This study aimed to determine the prevalence of PN and associated factors among children living with HIV who attended CTC follow up clinic at MNH. Results from this study shows that the prevalence of PN in HIV positive children attending CTC at MNH was 14.1 %. The prevalence of HIV associated PN in children varies greatly among studies from different countries ranging from 13 to 34 % [10,11,12,13]. The prevalence from this study was consistent with a study done in HIV positive Peruvian children who were diagnosed using electrophysiological tests . However, higher rates have been found in South African and Brazilian children who were diagnosed using clinical scoring tools like Neuropathy Symptom Score (NSS)/Neuropathy Disability Score (NDS) and electrophysiological studies respectively [10, 11, 15]. The variability in results could be attributed to the diversity of patient population and the various methods used to diagnose PN in different studies, where some clinicians used clinical scoring tools while others used electrophysiological studies. Despite the variation in the population demographics, the prevalence of PN obtained in HIV positive children using clinical scoring tool was almost similar to that obtained from electrophysiological studies . Based on our findings there are possibilities that such children are not been identified in their routine clinic visits as they may fail to express their symptoms and no formal assessment for PN was done.
Predictors of PN among HIV infected children
In this study the independent predictors of PN among HIV infected children attending CTC at MNH were severe immunosuppression as reflected by a low CD 4 count (< 350 cell/mm3), a high viral load (≥ 1000 copies/ml), use of NRTI’s plus PI’s and the last exposure to isoniazid more than 6 months ago. These factors have also been observed to be strong predictors of PN in both children and adults living with HIV in different settings [15, 17,18,19].
Using the Pedm TNS screening tool sensory symptoms were frequently reported by participants than motor symptoms and most did not experience functional impairments that interfered with their daily activities. This could possibly indicate that sensory neuropathy was common in children with HIV infection in our study. These findings were comparable to a study done by Remco et al., who assessed HIV associated PN in children using a different clinical neuropathy screening tool . In HIV positive adults in addition to the neuropathic symptoms patients have also been observed to have significant functional impairment like fatigue, slower gait, poor cognitive functioning and depression compared to those who did not have PN .
It has been highlighted in previous reports that many patients also have subclinical neuropathy during evaluation that was either co-incidentally detected by electrophysiology studies or during a skin biopsy . This could also explain the difference in reporting the clinical presentation across studies since many patients could be asymptomatic at presentation, and would not meet the diagnostic criteria of a clinical scoring tool and be missed during a clinical evaluation. However, despite the limitations of the clinical scoring tools, in this study the tool identified children with PN who had never been diagnosed before. This shows its usefulness in a routine care settings where healthcare workers often depend on caregivers to subjectively report history of such symptoms. Thus, findings from this study emphasize a role of regular active assessment of PN for all HIV positive children attending CTC follow up clinic using a standard tool.
Patient related factors
In this study PN was equally distributed among males and females. Floeter et al., reported that the risk of PN in HIV infected children was higher in older children above 13 years than younger ones . Few adult studies have also shown association of PN with older and taller patients regardless of whether they had received ART . When the two factors were combined neuropathy rates increased from 18 % in younger and shorter patients to 33 % in younger, taller patients, the cut off age being ≤ 40 years and height ≥ 170 cm . However, the association of this combination with PN was not observed in this study. Furthermore, there was no significant difference in relation to sex and hemoglobin levels among those with or without PN. Patients with HIV infection of all age groups are exposed to nutritional deficiencies and it is a strong predictor for the progress of the disease, survival, and functioning in the course of illness. One study reported that children with malnutrition  had a higher risk to develop distal sensory PN than those who did not have malnutrition however, we observed no association between malnutrition and PN in this study. Neurological manifestation associated with micronutrient deficiencies such as vitamin B12 has been reported more in HIV positive adults than in children . This could be explained by the fact that in our study very few children had malnutrition and those who had malnutrition did not have the severe forms.
Disease related factors
The odds of developing PN were significantly high among children with severe immunosuppression as reflected by a low CD4 count < 350 cell/mm3 and a high viral load ≥ 1000 copies/ml in this study. Similar observation has been reported in earlier studies involving adults before ART became widely available [20, 21]. In contrast, few reports involving children and adults during ART era have not shown association between immunosuppression and advanced disease with PN despite several studies suggesting that low CD4 cell counts represents a risk factor for HIV neuropathy [14, 22, 23]. This could be due to early initiation of ART and other unstudied risk factors that may have attributed to PN observed in these population.
Majority of children enrolled in the current study were using ART’s, 90.3 % (346/383) had CD4 counts > 350cell/mm3 and 68.4 % (262/383 ) had achieved viral suppression, out of those only some were observed to have neuropathic symptoms, suggests a possibility of a subclinical PN that was not detected before initiation of ART as baseline screening is not routinely done in children attending CTC follow up clinics .
Patients with long standing HIV infection could theoretically be at greater risk for peripheral nerve damage. However, in this study there was no significant association observed between PN and the duration of HIV infection. Similar findings were also reported in previous studies involving children [17, 18]. This could be possibly be explained by the fact that most of HIV infection in children results from vertical transmission from mother to child, thus unlike adults time of diagnosis does not reflect the time of infection in this population. However, longer duration of HIV related systemic symptoms have been observed in adults with PN compared to those who did not have PN . Possible risk factors for instance alcohol use, opportunistic infections, HIV related malignancies, prolonged exposure to neurotoxic medications and environmental exposures may at least partially account for the high neuropathy rates observed in adults with longer duration of HIV infection than in children [2, 15].
Drug related factors
There was a significant association between the use ARTregimethat contained NRTI’s plus PI’s with PN. Previous studies have shown that some of the NRTI’s can cause PN in both adults and children, particularly the dideoxy-NRTI’s (d – drugs) like stavudine, didanosine, and zalcitabine which are known to cause mitochondrial damage in the peripheral nerves [13, 24, 25]. These drugs have been phased out from the ART regimens for both children and adults living with HIV, and none of the participants in our study were using ART regime containing d-drugs. Few studies involving adults also showed that the use of PI’s like indinavir, lopinavir and saquinavir in the ART regime was associated with PN . However, the role of PI induced neuropathy is still unclear and the independent risk of neuropathy attributable to PI’s is likely to be small and should be outweighed by its vital role in viral suppression in the ART regimens . Furthermore, drug induced toxic neuropathy is dose dependent and reversible compared to HIV associated PN thus patients on ART need a close evaluation.
There was significant association between participants reported their last exposure to isoniazid more than 6 months ago and PN. Isoniazid is commonly prescribed in Tanzania, either for HIV-TB co-infection and as part of IPT for duration of 6 months in children and adults. Majority of the participants attending CTC were prescribed isoniazid either currently or in the past at a dose of 10 mg/kg for 6 months. Isoniazid induced neuropathy is dose dependent and it has been extensively reported in literature [13, 24]. There is no clear demarcation on the dose and duration of onset of symptoms after initiating isoniazid. Isoniazid reduces the biological active pyridoxine (Vitamin B6) that regenerates and nourishes nerve cells. Thus it is recommended that patients using isoniazid must also receive pyridoxine supplements, to prevent development of isoniazid-induced peripheral neuritis . Unfortunately, none of the participants in our study who were using isoniazid as part of IPT or TB treatment were receiving pyridoxine. Thus, the observed association between the use of isoniazid and occurrence of neuropathy in this study could be because the pyridoxine supplementation was not implemented as recommended.
Treatment PN is mostly symptomatic depending on the underlying cause. Several approaches have been used in adults to relieve these symptoms such as pain medication and physical therapy which can also be used in children to relieve the symptoms. Furthermore, in case of drug induced neuropathy early identification and stopping the offending ART medication can help to prevent neuropathy from getting worse.
This study had some limitations. Firstly, this was a cross sectional study limited by ability to establish a causal relationship. Secondly, HIV associated PN was based on a clinical diagnosis therefore its incidence may have been underestimated since electrophysiologic studies or skin biopsies were not performed. Furthermore, none of the participants had a baseline neuropathy screening done before initiating or changing ART which made it difficult to establish the attributing factor causing injury to the peripheral nerves whether it was HIV related or drug induced neurotoxicity. Lastly, other factors such vitamin B12 deficiency especially in malnourished children, diabetes and opportunistic infections that causes neurological complications in HIVinfectionwere not studied in this population. Despite the limitations this study has identified a neglected problem among HIV infected children, showing the importance of routine assessment for PN in HIV clinics especially in children with advance disease.