HIV Infections
Conditions
Keywords
Infant, Perinatal, HIV, Disease Transmission, Vertical, Anti-Retroviral Agents, Treatment Interruption, Treatment Naive, Acute Infection, Mother-to-Child Transmission
Brief summary
The purpose of this study is to compare the effects of anti-HIV drug courses of different lengths in infants who became HIV infected at birth.
Detailed description
In South Africa, an estimated 250,000 infants are born to HIV-infected mothers each year. A high percentage of perinatal HIV infections are due to inadequate or absent mother-to-child transmission prophylaxis. Unfortunately, even with optimal prophylaxis, relatively large numbers of HIV-infected infants will continue to be born and will require antiretroviral therapy (ART). Determining the appropriate times for initiating and interrupting treatment to benefit long-term prognosis in infants is a significant health challenge. Evidence suggests that starting ART early during acute infection will provide long-term benefits. However, longer duration of treatment increases the chance of developing drug-resistant virus, and continuous therapy begun early leads to long-term complications in children. This study will evaluate the efficacy of two different short-course ART strategies in HIV-infected infants from South Africa. This study will last at least 3.5 years. There are two parts to this study. In Part A, infants with a baseline CD4 percentage (CD4%) of at least 25% and HIV infection diagnosed between 6 and 12 weeks of age will be randomly assigned to one of two treatment strategy arms. Arm 2 infants will receive ART for approximately 40 weeks until their first birthday. Arm 3 infants will receive ART for approximately 96 weeks until their second birthday. Treatment in both arms of Part A will begin with first-line, continuous treatment of zidovudine, lamivudine, and lopinavir/ritonavir. Those who were initially deferred treatment in Arm 1 will be reassessed for initiation of first-line, continuous ART. First-line ART will be started in Arm 1 or restarted after interruption in Arms 2 and 3 if the appropriate criteria as defined in the protocol is met. First-line treatment of zidovudine, lamivudine, and lopinavir/ritonavir will continue until infants reach a study endpoint; when this occurs, infants will then change to second-line therapy. Second-line ART will consist of didanosine, abacavir sulfate, nevirapine and efavirenz. All the primary efficacy analysis for this study will focus on the children enrolled in the first phase of Part A (n=377) as proposed by the data safety and monitoring board. Follow-up visits will take place for 3.5 to 5 years, depending on time of enrollment. All infants will receive routine immunizations and cotrimoxazole (sulfamethoxazole/trimethoprim) prophylaxis from age 6 weeks until Week 40. Study visits will occur at study entry, Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, and 48; and every 12 weeks thereafter. At these visits, infants will have vital sign measurements, a physical exam, and a medical history evaluation. Blood and urine collection will occur at all study visits. Infants' parents or guardians will also be asked to complete an adherence questionnaire. Participants enrolled in CIPRA-ZA Project 2 are encouraged to enroll in an observational substudy organized by the Wistar Institute (Dr. Luis Montaner, Principal Investigator), in conjunction with the CIPRA team. This study is entitled,Pediatric Immune Correlates of Early Anti-HIV Therapy. The goal of this 5-year substudy is to evaluate 120 HIV infected children from the parent study twice a year and compare them to HIV uninfected age-matched controls. Children will be evaluated by (a) characterization and identification of the innate and adaptive immune reconstitution outcomes of early (9 or 21 months) therapy in infants infected with HIV at birth and (b) identification of immune correlate outcomes to clinical progression within a period of 2 to 3 years of follow-up after stopping therapy.
Interventions
DRUGAbacavir sulfate
Second Line Regimen: 8 mg/kg taken orally twice daily. Guidelines for switching from first line to second line therapy are available in the protocol.
DRUGDidanosine
Second Line Regimen: Either 100 mg/m\^2 or 120 mg/m\^2 taken orally twice daily. Dosage depends on age. Guidelines for switching from first line to second line therapy are available in the protocol.
DRUGLamivudine
First Line Regimen: 4 mg/kg taken orally twice daily
DRUGLopinavir/Ritonavir
First Line Regimen: taken orally twice daily. Dosage depends on age and weight.
DRUGEfavirenz
Second Line Regimen: taken orally once daily. Dosage depends on weight. Guidelines for switching from first line to second line therapy are available in the protocol.
DRUGNevirapine
Second Line Regimen: 150 - 200 mg/m\^2 taken orally twice daily. Guidelines for switching from first line to second line therapy are available in the protocol.
DRUGZidovudine
First Line Regimen: 240 mg/m\^2 taken orally twice daily
Sponsors
National Institute of Allergy and Infectious Diseases (NIAID)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
This study had two parts: Part A where children were enrolled with CD4% ≥ 25% and Part B where children were enrolled with CD4% \< 25%. Part A had three arms: ART-Deferred, ART-40W and ART-96W where ART-40W and ART-96W were the early therapy arms for 40 and 96 weeks respectively. Part B were enrolled into two Arms: ART-40W and ART-96W. The primary efficacy analysis for CHER was based on 377 children that were enrolled in Part A in the first phase of the study. The NIH African data safety and monitoring board recommended that primary analysis be focussed on 377 children enrolled in the first phase of Part A. Additionally, all the key manuscripts have been analysed using this group. Hence all the results presented in clinicaltrials.gov will be specific to this group with three arms.
Eligibility
Sex/Gender
ALL
Age
6 Weeks to 12 Weeks
Healthy volunteers
No
Inclusion criteria
for Infants: NOTE: Per Letter of Amendment dated 04/04/07, Part B of this study is no longer recruiting participants. Per Letter of Amendment dated 09/16/08 Arm 1 of this study is longer recruiting. * HIV infected * Antiretroviral naive. Infants who have previously received antiretroviral drugs used to prevent mother-to-child transmission are eligible for the study. * Parent or legal guardian willing to provide informed consent and comply with study requirements
Exclusion criteria
for Infants: * Any major life-threatening congenital abnormalities * Severe CDC Stage B or C disease * Liver enzyme, absolute neutrophil count, hemoglobin, electrolyte, creatinine, or clinical toxicity of Grade 3 or higher at screening * Any acute or clinically significant medical event that would preclude participation in the study. Randomization can take place as soon as the incurrent illness has resolved if the child is still less than or equal to 12 weeks of age. * Use of investigational drugs * Require certain medications. More information on this criterion can be found in the protocol. * Inability to tolerate oral medication * Birth weight less than 2 kg (4.4 lbs)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to Failure of First Line Therapy or Death | From date of randomization up to failure of first-line therapy or death from any cause, whichever came first, assessed up to 4.8 years | To compare time to failure of first line ART (due to clinical, virological or immunological disease progression, or regimen-limiting ART toxicities) or death among three randomized arms (infants who receive early ART in Arms 2 and 3 and infants in whom ART is deferred until clinical or immunological disease progression in Arm 1) during the study (up to 4.8 years). The number of participants experiencing the events did not reach the 50% survival and thus median time-to-event is not be presented. Therefore we report the number of participants experiencing the events per Arm. |
| Number of Participants Who Experienced Immunological Failure Defined as Failure of CD4% to Reach 20% or CD4% Falls Below 20% on Two Occasions, Within 4 Weeks, at Any Time After the First 24 Weeks of Therapy (Initial Therapy or Restart) | This outcome was assessed from the date of randomization to immunological failure. Immunological failure was assessed in the entire study duration of 4.8 years. | This was part of the primary outcome measure above. The primary outcome was a composite endpoint. The primary outcome analysis only considered the initially enrolled children that were 377 in total (ART-Deferred n=125, Early therapy 40 weeks n=126 and Early therapy 96 weeks n=126). This was part of the primary outcome measure that was a composite endpoint. |
| Number of Participants Who Experienced Regimen-limiting ART Drug Toxicity | Regimen limiting drug toxicity was monitored from randomization up to the entire study duration of 4.8 years. | Development of toxicity requiring more than one drug substitution within the same class or a switch to a new class of drugs (regimen-limiting toxicity failure) or requiring a permanent treatment discontinuation. This was part of the primary outcome measure that was a composite endpoint. |
| Number of Participants Who Experienced Clinical Failure (Defined as Development of Severe CDC Stage B or Stage C Disease.) on Therapy. | Clinical failure on therapy was assessed at each visit for the entire study duration of 4.8 years. | This included development of severe CDC Stage B or Stage C disease.This was part of the primary outcome measure that was a composite endpoint |
| Number of Participants Who Experienced Virological Failure Defined as Confirmed HIV-1 RNA Value of at Least 10,000 Copies Per/ml Recorded on Two Consecutive Separate Occasions After 24 Weeks of Treatment (Initial Therapy or Restart) | Virological failure was assessed from randomization through the entire study duration of 4.8 years. | This was part of the primary outcome measure that was a composite endpoint that included confirmed HIV-1 RNA value of at least 10,000 copies per/ml recorded on two consecutive separate occasions after 24 weeks of treatment (initial therapy or restart). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Death Alone or Death Plus Life Threatening Stage C Events or HIV Events Associated With Permanent End-organ Damage. | 4.8 years | This was a composite endpoint in which the number of children experiencing the events is reported. The number of participants experiencing the events did not reach the 50% survival and thus median time-to-event is not be presented. Therefore, we report the number of participants experiencing the events per Arm. |
| Hospitalization Rates | 4.8 years | Hospitalisation rates in the three arms enrolled in the CHER study |
| Number of Children Experiencing Severe CDC Stage B or Stage C Disease or Death (Cumulative After 3.5 Years) | Occurrence of severe CDC Stage B or Stage C disease or death (cumulative after 3.5 years), whichever came first, was assessed from randomization up to at least 3.5 years. | The outcome measure is defined as a number because it represents the number of children that experienced severe CDC Stage B or Stage C disease or death as defined in the outcome measure title above |
| Time to First Hospitalization | From randomization up to 4.8 years | To compare time to first hospitalization in the three randomized arms (infants who received early ART in Arms 2 and 3 and those who received deferred ART in Arm 1). Not all participants were hospitalized and thus the upper limits could not be evaluated. |
| Duration of Hospitalisation | 4.8 years, the study duration | This is the total number of days spent in hospital by the participants and is reported per arm |
| Total Occurrence of Grade 3 or 4 Clinical Events | 4.8 years | This was a secondary outcome measure that assessed the total count of Grade 3 or 4 (clinical or laboratory) adverse events. |
| Total Occurrence of Grade 3 or 4 Laboratory Events | From randomization up to 4.8 years | — |
| Time From Randomization to Starting or Needing to Start Continuous Therapy | 4.8 years | Time from randomization to starting (deferred therapy Arm) or needing to start continuous therapy (early therapy 40 or 96 weeks) |
| Number of Participants With Indicated Viral Resistance Mutations at the Time of Failure of First Line Therapy | 4.8 years | Resistance testing was performed on samples with a VL≥1000 c/ml together with the matched baseline sample, if available. Reverse transcriptase (NRTI and NNRTI) and protease (PI) inhibitor mutations were analysed using a validated in-house population-based sequencing assay and the IAS 2011 mutation list. |
Participant flow
Pre-assignment details
The results are presented for only 377 participants that were enrolled into the three arms (ART-Def 125, ART-40W 126 and ART-96W 126).
Participants by arm
| Arm | Count |
|---|---|
| Deferred Therapy For participants with a CD4% of at least 25%, ART deferred until necessary. Once ART therapy was initiated, it was taken continously.
Zidovudine: First Line Regimen: Given twice daily at a dose of 240 mg/m\^2 of body surface area. Dose was adjusted by age as the children grew older.
Lamivudine: First Line Regimen: 4 mg/kg taken orally twice daily
Lopinavir/Ritonavir: First Line Regimen: taken orally twice daily. Dosage depends on age and weight.
Ritonavir: First Line Regimen taken orally twice a day. Started at 250 mg/m\^2
Abacavir sulfate: Second Line Regimen: 8 mg/kg taken orally twice daily. Guidelines for switching from first line to second line therapy are available in the protocol.
Didanosine: Second Line Regimen: Either 100 mg/m\^2 or 120 mg/m\^2 taken orally twice daily. Dosage depends on age.
Efavirenz: Second Line Regimen: taken orally once daily. Dosage depends on weight.
Nevirapine: Second Line Regimen: 150 - 200 mg/m\^2 taken orally twice daily. | 125 |
| Early Therapy up to 40 Weeks For participants with a CD4% of at least 25%, receive 40 weeks of ART until first birthday
Zidovudine: First Line Regimen: 10 mg/mL taken orally twice per day. Dose was adjusted by age as the children grew older.
Lamivudine: First Line Regimen: 4 mg/kg taken orally twice daily
Lopinavir/Ritonavir: First Line Regimen: taken orally twice daily. Dosage depends on age and weight.
Ritonavir: First Line Regimen taken orally twice a day. Started at 250 mg/m\^2
Abacavir sulfate: Second Line Regimen: 8 mg/kg taken orally twice daily. Guidelines for switching from first line to second line therapy are available in the protocol.
Didanosine: Second Line Regimen: Either 100 mg/m\^2 or 120 mg/m\^2 taken orally twice daily. Dosage depends on age.
Efavirenz: Second Line Regimen: taken orally once daily. Dosage depends on weight.
Nevirapine: Second Line Regimen: 150 - 200 mg/m\^2 taken orally twice daily. | 126 |
| Early Therapy up to 96 Weeks For participants with a CD4% of at least 25%, receive ART for 96 weeks until second birthday
Zidovudine: First Line Regimen: 10 mg/mL taken orally twice per day. Dose was adjusted by age as the children grew older.
Lamivudine: First Line Regimen: 4 mg/kg taken orally twice daily
Lopinavir/Ritonavir: First Line Regimen: taken orally twice daily. Dosage depends on age and weight.
Ritonavir: First Line Regimen taken orally twice a day. Started at 250 mg/m\^2
Abacavir sulfate: Second Line Regimen: 8 mg/kg taken orally twice daily. Guidelines for switching from first line to second line therapy are available in the protocol.
Didanosine: Second Line Regimen: Either 100 mg/m\^2 or 120 mg/m\^2 taken orally twice daily. Dosage depends on age.
Efavirenz: Second Line Regimen: taken orally once daily. Dosage depends on weight.
Nevirapine: Second Line Regimen: 150 - 200 mg/m\^2 taken orally twice daily. | 126 |
| Total | 377 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Death | 23 | 11 | 11 |
| Overall Study | Lost to Follow-up | 6 | 12 | 16 |
| Overall Study | Withdrawal by Subject | 1 | 0 | 1 |
Baseline characteristics
| Characteristic | Deferred Therapy | Early Therapy up to 40 Weeks | Early Therapy up to 96 Weeks | Total |
|---|---|---|---|---|
| Age, Continuous | 7.1 Weeks | 7.4 Weeks | 7.5 Weeks | 7.3 Weeks |
| Region of Enrollment South Africa | 125 Participants | 126 Participants | 126 Participants | 377 Participants |
| Sex: Female, Male Female | 70 Participants | 76 Participants | 74 Participants | 220 Participants |
| Sex: Female, Male Male | 55 Participants | 50 Participants | 52 Participants | 157 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 23 / 125 | 11 / 126 | 11 / 126 |
| other Total, other adverse events | 123 / 125 | 122 / 126 | 125 / 126 |
| serious Total, serious adverse events | 79 / 125 | 60 / 126 | 53 / 126 |
Outcome results
Primary
Number of Participants Who Experienced Clinical Failure (Defined as Development of Severe CDC Stage B or Stage C Disease.) on Therapy.
This included development of severe CDC Stage B or Stage C disease.This was part of the primary outcome measure that was a composite endpoint
Time frame: Clinical failure on therapy was assessed at each visit for the entire study duration of 4.8 years.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Deferred Therapy | Number of Participants Who Experienced Clinical Failure (Defined as Development of Severe CDC Stage B or Stage C Disease.) on Therapy. | 8 Participants |
| Early Therapy up to 40 Weeks | Number of Participants Who Experienced Clinical Failure (Defined as Development of Severe CDC Stage B or Stage C Disease.) on Therapy. | 6 Participants |
| Early Therapy up to 96 Weeks | Number of Participants Who Experienced Clinical Failure (Defined as Development of Severe CDC Stage B or Stage C Disease.) on Therapy. | 5 Participants |
Primary
Number of Participants Who Experienced Immunological Failure Defined as Failure of CD4% to Reach 20% or CD4% Falls Below 20% on Two Occasions, Within 4 Weeks, at Any Time After the First 24 Weeks of Therapy (Initial Therapy or Restart)
This was part of the primary outcome measure above. The primary outcome was a composite endpoint. The primary outcome analysis only considered the initially enrolled children that were 377 in total (ART-Deferred n=125, Early therapy 40 weeks n=126 and Early therapy 96 weeks n=126). This was part of the primary outcome measure that was a composite endpoint.
Time frame: This outcome was assessed from the date of randomization to immunological failure. Immunological failure was assessed in the entire study duration of 4.8 years.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Deferred Therapy | Number of Participants Who Experienced Immunological Failure Defined as Failure of CD4% to Reach 20% or CD4% Falls Below 20% on Two Occasions, Within 4 Weeks, at Any Time After the First 24 Weeks of Therapy (Initial Therapy or Restart) | 9 Participants |
| Early Therapy up to 40 Weeks | Number of Participants Who Experienced Immunological Failure Defined as Failure of CD4% to Reach 20% or CD4% Falls Below 20% on Two Occasions, Within 4 Weeks, at Any Time After the First 24 Weeks of Therapy (Initial Therapy or Restart) | 14 Participants |
| Early Therapy up to 96 Weeks | Number of Participants Who Experienced Immunological Failure Defined as Failure of CD4% to Reach 20% or CD4% Falls Below 20% on Two Occasions, Within 4 Weeks, at Any Time After the First 24 Weeks of Therapy (Initial Therapy or Restart) | 11 Participants |
Primary
Number of Participants Who Experienced Regimen-limiting ART Drug Toxicity
Development of toxicity requiring more than one drug substitution within the same class or a switch to a new class of drugs (regimen-limiting toxicity failure) or requiring a permanent treatment discontinuation. This was part of the primary outcome measure that was a composite endpoint.
Time frame: Regimen limiting drug toxicity was monitored from randomization up to the entire study duration of 4.8 years.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Deferred Therapy | Number of Participants Who Experienced Regimen-limiting ART Drug Toxicity | 0 Participants |
| Early Therapy up to 40 Weeks | Number of Participants Who Experienced Regimen-limiting ART Drug Toxicity | 0 Participants |
| Early Therapy up to 96 Weeks | Number of Participants Who Experienced Regimen-limiting ART Drug Toxicity | 0 Participants |
Primary
Number of Participants Who Experienced Virological Failure Defined as Confirmed HIV-1 RNA Value of at Least 10,000 Copies Per/ml Recorded on Two Consecutive Separate Occasions After 24 Weeks of Treatment (Initial Therapy or Restart)
This was part of the primary outcome measure that was a composite endpoint that included confirmed HIV-1 RNA value of at least 10,000 copies per/ml recorded on two consecutive separate occasions after 24 weeks of treatment (initial therapy or restart).
Time frame: Virological failure was assessed from randomization through the entire study duration of 4.8 years.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Deferred Therapy | Number of Participants Who Experienced Virological Failure Defined as Confirmed HIV-1 RNA Value of at Least 10,000 Copies Per/ml Recorded on Two Consecutive Separate Occasions After 24 Weeks of Treatment (Initial Therapy or Restart) | 10 Participants |
| Early Therapy up to 40 Weeks | Number of Participants Who Experienced Virological Failure Defined as Confirmed HIV-1 RNA Value of at Least 10,000 Copies Per/ml Recorded on Two Consecutive Separate Occasions After 24 Weeks of Treatment (Initial Therapy or Restart) | 1 Participants |
| Early Therapy up to 96 Weeks | Number of Participants Who Experienced Virological Failure Defined as Confirmed HIV-1 RNA Value of at Least 10,000 Copies Per/ml Recorded on Two Consecutive Separate Occasions After 24 Weeks of Treatment (Initial Therapy or Restart) | 1 Participants |
Primary
Time to Failure of First Line Therapy or Death
To compare time to failure of first line ART (due to clinical, virological or immunological disease progression, or regimen-limiting ART toxicities) or death among three randomized arms (infants who receive early ART in Arms 2 and 3 and infants in whom ART is deferred until clinical or immunological disease progression in Arm 1) during the study (up to 4.8 years). The number of participants experiencing the events did not reach the 50% survival and thus median time-to-event is not be presented. Therefore we report the number of participants experiencing the events per Arm.
Time frame: From date of randomization up to failure of first-line therapy or death from any cause, whichever came first, assessed up to 4.8 years
Population: In the analysis of failure of first-line therapy, children enrolled in the ART-Deferred group were used as the reference category in the hazard ratio analysis.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Deferred Therapy | Time to Failure of First Line Therapy or Death | 48 Participants |
| Early Therapy up to 40 Weeks | Time to Failure of First Line Therapy or Death | 32 Participants |
| Early Therapy up to 96 Weeks | Time to Failure of First Line Therapy or Death | 26 Participants |
Comparison: Statistical analysis compares early therapy 40 weeks (ART-40W) relative to deferred therapy (ART-Def)p-value: 0.0295% CI: [0.38, 0.93]Regression, Cox
Comparison: Statistical analysis compares early therapy 96 weeks (ART-96W) relative to deferred therapy (ART-Def)p-value: 0.00295% CI: [0.27, 0.76]Regression, Cox
Secondary
Duration of Hospitalisation
This is the total number of days spent in hospital by the participants and is reported per arm
Time frame: 4.8 years, the study duration
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Deferred Therapy | Duration of Hospitalisation | 1018 Days |
| Early Therapy up to 40 Weeks | Duration of Hospitalisation | 533 Days |
| Early Therapy up to 96 Weeks | Duration of Hospitalisation | 414 Days |
p-value: 0.004Poisson regression
Secondary
Hospitalization Rates
Hospitalisation rates in the three arms enrolled in the CHER study
Time frame: 4.8 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Deferred Therapy | Hospitalization Rates | 27.6 Events per 100 person years |
| Early Therapy up to 40 Weeks | Hospitalization Rates | 16.4 Events per 100 person years |
| Early Therapy up to 96 Weeks | Hospitalization Rates | 14.2 Events per 100 person years |
Secondary
Number of Children Experiencing Severe CDC Stage B or Stage C Disease or Death (Cumulative After 3.5 Years)
The outcome measure is defined as a number because it represents the number of children that experienced severe CDC Stage B or Stage C disease or death as defined in the outcome measure title above
Time frame: Occurrence of severe CDC Stage B or Stage C disease or death (cumulative after 3.5 years), whichever came first, was assessed from randomization up to at least 3.5 years.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Deferred Therapy | Number of Children Experiencing Severe CDC Stage B or Stage C Disease or Death (Cumulative After 3.5 Years) | 41 Participants |
| Early Therapy up to 40 Weeks | Number of Children Experiencing Severe CDC Stage B or Stage C Disease or Death (Cumulative After 3.5 Years) | 28 Participants |
| Early Therapy up to 96 Weeks | Number of Children Experiencing Severe CDC Stage B or Stage C Disease or Death (Cumulative After 3.5 Years) | 21 Participants |
Comparison: Relative to ART-Def, ART-40W had a 13% difference in the cumulative probability of clinical disease progression or death at 3·5 yearsp-value: 0.0395% CI: [0.01, 0.25]Proportion test
Comparison: Relative to ART-Def, ART-96W had a 13% difference in the cumulative probability of clinical disease progression or death at 3·5 yearsp-value: 0.000695% CI: [0.09, 0.31]Proportion test
Secondary
Number of Participants With Indicated Viral Resistance Mutations at the Time of Failure of First Line Therapy
Resistance testing was performed on samples with a VL≥1000 c/ml together with the matched baseline sample, if available. Reverse transcriptase (NRTI and NNRTI) and protease (PI) inhibitor mutations were analysed using a validated in-house population-based sequencing assay and the IAS 2011 mutation list.
Time frame: 4.8 years
Population: Mutations presented descriptively were 1) Protease inhibitor mutations and 2) Met184Val mutations were reported. Only 32 participants with viral load above 1,000 copies/ml at their last visit while on treatment were analysed.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Deferred Therapy | Number of Participants With Indicated Viral Resistance Mutations at the Time of Failure of First Line Therapy | Met184Val mutations | 1 Participants |
| Deferred Therapy | Number of Participants With Indicated Viral Resistance Mutations at the Time of Failure of First Line Therapy | PI mutations | 1 Participants |
| Deferred Therapy | Number of Participants With Indicated Viral Resistance Mutations at the Time of Failure of First Line Therapy | No mutations | 3 Participants |
| Early Therapy up to 40 Weeks | Number of Participants With Indicated Viral Resistance Mutations at the Time of Failure of First Line Therapy | Met184Val mutations | 5 Participants |
| Early Therapy up to 40 Weeks | Number of Participants With Indicated Viral Resistance Mutations at the Time of Failure of First Line Therapy | PI mutations | 1 Participants |
| Early Therapy up to 40 Weeks | Number of Participants With Indicated Viral Resistance Mutations at the Time of Failure of First Line Therapy | No mutations | 8 Participants |
| Early Therapy up to 96 Weeks | Number of Participants With Indicated Viral Resistance Mutations at the Time of Failure of First Line Therapy | PI mutations | 0 Participants |
| Early Therapy up to 96 Weeks | Number of Participants With Indicated Viral Resistance Mutations at the Time of Failure of First Line Therapy | No mutations | 12 Participants |
| Early Therapy up to 96 Weeks | Number of Participants With Indicated Viral Resistance Mutations at the Time of Failure of First Line Therapy | Met184Val mutations | 1 Participants |
Secondary
Time From Randomization to Starting or Needing to Start Continuous Therapy
Time from randomization to starting (deferred therapy Arm) or needing to start continuous therapy (early therapy 40 or 96 weeks)
Time frame: 4.8 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Deferred Therapy | Time From Randomization to Starting or Needing to Start Continuous Therapy | 20 Weeks |
| Early Therapy up to 40 Weeks | Time From Randomization to Starting or Needing to Start Continuous Therapy | 33 Weeks |
| Early Therapy up to 96 Weeks | Time From Randomization to Starting or Needing to Start Continuous Therapy | 70 Weeks |
Secondary
Time to Death Alone or Death Plus Life Threatening Stage C Events or HIV Events Associated With Permanent End-organ Damage.
This was a composite endpoint in which the number of children experiencing the events is reported. The number of participants experiencing the events did not reach the 50% survival and thus median time-to-event is not be presented. Therefore, we report the number of participants experiencing the events per Arm.
Time frame: 4.8 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Deferred Therapy | Time to Death Alone or Death Plus Life Threatening Stage C Events or HIV Events Associated With Permanent End-organ Damage. | 34 Participants |
| Early Therapy up to 40 Weeks | Time to Death Alone or Death Plus Life Threatening Stage C Events or HIV Events Associated With Permanent End-organ Damage. | 18 Participants |
| Early Therapy up to 96 Weeks | Time to Death Alone or Death Plus Life Threatening Stage C Events or HIV Events Associated With Permanent End-organ Damage. | 13 Participants |
Comparison: The analysis compares ART-40W relative to the ART-Def arm.p-value: 0.01195% CI: [0.27, 0.84]Regression, Cox
Comparison: The analysis compares ART-96 Weeks relative to ART-Deferredp-value: 0.000995% CI: [0.18, 0.64]Regression, Cox
Secondary
Time to First Hospitalization
To compare time to first hospitalization in the three randomized arms (infants who received early ART in Arms 2 and 3 and those who received deferred ART in Arm 1). Not all participants were hospitalized and thus the upper limits could not be evaluated.
Time frame: From randomization up to 4.8 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Deferred Therapy | Time to First Hospitalization | 73.1 Weeks |
| Early Therapy up to 40 Weeks | Time to First Hospitalization | NA Weeks |
| Early Therapy up to 96 Weeks | Time to First Hospitalization | NA Weeks |
p-value: 0.002195% CI: [0.389, 0.811]Regression, Cox
p-value: 0.003895% CI: [0.405, 0.84]Regression, Cox
Secondary
Total Occurrence of Grade 3 or 4 Clinical Events
This was a secondary outcome measure that assessed the total count of Grade 3 or 4 (clinical or laboratory) adverse events.
Time frame: 4.8 years
Population: This analysis was only performed on the primary groups including a total of 377 participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Deferred Therapy | Total Occurrence of Grade 3 or 4 Clinical Events | 170 Count of events |
| Early Therapy up to 40 Weeks | Total Occurrence of Grade 3 or 4 Clinical Events | 118 Count of events |
| Early Therapy up to 96 Weeks | Total Occurrence of Grade 3 or 4 Clinical Events | 88 Count of events |
Comparison: The CHER study compared Grade 3 or 4 clinical event rates per 100 person-years between the three arms using Poisson regression modeling over the study duration of 4.8 years.p-value: <0.0001Poisson Regression
Secondary
Total Occurrence of Grade 3 or 4 Laboratory Events
Time frame: From randomization up to 4.8 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Deferred Therapy | Total Occurrence of Grade 3 or 4 Laboratory Events | 35 Count of events |
| Early Therapy up to 40 Weeks | Total Occurrence of Grade 3 or 4 Laboratory Events | 44 Count of events |
| Early Therapy up to 96 Weeks | Total Occurrence of Grade 3 or 4 Laboratory Events | 33 Count of events |
Comparison: The event rates per 100 person years were compared across the three armsp-value: 0.46Poisson regression