Anti-HIV Drug Regimens and Treatment-Switching Guidelines in HIV Infected Children

Antiretroviral therapy in children aims to prolong clinical and immunologic health.
Currently, there are no data defining a particular highly active antiretroviral therapy
(HAART) strategy as the optimal first-line therapy for children. This study evaluated the
long-term efficacy of two HAART regimens used as initial therapy: 1) two nucleoside reverse
transcriptase inhibitors (NRTIs) plus a protease inhibitor (PI), and 2) two NRTIs plus a
nonnucleoside reverse transcriptase inhibitor (NNRTI). It also evaluated different strategies
for switching therapy when the initial regimen fails. The long-term nature of this study
should clarify whether early switching of therapy improves immunologic and virologic
outcomes, or results in a more rapid exhaustion of treatment options. The study was conducted
in the United States and in Europe.

Participants in this study had a CD4 cell count and viral load test during a screening visit.
Participants had an entry visit that included blood and urine tests. Participants were then
randomly assigned to one of four groups: Groups PI/1K and PI/30K received two NRTIs plus a
PI; Groups NNRTI/1K and NNRTI/30K received two NRTIs plus an NNRTI. The medications allowed
in the study were: abacavir, didanosine, emtricitabine, emtricitabine/tenofovir disoproxil
fumarate, lamivudine, lamivudine/zidovudine, stavudine, tenofovir disoproxil fumarate,
zalcitabine, and zidovudine (NRTIs); efavirenz and nevirapine (NNRTIs);
efavirenz/emtricitabine/tenofovir disoproxil fumurate (NNRTI/NRTI); and
amprenavir,atazanavir, darunavir, fosamprenavir calcium, indinavir, lopinavir/ritonavir,
nelfinavir, saquinavir, ritonavir, and tipranavir (PIs). Note: Per the 06/28/05 amendment of
this trial, emtricitabine, emtricitabine/tenofovir disoproxil fumarate, and tenofovir
dioproxil fumarate were added to the list of medications that could be included in a
participant's treatment regimen.

For participants whose initial regimen failed, or who experienced clinical disease
progression (indicated by the development of a new CDC Category C diagnosis) or other
clinical disease progression at or after Week 24 of first-line therapy, second-line therapy
was strongly encouraged. (However, if poor adherence was suspected as a possible reason for
an increase in HIV viral load, the site and the clinician were to try to improve patient
adherence and obtain additional confirmatory viral load values within a five-week time
frame.) In second-line therapy, participants who initially took NRTIs with a PI switched to
NRTIs and an NNRTI. Participants who initially took NRTIs and an NNRTI switched to NRTIs and
a PI. The timing of the switch was based on the participant's group: Groups PI/1K and
NNRTI/1K switched to second-line treatment when viral load was 1,000 copies/ml or greater;
Groups PI/30K and NNRTI/30K switched to second-line treatment when viral load was 30,000
copies/ml or greater. Participants who failed second-line therapy discontinued study
treatment and were offered the best available therapy at the discretion of the clinician.

Participants had study visits at Weeks 2, 4, 8, 12, 16, 24, and every 12 weeks thereafter
until the drug regimen was switched to second-line treatment. Participants then had a
re-entry visit and the schedule of visits restarted. Participants were in the study between 4
and 7 years, depending on when they enrolled. All study visits included medical history, a
physical exam, and blood collection. Urine collection occurred at most visits. Participants
were asked to complete adherence questionnaires and PACTG participants underwent
neuropsychological assessments at selected visits.

All participants in this study were encouraged to coenroll in PACTG 219C, Long-Term Effects
of HIV Exposure and Infection in Children. Participants in the European portion of the study
may be asked to enroll in a substudy to observe the development and progression of
lipodystrophy syndrome in children.

Inclusion Criteria:

- Older than 30 days and younger than 18 years of age (may enroll up to the day before
their 18th birthday)

- HIV infected

- Not previously on HAART or received anti-HIV drugs for less than 56 consecutive days
after birth to prevent mother-to-infant HIV transmission. Participants who have
previously received nevirapine for the prevention of mother-to-infant HIV transmission
are not eligible for this study.

- Willing to use acceptable methods of contraception

Exclusion Criteria:

- Grade 3 or 4 clinical or laboratory toxicity. More information on this criterion can
be found in the protocol.

- Active opportunistic infection or a serious bacterial infection at the time of study
entry

- Pancreas, nervous system, blood, liver, or kidney problems that make it impossible to
take study medications

- Taking any medication that cannot be combined with the study medications in first-line
therapy

- Received therapy for cancer

- Pregnant or breastfeeding