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 naÔve 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 naÔve 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, naÔve 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 naÔve arm
and 773 in experienced, age was 4.8 years in naÔve and 5.7 in experienced, 2.3
years time since diagnosis in naÔve 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 naÔve 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