Peripheral neuropathy and associated factors among children living with HIV on antiretroviral therapy in Gamo zone, Southern Ethiopia: an institution-based cross-sectional study

Abstract

Background

Peripheral neuropathy (PN) is a common neurological complication of HIV (Human Immunodeficiency Virus) that can significantly affect patients’ quality of life. In Ethiopia, children living with HIV are at an increased risk of developing peripheral neuropathy due to comorbidities such as anemia, tuberculosis, malnutrition, and poor socio-economic status. Our study aims to evaluate the prevalence of peripheral neuropathy among children living with HIV in Ethiopia using a simple clinical screening tool.

Methods

A health institution-based cross-sectional study was conducted among 148 children aged 5 to 18 years living with HIV who are receiving treatment at the antiretroviral therapy (ART) clinic of the randomly selected public health institutions in the Gamo zone. An interview and neurologic examination were conducted. A binary logistic regression model was used to identify factors associated with the outcome variable. Variables with p-value < 0.25 in the bi-variable logistic regression analysis were entered and checked for association in a multivariable logistic regression model. The level of statistical significance was declared at the p-value < 0.05.

Result

In this study, 148 children participated, making a response rate of 97.5%. The mean ± standard deviation (SD) age of the respondents was 15.03 ± 2.99 years, and 81(54.7%) were male. The magnitude of PN was 20.9% (31/148). Children in the age category of 15–18 (adjusted odds ratio (AOR) = 1.88, 95%CI; 1.24–4.60), low BMI for age (AOR = 1.66, 95%CI; 1.12–4.15), last exposure to isoniazid within 1 year (AOR = 2.31, 95%CI; 1.12–8.53). Longer duration of HIV illness (AOR = 2.17, 95%CI; 1.54–4.64), and past tuberculosis (TB) treatment (AOR = 2.11, 95%CI; 1.08–7.48) were significantly associated factors with peripheral neuropathy.

Conclusion

Our analysis revealed that being in the age category of 15–18 years, low BMI for age, Isoniazid exposure, longer Duration of HIV illness, and past TB treatment were significantly associated with peripheral neuropathy in children living with HIV. These disease-related factors may contribute to the development and progression of peripheral neuropathy in this population.

Clinical trial number

Not applicable.

Background

Peripheral neuropathy is a condition that occurs when the nerves in the peripheral nervous system are damaged, affecting the sensory, motor, and autonomous nerves. In people living with HIV, HIV-associated peripheral neuropathy (HIV-PN) is one of the most common causes of chronic neuropathic pain, loss of sensation, paraesthesia, foot ulcers, unemployment, poor patient adherence to therapy and follow-ups, and poor quality of life. The lack of neuro-regenerative therapies and ineffective analgesics highlights the need for early diagnosis [1]. HIV-PN can be a result of cytopathic effects of the virus or the neurotoxic effects of certain antiretroviral medications that cause inflammatory mediated neuronal cell damage, and its incidence increases with advanced disease or severe immunosuppression [2]. The precise mechanisms of pathogenesis are still ambiguous. Based on several lines of experimental evidence, pathological changes of PN can be characterized by local axonal degeneration, with activated macrophages, lymphocytes, and glycoprotein 120 infiltrating the dorsal root ganglion, causing local inflammation and maintenance of pain status [3].

HIV-associated distal sensory neuropathy (DSPN) is typically identified by symptoms such as burning or tingling pain, numbness in a stocking-glove distribution, and reduced ankle reflexes. These symptoms are predominantly located in the distal lower extremities and can significantly impact patients’ quality of life, leading to disability in daily routines and loss of productivity exerting considerable living and economic burden on individuals as well as society [3, 4]. The diagnosis of PN is typically confirmed through electrophysiological tests or skin biopsy, both of which can be invasive, expensive, and require specialized interpretation. As a result, routine testing is often not feasible, particularly in resource-limited environments. Fortunately, several user-friendly and cost-effective clinical screening tools have been developed in recent years to help detect HIV-associated Peripheral neuropathy [5, 6].

The prevalence of HIV-PN varies considerably across different populations living with HIV, with estimates ranging from 1.73 to 69.4% globally. Developing countries in sub-Saharan Africa are home to around 50% of individuals living with HIV receiving ART [6, 7]. While there has been a decrease in HIV-related central nervous system (CNS) disease and opportunistic infections in recent years, peripheral sensory neuropathies associated with HIV remain a frequent and significant concern [8, 9]. Studies conducted in resource-limited settings in sub-Saharan Africa have reported a range of estimates for the risk of HIV-sensory neuropathy (SN) among people living with HIV/AIDS, from 30% to as high as 64% [10, 11].

In Ethiopia, children who are living with HIV and living in low-income areas face an increased risk of developing neurological complications. This is due to the presence of multiple comorbidities such as anemia, tuberculosis, syphilis, herpes, malnutrition, and poor socio-economic status, which can exacerbate the pathology and make management more complex [7]. Despite the many PN-inducing disease processes that affect children living with HIV, there is a lack of information available regarding the prevalence of HIV-PN in the pediatric population. As such, this study aims to evaluate the magnitude of peripheral neuropathy among children living with HIV.

Methods and materials

Study area

The study was conducted in selected public health institutions in the Gamo zone of the southern Ethiopia region, which is located at a distance of 443 km to the south of the capital city of Ethiopia, Addis Ababa. Based on the 2007 national census, the estimated population of the Zone is 1,659,310 of whom 779,332 are men and 879,782 women; with an area of 18,010.99 square kilometers. The Zone has 18 districts served by 6 hospitals, 55 health centers, and 305 health posts that provide health care services to the community.

Study design

A health institution-based cross-sectional study design was implemented.

Population

All children living with HIV on antiretroviral therapy in Gamo zone were a source population. All children living with HIV on antiretroviral therapy aged 5 to 18 years who were verbally competent and attended selected hospitals in Gamo Zone for antiretroviral therapy services were the study population. However, patients who were seriously ill during the data collection or cognitively impaired were excluded from the study.

Sample size determination

The required sample size was calculated by using the single population proportions formula by considering: a proportion of peripheral neuropathy (24%) taken from a previous study conducted in South Africa, a confidence interval of 95%, a margin of error of 5%, and an expected non-response rate of a 10%. Then,

sample size calculations n=$\:\frac{{z}^{2}*p(1-p)}{{d}^{2}}$ =$\:\frac{{\left(1.96\right)}^{2}*0.24\left(0.76\right)}{{\left(0.05\right)}^{2}}$= 280 with a 10% non-response rate gives 308.

Note

Due to the small population number, after the sample size correction formula, the final sample size was 152.

Sampling technique and procedure

The Gamo Zone has eleven health facilities providing ART services, all of which were included in the study. Due to the appointment spacing model, where clients return every six months, patient flow is reduced, making it difficult to gather an optimal study population within a study period.

The total sample size was proportionally allocated across the selected health facilities. Data from the last month’s registration was used to assess patient flow and estimate the source population. Study participants were then selected using a systematic random sampling method. For each facility, the sampling interval (K) was calculated by dividing the population size (N) by the sample size (n) based on the one-month report. A random number between 1 and K was selected, and the Kth patient from that starting point was chosen. Then, every Kth patient thereafter was included in the sample.

Data collection tools and procedures

The data was collected by using an interviewer-administered semi-structured questionnaire adapted by reviewing different works of literature and neurologic examination was performed by using a pediatric modified total neuropathy screening tool (Ped m TNS). The pilot study results showed that the tool had a sensitivity of 85.5% and a specificity of 80.9%, respectively. Internal consistency was evaluated using Cronbach’s alpha and item–total score correlations. The ped mTNS exhibited satisfactory internal consistency, with all items scoring above 0.3 on the corrected item-total correlation and an overall Cronbach’s alpha of 0.94. Six general practitioners and two supervisors collected the data. Nutritional status was determined by using the Waterlow classification to group children into 2 indexes: weight for height and height for age, following standard National Center for Health Statistics growth tables. Clinical histories were used to determine the method and date of HIV acquisition, the most recent CD4 count, viral load, and clinical status of the patient (using Center for Disease Control and Prevention HIV Classification) and any prior history, testing, and treatment of peripheral neuropathy. Haemoglobin analysis was carried out in the respective hospitals.

The Ped m TNS screening tool consists of subjective and objective assessment of sensory, motor, and autonomic domains of the peripheral nervous system together with a 5-part neurologic examination. This tool has been used to screen PN in children with chronic illnesses such as cancer and diabetes mellitus.

Using Ped m TNS, objective assessment was done to determine light touch and pain sensation that were elicited in different dermatomes in the distal extremities using 10 g Semmes Weinstein monofilament and Medipin (with the patient’s eyes closed), respectively. If the subject responded to the stimuli, then it was considered “normal” for that extremity. Otherwise, further testing was done in more proximal areas of the limb. Vibration sensation was elicited by a 128 Hz tuning fork placed perpendicular to the bony prominences (fingers, wrist, elbows, toes, and ankles) with a cut-off of at least 10 s followed by testing for deep tendon reflexes. A score of 5 or greater on the Ped m TNS indicated PN.

Operational definitions

Peripheral neuropathy: PN is diagnosed by using Ped m TNS if a score of 5 or greater on the Ped m TNS (4).

Children: In this study, children are defined as ages 5–18 who are verbally competent.

BMI for age: BMI for age was categorized into Overweight: >+1SD (equivalent to BMI 25 kg/m2 at 19 years), Obesity: >+2SD (equivalent to BMI 30 kg/m2 at 19 years), and Thinness: <-2sd>.

Stunting is defined as height for age Z-scores below minus two ( < − 2) Zscorese of the reference population.

Severe stunting is defined as HAZ scores below minus three ( < − 3) Z score of the reference population.

Data analysis

Data was coded and entered using EpiData v3.1 and analyzed using SPSS v23. Descriptive statistics such as frequency, proportion, mean, and standard deviation were computed to determine the characteristics of the study subjects. In addition, numeric variables were further explored for normality by using the Shapiro‒Wilk test. To identify the associated factors, a binary logistic regression model was applied. Both bivariable and multivariable binary logistic regression were fitted. Independent variables with a P-value ≤ 0.25 in the bivariable regression analysis were entered into multivariable regression. To assess the strength of association, AORs with 95% CIs were computed. A significant association was declared at a P-value < 0.05. The presence of multicollinearity in the model was evaluated through the use of variance inflation factor (VIF).

Data quality management

The Ped m TNS screening tool was translated to Amharic and back-translated to English before data collection. A pretest was conducted to ensure the reliability, consistency, and completeness of the questionnaires. The data collectors and supervisor underwent training, and data quality was monitored by the supervisor and principal investigator.

Results

Socio-demographic characteristics

In this study, an interview and neurologic examination were both performed for one hundred forty-eight participants with a response rate of 97.5%. The mean ± SD age of the respondents was 15.03 ± 2.99 years, and 81(54.7%) were male. Caretakers who had not attended formal education were 56(37.8%). More than half of the participants had a BMI-for-age (63.5%) and height-for-age 97(65.5%) within the normal range. The average monthly income of families between 2000 and 4000 was 74(50%) and 72(48.7%) of the caretakers were government employees. (Table 1).

Table 1 Socio-demographic characteristics of children living with HIV attending ART clinics in Gamo Zone, Ethiopia, 2022

Disease and ART drug related factors

Of the 148 children living with HIV enrolled, the majority, 141(95.2%) had acquired HIV infection via vertical transmission. The median baseline and recent CD4 cell count were 381 cells/mm3 (IQR; 253.5- 479.75) and 845 cells/mm3 (IQR; 678–979) respectively. Viral load was suppressed (< 1000 copies/mL) in 95.3% of children with viral load determined in the last 6 months. Among 148 participants, 28(18.9%) participants reported a history of anti-TB treatment, and 51(34.5%) of the participants had an ART regimen change during the study period. Additionally, 100% of the participants were exposed to isoniazid from either routine Isoniazid preventive therapy (IPT) or anti-TB treatment, 62(41.9%) had their last exposure to Isoniazid in the recent one year. Lastly, 76.4% of the participants were on Cotrimoxazole Prophylaxis. Based on these findings, it can be concluded that a significant proportion of the participants had experienced changes in their ART regimen and exposure to Isoniazid, while the majority were on Cotrimoxazole Prophylaxis. (Table 2).

Table 2 Disease- and ART drug-related factors of children living with HIV attending ART clinics in Gamo Zone, Ethiopia, 2022

Magnitude of peripheral neuropathy

In the current study, the magnitude of PN was 20.9% (31/148). Out of the participants who were symptomatic, 41.9% (13/31) were females and belonged to the older age group of 15–18 years. Symptomatic participants frequently reported sensory symptoms such as numbness (83.8%; 26/31), tingling sensation (77.4%; 24/31), reduced ankle reflexes (61.2%; 19/31), reduced sensation to light touch (70.9%; 22/31) and reduced pain sensation (51.6%; 16/31). (58.1%; 18/31) had symptoms that were limited to the fingers and toes. Additionally, when the participants were questioned about any functional symptoms from the screening tool, the majority stated that they did not encounter any challenges in performing their daily tasks. (Fig. 1).

Fig. 1

Magnitude of symptoms and signs of PN among children living with HIV

Factors associated with peripheral neuropathy among children

Bi-variable logistic regression was conducted to identify candidate variables with a p-value < 0.25. The identified variables age, sex, BMI for age, Height for age, Caretakers’ educational status, WHO clinical stage at enrollment, last exposure to Isoniazid, duration of HIV illness, recent Viral Load (copies/ml, current Opportunistic Infections, and Past TB treatment were entered to multivariable binary logistic regression to identify the possible association with peripheral neuropathy.

In the multivariable binary logistic regression analysis age, BMI for age, last exposure to Isoniazid, Duration of HIV illness, and past anti-TB treatment, were significantly associated factors with Peripheral neuropathy.

Children in the age category of 15–18 years were 1.88 times more likely to have peripheral neuropathy than those children in the age category of 10–14 (AOR = 1.88, 95%CI; 1.24–4.60). Participants with low BMI for age were 1.66 times more likely to develop peripheral neuropathy than participants with normal BMI for age (AOR = 1.66, 95%CI; 1.12–4.15). Children who were exposed to Isoniazid as either IPT or anti-TB treatment within one year were 2.31 times more likely to have peripheral neuropathy than those who were exposed to Isoniazid more than one year ago (AOR = 2.31, 95%CI; 1.12–8.53). Children who had a longer duration of HIV illness were 2.17 times more likely to have peripheral neuropathy than those who were diagnosed recently (AOR = 2.17, 95%CI; 1.54–4.64). Children with a history of past TB treatment were 2.11 times more likely to have peripheral neuropathy than those who had not had past TB treatment (AOR = 2.11, 95%CI; 1.08–7.48). (Table 3)

Table 3 Bivariable and multivariable logistic regression analysis on factors associated with peripheral neuropathy for children living with HIV attending ART clinic Gamo Zone, Ethiopia, 2022

Discussion

This study was conducted to assess the magnitude of peripheral neuropathy among children living with HIV attending ART service at health facilities in Gamo Zone, southern Ethiopia. The magnitude of peripheral neuropathy among children living with HIV was 20.9%. The finding of a 20.9% magnitude PN among children living with HIV in the current study is consistent with a study conducted in South Africa found a 24% prevalence.¹⁰ These findings suggest that PN is a common complication of HIV infection in children, particularly in resource-limited settings. Some studies have reported lower prevalence rates. For example, a study conducted in Tanzania found a PN prevalence of 14.1% and another study in Peru reported a 13.3% prevalence of children with HIV infection [12, 13]. This difference in prevalence rates may be due to differences in study populations, PN assessment methods, and ART regimens. The current study used the Ped m-TNS to assess PN. In contrast, other studies have used different tools, such as the Brief Peripheral Neuropathy Screen (BPNS) or the Clinical Neurotoxicity Scale (CNS). The use of different assessment tools may lead to variations in PN prevalence estimates.

In this study, children in the age category of 15–18 years were significantly associated with peripheral neuropathy. This finding is consistent with previous studies that have shown an increased risk of peripheral neuropathy with increasing age in individuals living with HIV. The study conducted in Tanzania and the USA found that older children with HIV were more likely to develop peripheral neuropathy than younger children [12, 14]. These findings suggest that age is an important factor in the development of peripheral neuropathy in individuals living with HIV. Given the rapidly aging HIV population due to successful therapy, the intersection of aging and increased risk of neuropathy portends ongoing challenges from this complication for HIV therapeutics.

In the current study under-nutrition in terms of low BMI for age is significantly associated with Peripheral neuropathy. Several studies revealed malnutrition could be one of the leading risk factors for PN among children living with HIV. A study conducted in Uganda reported that malnutrition was significantly associated with peripheral neuropathy in children living with HIV aged 5–12 years. The study found that children with severe malnutrition were at a higher risk of developing peripheral neuropathy compared to those with normal nutrition status [15]. Another study conducted in Peru reported similar findings, where malnutrition was found to be a significant risk factor for peripheral neuropathy in children living with HIV. The study found that children with severe acute malnutrition had a higher prevalence of peripheral neuropathy compared to those with mild or moderate malnutrition [13].

There was a significant association between participants who reported their last Isoniazid exposure within one year and PN. The statement that there is a relationship between Isoniazid exposure and peripheral neuropathy in children is supported by several studies. One study conducted in India found that prolonged exposure to Isoniazid was associated with an increased risk of peripheral neuropathy in children [16]. Another study conducted in Tunisia also found a similar association between Isoniazid exposure and peripheral neuropathy in children [8].

Patients with INH-induced neuropathy initially report tingling and numbness in their feet, which can migrate to their knees and develop in their hands and fingers in bilateral stocking and glove distribution. Other symptoms include myalgia, ataxia, a decrease in vibratory and position awareness, increased or diminished tendon reflexes, and, in later stages, muscle paralysis. Children remain asymptomatic during pyridoxine deficiency because tissue levels of pyridoxine are maintained by nutrition even when serum levels are deficient. Other side effects of INH therapy include encephalopathy, psychosis, optic atrophy, and pyridoxine-responsive anemia. Symptoms are reversible after a few weeks of discontinuing INH, but they take longer to resolve the longer they continue [17]. Isoniazid is frequently prescribed in Ethiopia, either for HIV- TB co-infection or as part of a treatment regimen of isoniazid preventive therapy (IPT) for 6 months in both children and adults. Isoniazid lowers the biologically active pyridoxinedoxine (Vitamin B6), which regenerates and feeds nerve cells. To prevent the occurrence of peripheral neuritis caused by Isoniazid, it is advised that patients taking Isoniazid should also take pyridoxine supplements [18]. In the current study none of the participants who received Isoniazid as part of their IPT or TB treatment received pyridoxine. The presence of neuropathy in this study could be attributed to the fact that pyridoxine supplementation was not carried out as indicated.

Longer duration of HIV illness was significantly associated with peripheral neuropathy. Children who had a longer duration of HIV illness were approximately 2 times more likely to develop peripheral neuropathy. This study is consistent with prior studies in Uganda, Tanzania, and Australia [3, 15, 19]. Other studies have also reported conflicting findings regarding the association between the duration of HIV illness and PN in individuals living with HIV. A study conducted in the USA found no significant difference in the prevalence of PN between individuals living with HIV with a longer duration of HIV illness and those with a shorter duration [20]. These conflicting findings may be due to differences in study populations, ART regimens, and methods of diagnosing PN. Further research is needed to better understand the relationship between the duration of HIV illness and PN.

Children having a history of past TB treatment were significantly associated with peripheral neuropathy. This finding is consistent with previous studies that have also found an association between TB treatment and peripheral neuropathy in individuals living with HIV. A study conducted in Ethiopia found that people living with HIV with a history of past TB treatment were more likely to have peripheral neuropathy than those who had not received TB treatment [21]. Similarly, two studies conducted in the USA found that individuals living with HIV with a history of TB treatment had a higher incidence of peripheral neuropathy during antiretroviral therapy compared to those with no TB treatment history [15, 22]. The mechanism underlying the association between TB treatment and peripheral neuropathy in individuals living with HIV is not fully understood. However, it has been suggested that TB treatment may cause nerve damage due to the toxic effects of anti-TB drugs, which can lead to the development of peripheral neuropathy in individuals living with HIV.

Some studies have found no association between TB treatment and peripheral neuropathy in individuals living with HIV. For example, a study done in South Africa found no significant difference in the prevalence of peripheral neuropathy between individuals living with HIV with and without a history of TB treatment in a cohort of individuals living with HIV receiving antiretroviral therapy [23]. The reasons for these conflicting findings are not entirely clear, but differences in study populations, TB treatment regimens, and methods of diagnosing peripheral neuropathy may contribute to the discrepancies. It is also possible that other factors, such as comorbidities or genetic predisposition, may play a role in the development of peripheral neuropathy in HIV-positive individuals living with HIV.

Limitation of the study

The study was cross-sectional and couldn’t establish a direct cause-and-effect relationship. The diagnosis of HIV-associated peripheral neuropathy relied solely on clinical observation, leading to a possible underestimation of its incidence. The Biothesiometer, which measures quantitative vibration perception thresholds, could have provided a more rigorous and precise assessment. Also, no baseline neuropathy screening was done before starting or changing ART, making it difficult to determine the cause of peripheral nerve damage. The other is the relatively small sample size, which was constrained by the limited number of eligible participants within the source population.

Conclusions

The study found that 20.9% of children living with HIV had peripheral neuropathy, with distal sensory loss, burning pain, and paresthesia being the most common clinical presentations. The risk factors included age group of 15–18 years, low BMI for age, isoniazid exposure, longer duration of HIV illness, and past TB treatment. Healthcare providers should screen children living with HIV for peripheral neuropathy, especially those who are in the age category of 15–18 years, have low BMI for age, longer duration of HIV illness, past TB treatment. Early screening and management of peripheral neuropathy can improve the health outcomes of children living with HIV. Health policymakers should prioritize the implementation of nutritional interventions in the management of peripheral neuropathy in children living with HIV. This can include the provision of nutrient-dense foods, vitamin and mineral supplements, and nutrition education to caregivers. Further longitudinal research needs to be conducted to obtain an in-depth understanding of the risk factors for peripheral neuropathy.