Lipoatrophy common in children receiving d4T in South Africa

Exposure to d4T (stavudine) among young children in sub-Saharan Africa remains the greatest risk factor for lipodystrophy syndrome (that includes lipoatrophy and lipohypertrophy) for a significant proportion of children, urgently highlighting the need for early detection of abnormal body fat changes, researchers reported at a poster session at the 19th Conference on Retroviruses and Opportunistic Infections in Seattle this week.

Treatment with d4T is a well-established risk factor for the loss of subcutaneous body fat (lipoatrophy) in adults after starting antiretroviral therapy. Lipoatrophy is much less frequent in people who receive tenofovir-based treatment and for this reason the World Health Organization has urged national treatment programmes to drop d4T and move to tenofovir- or AZT-based treatment wherever affordable.

Few data exist on the extent of abnormal body fat changes among HIV-positive children in sub-Saharan Africa where d4T is in common use. Among the estimated 2.3 million HIV-positive children, from 2008 to 2009, approximately 88% were on an ART regimen containing d4T. 

Dr Steve Innes of Tygerberg Children’s Hospital, Cape Town, presented findings from a cross-sectional study of the first 100 of 300 children aged 3 to 12 on ART along with 34 controls attending a family HIV clinic. Dr Innes and colleagues looked at the extent, accurate diagnosis and risk factors for lipoatrophy in pre-pubertal African children.

An expert HIV paediatrician visually graded for lipoatrophy. Anthropometric measurements of trunk and limb skinfold thickness and circumference measurements were done. Dual-energy X-ray absorptiometry (DEXA) scans were performed on 42 patients and the 34 controls. Length of time on ART was noted.

Over one-third (36%, CI: 27%-45%) of the children had clinical lipoatrophy.

Fat distribution according to DEXA and anthropometrics was compared among children who were HIV-negative, HIV-positive with lipoatrophy and HIV-positive without lipoatrophy adjusting for age and sex. These objective measures confirmed the clinical assessment of visually obvious lipoatrophy.

Mean adjusted DEXA total extremity fat was 2.7 kg in HIV-negative children, 1.7 kg in HIV-positive children with lipoatrophy and 2.3 kg in HIV-positive children without lipoatrophy, a statistically significant difference (p = 0.0001).

Mean adjusted anthropometrics showed biceps skinfold thickness was 5.5, 4.2 and 5.3 in HIV-negative children, HIV-positive children with lipoatrophy and HIV-positive children without lipoatrophy, respectively (p<0.0001).

Children who were graded as having lipoatrophy were no sicker and did not start ART at a different time from those without lipoatrophy.

The greatest risk factor for clinical lipoatrophy, controlling for age, sex and CD4 percentage was the cumulative length of time on d4T (p = 0.0008). The odds ratio nearly doubled for each additional year of accumulated d4T exposure (OR = 1.9, 95% CI: 1.3-2.9, p = 0.002).

Dr Innes concluded that these findings show that diagnosis by visual grading in resource-limited settings where precise anthropometry and DEXA are routinely not available is a reliable alternative.

in his presentation, he stressed the stigmatising nature of lipoatrophy, uniquely relevant to sub-Saharan Africa. The effect can be life-threatening since community acceptance is critical to accessing communally-held resources including healthcare.

Stephanie Shiaul, on behalf of the NEVEREST team, presented findings comparing the metabolic profiles and fat distribution of HIV-positive South African children with and without clinical lipodystrophy (LD) who began ART before the age of two.

One hundred and fifty-six perinatally HIV-infected children who had achieved viral suppression on lopinavir/ritonavir (LPV/r) and had been randomised to remain on LPV/r or switched to nevirapine with d4T and 3TC (lamivudine) as a backbone were evaluated for visible signs of lipodystrophy.

Clinicians assessed the children. The children were classified as follows: lipodystrophy, possible lipodystrophy or no lipodystrophy if two or more, one or none, respectively, of the following were present:

• Lipoatrophy: sunken cheeks, temporal wasting, skinny limbs, wasting of buttocks.
• Lipohypertrophy: increased abdominal girth, dorsal cervical or breast enlargement.

Anthropometrics, bio-impedance analysis, viral load, CD4, fasting total cholesterol, HDL, LDL and triglycerides were measured. Estimates of measures of regional fat including trunk-extremity skinfold ratios were done. The outcomes were then compared with the clinician-defined lipodystrophy groups.

The mean age of the children was 5.1 ±0.8 years with ART started at a mean age of 10.7 ±6.0 months. Thirteen (8.4%) were classified as lipodystrophy cases; 18 (11.5%) as possible lipodystrophy; and 125 (80.1%) as no lipodystrophy. 

Among the three groups no differences were seen in age, gender, age when starting ART, time on ART, weight, height, body mass index or proportion with a viral load under 50 copies/ml.

The proportion of children with lipodystrophy who remained on LPV/r-based ART or switched to nevirapine-based ART were similar, 7.1% compared to 9.9%, p = 0.51, respectively.

Children with lipodystrophy had less body fat compared to children without lipodystrophy according to mean cumulative skinfold thickness (34.1 ±5.7 compared to 42.0 ±11.1 mm, p = 0.016).

Adjusting for age, sex and total fat, a similar pattern of differences in arm, trunk and leg fat between those with and without lipodystrophy was seen.

The proportion of children with triglycerides greater than 150 mg/dL was significantly higher for children with lipodystrophy and possible LD than in those without lipodystrophy (23.1, 22.2 and 4.8%, respectively).

Dr Shiau concluded that a substantial proportion of children who start d4T-containing ART regimens before two years of age have clinical signs of lipodystrophy.

As with Dr Innes’ findings, use of objective anthropometry confirmed the clinical assessment.

In many resource-poor settings, d4T is part of a fixed-dose combination. Dr Innes stressed that little is known about the long-term effects of d4T on children. A lot of work remains to be done in learning how to care for these children going forward, he added.

Financial constraints and limited alternatives mean that it is likely d4T will remain part of first-line ART in resource-poor settings for a considerable time to come.

Questions from the audience highlighted many unanswered concerns including knowing the best time to switch. While it was suggested that lipodystrophy was irreversible, some participants questioned whether this was in fact true. An ongoing trial looking at switching from d4T to abacavir may be able to shed light on the reversibility of its effects on body fat changes. Other participants raised the issue of a dose effect on toxicity; a lower dose of d4T may reduce the metabolic consequences and be effective.

Both studies found a visual grading scale is reliable and easy to use to catch changes in body fat at the earliest stage. This is critical given the high prevalence of lipodystrophy in young children and its stigmatising effects in sub-Saharan Africa.

Innes S et al. High prevalence of objectively verified clinical lipoatrophy in pre-pubertal children is associated with stavudine-the clock is ticking: sub-Saharan Africa. 19th Conference on Retroviruses and Opportunistic Infections, Seattle, poster 972, 2012. The abstract is available on the official conference website.

Shiaul S et al. Lipodstrophy syndrome in young HIV+ children who initiate ART before 2 years of age: South Africa. 19th Conference on Retroviruses and Opportunistic Infections, Seattle, poster 973, 2012. The abstract is available on the official conference website.

A webcast of the session, Complications of HIV and ART in Children and Adolescents, is available through the official conference website.