Treating children in resource-limited settings

Polly Clayden, HIV I-Base

Several posters and a number of oral presentations presented data showing that HIV-positive children in resource limited settings:

can be treated and respond to treatment well and can achieve similar results to children in resource rich settings,
usually initiate treatment at a later disease stage than those in resource rich settings, and
are still lagging behind adults with access to antiretrovirals.

KIDS-ART-LINC

The KIDS-ART-LINC cohort collaboration reported 12 months survival data from 2,142 children with evaluable records, from eight clinical centres in sub-Saharan Africa. [1]

In this cohort, at 12 months from initiation of antiretroviral therapy, the majority of the children were >/= 5 years old, n=1,147 (53.5%). Of the younger children 194 (9.1%), 447 (20.9%), 354 (16.5%) were >12, 12 to 35 and 35 to 59 months respectively. 1,238 (57.8%) children received an NNRTI-based regimen and 792 (37.0%) received a PI-based regimen. 94 (4.4%) children died and 261 (12.2%) were lost to follow-up.

The investigators found the cumulative mortality risk was 3.1% at 3 months, 4.0% at 6 month, 4.5% at 9 months and 4.9% at 12 months. In an analysis by age group, young infants initiating treatment had a 16.8% cumulative mortality risk, which reduced to 4.3%, 4.0% and 1.8% in age groups >/=5years, 12 to 35 months and 36 to 59 months respectively. They also found that severe immunodeficiency and severe anaemia when starting treatment was associated with risk of death.

In multivariate analysis, factors associated with risk of death were: younger age group (<12 months, HR, 1; 12 to 35 months HR, 0.3 (95% CI, 0.1 to 0.7), 36 to 59 months HR, 0.2 (95% CI, 0.0 to 0.6), >/= 5 years, HR, 0.5 (95% CI, 0.2 to 1.1); severe immunodeficiency HR, 3.3 (95% CI, 1.6 to 6.7), and severe anaemia HR, 3.1 (95% CI, 1.6 to 5.8). There was no difference in risk of death in children initiating treatment with an NNRTI or PI regimen.

Overall, the researchers found that treatment was mainly initiated in advanced stage disease. Mortality was limited in the 12 months after ART initiation, but these estimates do not take into account children lost to follow up. They wrote: These data emphasise the need for early diagnosis of HIV-infection. The few infants starting ART now are likely to be a biased sample at high risk. The early institution of care and treatment plans for children could greatly improve the paediatric survival patterns in sub-Saharan Africa.

Response to treatment at MTCT-Plus sites

Carter and colleagues compared response in terms of CD4 percentage among five age groups of children initiating therapy within the MTCT-Plus programme in nine countries and evaluated factors associated with immune response. [2]

303 children from this cohort were evaluated. The median age at initiation was 19 months (range: 2 months to 11 years) and the children fell into the following five age groups: 2 to 6 months, n = 64, 7 to 11 months, n= 53, 12 to 35 months, n= 82, 36 to 59 months, n= 43, and >/=5 years n= 61.

At initiation of therapy, the median CD4 percentage was 13%; and 27% had CDC clinical stage C disease. Initial regimens included d4T/3TC or AZT/3TC plus an NNRTI) (84%), a PI (12%) or a third NRTI (4%).

Of 26 deaths, occurring over 354 person-years, 12 (46%) occurred less than 6 months from ART initiation.

In a multivariate analysis of data from 229 children with baseline and one or more follow-up CD4 percentage, overall, CD4 percentage increased after starting ART: the mean 6-month change in CD4 percentage from baseline by age group was 9.8% (children less than <6 months), 13.3% (7 to 11 months), 13.8% (12 to 35 months), 11.8% (36 to 59 months), and 11.6% (>/=5 years). They found age group (p<0.05), baseline CD4 percentage (p<0.01), and time on ART (p<0.001) were significantly associated with an increase in CD4 percentage. Within all age groups, except for <6 months, baseline values were significantly related to CD4 percentage change over time (p<0.05).

The investigators wrote: Children initiating ART at MTCT-Plus sites demonstrated a robust immune response to treatment including those <6 months of age. However, unlike in older children, baseline CD4 percentage was not a useful predictor of immune response in this age group.

Predictors of virological failure from Uganda

A Ugandan study of 250 children and 526 adults evaluated predictors of virological failure and documented genotypic mutations in a sub-set of patients with virological failure after 12 months on ART. [3]

The investigators were unable to assess outcomes for 14% of adults (63 died, 9 withdrew) and 11% of children (12 died, 16 withdrew).

They reported that in this cohort children were almost twice as likely to have virological failure compared to adults (26% vs 14%, p=0.0001).

In multivariate analysis, for adults in this cohort, independent predictor of virological failure at 12 months was initiation of treatment with d4T/3TC/NVP vs AZT/3TC/EFV, OR, 2.59 (95% CI, 1.20 to 5.59), p=0.02.

In children, independent predictors of virological failure included male gender, OR 2.44, (95% CI, 1.20 to 4.93, p=0.01); initiation of treatment with d4T/3TC/NVP vs AZT/3TC/EFV, OR 2.46 (95% CI, 1.23 to 4.90, p=0.01) and having a baseline CD4 percentage <5%, OR 2.69 (95% CI, 1.28 to 5.63, p=0.009).

Data were available for 8/120 patients with virological failure (58 children and 62 adults). All 8 patients had NNRTI-associated mutations (5 with K103N and MI84V; and 2 patients had TAMs including T215Y.

The investigators wrote: These data indicate that nearly all patients with viral failure at 6 or more months after starting these common ART regimens will have NNRTI and 3TC-resistant virus.

Early outcomes from five Baylor College of Medicine centres

In an oral presentation Mark Kline from the Baylor International Pediatric AIDS Initiative (BIPAI) presented data from their database and medical records for all children who, had received care from any of the programmes and centres in Africa. [4]

Dr Kline reported that to January 2007 the five BIPAI centres in Africa had 11,926 children in care, 5151 of whom were receiving HAART. The childrens mean age at initiation of treatment in the five centres ranged from 5.1 to 7.8 years. Between 50 and 92% of treated children had WHO stage 3 or 4 HIV disease at initiation and 47 to 77% of children were in CDC immunologic category 3.

The median CD4 percentage for children receiving HAART in the Botswana centre increased from 15% at baseline to 27%, 30%, and 32% at 6, 12, and 36 months, respectively. In Uganda, the median CD4 percentage increased from 8% to 18%, 23% and 26% at 6, 12, and 24 months, respectively. In Botswana, viral load was <400 copies/mL in 79%, 81%, and 71% of children at 6, 12, and 36 months, respectively. At the same centre, the annual pediatric mortality rate declined from 4.7% in 2003 to 2.1%, 1.1%, and 0.3% in 2004, 2005, and 2006, respectively. Approximately 90% of children followed for 2 years or more were alive and on treatment; about 10% had switched to second or third line HAART.

The investigators concluded: State-of-the-art HIV/AIDS care and treatment can be administered to large numbers of children in resource-poor African settings with rates of success comparable to those observed in the United States. And Pilot programmes must be scaled up quickly to serve about 800,000 children in urgent need of HIV care and treatment.

References:

All references are to the Programme and Abstracts of the 14th Conference on Retroviruses and Opportunistic Infections, 25-28 February 2007, Los Angeles.

Arrivé E, Marquis B, Tumwesiye N, et al. Response to ART in children in sub-Saharan Africa: A pooled analysis of clinical databases, the KIDS-ART-LINC Collaboration. 14th CROI. Abstract 727.
Carter R, Katyal M, Austin J, et al. Age and CD4 percentage at ART initiation: relationship to CD4 response over time among children enrolled in MTCT-Plus initiative sites. 14th CROI. Abstract 730.
Kamya MR, Mayanja-Kizza H, Kambugu A, et al. Predictors of long-term viral failure among Ugandan children and adults treated with ART and monitored using clinical and immunologic criteria. 14th CROI. Abstract 732.
Kline M, Anabwani G, Kekitiinwa A, et al. Catalyzing the Care and Treatment of HIV-infected Children in Sub-Saharan Africa: Early Outcomes from 5 Baylor College of Medicine Centers. 14th CRO. Abstract 79.