – categorised into detectable (>/more 200 copies/ml) and undetectable viral load (<200
copies/ml)
Co – morbidity (Vitamin B12 deficiency, hypertension and diabetes mellitus)
Concomitant Tuberculosis treatment or cancer chemotherapy
Alcohol consumption
Sensory impairment
Duration of Stavudine therapy – dichotomised into 24 months or more and less than 24 months.
Duration off Stavudine therapy
Concurrent therapy for peripheral neuropathy
Outcome factors
Primary outcome factors –
The proportion of participants with persistent peripheral neuropathy following cessation of Stavudine as
determined symptomatically and by clinical examination using the ACTG – Brief Peripheral Neuropathy
Tool.
Secondary outcome factors – Demographic and clinical factors associated with persistence of symptoms of
Stavudine induced peripheral neuropathy despite cessation.
25
Statistical Analysis
Data entry and analysis was in Epi info version 7. To obtain an estimate of the sample size it was assumed
that Stavudine induced peripheral neuropathy would persist for more than a month in at least 50% of the
population under study. These figures had been suggested in a previous study in Johannesburg, South
Africa which sought to establish the prevalence and associated risk factors of Stavudine induced peripheral
neuropathy.⁽³¶⁾ Using the Brief Peripheral Neuropathy Score, peripheral neuropathy was categorized as
either present or absent and compared with other variables using the Pearson’s chi-square test and Fisher
exact test when required. Crude odds ratio with the corresponding confidence intervals and p values were
reported. A two sided p value of less than 0.05 was considered statistically significant. The variables with a
p value of less than 0.05 were analysed in the multivariate model.
26
Ethical considerations
Ethical approval was obtained from the Joint Parirenyatwa University of Zimbabwe College Of Health
Sciences Ethics Committee and the Medical Research Council of Zimbabwe.
All participants gave written informed consent prior to recruitment. Confidentiality was maintained by the
use of study numbers instead of names or other identifiers. All identifiable records bore study numbers. All
records were kept locked in cupboards accessible only to the study team. Participants in need of medical
attention were treated accordingly or referred appropriately for expert management.
27
Results
Patient Characteristics
The demographic characteristics of participants screened for Stavudine induced peripheral neuropathy
were assessed (see table 5 and table 6)
Table 5: Demographic characteristics of study participants.
Characteristic
n = 385
Age – mean (range) years
42.7 (18-79)
Sex - Males
129 (33.5%)
Height- mean (range)cm
163.7 (135-192)
Weight –mean (range) (kg)
69.3 (39-124)
BMI – mean (range) kg/cm²
25.9 (14-45)
A total of 385 participants were recruited into the study. Most of the patients were below the age of 40
(59%) and were mostly female (66.5%). The mean age, weight and height were 42.7 11.7 yrs, 69.3
14.8 kg and 163.7 8.83 cm respectively.
Table 6: Categorized demographic characteristics of study participants.
Characteristic n %
Age group 40 years >40 years
156 229
40.52 59.48
Height 1.70m >1.70m
314 71
81.56 18.44
Weight 60 kg >60 kg
112 273
29.09 70.91
28
Results of this study show there was a greater proportion of participants above the age of 40 (59.5%) than
those below this age cut-off. Also, there were more participants with a height below 170cm (81.6%) and
more participants with a weight of 60kg and above (70.9%).
29
Table 7 below summarizes the clinical characteristics of study participants
Table 7 : Clinical characteristics of participants.
Characteristic n =385
Initial CD4+ count – median (IQR)
86 (50.5 - 192)
Duration of Stavudine therapy – median (IQR)
months
39 (19.5 – 63.0)
Duration off Stavudine therapy – median (IQR)
months
23 (12.5 – 36.5)
The median CD4+ count was 86cells/ L (IQR 50.5 – 192), with only a quarter of the participants with a
CD4+ count above 200cells/ L. The respective times the participants were on, as well as off Stavudine
therapy are also shown above. The median duration on Stavudine therapy was 39 months (IQR 19.5 -63),
and the median duration the participants were off Stavudine was 23 months (IQR 12.5 -36.5).
Table 8 : Categorized clinical characteristics of study participants.
Characteristic n %
Initial CD4+ count
200
>200
295
90
76.62
23.38
Viral Load
200 (suppressed)
Detectable viral load
311
74
80.66
19.34
Duration of Stavudine therapy
24 months
>24 months
128
257
33.25
66.75
Duration off Stavudine therapy
24 months
>24 months
196
189
50.91
49.09
30
There were more patients (76.6%) with a CD4+ count of below 200 at the onset of Stavudine therapy. A
greater proportion (66.8%) were on Stavudine for a period exceeding a duration of 24 months.
Approximately half of the participants recruited into the study were off Stavudine for a period of less than
24 months.
31
Table 9: Clinical history and drug history of study participants.
Characteristic n %
Hypertension Yes No
61 324
15.84 84.16
Diabetes Mellitus Yes No
13 372
3.38 96.62
Current Anti-Tuberculous therapy Yes No
11 374
2.86 84.16
Vitamin B12 Deficiency Yes No
8 377
2.08 97.92
History of alcohol intake Yes No
77 308
20.00 80.00
Current didanosine therapy Yes No
10 375
2.60 97.40
Current Amitriptyline therapy Yes No
114 271
29.61 70.39
Pyridoxine therapy Yes No
10 375
2.60 97.40
Chemotherapy Yes No
1 384
0.26 99.74
Herbal medicines Yes No
2 383
0.52 99.48
Gabapentin therapy Yes No
2 383
0.52 99.48
Carbamazepine therapy Yes No
5 380
1.30 98.70
Over-the-counter Analgesia Yes No
28 357
7.27 92.73
32
Table 9 above summarizes the proportion of participants who had concurrent hypertension, diabetes
mellitus, vitamin B12 deficiency as well as concurrent tuberculosis diagnosis at time of enrolment. The
proportion of participants who were on treatment for peripheral neuropathy as well as the respective drug
therapies are also illustrated above. 29.6 % of the participants were on Amitriptyline for the treatment of
peripheral neuropathy and less than 1% were on Gabapentin.
33
Stavudine Induced peripheral neuropathy
Table 10: Prevalence of peripheral neuropathy and signs and symptoms consistent with peripheral neuropathy .
Characteristics N %
Peripheral neuropathy according to BPNS Yes No
174 211
45.19 54.81
Symptoms Grade 0 Grade 1 Grade 2 Grade 3 Grade 4
195 59 64 32 35
50.65 15.32 16.62 8.31 9.09
Perception of tuning fork vibration on great toes Grade 0 felt >10 seconds (normal) Grade 1 felt 6-10 seconds (mild loss) Grade 2 felt <5 seconds (moderate loss) Grade 3 not felt (severe loss)
229 98 37 21
59.48 25.45 9.61 5.45
Ankle jerk reflex Grade 0 Absent reflex Grade 1 Hypoactive Grade 2 Normal Grade 3 Hyperactive Grade 4 Clonus
100 92 190 3 0
25.97 23.90 49.35 0.78 0.00
The prevalence of persistent symptoms of peripheral neuropathy (i.e participants who self reported either
one of the symptoms of pain, numbness or paraethesiae) was 49.4% (190/385). The highest proportion of
participants had grade 2 symptoms (16.6%). Upon examination, 40.5% (156/385) had abnormal perception
of vibration and 50.6% (195/385) had abnormal ankle jerk reflexes.
According to the Brief Peripheral Neuropathy Score (BPNS), the prevalence of persistent Stavudine induced
peripheral neuropathy was 45.2% (174/385) in this study population. It is worth mentioning that out of the
total participants who did not report symptoms of peripheral neuropathy, 24.6% (48/195) had abnormal
ankle jerks and 11.3% (22/195) had diminished vibration sense. Conversely 24.5% (56/229) of the
34
participants who had a normal vibration sense and 24.2% (46/190) of those with normal ankle reflexes
reported symptoms consistent with peripheral neuropathy.
Association between Stavudine induced peripheral neuropathy and patient characteristics
Table 11: Demographic factors associated with Stavudine induced peripheral neuropathy.
Variable PN
N=174
No PN
N=211
OR (95%CI) P value
Age
<40
>40
62 (34.44)
118 (65.56)
94 (45.85)
111 (54.15)
1.61 (1.07-2.43)
0.023
Sex
Male
Female
71 (39.44)
109 (60.56)
58 (28.29)
147 (71.71)
0.63 (0.41 -0.97)
0.035
Height
<1.70m
>1.70 m
141 (78.33)
39 (21.67)
173 (84.39)
32 (15.61)
1.50 (0.89-2.51)
0.126
Weight
<60kg
>60kg
48 (26.67)
132 (73.33)
64 (31.22)
141 (68.78)
1.25 (0.80 -1.94)
0.326
From the table above, only age above 40 and male -sex were statistically significant factors associated with
Stavudine induced peripheral neuropathy. In fact, those who were above 40 were 1.6 times more likely to
develop peripheral neuropathy. The mean age for these participants who were more likely to have
persistent peripheral neuropathy was 44.9 years (SD 9.99). Females were 37% less likely to develop
peripheral neuropathy compared to the males.
35
Table 12: Clinical factors associated with Stavudine induced peripheral neuropathy
Variable PN
N=174
No PN
N=211
OR (95%CI) P value
CD4+ count
<200
>200
154 (85.56)
26 (14.44)
141 (68.78)
64 (31.22)
2.69 (1.61 -4.48)
0.0001
Viral load
Detectable
Suppressed
36 (22.64)
123 (77.36)
28 (16.28)
144 (83.72)
1.51 (0.87-2.61)
0.143
Hypertension
Yes
No
42 (23.33)
138 (76.67)
19 (9.27)
186 (90.73)
2.98 (1.66 – 5.35)
0.0002
Diabetes Mellitus
Yes
No
8 (4.44)
172 (95.56)
5 (2.44)
200 (97.56)
1.86 (0.60 – 5.79)
0.277
Current TB
treatment
Yes
No
6 (3.33)
174 (96.67)
1 (0.49)
204 (99.51)
7.03 (0.84 – 58.99)
0.037
Vitamin B12
Deficiency
Yes
No
4 (2.22)
176 (97.78)
4 (1.95)
201 (98.05)
1.14 (0.28 – 4.63)
0.852
Alcohol intake
Yes
No
43 (23.89)
137 (76.11)
34 (16.59)
171 (83.41)
1.58 (0.95 – 2.61)
0.074
Duration of
Stavudine therapy
<24 months
>24 months
73 (40.56)
107 (59.44)
55 (26.83)
150 (73.17)
0.54 (0.35 – 0.82)
0.004
Duration off
Stavudine
<24 months
>24 months
91 (50.56)
89 (49.44)
105 (51.22)
100 (48.78)
1.03 (0.69 – 1.53)
0.897
36
From the table above Stavudine induced peripheral neuropathy was strongly associated with a low CD4+
count, concurrent hypertension, Tuberculosis therapy as well as a longer duration on Stavudine therapy.
Participants with a CD4+ count below 200 cells/ L were 2.7 more likely to develop neuropathy. The
median CD4+ count in this subgroup of participants was 77.5cells/ L (44.5 – 161). Hypertensive
participants were 2.98 times more likely to develop peripheral neuropathy. Participants who had
concurrent tuberculosis and hence on anti-tuberculous therapy, had a 7 fold greater likelihood of
developing peripheral neuropathy. Lastly, those individuals who had been exposed to Stavudine for a
longer duration of beyond 24 months were 46% less likely to develop peripheral neuropathy. The median
duration on Stavudine for these participants was 33 months (IQR 16.5-60).
Table 13 : Multivariate analysis of associated factors for Stavudine induced peripheral neuropathy,
adjusted for sex, age, and alcohol consumption
Variable Adjusted odds ratio
(AOR)
95% CI P value
Concurrent TB
treatment
5.46 0.61 – 49.07 0.13
Low CD 4+ count 2.64 1.57 – 4.46 0.0003
Duration of therapy >24
months
2.07 1.30 – 3.31 0.002
Hypertension 2.89 1.55 – 5.39 0.0009
As shown above, after adjusting for age, sex and alcohol consumption, a low CD4+ count, hypertension and
a longer duration of Stavudine therapy were still associated with a greater risk of Stavudine induced
peripheral neuropathy. Variables with a p value of less than 0.05 in the univariate analysis were analysed
in the multivariate model.
37
Discussion
In this study we found the prevalence of persistent Stavudine Induced peripheral neuropathy following
discontinuation of a Stavudine containing regimen to be 45.2% using the BPNS tool. The prevalence has
varied greatly within Sub-Saharan Africa from as low as 13% in Lilongwe, Malawi ³¹ to as high as 57% in
Johannesburg, South Africa.³¸The prevalence in this study is closer to that found in the South African study.
This study was a cross-sectional study of 598 participants which used the BPNS tool as well as a modified
version of the Total Neuropathy Score to identify patients with peripheral neuropathy.³¸
Females were less likely than the males to develop progressive peripheral neuropathy. The larger
proportion of females recruited into the study may be a reflection of the health seeking behaviour of
women compared to that of males. Women are more likely to seek medical care earlier therefore they
could have been switched to a non-Stavudine regimen with lower grades of peripheral neuropathy
compared to the males. The lower grades of peripheral neuropathy have been shown in the literature to
resolve sooner than higher grades. ³´ One can also postulate that the greater proportion of males who
consumed alcohol compared to the females (45% vs 7%) could explain why males were more likey to have
progressive neuropathy. This difference however was shown on multivariate analysis not to have an
influence on the persistence of neuropathy in the males. AOR =1.23 [(95% CI – 0.70 – 2.15) p =0.46]
Participants who were older than 40 years were found to have a higher prevalence of ongoing peripheral
neuropathy secondary to Stavudine. These findings are similar to a study by Cherry CL et al which showed
a strong association between an age above 40 years and the development of Stavudine induced peripheral
neuropathy.³· This is because age has been shown to increase the vulnerability of the peripheral nerves,
with the longer fibres more susceptible to injury from toxic substances such as drugs and alcohol. ³¸In
addition, older people tend to also have concurrent vitamin deficiencies such as vitamin B12 and vitamin
B6 which are both essential for nerve repair and function. Moreover, the older population tend to also
have co-morbid conditions such as hypertension and diabetes mellitus which have been shown in various
38
literature to be also independently associated with peripheral neuropathy.³¹ On multivariate analysis, a
concurrent diagnosis of hypertension was shown to be a significant factor in influencing the progression of
peripheral neuropathy in those older than 40 years. AOR- 2.84 [(95% CI – 1.55 -5.19), p =0.007]
Persistent Stavudine induced peripheral neuropathy was also found to be also strongly associated with a
CD4+ count of less than 200cells/ L. This is similar to the results of a study performed by Gerald et al in
Uganda.¶ The Ugandan study showed a higher likelihood of developing peripheral neuropathy with a lower
CD4+ count , and a poorer outcome of peripheral neuropathy following substitution of Stavudine with
Zidovudine. It is worth mentioning that a low CD4+ count has also been shown to be associated with the
development of HIV associated peripheral neuropathy, which is clinically indistinguishable from Stavudine
induced peripheral neuropathy.³⁰ It is therefore possible, that a certain proportion of the participants
whose symptoms were attributed to Stavudine may have underlying subclinical axonal injury from the HIV
notwithstanding the fact that the study excluded participants without symptoms of peripheral neuropathy
prior to Stavudine initiation.
We also showed that participants with established hypertension were almost three times more likely to
have ongoing peripheral neuropathy compared to those without. Hypertension has been shown in a few
studies to be independently associated with peripheral neuropathy. It has also been shown to have an
effect on the autonomic nervous system.µ·˒µ¸ Rebecca Louise in 2011 conducted a study to assess the
relationship between hypertension and peripheral neuropathy and found that hypertensives had higher
vibration thresholds compared to normotensives. µ¶Previously, similar results were obtained in a study by
Rosa et al.µ¸ Zarrelli et al showed that hypertension was strongly associated with peripheral neuropathy in
the elderly.µ¹
Concurrent anti-tuberculous therapy was found to be strongly associated with progressive Stavudine
induced peripheral neuropathy in this study. A study done in Tororo, Uganda showed a strong association
between isoniazid exposure and the development of Stavudine induced peripheral neuropathy.´² Isoniazid,
39
which is a component of anti-tuberculous therapy, has been known in the literature from as far back as
1959 to be associated with a dose related peripheral neuropathy. ¶⁰ The mechanism by which this drug
causes this effect is by interfering with the metabolism of pyridoxine. ¶¹˒¶²
In this study, a longer duration of exposure to Stavudine was found to have a negative association with the
development of peripheral neuropathy. This is in contrast to the results of the study by Scarsella et al
which showed a doubling in the incidence of peripheral neuropathy in participants exposed to Stavudine
for more than 24 months compared to those exposed to the drug for less.² This may be because of survivor
bias whereby the participants who continued on Stavudine for more than 24 months had lower grades of
neuropathy and therefore tolerated the drug for a longer period.
It is also worth mentioning that out of those participants who had progressive peripheral neuropathy,
about 30% were on Amitriptyline for their symptoms, 1.3% were on Carbamazepine , 7.3% were on over-
the counter analgesia and only 0.5% required Gabapentin for relief of their symptoms. This may have had
an effect on the results. Participants with lower grades of peripheral neuropathy may have presented with
no symptoms at enrolment leading to an underestimate of the actual prevalence of persistent peripheral
neuropathy.
This study had a few limitations however. Firstly the Brief Peripheral Neuropathy Score (BPNS) may give an
underestimate of the true number of participants with peripheral neuropathy by excluding participants
with subclinical disease. To make a diagnosis of peripheral neuropathy using the BPNS a participant needs
to have at least one subjective symptom of peripheral neuropathy as well as an abnormal objective finding
on examination. This tool therefore excludes both those participants who may not report any symptoms
but have objective evidence of peripheral nerve damage and the ones who report symptoms but lack
clinical evidence of neuropathy on examination. Electrophysiologic studies may give a more objective
assessment of the true prevalence of Stavudine induced peripheral neuropathy as shown in a study by
40
Skopelitis et al in which the investigators utilised both a clinical assessment using the BPNS as well as
nerve conduction studies. The study showed that over 60 % of the peripheral neuropathy was subclinical.¶³
In addition, as already alluded to earlier, the BPNS cannot clinically distinguish HIV associated peripheral
neuropathy from Stavudine induced peripheral neuropathy so participants with subclinical HIV associated
peripheral neuropathy prior to Stavudine initiation may have their symptoms attributed entirely to the use
of Stavudine. Screening of participants at baseline for the presence of peripheral neuropathy might help
overcome this discrepancy. Another limitation of the BPNS is that it allows the participant to give a
subjective assessment of their own symptoms on a numerical rating scale. The participant’s subjective
report of their symptoms may have introduced bias in the study because thresholds of either of the
symptoms of pain, paraeesthesia or numbess can differ from one individual to the other.
Moreover, the sampling technique utilised in the study was a convenience sampling method which may
have introduced some selection bias in the study. This sampling method does not provide equal chance for
selection of participants therefore limiting generalisability of the results. Another limitation of the study is
that it was not possible to know for certain that all participants under study truly had peripheral
neuropathy attributable to Stavudine at the time of switch of antiretroviral therapy since no objective tests
were done at that time. Lastly, a cohort study unlike a cross-sectional study would have been more
appropriate to establish the nature of the association between various variables and Stavudine induced
peripheral neuropathy, as well as the temporal relationship between the various variables and Stavudine
Induced peripheral neuropathy.
41
Conclusion
Stavudine induced peripheral neuropathy persists in a significant number of HIV positive patients being
followed up at Parirenyatwa Hospital Opportunistic Clinic despite its cessation. Its continued use for the
treatment of HIV should therefore be discouraged. The factors which have been shown to contribute to its
persistence are older age, male sex, a CD4+ count below 200cells/ concurrent anti-tuberculous therapy
and hypertension. A prospective longitudinal study would better characterize the temporal relationship
between these associated factors with persistent Stavudine induced peripheral neuropathy. The BPNS is a
useful simple screening tool to identify patients with symptoms as well as signs of peripheral neuropathy
secondary to Stavudine or HIV. Unfortunately, treatment of this ailment can be difficult as well as
challenging given the proportion of patients who continued to take medication with only limited relief of
their symptoms.
42
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APPENDIX
A. QUESTIONNAIRE AND DATA COLLECTION SHEET
Outcome of Stavudine Induced Peripheral Neuropathy
Demographics:
Name :.......................................................................................................................................
Age:...................................................... Occupation: ...........................................................
Sex: male female
Clinical Data
Weight (kg)........................................... Height (m)............................................................
BMI(kg/m2)
CD4+..................................................... Viral load...............................................................
Past medical history
Co-morbidity yes no
Hypertension year.........
Diabetes mellitus year.........
Vitamin B12 deficiency year.........
Current Tuberculosis
HIV and ART history
Year of diagnosis:.............................................................................................................................
ARV regimen:....................................................................................................................................
Date of commencement :..................................................................................................................
Did you ever switch to another regimen? yes
no
If yes , which one..................................................
Date of last dose of Stavudine..........................................................................................................
Drug History yes no
Alcohol pnts/wk...............
Smoking pack yrs................
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Anti TB treatment
Didanosine
Herbal medicines
Amitriptyline
Carbamazepine
Gabapentin
Analgesia
Vitamin B6
Chemotherapy
B. Peripheral Neuropathy
1. Subjective symptoms
Rate the severity of each of these symptoms below on a scale of 01 (MILD) to 10 (MOST SEVERE) for the
right and left feet and legs. If the symptom has always been normal it’s rated 11, and currently absent 00.
Symptoms Right Left
Pain
Parasthesia
Numbness
Always been
normal
Currently absent Mild to severe
11 00 01 02 03 04 05 06 07 08 09 10
Grading subjective symptoms
Use the single highest severity score from Question 1 above to obtain a subjective sensory neuropathy score. If all
severity scores are "00" or "11," the subjective sensory neuropathy score will equal "0."
Subjective Sensory Neuropathy Score (based on highest severity rating)
Grade 1 – BPNS severity score 1-2
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Grade 2 – BPNS severity score 3-5
Grade 3 – BPNS severity score 6-7
Grade 4 – BPNS severity score 8-10
Scores -
Right Left
2. Neurological examination
Evaluation of vibration sense
Vibration perception score
0 felt >10 seconds (normal)
1 felt 6-10 seconds (mild loss)
2 felt <5 seconds (moderate loss)
3 not felt (severe loss)
8 unable to or did not assess
Scores -
Right Left
Evaluation of deep tendon reflexes
Ankle Jerk Reflexes Score
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Grade – 0 absent despite use of a Jendrassik maneuver
1 reduced visible contraction present
2 normal
3 mildly hyperactive with reflex spread to the other muscles
4 clonus
8 unable or did not assess
Scores -
Right Left
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CONSENT FORM – ENGLISH
PROTOCOL TITLE : Outcome of Stavudine Induced peripheral neuropathy in HIV-1 positive patients
switched or substituted to a non-Stavudine based regimen.
NAME OF RESEARCHER : Dr Pamela Gorejena
PHONE : 0772844565
PROJECT DESCRIPTION : I am a postgraduate student in the Department of Medicine at the University of
Zimbabwe. I am carrying out a study that assesses the outcome of Stavudine induced peripheral
neuropathy in people living with HIV.
YOUR RIGHTS : Before you decide onwhether or not to take part in this study , you must comprehend the
purpose of the study, the benefits, the risks to you, and what is expected of you. This process is known as
informed consent.
PURPOSE OF STUDY : Since 2004, Stavudine is one of the drugs useful in the treatment of HIV in
Zimbabwe and has been part of the first line combination drugs used in antiretroviral treatment
i.e.STALANEV or TRIVIRO.
One of the major side effects of this drug is peripheral neuropathy. This arises when Stavudine causes
damage to the nerves of the feet leading to loss of sensation in the feet or abnormal sensation. Some of
the problems one may experience when on this drug are ‘pins and needles’ sensation in the feet , burning
sensation or an unusual pain which can be severe enough to interfere with walking or daily activities.
This study aims to identify those patients who have experienced the symptoms of peripheral neuropathy
after taking an antiretroviral regimen containing Stavudine. The study also assesses whether these
symptoms get better, remain the same or worsen after stopping use of the drug. The study will also be
able to identify the reasons why some patients with symptoms of peripheral neuropathy do not improve
despite stopping Stavudine.
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PROCEDURES INVOLVED IN THE STUDY: I will be physically examining your legs and feet for signs
consistent with the presence of peripheral neuropathy.
DISCOMFORTS AND RISKS: You will not experience any risks from taking part in the study.
POTENTIAL BENEFITS: Those with symptoms that persist will receive appropriate treatment to improve
their symptoms.
STUDY WITHDRAWAL : You are free to withdraw from the study at any point that you may so wish.
CONFIDENTIALITY OF RECORDS : All records of information obtained in this study will be kept confidential.
In addition, no names will be used for identification in this study. Once you agree to participate in the
study you will be assigned a number which you will use during the study.
PROBLEMS/QUESTIONS : Please ask any relevant questions concerning the study or consent now. Feel free
to ask questions in the future.
AUTHORIZATION :
I have read and understood this paper and it was explained to me. I comprehend the potential risks and
benefits of this research. I volunteer to take part in the study with the knowledge that I am free to
withdraw at will. I will keep a copy of the consent form. (Initial all previous pages of the document)
--------------------------------------------------------------------------------------------------------------------------------------
Signature of client date
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Name of client (Print)
--------------------------------------------------------------------------------------------------------------------------------------
Signature of researcher date
--------------------------------------------------------------------------------------------------------------------------------------
Signature of witness date
58
CONSENT FORM – SHONA
MUSORO WECHIRONGWA : Kuongorora kushanda kwemushonga (Stavudine) kuna avovane utachiona
weHIV.
MUONGORORI : Dr Pamela Gorejena
PHONE : 0772844565
CHINANGWA CHECHIRONGWA : Ndiriuyo wevamwe varikudzidzira kuita mazvikokota munyaya dzekurapa.
Ndizvo zvaita kuti ndinge ndichiferefeta nekunyatsonzwisisa nezve mushonga unoshandiswa kurapa
chirwere cheshuramatongo, cheutachiwana weHIV.
KODZERO YENYU : Musati mapinda muchirongwa ichi munofanira kutanga maziva zvinoreva chirongwa
ichi.
TARISIRO YECHIRONGWA : Zvakadaro ndichange ndichida kuti ndinge ndichishanda neavo vange
vachishandisa mushonga unonzi Stavudine, kuti ndione kuti pane kumwe kurwadziwa here kwakavepo
apo makabvira kushandisa mushonga uyu. Kurwadziwa kunogona kuvapo kunobvira kubatwa nechiveve
kutsoka, kana kunzwa kupiswa kwetsoka zvichibatanidzira nekunge murikubayiwa bayiwa netsono kana
munzwa, zvinova zvinoita kuti musanyatsofambe zvakanaka.
Ndichange ndichida kunyatsonzwisisa kuti mainzwawo sei pamaishandisa mushonga uyu. Ko
pamakambomira kuushandisa zvakabva zvapera here kana kuti zvakatowedzera?
Izvi zvichatibatsira kuti tinge tichinyatsoziva kushanda kwemushonga uyu.
NZIRA ICHASHANDISWA KUONGORORA : Ndichange ndichiongorora makumbo enyu netsoka dzenyu kuti
ndione kuti ane chiveve here nekubayiwa bayiwa.
ZVIMHINGAMUPINYI : Hapana zvimhingamupinyi zvinotarirwa kuti mungasangane nazvo.
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ZVINGANGOKUBATSIREI : Muchabatsirwa nemishonga kuti marwadzi nechiveve zvipere.
KUBUDA MUCHIRONGWA : Makasununguka kubuda muchirongwa kana muchiona zvakakodzera.
KUCHENGETEDZWA KWEWONGORORO : Kushanda kwedu kuchange kuri pakati pedu chete. Zvichireva
kuti hapana umwezve achange achizoziva zvatinenge tataura zvisina mvumo yenyu.
MIBVUNZO : Munobvumirwa kubvunza mibvunzo pamunodira kubvira pakutanga kwechirongwa
zvichienda mberi.
MVUMIRWA : Kana murikuona zvakakodzera kuti munge muri muchirongwa ichi, mondinyorerawo zita
renyu pasi apa semucherechedzo wekuti tinge tichienderera mberi.
Ini .................................................................................................................................................(Zita)
ndazvipira kuva mubatsiri wechino chirongwa.
............................................................................................................................. ............................
Signature yenyu date
................................................................................................................ .........................................
Signature yemuongorori date
.........................................................................................................................................................
Signature yewitness date
60