Peripheral neuropathy in South African children highlights limited ARV choices

Peripheral neuropathy was identified in one-in-four children on HIV treatment in rural Mopani District, one of the poorest and least well-resourced areas in South Africa, Dr Remco Peters reported today at the 19^th International AIDS Conference (AIDS 2012) in Washington, DC.

The findings underline the importance of improving paediatric antiretroviral formulations suitable for use in sub-Saharan Africa.

In this cross-sectional study of 182 children, aged from 5 to 15, 86% were receiving an antiretroviral (ART) regimen that included d4T (stavudine, Zerit).

Among HIV-infected adults, peripheral neuropathy is common and well recognised. It affects between 30 and 60% of people with HIV and may be related to HIV infection and/or the drugs used to treat HIV. Few studies have been able to distinguish between peripheral neuropathy as a result of HIV itself and neuropathy as a side-effect of ART. Other contributing factors include vitamin and mineral deficiencies and autoimmune effects.

Peripheral nerves are responsible for sensation-pain, pressure, heat sensation (sensory nerves) movement (motor nerves) and automatic bodily functions such as breathing, heartbeat, sweating and emptying of the stomach (autonomic nerves). Damage to these nerves is called neuropathy.

In most people with HIV, nerve damage usually starts in the hands or feet (hence the term 'peripheral' neuropathy), affecting both sides of the body and involving multiple nerves. It can range from mild numbness or pain to debilitating pain. Other symptoms include increased sensitivity to touch, diminished reflexes and weakness. It can severely affect quality of life.

Stavudine (d4T) and didanosine (ddI, Videx, Videx EC) are two of the anti-HIV drugs known as dideoxynucleoside reverse transcriptase inhibitors or ‘d-drugs’, which can cause peripheral neuropathy.

The World Health Organization (WHO), concerned about the side effects of d4T (principally abnormal body fat loss, or lipoatrophy, and peripheral neuropathy in adults) has urged national treatment programmes – wherever affordable – to drop d4T and move to tenofovir- (Viread) or AZT-based treatment regimens in adults.

The findings of the study presented today are likely to reinforce calls for access to paediatric formulations of abacavir (Ziagen) in settings where d4T is the only current alternative. Abacavir is already available for paediatric use in southern Africa, and is recommended by the World Health Organization as a component of first-line paediatric treatment, but remains substantially more expensive than stavudine.

A powder version of tenofovir suitable for use in children aged two to five years is licensed for use in the United States, but safety studies have not been carried out in children in sub-Saharan Africa to evaluate any potential risk of kidney toxicity or decreased bone mineral density. The South African HIV Clinicians Society has suggested that tenofovir should be used with caution in young children until further safety data are available.

In June of this year, WHO issued guidance on the best use of tenofovir in adolescents and children over two years of age The recommended dose is 8 mg/kg body weight (up to a maximum of 300 mg), administered once daily using either an oral powder formulation or low-strength tablets. Caution is needed nonetheless since tenofovir in combination with ddI increases the risk of ddI-related toxicities, including peripheral neuropathy.

Peripheral neuropathy is diagnosed based on symptoms and is more difficult to diagnose in children. Few tools exist for clinical screening for peripheral neuropathy in children. Children may find it difficult to describe their symptoms.

Few data exist on the extent, symptoms or causes of peripheral neuropathy among HIV-positive children in sub-Saharan Africa, where d4T is in common use. Among the estimated 2.3 million HIV-positive children, between 2008 and 2009, approximately 90% were on an ART regimen containing d4T.  

The researchers chose to use neuropathy symptom score (NSS) and neuropathy disability score (NDS) to screen for peripheral neuropathy in this cohort of children.

NSS, a subjective assessment tool, includes a series of questions about location and severity of  pain and pain relief (for example, does sitting help?) in the feet and legs. Each response is given a score of 0, 1 or 2. Total scores of 3, 5 and 7 indicate mild, moderate and severe neuropathy, respectively.

The NDS, an objective assessment tool, looks at ankle reflex (0, 1 or 2), vibration perception (0 or 1), pin-prick perception (0 or 1) and temperature perception (0 or 1) and scored. A reflex hammer, cotton swabs, a toothpick and cold water are all that is needed to carry out the test.

An NSS score equal to or above 3 or an NDS score equal to or above 2 was used as a definitive diagnosis of peripheral neuropathy. Dr Remco noted these were conservative cut-off points.

In total, 96% (174/182) of this cohort of children, all collecting ART from nurse-managed treatment programmes, completed screening for peripheral neuropathy. This included a questionnaire, physical exam, NSS and NDS scores.

The median age was 9.2 years with median time on ART of two years (2 months to 6.4 years).

Forty-nine children (27%) reported symptoms related to neuropathy, while 25 children (14%) met the NDS criteria. Overall, 43 children (25%) were identified as having peripheral neuropathy.  Examples of children's descriptions of symptoms included:

• “My feet are burning, I must take off my shoes in class otherwise I can’t concentrate.”

• “I can’t sleep at night because of the tingling in my feet; I’m tired during the day.” 

Dr Remco noted that, while the cause of peripheral neuropathy was not addressed in depth, being on ART for a longer period of time (p=0.06) was a major contributor.

Dr Remco concluded that, in this region, peripheral neuropathy among children is common and often goes undiagnosed. Simple and easy to use, the NSS and NDS are valuable tools for assessing peripheral neuropathy in a resource-poor and skills-limited setting.

The most important lesson learned is “quite simply, to talk to the child”, he added. In these settings, “We [healthcare workers] do not talk to the children, we will talk to the mother or caregiver about the child but never directly to the child.”

van Ramshorst R et al. Clinical screening shows high prevalence of peripheral neuropathy in children taking antiretroviral therapy in rural South Africa. 19^th International Conference on AIDS, abstract MOAB0205, Washington, DC, July 2012.

View the abstract on the conference website.

View the webcast of the session on the conference website.