Report from the Durban WORLD AIDS CONFERENCE
Durban, South Africa
Monday July 10, 6:30 pm
reported by Jules Levin

Report 8

Pediatrics
Antiretroviral Treatment
Lipodystrophy
ABT-378 in Naive & Experienced Children


People are still talking about Mbeki's statement today and will probably continue talking about it for the remainder of the conference and beyond. There are many theories as to why he has not really budged his positions. One theory that rings true to me is that he has a plan in mind. It appears as though he may want to attract economic attention to South Africa but this is at the expense of people suffering with AIDS. I think history will not be kind to him. As I reported earlier, Merck and Bill Gates are donating $100 million to Botswana because Botswana is committed to taking action against AIDS. But since South Africa is not willing to commit they won't attract such assistance until Mbeki changes his position. After this report I'm off to the UAB meeting on Women & HIV and then dinner. Just had chips at 6:30pm. Weather is great, like Miami Beach in Winter. All the US researchers are here. Just left an oral session on resistance testing. You'll receive report on that.

Immunological reconstitution in HIV infected newborns treated with HAART
C. Cancrini Bambino Ges Hospital,Rome, Italy

Mother to newborn HIV-1 infection is a way of primary infection (PHI). Several studies indicated that during PHI, high perturbations in (TCR: T-cell repertoire) occur in CD8+ and CD4+ T lymphocytes  expressing distinct Vb-genes and that their persistence is related to distinct clinical progression. In other words during primary infection there are changes in the T-cells that make up the immune system that the authors say lead to clinical progresion.The objective of this study is to evaluate the effects of early triple combination therapy  (HAART) on the immune system development of HIV infected newborns.

Fresh blood samples from two HIV infected and two uninfected  newborns have been analysed and CDR3 fragment length analyses  were performed at different time points.

The two infected newborns were called N1 and  C2. Baseline viral load values were 624,600 (log 5.79) and 490,000  (log 4.71) copies/ml, respectively. In the first newborn, a marked  reduction of viral load value was observed within 4 weeks of  therapy and HIV-1 RNA copy number was undetectable (<200 copies/ml)  in the following year, and the number of CD4+T cells was constant.  In the second newborn, a reduction of HIV-RNA level was detected  at 4 weeks (80,000 cp/ml) and an undetectable level was reached  at 5 months of therapy with a good increase of CD4+T cells. At  baseline, CD4 TCR repertoire was normal in the first child while  was widely altered in the second one. However, the CD8 TCR distribution  was deeply altered in both children. After 12 months of therapy  the CD8 TCR-Vb patterns were completely normalised in the first  child and partially in the second. CD4 TCR distribution was highly conserved during the first year of therapy in one and improved in the second. Therefore, the authors concluded that early HAART given to HIV-1 infected newborns completely restores immunological parameters after 12 months.

Prevalence of morphologic and serum lipid changes in children and adolescents in use of antiretroviral therapy
N.P.N. Rubin} University of Rio de Janeiro, Laranjeiras - Rio de Janeiro, Brazil

The morphologic and metabolic changes associated  with antiretroviral therapy (ART) has been amply investigated  in adults. Nonetheless, the same data in children and adolescents  are very limited. This study investigated the prevalence of lipodistrophy  and serum lipid changes in children and adolescents in use of  ART and their relationship with predisposing factors.

66 HIV-infected patients  under 18 years of age in use of ART with or without a protease  inhibitor (PI) for at least 6 months were retrospectively analyzed. The patients were monitored  for changes in the distribution of corporal fat and serum levels  of cholesterol, triglicerides, HDL and LDL. The frequency of  body and serum lipid changes was compared with the following  parameters: whether a PI was included in the regimen, how long  the ART was used, age, time of active disease, and severity of  immunosuppression. Statistical analyses was carried out using  the chi-squared test and Fisher's exact test. About 8% in each arm had prior therapy experience.

Of the 66 patients analysed (38 males), 53 were children  and 13 adolescents (average age, 8 4.6; median, 8), 37  were in use of double NRTI therapy and 29 with triple therapy  consisting of 2 NRTIs and 1 PI, for periods which varied from  6 to 96 months in the NRTI arm and 6-192 months in the PI arm (mean, 17.7), and with  duration of the disease varying between 6 and 192 months (average,  57.2 42.9; median, 43).

In the NRTI arm 30 (81%) had AZT experience, 33 (89%) had 3TC experience, 8 (21%) d4T, and 3 (8%) ddI. In the PI arm, 8 (27%) had AZT experience, 27 (93%) 3TC, 21 (72%) d4T, and 2 (7%) ddI. Prior PI experience in the PI arm was 11 (38%) ritonavir, 6 (21%) nelfinavir, and 12 (41%) indinavir.

PREVALENCE OF ABNORMAL FAT REDISTRIBUTION AND SERUM LIPID CHANGES

In the PI arm, 17% were reported to experience abnormal fat redistribution, while 2.7% reportedly experienced it in the NRTI arm (p=0.04). The author was questioned about how she measured fat changes. She said she looked at the waist and arms and legs. But she was questioned on her method of evaluation and I'm unsure what she said in response.Serum lipid changes were seen in 54% in the NRTI arm and 48% in the PI arm (p = 0.64).

Cholesterol increased 70% in the PI arm and 20% in the NRTI arm. Triglycerides increased 84% in the PI arm and 20% in the NRTI arm. And she said these differences were statistically significant.

The average levels of the serum lipids (mg/dl) were: cholesterol, 227 23; triglycerides, 243 92; HDL, 31 7; and LDL, 147 14. The author reported that she felt protease inhibitors play a role in lipodystrophy (body changes & lipid changes) but cautioned that many factors may also be at play including--cytokine dysfunction, HIV, immune system changes. But when questioned from the audience she said the causes for lipodystrophy remain "unclear".

Changes in serum lipids were seen in 26(49%) children and  8 (61%) adolescents (p = 0.41); in 9 (39%) patients using the study  regime for 12 months or less and in 25 (58%) using the regime  for more than 12 months (p = 0.14); in 10 (34%) patients with  symptoms for 3 years or less and in 24 (64%) patients with symptoms  for more than 3 years (p = 0.01); and in 14 (50%) patients with  severe immunossuppression and 20 (52%) with moderate immunossuppression  (p = 0.83).

The author concluded that patients with a  longer disease duration seem to have a larger risk of developing  serum lipid changes, therefore some affect of HIV may be at play. In the PI arm, patients experienced increased cholesterol and tirglycerides , and a decrease in HDL levels, whereas in the group not treated with a PI, the main change was a decrease in the levels of HDL.

ABT-378 in HIV-Infected Children

This was a study of safety, tolerability, and anitiviral activity of ABT-378 (liquid formulation) in children. Age was 3 months to 12 years, and there was no prior NNRTI experience. One hundred treatment nave and experienced children were randomized to two dose levels of ABT-378 (Kaletra) (230/57.5 mg/m2 Q12H or 300/75 mg/m2 Q12H). Kids were defined as nave if they had received <3 months of prior therapy or <1 week of treatment with 3TC. Children were considered experienced if they received >3 months prior therapy or >1 week treatment with 3TC. In addition to ABT-378, nave kids received d4T+3TC and experienced kids received treatment with nevirapine and 1 or 2 NRTIs of the investigator's choice. At week 3 PK was looked at and kids switched to higher dose.

At baseline, viral load was about 50,000 (4.7 log), CD4s were 920 in nave arm and 773 in experienced, age was 4.8 years in nave and 5.7 in experienced, 2.3 years time since diagnosis in nave and 3.8 in experienced.

PRIOR TREATMENT EXPERIENCE

In the NRTI experienced kids (n=32), 13% had experience with ddI, 88% with 3TC, 94% with AZT, 6% d4T, and 19% with abacavir. In PI experienced (n=24), 46% had experience with ddI, 88% with 3TC, 92% with AZT, 38% with d4T, 4% ddC, and 38% abacavir. Their PI experience was--8% indinavir, 88% ritonavir, 21% saquinavir, 25% nelfinavir, and 29% (n=7) with multiple protease inhibitors. Baseline resistance was collected and is being analyzed with regards to response.

One person discontinued prior to week 24 due to symptoms of Burkitt's lymphoma and complications of its treatment.

VIRAL LOAD SUPPRESSION AT WEEK 24 (ITT)

--In the nave group (n=44) 82% had <400 copies/ml

--NRTI experienced (n=32)-- 72% had <400 copies/ml

--PI experienced (n=24)-- 58% had <400 copies/ml

--CD4s increased about 330 in both groups

ADVERSE EVENTS (at least moderate severity and probably, possibly due to ABT-378)
N=1 each for allergic reaction, fever, viral infection, constipation, hepatomegy, vomiting, dry skin, taste perversion; 2 rash.

GRADE 3 or 4 LAB ABNORMALITIES

The author said 3 had elevated amylase at baseline, and 1 had elevated cholesterol at baseline. She also said that for those who did not go to undetectable viral load they had a significant reduction in viral load and increased CD4 and clinical improvement. She said the taste of the liquid was not good but kids got used to it and the taste could be masked. She concluded ABT-378 was tolerable