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

A Phase II/III Randomized, Open-Label Study of Combination Antiretroviral Regimens and Treatment-Switching Strategies in HIV-1-Infected Antiretroviral Naive Children Between 30 Days and 18 Years of Age

Status

Completed

Phases

Phase 2Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT00039741

Enrollment

266

Registered

2002-06-11

Start date

2002-08-31

Completion date

2010-03-31

Last updated

2021-11-05

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

HIV Infections

Keywords

Drug Therapy, Combination, HIV Protease Inhibitors, Reverse Transcriptase Inhibitors, Viral Load, Treatment Naive

Brief summary

Little is known about what treatment combinations are best for HIV infected children. This study examined the long-term effectiveness of different anti-HIV drug combinations in children and strategies for switching treatment if the first treatment does not work. The study enrolled children who had not previously taken anti-HIV medication. Participants in this study were recruited in the United States, South America and Europe. Some European children may also enroll in a substudy that will observe changes in body fat in children taking anti-HIV medications.

Detailed description

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.

Interventions

DRUGNRTIs (ABC, FTC, FTC/TDF, 3TC, 3TC/AZT, d4T, TDF, ddC, AZT)

Accepted NRTIs: abacavir sulfate (ABC), emtricitabine (FTC), emtricitabine/Tenofovir disoproxil fumarate (FTC/TDF), lamivudine (3TC), lamivudine/zidovudine (3TC/AZT), stavudine (d4T), tenofovir disoproxil fumarate (TDF), zalcitabine (ddC), zidovudine (AZT) Prescribed per participant's doctor

DRUGNNRTIs (EFV, NVP)

Accepted NNRTIs: efavirenz (EFV), nevirapine (NVP) Prescribed per participant's doctor

DRUGPIs (AMP, IDV, LPV/r, NFV, SQV, RTV)

Accepted PIs: amprenavir (APV). indinavir sulfate (IDV), lopinavir/ritonavir (LPV/r), nelfinavir mesylate (NFV), saquinavir (SQV), ritonavir (RTV) Prescribed per participant's doctor

Study design

Allocation

RANDOMIZED

Intervention model

FACTORIAL

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

30 Days to 18 Years

Healthy volunteers

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

Design outcomes

Primary

Measure	Time frame
Change in Viral Load Measured in log10 HIV-1 RNA Copies/ml	Baseline visit and 4 years after Study Entry

Secondary

Measure	Time frame	Description
Participants With Significant HIV-related Clinical Events, Defined as CDC Category C (AIDS Defining) Diagnoses (Except for Recurrent Bacterial Infections)or Death	Up to 6 yrs. (average 4.85 yrs.)	—
Time to Switching to an Alternative Class ART Regimen (Based on Initial Randomized Regimen)	Up to 6 yrs. (average 4.85 yrs.)	25th Percentiles in weeks from randomization to starting an alternative class ART regimen (based on initial randomized regimen)
Time to HIV-1 RNA of 400 Copies/ml or Greater During First-line Therapy or Permanent Discontinuation of First-line Therapy	Up to 6 yrs. (average 4.85 yrs.)	25th Percentiles in weeks from randomization HIV-1 RNA of 400 copies/ml or greater during first-line therapy or permanent discontinuation of first-line therapy.
Rate of Grade 3 or Higher Signs, Symptoms, or Laboratory Abnormalities Experienced	Up to 6 yrs. (average 4.85 yrs.)	Adverse events were graded according to the following guidelines: PACTG: The Manual for Expedited Reporting of Adverse Events to DAIDS (DAIDS EAE Manual) dated May 6, 2004. PENTA: International Conference for Harmonization (ICH) requirements and the EU Clinical Trials Directive 2001/20/EC (20). A rating of Grade 3 is severe and Grade 4 is life-threatening. The rate of serious (Grade 3 or above)events is reported as the number of events per 100 child/years.
Number of Children With an HIV-1 RNA Level Less Than 400 Copies/ml Regardless of Therapy at Week 204	Week 204	—
Change in CD4% From Randomization to 4 Years	Randomization to 4 years	—
Number of Children With HIV-1 RNA Less Than 400 Copies/ml and on Original Randomized Therapy at 24 Weeks	24 weeks	—
Time to HIV-1 RNA of 30,000 Copies/ml or Greater During Second-line Therapy or Permanent Discontinuation of Second-line Therapy	Up to 6 yrs. (average 4.85 yrs.)	25th Percentiles in weeks from randomization to HIV-1 RNA of 30,000 copies/ml or greater during second-line therapy or permanent discontinuation of second-line therapy

Countries

Puerto Rico, United States

Participant flow

Recruitment details

Recruited at Pediatric AIDS Clinical Trials Group (PACTG) units in the U.S. and Puerto Rico, and Paediatric European Network for Treatment of AIDS (PENTA) units in Argentina, Austria, the Bahamas, Brazil, France, Germany, Italy, Romania, Spain, the United Kingdom and Ireland. Enrollment started 9/25/02 and ended 9/7/05.

Pre-assignment details

Participants were stratified by age (\<3 years versus 3+ years), origin (PACTG site or PENTA site), and exposure versus no exposure to antiretroviral therapy perinatally. 266 children were randomized, of whom 3 are excluded from all analyses (2 had consent withdrawn by parents after randomization, 1 was ineligible).

Participants by arm

Arm	Count
PI/1K Two nucleoside reverse transcriptase inhibitors (NRTI) plus a protease inhibitor (PI)with a regimen change recommended when viral load is 1000 copies/ml or higher	66
NNRTI/1K 2 NRTIs plus a nonnucleoside reverse transcriptase inhibitor (NNRTI) with a regimen change recommended when viral load reaches 1,000 copies/ml or higher	68
PI/30K Two NRTIs plus a PIwith a regimen change recommended when viral load is 30,000 copies/ml or higher	65
NNRTI/30K 2 NRTIs plus an NNRTI with a regimen change recommended when viral load reaches 30,000 copies/ml or higher	64
Total	263

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002	FG003
Overall Study	Confounding medical condition	1	0	0	0
Overall Study	Death	0	1	0	0
Overall Study	Lost to Follow-up	3	1	5	2
Overall Study	Missed final visit	2	1	2	2
Overall Study	Moved	3	2	3	6
Overall Study	Non-compliance with protocol	1	0	1	0
Overall Study	Not able to get to clinic	5	2	0	3
Overall Study	Withdrew consent	0	5	0	1

Baseline characteristics

Characteristic	NNRTI/1K	Total	NNRTI/30K	PI/1K	PI/30K
Age, Continuous	7.0 years STANDARD_DEVIATION 5.4	7.5 years STANDARD_DEVIATION 5.4	6.9 years STANDARD_DEVIATION 5	8.0 years STANDARD_DEVIATION 5.7	7.9 years STANDARD_DEVIATION 5.4
Age, Customized >12 months to <=3 years	7 participants	28 participants	5 participants	8 participants	8 participants
Age, Customized >14 years to <18 years	9 participants	46 participants	9 participants	15 participants	13 participants
Age, Customized >30 days to <=12 months	12 participants	40 participants	11 participants	10 participants	7 participants
Age, Customized >3 to <=9 years	27 participants	99 participants	29 participants	19 participants	24 participants
Age, Customized >9 to <=14 years	13 participants	50 participants	10 participants	14 participants	13 participants
CD4 percent (percentage of total lymphocytes that are CD4 cells)	18 CD4% STANDARD_DEVIATION 10	18 CD4% STANDARD_DEVIATION 11	17 CD4% STANDARD_DEVIATION 12	18 CD4% STANDARD_DEVIATION 12	18 CD4% STANDARD_DEVIATION 11
PENTA/PACTG site PACTG	21 participants	75 participants	18 participants	19 participants	17 participants
PENTA/PACTG site PENTA	47 participants	188 participants	46 participants	47 participants	48 participants
Region of Enrollment Argentina	4 participants	11 participants	3 participants	1 participants	3 participants
Region of Enrollment Austria	0 participants	2 participants	1 participants	1 participants	0 participants
Region of Enrollment Bahamas	0 participants	4 participants	0 participants	2 participants	2 participants
Region of Enrollment Brazil	11 participants	41 participants	9 participants	12 participants	9 participants
Region of Enrollment France	3 participants	17 participants	6 participants	3 participants	5 participants
Region of Enrollment Germany	6 participants	21 participants	7 participants	5 participants	3 participants
Region of Enrollment Ireland	1 participants	4 participants	1 participants	0 participants	2 participants
Region of Enrollment Italy	4 participants	22 participants	6 participants	7 participants	5 participants
Region of Enrollment Puerto Rico	1 participants	3 participants	0 participants	1 participants	1 participants
Region of Enrollment Romania	7 participants	31 participants	7 participants	8 participants	9 participants
Region of Enrollment Spain	0 participants	2 participants	0 participants	1 participants	1 participants
Region of Enrollment United Kingdom	11 participants	33 participants	6 participants	7 participants	9 participants
Region of Enrollment United States	20 participants	72 participants	18 participants	18 participants	16 participants
Sex: Female, Male Female	33 Participants	127 Participants	32 Participants	30 Participants	32 Participants
Sex: Female, Male Male	35 Participants	136 Participants	32 Participants	36 Participants	33 Participants
Viral Load	5.0 Log10 copies/ml STANDARD_DEVIATION 0.8	5.1 Log10 copies/ml STANDARD_DEVIATION 0.8	5.1 Log10 copies/ml STANDARD_DEVIATION 0.8	5.2 Log10 copies/ml STANDARD_DEVIATION 0.8	5.0 Log10 copies/ml STANDARD_DEVIATION 0.8

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk
deaths Total, all-cause mortality	— / —	— / —	— / —	— / —
other Total, other adverse events	0 / 66	0 / 68	0 / 65	0 / 64
serious Total, serious adverse events	9 / 66	10 / 68	14 / 65	15 / 64

Outcome results

Primary

Change in Viral Load Measured in log10 HIV-1 RNA Copies/ml

Time frame: Baseline visit and 4 years after Study Entry

Population: Intent-to-treat analyses for those subjects who had data at baseline and 4 years. Analyses were done by collapsing groups to examine drug class (regardless of switch point) and switch point (regardless of drug class).

Arm	Measure	Value (MEAN)	Dispersion
Drug Class/PI	Change in Viral Load Measured in log10 HIV-1 RNA Copies/ml	-3.16 log10 HIV-1 RNA	Standard Error 0.09
Drug Class/NNRTI	Change in Viral Load Measured in log10 HIV-1 RNA Copies/ml	-3.31 log10 HIV-1 RNA	Standard Error 0.09
Switch Point (1K)	Change in Viral Load Measured in log10 HIV-1 RNA Copies/ml	-3.26 log10 HIV-1 RNA	Standard Error 0.09
Switch Point (30K)	Change in Viral Load Measured in log10 HIV-1 RNA Copies/ml	-3.20 log10 HIV-1 RNA	Standard Error 0.09

p-value: 0.2695% CI: [-0.41, 0.11]Interval regression

p-value: 0.5695% CI: [-0.2, 0.32]Interval regression

Secondary

Change in CD4% From Randomization to 4 Years

Time frame: Randomization to 4 years

Population: Intent to treat, for participants who had CD4% values available at 4 years and at baseline.

Arm	Measure	Value (MEAN)	Dispersion
Drug Class/PI	Change in CD4% From Randomization to 4 Years	13.7 CD4 percent (% of total lymphocytes)	Standard Deviation 0.8
Drug Class/NNRTI	Change in CD4% From Randomization to 4 Years	15.2 CD4 percent (% of total lymphocytes)	Standard Deviation 0.8
Switch Point (1K)	Change in CD4% From Randomization to 4 Years	15.1 CD4 percent (% of total lymphocytes)	Standard Deviation 0.8
Switch Point (30K)	Change in CD4% From Randomization to 4 Years	13.9 CD4 percent (% of total lymphocytes)	Standard Deviation 0.8

Secondary

Number of Children With an HIV-1 RNA Level Less Than 400 Copies/ml Regardless of Therapy at Week 204

Time frame: Week 204

Population: Intent to treat. Numbers are reported among participants who had an HIV-1 RNA value and were in follow-up at week 204.

Arm	Measure	Value (NUMBER)
Drug Class/PI	Number of Children With an HIV-1 RNA Level Less Than 400 Copies/ml Regardless of Therapy at Week 204	92 participants
Drug Class/NNRTI	Number of Children With an HIV-1 RNA Level Less Than 400 Copies/ml Regardless of Therapy at Week 204	93 participants
Switch Point (1K)	Number of Children With an HIV-1 RNA Level Less Than 400 Copies/ml Regardless of Therapy at Week 204	95 participants
Switch Point (30K)	Number of Children With an HIV-1 RNA Level Less Than 400 Copies/ml Regardless of Therapy at Week 204	90 participants

Secondary

Number of Children With HIV-1 RNA Less Than 400 Copies/ml and on Original Randomized Therapy at 24 Weeks

Time frame: 24 weeks

Population: Intent to treat - numbers are reported among participants who had an HIV-1 RNA value and were in follow-up at week 24.

Arm	Measure	Value (NUMBER)
Drug Class/PI	Number of Children With HIV-1 RNA Less Than 400 Copies/ml and on Original Randomized Therapy at 24 Weeks	92 participants
Drug Class/NNRTI	Number of Children With HIV-1 RNA Less Than 400 Copies/ml and on Original Randomized Therapy at 24 Weeks	98 participants
Switch Point (1K)	Number of Children With HIV-1 RNA Less Than 400 Copies/ml and on Original Randomized Therapy at 24 Weeks	99 participants
Switch Point (30K)	Number of Children With HIV-1 RNA Less Than 400 Copies/ml and on Original Randomized Therapy at 24 Weeks	91 participants

Secondary