This is the first data from sub-Saharan Africa to show the severity and extent of antiretroviral-related lipoatrophy in children. Visually obvious lipoatrophy was present in a third of pre-pubertal children on ART. Children with visually obvious lipoatrophy had 25-40% less extremity fat (depending on the choice of measurement) than HIV-infected children without lipoatrophy. Children with lipoatrophy were not sicker and did not start ART at a different age, compared to those without lipoatrophy. Since cumulative time on standard dose stavudine is the greatest risk factor for lipoatrophy, it is not surprising that older children, who had amassed greater stavudine exposure, had more lipoatrophy. Other potential confounding effects associated with the difference in age were adjusted for in the multivariate model.
Although DXA and anthropometry may be more precise measures of subcutaneous fat amount and distribution, a visual grading scale was chosen as the primary outcome measure in this study because the greatest danger of lipoatrophy in sub-Saharan Africa stems from stigmatization. Subtle changes in fat distribution that are not visually obvious are less relevant since they are unlikely to result in stigmatization.
As there is evidence of a genetic determinant in lipoatrophy [13
], it is important to study lipoatrophy specifically in sub-Saharan African populations. Our data suggest that the prevalence of visually obvious lipoatrophy in pre-pubertal South African children on ART is higher than the prevalence among most non-African cohorts (typically 10 to 20%) [9
]. Earlier studies from the developed world have included immigrant children from sub-Saharan Africa living in Paris [14
], London [16
] and Brussels [15
], and found a lipoatrophy prevalence of 11%, 8% and 20% respectively. In the largest and most comprehensive study to date, Alam et al. [17
] found a 28% prevalence in a cross-sectional study of 426 European children, including 85 pubertal and 154 post-pubertal children and 107 black children. The authors of that study noted that their prevalence was significantly higher than previous pediatric studies, in line with our data. Since survival rates are high in medication-adherent HIV-infected children, and established lipoatrophy changes are largely irreversible, prevalence can be expected to increase progressively if incidence remains constant. Alam et al. found that Caucasian rather than African ethnicity was a risk factor for lipoatrophy. However, none of our recruits were Caucasian and our pre-pubertal South African group had a higher prevalence than Alam’s cohort. This is most likely due to higher rates of stavudine exposure in our context. The magnitude of this difference suggests that data from immigrant African populations in Europe cannot be extrapolated to populations living in sub-Saharan Africa and emphasizes how crucial it is to study sub-Saharan populations directly, as >90% of HIV-infected children live in these regions.
Ten percent of the cohort reported by Alam et al. was currently exposed to stavudine [17
], compared to 62% of ours. While Alam et al. found an association between lipoatrophy and current stavudine exposure, our results go one step further to show that the risk of lipoatrophy increases progressively as exposure to stavudine accumulates. This finding is in line with that of the Asian cohort reported by Aurpibul et al., which found an increasing prevalence of fat distribution abnormalities as cumulative exposure to ART increased [11
]. This is significant since Asian cohorts have similar conditions to sub-Saharan Africa in that malnutrition is common, access to ART for children is incomplete, and stavudine has been the most widely used first-line antiretroviral agent.
The PACT 1045 study [18
] compared morphologic changes using DXA in HIV-positive children compared to HIV-negative matched controls in a cross-sectional study. DXA-measured total body and limb fat were lower in the HIV-positive subjects than in the HIV-negative group in models adjusted for race, disease stage, weight, height and Tanner stage. Among HIV-infected subjects, there was no difference in limb fat between subjects who used non-nucleoside reverse transcriptase inhibitors versus protease inhibitors. Duration and use of nucleoside reverse transcriptase inhibitors (including stavudine) were not evaluated in that study.
Objective anthropometric and DXA measurements confirmed the clinical assessment of visually obvious lipoatrophy. Thus, diagnosis of lipoatrophy in African children by skilled visual assessment is reliable and, whilst it requires specific training and experience, no additional investigations are needed in a developing-country context. In our context, specific training to recognize lipoatrophy in children typically includes didactic training followed by supervised practice in a clinic setting over a period of time until competence is reached to the satisfaction of the trainer. However, basic competence might be gained through review of an array of photographs of mild to moderate lipoatrophy at varying ages, combined with diligent vigilance during clinical practice. The authors have not studied the adequacy of photograph-based training.
The prevalence of visually obvious lipoatrophy in pre-pubertal South African children on ART is higher than previously anticipated, affecting a third of children on ART. This is most likely due to more extensive use of stavudine than elsewhere. Whilst ART is life-saving for HIV-infected children, surveillance and early diagnosis of lipoatrophy with appropriate drug-switches is critical. The use of agents associated with potentially stigmatizing face and limb changes is undesirable. The antiretroviral agent most commonly associated with lipoatrophy in adults is stavudine [19
] and our findings substantiate this in the pre-pubertal pediatric South African population. The 2010 World Health Organization (WHO) antiretroviral guidelines advise that stavudine should be phased out where possible. However, stavudine remains within the nationally recommended pediatric first-line ART guidelines for numerous developing countries. In South Africa, stavudine was the first choice nucleoside reverse transcriptase inhibitor for children, together with lamivudine, from the beginning of the ART access program in 2004 until 2010, when it was replaced with abacavir. Current South African guidelines state that children taking stavudine should continue unless side-effects develop. Thus the majority of children treated for HIV in South Africa remain on stavudine. The effect of stavudine in causing lipoatrophy appears to be strongly dose-related [20
]. The current standard pediatric dose of stavudine was determined by extrapolation from the pharmacokinetic parameters of the adult dose of 40
mg twice daily using data from pediatric pharmacokinetic studies [24
]. Those studies showed that an oral dose of 1
mg/kg/dose twice daily in children under 30
kg results in plasma exposure similar to that of an adult over 60
kg taking 40
mg twice daily; and that an oral dose of 0.5
mg/kg/dose twice daily in children results in plasma exposure similar to that of an adult over 60
kg taking 20
mg twice daily. In 2007 an influential review by Hill et al. of evidence accumulated over the previous 15 years suggested that stavudine given at the dose of 20 or 30
mg twice daily leads to a significantly lower rate of lipoatrophy and of other mitochondrial adverse effects while maintaining excellent antiviral efficacy [20
]. In response, the World Health Organization advised that the recommended adult dose be lowered from 40 to 30
mg BD [26
]. The children’s dose, however, has not yet been reduced. Consequently children on stavudine continue to be exposed to a disproportionately high dose, which may result in more rapid accumulation of metabolic adverse effects than adults on the reduced dose.
Lipoatrophy was previously thought to be uncommon in children on stavudine. For that reason, the global transition away from stavudine-based regimens has focused on adult services, while children on stavudine-based regimens have not received equal attention. Stavudine remains the most commonly used pediatric antiretroviral in sub-Saharan Africa. The Clinton Health Access Initiative and UNITAID have worked since 2002 to improve antiretroviral drug supply chains for adult formulations in sub-Saharan Africa by facilitating procurement and providing funding for purchases where necessary. Similar efforts are critical to the successful transition away from stavudine-based regimens for children.
Our study has the following limitations: we selected subjects for enrollment based on meeting eligibility requirements and having a routine clinic appointment during the study-screening period. This could represent a biased subset of all available subjects in our clinic population, but there is no reason to think that temporal factors (when a subject had a clinic visit) would be related to the study outcome of lipoatrophy. The relatively high rate of drop-out from study screening to the actual study visit could also bias the sample, but basic demographics were not different and logistic difficulties, due to extreme poverty, often interfere with clinic attendance; patients’ arrival for appointments is typically erratic. Considering these obstacles, a sample size of 100 children is a significant achievement. The subsets of recruits exposed to zidovudine and other nucleoside reverse transcriptase inhibitors were small, and did not allow comment on their relationship to lipoatrophy. The two clinicians who performed the visual assessment could not be blinded to the children’s ART status, which may have biased their assessment. However, since the children were well-known, the clinicians had a longitudinal perspective on which to base their assessment. DXA was requested for all recruits; however, as DXA is a rare commodity in the developing world, DXA was not always available. The possibility of selection bias in the DXA substudy cannot be excluded.
As with the cohort reported by Alam et al., we are collecting longitudinal data on our cohort, which will allow calculation of incidence and will document the degree and rate of regression after antiretroviral switching.