Antiviral Responses to NNRTI-Based vs. PI-Based ARV Therapy in HIV Infected Infants Who Have or Have Not Received Single Dose NVP for Prevention of Mother-to-Child Transmission of HIV (P1060)

This study is ongoing, but not recruiting participants.

Sponsor:

Collaborators:

National Institute of Allergy and Infectious Diseases (NIAID)

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Information provided by (Responsible Party):

International Maternal Pediatric Adolescent AIDS Clinical Trials Group

ClinicalTrials.gov Identifier:

NCT00307151

First received: March 24, 2006

Last updated: May 16, 2012

Last verified: May 2012

History of Changes

Results First Received: July 5, 2011

Study Type:	Interventional
Study Design:	Allocation: Randomized; Endpoint Classification: Efficacy Study; Intervention Model: Parallel Assignment; Masking: Open Label; Primary Purpose: Treatment
Condition:	HIV Infections
Interventions:	Drug: Lamivudine Drug: Lopinavir/ritonavir Drug: Nevirapine Drug: Zidovudine

Participant Flow

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Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
Study participants were recruited at 10 study sites, 4 in South Africa and 1 each in Uganda, Zimbabwe, Zambia, Malawi, Tanzania and India between November 9, 2006 and March 19, 2010.

Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
Infants and children 6 - 36 months of age (lower age limit changed to 2 months in Protocol Version 4.0) were stratified by age (2-<6 months, 6-<12 months and >=12 months) and randomly assigned to receive either AZT/3TC/NVP or AZT/3TC/LPV/r. One subject was randomized but never started study treatment.

Reporting Groups

	Description
Coh I: NVP	Cohort I: Previously received single dose nevirapine (SD NVP). Randomly assigned to receive an NNRTI-based regimen.
Coh I: LPV/r	Cohort I: Previously received SD NVP. Randomly assigned to receive a PI-based regimen.
Coh II: NVP	Cohort II: Did not previously receive SD NVP. Randomly assigned to receive an NNRTI-based regimen
Coh II: LPV/r	Cohort II: Did not previously receive SD NVP. Randomly assigned to receive a PI-based regimen

Participant Flow: Overall Study

	Coh I: NVP	Coh I: LPV/r	Coh II: NVP	Coh II: LPV/r
STARTED	82	82	147	140 ^[1]
COMPLETED	71 ^[2]	75 ^[2]	127 ^[3]	129 ^[3]
NOT COMPLETED	11	7	20	11
Death	4	3	10	3
Severe debilitation, unable to continue	1	0	0	0
Subject unable to get to clinic	1	0	6	2
Withdrew consent	0	1	1	3
Not willing to adhere to study reqs	2	0	2	2
Clinic unable to contact subject	3	3	1	1

[1]	One participant never started treatment, were not followed and not included in analysis.
[2]	Results are through date DSMB closed Cohort I to accrual (April 20, 2009)
[3]	Results are through date DSMB recommended Cohort II results be unblinded (October 27, 2010)

Baseline Characteristics

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Reporting Groups

	Description
Coh I: NVP	Cohort I: Previously received single dose nevirapine (SD NVP). Randomly assigned to receive an NNRTI-based regimen.
Coh I: LPV/r	Cohort I: Previously received SD NVP. Randomly assigned to receive a PI-based regimen.
Coh II: NVP	Cohort II: Did not previously receive SD NVP. Randomly assigned to receive an NNRTI-based regimen
Coh II: LPV/r	Cohort II: Did not previously receive SD NVP. Randomly assigned to receive a PI-based regimen
Total	Total of all reporting groups

Baseline Measures

	Coh I: NVP	Coh I: LPV/r	Coh II: NVP	Coh II: LPV/r	Total
Number of Participants [units: participants]	82	82	147	140	451
Age, Customized [units: participants]
<12 months	60	63	41	36	200
>=12 months	22	19	106	104	251
Gender [units: participants]
Female	46	41	78	72	237
Male	36	41	69	68	214
Race/Ethnicity, Customized [units: participants]
Black African	81	81	132	134	428
Coloured	1	1	1	2	5
Native of India	0	0	12	4	16
Not available	0	0	2	0	2
Region of Enrollment [units: participants]
Tanzania	2	0	8	7	17
Zambia	2	4	14	18	38
Uganda	1	4	20	20	45
Malawi	2	0	16	20	38
South Africa	71	65	41	36	213
Zimbabwe	4	9	36	35	84
India	0	0	12	4	16
Ever breastfed [units: participants]
Yes	15	19	118	115	267
No	67	63	29	25	184
Documentation of SD NVP use at birth [units: participants]
Born before NVP available/mother known to have HIV	0	0	116	104	220
Medical record review	62	63	10	12	147
Verbal evidence only	20	19	19	22	80
Found to have received SD NVP	0	0	2	2	4
WHO Stage ^[1] [units: participants]
I	7	18	29	25	79
II	23	22	26	27	98
III	39	38	80	77	234
IV	13	4	12	11	40
HIV-1 RNA [units: participants]
<100,000 copies/ml	6	5	20	27	58
100,000 - < 750,000 copies/ml	27	34	70	53	184
>=750,000 copies/ml	49	43	57	60	209
CD4 Percent [units: participants]
<15 Percent	24	21	73	69	187
15 Percent - < 25 Percent	37	37	60	54	188
>= 25 Percent	21	24	13	17	75
Missing	0	0	1	0	1
NVP resistance [units: participants]
Yes	7	11	1	4	23
No	68	62	110	91	331
Not available	7	9	36	45	97

[1]	World Health Organization (WHO) staging system for HIV infection and disease.

Outcome Measures

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1. Primary:

Percent of Participants With Treatment Failure, Defined as a Confirmed Virologic Failure or Permanent Discontinuation of the Randomized NNRTI or PI Component of Study Treatment [ Time Frame: Earlier of 24 weeks or date of DSMB decision to unblind Cohort results (Coh I: April 20, 2009; Coh II: October 27, 2010) ]

Show Outcome Measure 1

2. Secondary:

Time From Randomization to Treatment Failure, Defined as Virologic Failure or Permanent Discontinuation of the Randomized NNRTI or PI Component of Study Treatment [ Time Frame: Until date of DSMB decision to unblind Cohort results (Coh I: April 20, 2009 - median follow-up 48 weeks and range 0 - 125 weeks; Coh II: October 27, 2010 - median follow-up 72 weeks and range from 0 to 204 weeks) ]

Show Outcome Measure 2

3. Secondary:

Percent of Participants Experiencing Virologic Failure [ Time Frame: Earlier of 24 weeks or date of DSMB decision to unblind Cohort results (Coh I: April 20, 2009; Coh II: October 27, 2010) ]

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Measure Type	Secondary
Measure Title	Percent of Participants Experiencing Virologic Failure
Measure Description	Virologic failure is defined as a confirmed plasma HIV-1 RNA level that is <1 log10 copies/mL below the study entry value at 12 to 24 weeks after treatment is initiated OR a confirmed plasma HIV-1 RNA level >400 copies/mL at 24 weeks OR death on or before 24 weeks. Results report percent of participants reaching a virologic failure endpoint by week 24 calculated using the Kaplan-Meier method.
Time Frame	Earlier of 24 weeks or date of DSMB decision to unblind Cohort results (Coh I: April 20, 2009; Coh II: October 27, 2010)
Safety Issue	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Analysis uses intent to treat population.

Reporting Groups

	Description
Coh I: NVP	Cohort I: Previously received single dose nevirapine (SD NVP). Randomly assigned to receive an NNRTI-based regimen.
Coh I: LPV/r	Cohort I: Previously received SD NVP. Randomly assigned to receive a PI-based regimen.
Coh II: NVP	Cohort II: Did not previously receive SD NVP. Randomly assigned to receive an NNRTI-based regimen
Coh II: LPV/r	Cohort II: Did not previously receive SD NVP. Randomly assigned to receive a PI-based regimen

Measured Values

	Coh I: NVP	Coh I: LPV/r	Coh II: NVP	Coh II: LPV/r
Number of Participants Analyzed [units: participants]	82	82	147	140
Percent of Participants Experiencing Virologic Failure [units: Percent of participants]	27.4	10.4	28.6	12.9

No statistical analysis provided for Percent of Participants Experiencing Virologic Failure

4. Secondary:

Time From Randomization to Virologic Failure [ Time Frame: Until date of DSMB decision to unblind Cohort results (Coh I: April 20, 2009 - median follow-up 48 weeks and range 0 - 125 weeks; Coh II: October 27, 2010 - median follow-up 72 weeks and range from 0 to 204 weeks) ]

Show Outcome Measure 4

5. Secondary:

Time From Start of Study Treatment to First New Grade >=3 Lab Abnormality, Sign or Symptom Occurring on Study Treatment [ Time Frame: On randomized NNRTI or PI component of study treatment and until date of DSMB decision to unblind Cohort results (Coh I: April 20, 2009; Coh II: October 27, 2010) ]

Show Outcome Measure 5

6. Secondary:

Number of Participants Developing New NRTI, NNRTI or PI-resistant Virus [ Time Frame: Until date of DSMB decision to unblind Cohort results (Coh I: April 20, 2009 - median follow-up 48 weeks and range 0 - 125 weeks; Coh II: October 27, 2010 - median follow-up 72 weeks and range from 0 to 204 weeks) ]

Show Outcome Measure 6

7. Secondary:

Change in CD4 Percent From Entry to Week 48 [ Time Frame: 48 weeks if before date of DSMB decision to unblind Cohort results (Coh I: April 20, 2009; Coh II: October 27, 2010) ]

Show Outcome Measure 7

8. Secondary:

Time From Randomization to HIV-related Disease Progression or Death [ Time Frame: Until date of DSMB decision to unblind Cohort results (Coh I: April 20, 2009 - median follow-up 48 weeks and range 0 - 125 weeks; Coh II: October 27, 2010 - median follow-up 72 weeks and range from 0 to 204 weeks) ]

Show Outcome Measure 8

9. Secondary:

Time From Randomization to Death [ Time Frame: Until date of DSMB decision to unblind Cohort results (Coh I: April 20, 2009 - median follow-up 48 weeks and range 0 - 125 weeks; Coh II: October 27, 2010 - median follow-up 72 weeks and range from 0 to 204 weeks) ]

Show Outcome Measure 9

Serious Adverse Events

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Other Adverse Events

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More Information

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Certain Agreements:

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

The agreement is:

	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed. Restriction Description: In accordance with the Clinical Trial Agreement between NIAID (DAIDS) and company collaborators, NIAID (DAIDS) provides companies with a copy of any abstract, press release, or manuscript prior to submission for publication with sufficient time for company review and comment. The publication/other disclosure can be delayed for up to 30 additional business days for manuscript and five (5) business days for abstracts, to preserve U.S. or foreign patent or other intellectual property rights.

Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
Accrual to Cohort I was terminated early by the Data Safety Monitoring Committee after enrollment of 164 of the planned 288 subjects.

Results Point of Contact:

Name/Title: Clinicaltrials.gov Coordinator
Organization: Center for Biostatistics in AIDS Research, Harvard School of Public Health
phone: (617) 432-2829
e-mail: CBAR.ClinicalTrials.Gov@sdac.harvard.edu

Publications of Results:

Palumbo P, Lindsey JC, Hughes MD, Cotton MF, Bobat R, Meyers T, Bwakura-Dangarembizi M, Chi BH, Musoke P, Kamthunzi P, Schimana W, Purdue L, Eshleman SH, Abrams EJ, Millar L, Petzold E, Mofenson LM, Jean-Philippe P, Violari A. Antiretroviral treatment for children with peripartum nevirapine exposure. N Engl J Med. 2010 Oct 14;363(16):1510-20.

Other Publications:

Arrive E, Newell ML, Ekouevi DK, Chaix ML, Thiebaut R, Masquelier B, Leroy V, Perre PV, Rouzioux C, Dabis F. Prevalence of resistance to nevirapine in mothers and children after single-dose exposure to prevent vertical transmission of HIV-1: a meta-analysis. Int J Epidemiol. 2007 May 28; [Epub ahead of print]

Chi BH, Sinkala M, Stringer EM, Cantrell RA, Mtonga V, Bulterys M, Zulu I, Kankasa C, Wilfert C, Weidle PJ, Vermund SH, Stringer JS. Early clinical and immune response to NNRTI-based antiretroviral therapy among women with prior exposure to single-dose nevirapine. AIDS. 2007 May 11;21(8):957-964.

Eshleman SH, Hoover DR, Hudelson SE, Chen S, Fiscus SA, Piwowar-Manning E, Jackson JB, Kumwenda NI, Taha TE. Development of nevirapine resistance in infants is reduced by use of infant-only single-dose nevirapine plus zidovudine postexposure prophylaxis for the prevention of mother-to-child transmission of HIV-1. J Infect Dis. 2006 Feb 15;193(4):479-81. Epub 2006 Jan 11.

White PD. What Causes Prolonged Fatigue after Infectious Mononucleosis--and Does It Tell Us Anything about Chronic Fatigue Syndrome? J Infect Dis. 2007 Jul 1;196(1):4-5. Epub 2007 May 24. No abstract available.

Sankatsing RR, Wit FW, Pakker N, Vyankandondera J, Mmiro F, Okong P, Kastelein JJ, Lange JM, Stroes ES, Reiss P. Effects of Nevirapine, Compared with Lamivudine, on Lipids and Lipoproteins in HIV-1-Uninfected Newborns: The Stopping Infection from Mother-to-Child via Breast-Feeding in Africa Lipid Substudy. J Infect Dis. 2007 Jul 1;196(1):15-22. Epub 2007 May 16.

Publications automatically indexed to this study:

Violari A, Lindsey JC, Hughes MD, Mujuru HA, Barlow-Mosha L, Kamthunzi P, Chi BH, Cotton MF, Moultrie H, Khadse S, Schimana W, Bobat R, Purdue L, Eshleman SH, Abrams EJ, Millar L, Petzold E, Mofenson LM, Jean-Philippe P, Palumbo P. Nevirapine versus ritonavir-boosted lopinavir for HIV-infected children. N Engl J Med. 2012 Jun 21;366(25):2380-9.

Responsible Party:	International Maternal Pediatric Adolescent AIDS Clinical Trials Group
ClinicalTrials.gov Identifier:	NCT00307151 History of Changes
Other Study ID Numbers:	IMPAACT P1060, U01AI068632
Study First Received:	March 24, 2006
Results First Received:	July 5, 2011
Last Updated:	May 16, 2012
Health Authority:	United States: Federal Government

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