HIV-1 Infection, Kaposi's Sarcoma
Conditions
Brief summary
AIDS-related Kaposi's sarcoma (AIDS-KS) occurs in persons with HIV infection who are also infected with the Kaposi's sarcoma herpesvirus (KSHV). Several chemotherapy (anti-cancer) drugs work well in treating KS, but there is no treatment that cures KSHV infection. One chemotherapy drug called etoposide (VePesid®, ET) has caused KS tumors to get smaller in some people. Antiretroviral therapy (anti-HIV drugs or ART) is a group of medicines taken together to treat HIV infection. These medicines help to stop HIV from growing in the body. When this happens, the immune system, which fights infection and some cancers like KS, gets stronger. For some people, limited stage KS often improves or stays the same when they take ART. However, in some people KS continues to get worse when taking ART. These people may need chemotherapy at a later date. This study was done to find out if taking ART with immediate etoposide (ET) is better than taking ART alone or ART with delayed ET to treat limited stage KS. The study also tried to better understand KSHV and to see what kind of side effects are caused by ART and ET and how safe ART and ET are.
Detailed description
The study consisted of three steps. At the study Step 1 entry, the participants were randomized (1:1) to receive ART alone (Arm A) or ART with immediate ET (Arm B). Study participants in Arm A who experienced KS progression that was confirmed by the Independent Endpoint Review Committee (IERC) could receive etoposide (ET) in addition to ART by entering Step 2 between study weeks 8 and 80. The target sample size was 468, 234 per arm. Randomization was stratified by: 1. Screening CD4 cell count (\<200 or ≥200 cells/mm\^3) and 2. ART history (naïve or experienced). The duration of Step 1 or Step 1 and 2 combined was 96 weeks. After 96 weeks on study, participants who received ET (Arm B participants and Arm A participants who entered Step 2) entered Step 3 for a total of 144 weeks of safety follow-up. Step 1 visits occurred at screening, entry and weeks 2, 4, 6, 8, 10, 12, 14, 16, 20, 24, 32, 40, 48, 60, 72, 84 and 96 from study entry. Step 2 visits were scheduled at entry and weeks 2, 4, 6, 8, 10, 12, 14, 16, 20, 24, 32, 40, 48, 60, 72, 84 from Step 2 entry until up to 96 weeks on study. The key evaluations included physical examination, clinical assessments, KS exam, CD4 cell count, HIV viral load, hematology, chemistry and pregnancy testing (for women of reproductive potential). Plasma, serum, peripheral blood mononuclear cells (PBMCs), KS tumor punch biopsy were be stored for use in future analyses. Participants also completed ET and ART adherence evaluations and quality of life questionnaires. Step 3 visits were scheduled every 24 weeks and were limited to safety evaluations including targeted physical exam, clinical assessments and hematology. Study accrual terminated early, based on the Data and Safety Monitoring Board (DSMB) recommendation in March 2016. The participants in Steps 1 and 2 at that time were arranged to enter either Step 3 for safety follow-up after ET or, if they did not receive ET, to be taken off study.
Interventions
600 mg efavirenz/200 mg emtricitabine/300 mg tenofovir disoproxil fumarate taken orally at night
DRUGetoposide
50 mg taken orally daily from days 1-7 of each 2-week cycle. For participants without PR or CR after two cycles of therapy and no toxicity greater than Grade 2, the dose of ET was escalated to 100 mg/day orally, days 1-7, every 2 weeks. A cycle could be delayed for a maximum of 14 days. ET could not be initiated prior to 7 days after the last dose in previous cycle. ET could be administered up to a maximum of eight cycles (2 cycles during dose titration and 6 cycles at maximum dose). Participants who could not tolerate escalation of the ET dose to 100 mg/day were treated for a maximum of six cycles.
Sponsors
National Institute of Allergy and Infectious Diseases (NIAID)
Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Step 1: Inclusion Criteria 1. HIV-1 infection. 2. Biopsy diagnostic of KS at any time prior to study entry. 3. Limited stage KS defined as stage T0 and some presentations of stage T1. Stage T0 was confined to skin and/or lymph nodes and/or minimal oral disease defined as non-nodular KS confined to the palate. The following presentations of stage T1 KS were also eligible at the discretion of the site investigator: * Tumor-associated edema limited to the area(s) of KS without significant functional impairment. * Oral KS that consists of flat (non-nodular and non-ulcerating) lesions confined to the soft palate, hard palate, gums, and buccal mucosa. * Asymptomatic gastrointestinal KS (i.e., no unexplained abdominal pain or gastrointestinal bleeding). 4. A minimum of 5 cutaneous marker lesions 5. Certain laboratory values obtained within 14 days prior to study entry. 6. For female participants of reproductive potential, a negative serum or urine pregnancy test performed within 7 days prior to study entry. 7. All participants must have agreed not to participate in a conception process (e.g., active attempt to become pregnant or to impregnate, donate sperm, in vitro fertilization). 8. Participants who are participating in sexual activity that could lead to pregnancy must have agreed to use a combination of TWO of the following methods- Condoms (male or female) with or without a spermicidal agent, diaphragm or cervical cap with spermicide, IUD, tubal ligation, and/or hormone-based contraception. For Etoposide, confirmation of lack of reproductive potential was required for all participants. More information on this criterion can be found in the study protocol. 9. Ability to swallow oral medications. 10. Karnofsky performance score \>= 60 within 30 days prior to entry. 11. Ability and willingness of participant or legal guardian/representative to provide informed consent. 12. Peripheral blood CD4+ lymphocyte cell count obtained within 30 days prior to study entry at a DAIDS-approved laboratory. 13. For treatment-experienced patients, the availability of an ART regimen that includes at least two ART drugs that in the opinion of the site investigator are expected to have activity based on historical genotypic testing (if available) and treatment history. 14. For participants who were to receive ART other than EFV/TDF/FTC, the availability of those ART components. Step 2: Inclusion Criteria 1. KS progression compared to study entry or best response with ART alone while on Step 1, between weeks 8 and 80. 2. Need for ET for treatment of KS progression, in the opinion of the site investigator, after confirmation of KS progression by the IERC. 3. Willingness to receive ET for treatment of KS progression. 4. For female participants of reproductive potential, a negative serum or urine pregnancy test performed within 7 days prior to initiating ET. 5. Karnofsky Performance Score \>= 50. 6. Certain laboratory values obtained within 14 days prior to Step 2 entry. 7. Ability to swallow oral medications. 8. All participants must have agreed not to participate in a conception process (e.g., active attempt to become pregnant or to impregnate, donate sperm, in vitro fertilization). 9. Participants who are participating in sexual activity that could lead to pregnancy must have agreed to use a combination of TWO of the following methods- Condoms (male or female) with or without a spermicidal agent, diaphragm or cervical cap with spermicide, IUD, tubal ligation, hormone-based contraception. For Etoposide, confirmation of lack of reproductive potential was required for all participants. More information on this criterion can be found in the study protocol. Step 3: Inclusion Criteria 1\. Received at least one dose of ET (Arm B participants and Arm A participants who entered Step 2) Step 1:
Exclusion criteria
1. Any manifestation of KS which, in the opinion of the site investigator, requires immediate chemotherapy. 2. More than 14 days of ART after onset of KS within 6 months prior to study entry. 3. Biopsy proven KS during previous ART. 4. Breastfeeding. 5. Allergy/sensitivity to any study drug or its formulations. 6. Any prior systemic anti-neoplastic treatment for KS (including chemotherapy, biological therapy, immunotherapy or investigational therapy). 7. Any prior local treatment of cutaneous marker lesions unless there was evidence of a clear-cut progression of the lesion. 8. Receipt of any investigational therapy within 30 days prior to study entry. 9. Current or anticipated receipt of any of the prohibited medications indicated in the study protocol. 10. In the opinion of the site investigator, any psychological or social condition, or addictive disorder that would have precluded compliance with the protocol. 11. Chronic, acute, or recurrent infections that were serious, in the opinion of the site investigator, for which the participant had not completed at least 14 days of therapy prior to study entry and/or was not clinically stable. Step 2:
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Kaposi Sarcoma (KS) Status at Week 48 Compared to Study Entry | Entry through Week 48. | KS status is a composite, categorical outcome, ordered from worst to best as E1 (Failure: KS progression (PD), initiation of an alternate KS treatment, or no follow-up at Week 48 including death and missed visit), E2 (Stable: in follow-up at Week 48 with no KS PD nor response and without initiation of an alternate KS treatment) and E3 (Response: in follow-up at Week 48, with KS partial or complete response (PR or CR) and without initiation of an alternate KS treatment). Alternate KS treatment was defined as chemotherapy agent other than ET or other treatment triggered by worsening KS. KS outcome status (PR, stable, PR, CR) compared to study entry was evaluated at Week 48 based on clinical assessment of KS cutaneous lesions (count, character and marker lesion area), oral KS, visceral KS and tumor-associated edema and as described in the publications (Krown et al 1989, Cianfrocca et al 2002). Data on initiation of alternate KS treatment, loss to follow-up and dea |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| KS Partial Response at Week 48 Compared to Study Entry | Entry and Week 48 | KS partial response (PR) compared to study entry based on clinical assessment of KS cutaneous lesions (count, character and marker lesion area), oral KS, visceral KS and tumor-associated edema and as described in the publications (Krown et al 1989, Cianfrocca et al 2002). |
| KS Complete Response at Week 48 Compared to Study Entry | Entry and Week 48 | KS complete response (CR) compared to study entry based on clinical assessment of KS cutaneous lesions (count, character and marker lesion area), oral KS, visceral KS and tumor-associated edema and as described in the publications (Krown et al 1989, Cianfrocca et al 2002). |
| KS Partial or Complete Response at Week 48 Compared to Study Entry | Entry and Week 48 | KS partial response (PR) or complete response (CR) compared to study entry based on clinical assessment of KS cutaneous lesions (count, character and marker lesion area), oral KS, visceral KS and tumor-associated edema and as described in the publications (Krown et al 1989, Cianfrocca et al 2002). |
| Premature Study Discontinuation by Week 48 | Entry through Week 48 | Premature study discontinuation by Week 48 due to any reason, including death. |
| Kaposi Sarcoma (KS) Status at Week 96 Compared to Study Entry | Entry through Week 96. | KS status is a composite, categorical outcome, ordered from worst to best as E1 (Failure: KS PD, initiation of an alternate KS treatment, or no follow-up at Week 96 including death and missed visit), E2 (Stable: in follow-up at Week 96 with no KS progression nor response and without initiation of an alternate KS treatment) and E3 (Response: in follow-up at Week 96, with KS PR or CR and without initiation of an alternate KS treatment). Alternate KS treatment was defined as chemotherapy agent other than ET or other treatment triggered by worsening KS. KS outcome status (PD, stable, PR or CR) compared to study entry was evaluated at Week 96 based on clinical assessment of KS cutaneous lesions (count, character and marker lesion area), oral KS, visceral KS and tumor-associated edema and as described in the publications (Krown et al 1989, Cianfrocca et al 2002). Data on initiation of alternate KS treatment, loss to follow-up and deaths are from entry through Week 96. |
| KS Progressive Disease at Week 96 Compared to Study Entry | Entry and Week 96 | KS progressive disease (PD) compared to study entry based on clinical assessment of KS cutaneous lesions (count, character and marker lesion area), oral KS, visceral KS and tumor-associated edema and as described in the publications (Krown et al 1989, Cianfrocca et al 2002). |
| KS Partial Response at Week 96 Compared to Study Entry | Entry and Week 96 | KS partial response (PR) compared to study entry based on clinical assessment of KS cutaneous lesions (count, character and marker lesion area), oral KS, visceral KS and tumor-associated edema and as described in the publications (Krown et al 1989, Cianfrocca et al 2002). |
| KS Complete Response at Week 96 Compared to Study Entry | Entry and Week 96 | KS complete response (CR) compared to study entry based on clinical assessment of KS cutaneous lesions (count, character and marker lesion area), oral KS, visceral KS and tumor-associated edema and as described in the publications (Krown et al 1989, Cianfrocca et al 2002). |
| KS Partial or Complete Response at Week 96 Compared to Study Entry | Entry and Week 96 | KS partial response (PR) or complete response (CR) compared to study entry based on clinical assessment of KS cutaneous lesions (count, character and marker lesion area), oral KS, visceral KS and tumor-associated edema and as described in the publications (Krown et al 1989, Cianfrocca et al 2002). |
| Premature Study Discontinuation by Week 96 | Entry through Week 96 | Premature study discontinuation by Week 96 due to any reason, including death. |
| Cumulative Incidence of Initial KS Progressive Disease by Week 96 | From entry through 96 weeks | KS progressive disease (PD) compared to study entry or best response based on clinical assessment of KS cutaneous lesions (count, character and marker lesion area), oral KS, visceral KS and tumor-associated edema and as described in the publications (Krown et al 1989, Cianfrocca et al 2002). Cumulative incidence was estimated with death and initiation of alternate KS treatment as competing risks. Time at risk was censored at the end of Step 1 (Week 96 or premature study discontinuation) or on the date when the DSMB's recommendation to close the study became public, whichever occurred earlier. |
| KS Progressive Disease at Week 48 Compared to Study Entry | Entry and Week 48 | KS progressive disease (PD) compared to study entry based on clinical assessment of KS cutaneous lesions (count, character and marker lesion area), oral KS, visceral KS and tumor-associated edema and as described in the publications (Krown et al 1989, Cianfrocca et al 2002). |
| Cumulative Incidence of Initial KS Partial Response by Week 96 | From study treatment initiation to 96 weeks | KS partial response (PR) compared to study entry based on clinical assessment of KS cutaneous lesions (count, character and marker lesion area), oral KS, visceral KS and tumor-associated edema and as described in the publications (Krown et al 1989, Cianfrocca et al 2002). This was initially part of the outcome specified in the study protocol as PR and CR combined and separately to address the secondary objective on the KS response. Due to the extremely limited number of participants with KS complete response, the Statistical Analysis Plan was updated, and the Final Analysis was conducted only on the combined KS response. The outcome on PR separately was withdrawn. |
| Cumulative Incidence of Initial KS Complete Response by Week 96 | From study treatment initiation to 96 weeks | KS complete response (CR) compared to study entry based on clinical evaluation of KS cutaneous lesions (count, character and marker lesion area), oral KS, visceral KS and tumor-associated edema and as described in the publications (Krown et al 1989, Cianfrocca et al 2002). This was initially part of the outcome specified in the study protocol as PR and CR combined and separately to address the secondary objective on the KS response. Due to the extremely limited number of participants with KS CR, the Statistical Analysis Plan was updated, and the Final Analysis was conducted only on the combined KS response. The outcome on CR separately was withdrawn. |
| Number of Participants With Grade 3 or Higher Adverse Events | From study treatment dispensation through up to Week 96, until long-term follow-up began in Step 3 or until study discontinuation. | Number of participants who experienced an AE (sign/symptom or laboratory abnormality) of Grade 3 or higher. The AEs were graded by the clinicians according to the Division of AIDS (DAIDS) AE Grading Table (see reference in the Protocol Section) as follows: Grade 1=Mild, Grade 2=Moderate, Grade 3=Severe, Grade 4=Potentially Life-Threatening. |
| Cumulative Incidence of KS-IRIS | From study entry to Week 12 | KS-IRIS was defined as KS progressive disease that occurs within 12 weeks of initiation of ART that is associated with an increase in peripheral blood CD4+ lymphocyte cell count of at least 50 cells/mm\^3 above the study screening value and/or a decrease in the HIV RNA level by at least 0.5 log10 below the study entry value prior to, or at the time of, documented KS progressive disease. Cumulative incidence was estimated with death and initiation of alternate KS treatment as competing risks. Time at risk was censored (1) when lost to follow-up, (2) at the study visit following Week 12 or (3) on the date when the DSMB's recommendation to close the study became public, whichever occurred earlier. Time of KS-IRIS was defined as the time of the initial KS progressive disease. |
| Percentage of Participants With Etoposide Dose Modification | From ET dispensation to ET discontinuation (total duration of ET was up to 16 weeks) | Etoposide (ET) was administered for a maximum of 8 cycles (16 weeks) from study entry (Arm B) or from Step 2 entry (Arm A). Dose modifications were reported as temporarily held, resumed at a different dose, deferred, prematurely discontinued and underdosed. The percentage of participants who experienced each dose modification is provided in the data table below. The categories are not mutually exclusive. A participant may have experienced multiple dose modifications and may be counted in more than one category. Each participant is counted at most once within category. |
| Percentage of Participants With HIV-1 RNA Suppression | Entry and Weeks 12, 24, 32, 48, 72, 96; Step 2 entry and Weeks 12, 24, 32, 48 and 72. | HIV-1 RNA suppression was defined as plasma HIV-1 RNA \<400 copies/mL. Only Arm A participants could enter Step 2 to initiate delayed ET. |
| Percentage of Participants With ARV Dose Modification | From treatment dispensation to Week 96 | ARV dose modifications were reported as temporarily held, prematurely discontinued and increased. The percentage of participants who experienced each dose modification is provided in the data table below. The categories are not mutually exclusive. A participant may have experienced multiple dose modifications and may be counted in more than one category. Each participant is counted at most once within category. |
| Change in log10 HIV-1 Plasma Viral Load From Entry | Entry and Weeks 12, 24, 32, 48, 72, 96; Step 2 entry and Weeks 12, 24, 32, 48 and 72. | Absolute change in log10 HIV-1 RNA from entry at study visits calculated as value at a given time point minus value at entry. This outcome was initially specified in the study protocol. However, at the first post-entry visit, most participants had unquantifiable HIV-1 RNA levels. It would be misleading to calculate change from entry to HIV RNA-1 levels that could not be quantified. Therefore, the data collected did not support the outcome and the analytic method initially proposed in the study protocol, and this outcome measure could not be analyzed. The SAP updated the HIV-1 RNA outcome measure to HIV-1 RNA suppression at study visits (please refer to the secondary outcome measure #20). |
| Change in Peripheral Blood CD4+ Lymphocyte Cell Count | Screening and Weeks 12, 24, 32, 48, 72, 96; Step 2 entry and Weeks 12, 24, 32, 48 and 72. | Absolute change in CD4+ cell count was calculated as value at a given visit minus the value at study screening in Step 1, and as value at a given visit minus Step 2 entry in Step 2. Only participants in Arm A could enter Step 2 to initiate delayed ET. |
| Cumulative Incidence of KS Progressive Disease After Initiation of Delayed Etoposide in Arm A | From initiation of etoposide (Step 2 entry) to up to 84 weeks (end of Step 2) | KS progressive disease (PD) compared to Step 2 entry (prior to initiation of delayed ET) or Step 2 best response based on clinical assessment of KS cutaneous lesions (count, character and marker lesion area), oral KS, visceral KS and tumor-associated edema and as described in the publications (Krown et al 1989, Cianfrocca et al 2002). Cumulative incidence was estimated with death and initiation of alternate KS treatment as competing risks. Time at risk was censored at the end of Step 2 (at up to 84 weeks or premature study discontinuation) or on the date when the DSMB's recommendation to close the study became public, whichever occurred earlier. |
| Cumulative Incidence of KS Response After Initiation of Delayed Etoposide in Arm A | From initiation of etoposide (Step 2 entry) to up to 84 weeks (end of Step 2) | KS response, partial or complete (PR or CR) compared to Step 2 entry (prior to initiation of delayed ET) based on clinical assessment of KS cutaneous lesions (count, character and marker lesion area), oral KS, visceral KS and tumor-associated edema and as described in the publications (Krown et al 1989, Cianfrocca et al 2002). Cumulative incidence was estimated with death and initiation of alternate KS treatment as competing risks. Time at risk was censored at the end of Step 2 (at up to 84 weeks or premature study discontinuation) or on the date when the DSMB's recommendation to close the study became public, whichever occurred earlier. |
| Cumulative Incidence of Initial KS Partial or Complete Response by Week 96 | From entry through 96 weeks | KS partial response (PR) or complete response (CR) compared to study entry based on clinical assessment of KS cutaneous lesions (count, character and marker lesion area), oral KS, visceral KS and tumor-associated edema and as described in the publications (Krown et al 1989, Cianfrocca et al 2002). Cumulative incidence was estimated with death and initiation of delayed KS treatment (alternate KS treatment or delayed ET in Arm A) as competing risks. Time at risk was censored at the end of Step 1 (Week 96 or premature study discontinuation) or on the date when the DSMB's recommendation to close the study became public, whichever occurred earlier. |
Countries
Brazil, Kenya, Malawi, Peru, South Africa, Uganda
Participant flow
Recruitment details
Participants were recruited from November 2011 to February 2016 at 10 sites in Africa and South America.
Participants by arm
| Arm | Count |
|---|---|
| Arm A: ART Alone or With Delayed ET Participants were prescribed ART for 96 weeks. Arm A participants who experienced KS progression on ART alone could receive etoposide (ET) in addition to ART in Step 2 of the study. | 94 |
| Arm B: ART With Immediate ET Participants were prescribed ART for 96 weeks with immediate etoposide (ET) for up to 16 weeks. | 96 |
| Total | 190 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 15 | 16 |
| Overall Study | Did not initiate study treatment | 1 | 0 |
| Overall Study | Ineligible (no KS diagnosis) | 1 | 0 |
| Overall Study | Lost to Follow-up | 2 | 7 |
| Overall Study | Non-adherent to study requirements | 1 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Arm A: ART Alone or With Delayed ET | Arm B: ART With Immediate ET | Total |
|---|---|---|---|
| Age, Continuous | 34 years | 35 years | 34 years |
| ART experience ART-experienced | 0 Participants | 1 Participants | 1 Participants |
| ART experience ART-naive | 94 Participants | 95 Participants | 189 Participants |
| CD4 cell count, categorized <200 cells/mm^3 | 50 Participants | 53 Participants | 103 Participants |
| CD4 cell count, categorized >=200 cells/mm^3 | 44 Participants | 43 Participants | 87 Participants |
| CD4 cell count, continuous | 190 cells/mm^3 | 165 cells/mm^3 | 184 cells/mm^3 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 8 Participants | 8 Participants | 16 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 83 Participants | 86 Participants | 169 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 3 Participants | 2 Participants | 5 Participants |
| HIV-1 RNA | 5.11 log10 copies/mL | 5.10 log10 copies/mL | 5.11 log10 copies/mL |
| Karnofsky score 100 | 5 Participants | 5 Participants | 10 Participants |
| Karnofsky score 60 | 1 Participants | 0 Participants | 1 Participants |
| Karnofsky score 70 | 8 Participants | 5 Participants | 13 Participants |
| Karnofsky score 80 | 26 Participants | 26 Participants | 52 Participants |
| Karnofsky score 90 | 54 Participants | 60 Participants | 114 Participants |
| KS stage KS tumor Stage T0 | 35 Participants | 40 Participants | 75 Participants |
| KS stage KS tumor Stage T1 | 59 Participants | 56 Participants | 115 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 89 Participants | 88 Participants | 177 Participants |
| Race (NIH/OMB) Other | 3 Participants | 2 Participants | 5 Participants |
| Race (NIH/OMB) White | 2 Participants | 5 Participants | 7 Participants |
| Region of Enrollment Brazil | 4 Participants | 5 Participants | 9 Participants |
| Region of Enrollment Kenya | 15 Participants | 13 Participants | 28 Participants |
| Region of Enrollment Malawi | 30 Participants | 32 Participants | 62 Participants |
| Region of Enrollment Peru | 2 Participants | 3 Participants | 5 Participants |
| Region of Enrollment South Africa | 6 Participants | 6 Participants | 12 Participants |
| Region of Enrollment Uganda | 28 Participants | 30 Participants | 58 Participants |
| Region of Enrollment Zimbabwe | 9 Participants | 7 Participants | 16 Participants |
| Sex: Female, Male Female | 66 Participants | 69 Participants | 135 Participants |
| Sex: Female, Male Male | 28 Participants | 27 Participants | 55 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 15 / 94 | 16 / 96 |
| other Total, other adverse events | 83 / 94 | 88 / 96 |
| serious Total, serious adverse events | 34 / 94 | 34 / 96 |
Outcome results
Primary
Kaposi Sarcoma (KS) Status at Week 48 Compared to Study Entry
KS status is a composite, categorical outcome, ordered from worst to best as E1 (Failure: KS progression (PD), initiation of an alternate KS treatment, or no follow-up at Week 48 including death and missed visit), E2 (Stable: in follow-up at Week 48 with no KS PD nor response and without initiation of an alternate KS treatment) and E3 (Response: in follow-up at Week 48, with KS partial or complete response (PR or CR) and without initiation of an alternate KS treatment). Alternate KS treatment was defined as chemotherapy agent other than ET or other treatment triggered by worsening KS. KS outcome status (PR, stable, PR, CR) compared to study entry was evaluated at Week 48 based on clinical assessment of KS cutaneous lesions (count, character and marker lesion area), oral KS, visceral KS and tumor-associated edema and as described in the publications (Krown et al 1989, Cianfrocca et al 2002). Data on initiation of alternate KS treatment, loss to follow-up and dea
Time frame: Entry through Week 48.
Population: All eligible participants who initiated study treatment and had Study Week 48 data potential (i.e. participants enrolled at least 45 weeks prior to the date when the Data and Safety Monitoring Board's \[DSMB\] recommendation to close the study became public).
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm A: ART Alone or With Delayed ET | Kaposi Sarcoma (KS) Status at Week 48 Compared to Study Entry | E2 (Stable) | 13 Participants |
| Arm A: ART Alone or With Delayed ET | Kaposi Sarcoma (KS) Status at Week 48 Compared to Study Entry | E3 (Response) | 24 Participants |
| Arm A: ART Alone or With Delayed ET | Kaposi Sarcoma (KS) Status at Week 48 Compared to Study Entry | E1 (Failure) | 43 Participants |
| Arm B: ART With Immediate ET | Kaposi Sarcoma (KS) Status at Week 48 Compared to Study Entry | E1 (Failure) | 47 Participants |
| Arm B: ART With Immediate ET | Kaposi Sarcoma (KS) Status at Week 48 Compared to Study Entry | E2 (Stable) | 9 Participants |
| Arm B: ART With Immediate ET | Kaposi Sarcoma (KS) Status at Week 48 Compared to Study Entry | E3 (Response) | 27 Participants |
p-value: 0.911Wilcoxon (Mann-Whitney)
Secondary
Change in log10 HIV-1 Plasma Viral Load From Entry
Absolute change in log10 HIV-1 RNA from entry at study visits calculated as value at a given time point minus value at entry. This outcome was initially specified in the study protocol. However, at the first post-entry visit, most participants had unquantifiable HIV-1 RNA levels. It would be misleading to calculate change from entry to HIV RNA-1 levels that could not be quantified. Therefore, the data collected did not support the outcome and the analytic method initially proposed in the study protocol, and this outcome measure could not be analyzed. The SAP updated the HIV-1 RNA outcome measure to HIV-1 RNA suppression at study visits (please refer to the secondary outcome measure #20).
Time frame: Entry and Weeks 12, 24, 32, 48, 72, 96; Step 2 entry and Weeks 12, 24, 32, 48 and 72.
Population: At the first post-entry visit, most participants had unquantifiable HIV-1 RNA levels. Therefore, this outcome measure could not be analyzed.
Secondary
Change in Peripheral Blood CD4+ Lymphocyte Cell Count
Absolute change in CD4+ cell count was calculated as value at a given visit minus the value at study screening in Step 1, and as value at a given visit minus Step 2 entry in Step 2. Only participants in Arm A could enter Step 2 to initiate delayed ET.
Time frame: Screening and Weeks 12, 24, 32, 48, 72, 96; Step 2 entry and Weeks 12, 24, 32, 48 and 72.
Population: All eligible participants who initiated study treatment and had CD4 cell count results available at screening and the respective Step 1 visit or at Step 2 entry and the respective Step 2 visit.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Arm A: ART Alone or With Delayed ET | Change in Peripheral Blood CD4+ Lymphocyte Cell Count | Step 2 Week 12: CD4 change | -13 cells/mm^3 |
| Arm A: ART Alone or With Delayed ET | Change in Peripheral Blood CD4+ Lymphocyte Cell Count | Step 2 Week 24: CD4 change | -15 cells/mm^3 |
| Arm A: ART Alone or With Delayed ET | Change in Peripheral Blood CD4+ Lymphocyte Cell Count | Step 2 Week 32: CD4 change | 28 cells/mm^3 |
| Arm A: ART Alone or With Delayed ET | Change in Peripheral Blood CD4+ Lymphocyte Cell Count | Step 2 Week 48: CD4 change | 2 cells/mm^3 |
| Arm A: ART Alone or With Delayed ET | Change in Peripheral Blood CD4+ Lymphocyte Cell Count | Step 2 Week 72: CD4 change | 51 cells/mm^3 |
| Arm A: ART Alone or With Delayed ET | Change in Peripheral Blood CD4+ Lymphocyte Cell Count | Week 48: CD4 change | 125 cells/mm^3 |
| Arm A: ART Alone or With Delayed ET | Change in Peripheral Blood CD4+ Lymphocyte Cell Count | Week 24: CD4 change | 57 cells/mm^3 |
| Arm A: ART Alone or With Delayed ET | Change in Peripheral Blood CD4+ Lymphocyte Cell Count | Week 72: CD4 change | 143 cells/mm^3 |
| Arm A: ART Alone or With Delayed ET | Change in Peripheral Blood CD4+ Lymphocyte Cell Count | Week 32: CD4 change | 90 cells/mm^3 |
| Arm A: ART Alone or With Delayed ET | Change in Peripheral Blood CD4+ Lymphocyte Cell Count | Week 96: CD4 change | 149 cells/mm^3 |
| Arm A: ART Alone or With Delayed ET | Change in Peripheral Blood CD4+ Lymphocyte Cell Count | Week 12: CD4 change | 40 cells/mm^3 |
| Arm B: ART With Immediate ET | Change in Peripheral Blood CD4+ Lymphocyte Cell Count | Week 72: CD4 change | 125 cells/mm^3 |
| Arm B: ART With Immediate ET | Change in Peripheral Blood CD4+ Lymphocyte Cell Count | Week 24: CD4 change | 121 cells/mm^3 |
| Arm B: ART With Immediate ET | Change in Peripheral Blood CD4+ Lymphocyte Cell Count | Week 32: CD4 change | 119 cells/mm^3 |
| Arm B: ART With Immediate ET | Change in Peripheral Blood CD4+ Lymphocyte Cell Count | Week 48: CD4 change | 121 cells/mm^3 |
| Arm B: ART With Immediate ET | Change in Peripheral Blood CD4+ Lymphocyte Cell Count | Week 12: CD4 change | 67 cells/mm^3 |
| Arm B: ART With Immediate ET | Change in Peripheral Blood CD4+ Lymphocyte Cell Count | Week 96: CD4 change | 206 cells/mm^3 |
Secondary
Cumulative Incidence of Initial KS Complete Response by Week 96
KS complete response (CR) compared to study entry based on clinical evaluation of KS cutaneous lesions (count, character and marker lesion area), oral KS, visceral KS and tumor-associated edema and as described in the publications (Krown et al 1989, Cianfrocca et al 2002). This was initially part of the outcome specified in the study protocol as PR and CR combined and separately to address the secondary objective on the KS response. Due to the extremely limited number of participants with KS CR, the Statistical Analysis Plan was updated, and the Final Analysis was conducted only on the combined KS response. The outcome on CR separately was withdrawn.
Time frame: From study treatment initiation to 96 weeks
Population: Due to the extremely limited number of participants with KS CR, KS partial response (PR) and CR were combined. The analyses of CR and PR separately which were initially specified in the study protocol were withdrawn.
Secondary
Cumulative Incidence of Initial KS Partial or Complete Response by Week 96
KS partial response (PR) or complete response (CR) compared to study entry based on clinical assessment of KS cutaneous lesions (count, character and marker lesion area), oral KS, visceral KS and tumor-associated edema and as described in the publications (Krown et al 1989, Cianfrocca et al 2002). Cumulative incidence was estimated with death and initiation of delayed KS treatment (alternate KS treatment or delayed ET in Arm A) as competing risks. Time at risk was censored at the end of Step 1 (Week 96 or premature study discontinuation) or on the date when the DSMB's recommendation to close the study became public, whichever occurred earlier.
Time frame: From entry through 96 weeks
Population: All eligible participants who initiated study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A: ART Alone or With Delayed ET | Cumulative Incidence of Initial KS Partial or Complete Response by Week 96 | 39.89 cumulative events per 100 participants |
| Arm B: ART With Immediate ET | Cumulative Incidence of Initial KS Partial or Complete Response by Week 96 | 64.08 cumulative events per 100 participants |
Secondary
Cumulative Incidence of Initial KS Partial Response by Week 96
KS partial response (PR) compared to study entry based on clinical assessment of KS cutaneous lesions (count, character and marker lesion area), oral KS, visceral KS and tumor-associated edema and as described in the publications (Krown et al 1989, Cianfrocca et al 2002). This was initially part of the outcome specified in the study protocol as PR and CR combined and separately to address the secondary objective on the KS response. Due to the extremely limited number of participants with KS complete response, the Statistical Analysis Plan was updated, and the Final Analysis was conducted only on the combined KS response. The outcome on PR separately was withdrawn.
Time frame: From study treatment initiation to 96 weeks
Population: Due to the extremely limited number of participants with KS CR, KS partial response (PR) and CR were combined. The analyses of CR and PR separately which were initially specified in the study protocol were withdrawn.
Secondary
Cumulative Incidence of Initial KS Progressive Disease by Week 96
KS progressive disease (PD) compared to study entry or best response based on clinical assessment of KS cutaneous lesions (count, character and marker lesion area), oral KS, visceral KS and tumor-associated edema and as described in the publications (Krown et al 1989, Cianfrocca et al 2002). Cumulative incidence was estimated with death and initiation of alternate KS treatment as competing risks. Time at risk was censored at the end of Step 1 (Week 96 or premature study discontinuation) or on the date when the DSMB's recommendation to close the study became public, whichever occurred earlier.
Time frame: From entry through 96 weeks
Population: All eligible participants who initiated study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A: ART Alone or With Delayed ET | Cumulative Incidence of Initial KS Progressive Disease by Week 96 | 60.61 cumulative events per 100 participants |
| Arm B: ART With Immediate ET | Cumulative Incidence of Initial KS Progressive Disease by Week 96 | 52.73 cumulative events per 100 participants |
Secondary
Cumulative Incidence of KS-IRIS
KS-IRIS was defined as KS progressive disease that occurs within 12 weeks of initiation of ART that is associated with an increase in peripheral blood CD4+ lymphocyte cell count of at least 50 cells/mm\^3 above the study screening value and/or a decrease in the HIV RNA level by at least 0.5 log10 below the study entry value prior to, or at the time of, documented KS progressive disease. Cumulative incidence was estimated with death and initiation of alternate KS treatment as competing risks. Time at risk was censored (1) when lost to follow-up, (2) at the study visit following Week 12 or (3) on the date when the DSMB's recommendation to close the study became public, whichever occurred earlier. Time of KS-IRIS was defined as the time of the initial KS progressive disease.
Time frame: From study entry to Week 12
Population: All eligible participants who initiated study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A: ART Alone or With Delayed ET | Cumulative Incidence of KS-IRIS | 23.14 cumulative events per 100 participants |
| Arm B: ART With Immediate ET | Cumulative Incidence of KS-IRIS | 7.40 cumulative events per 100 participants |
Secondary
Cumulative Incidence of KS Progressive Disease After Initiation of Delayed Etoposide in Arm A
KS progressive disease (PD) compared to Step 2 entry (prior to initiation of delayed ET) or Step 2 best response based on clinical assessment of KS cutaneous lesions (count, character and marker lesion area), oral KS, visceral KS and tumor-associated edema and as described in the publications (Krown et al 1989, Cianfrocca et al 2002). Cumulative incidence was estimated with death and initiation of alternate KS treatment as competing risks. Time at risk was censored at the end of Step 2 (at up to 84 weeks or premature study discontinuation) or on the date when the DSMB's recommendation to close the study became public, whichever occurred earlier.
Time frame: From initiation of etoposide (Step 2 entry) to up to 84 weeks (end of Step 2)
Population: All Arm A participants who experienced KS progression and entered Step 2 to initiate delayed ET.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A: ART Alone or With Delayed ET | Cumulative Incidence of KS Progressive Disease After Initiation of Delayed Etoposide in Arm A | 35.78 cumulative events per 100 participants |
Secondary
Cumulative Incidence of KS Response After Initiation of Delayed Etoposide in Arm A
KS response, partial or complete (PR or CR) compared to Step 2 entry (prior to initiation of delayed ET) based on clinical assessment of KS cutaneous lesions (count, character and marker lesion area), oral KS, visceral KS and tumor-associated edema and as described in the publications (Krown et al 1989, Cianfrocca et al 2002). Cumulative incidence was estimated with death and initiation of alternate KS treatment as competing risks. Time at risk was censored at the end of Step 2 (at up to 84 weeks or premature study discontinuation) or on the date when the DSMB's recommendation to close the study became public, whichever occurred earlier.
Time frame: From initiation of etoposide (Step 2 entry) to up to 84 weeks (end of Step 2)
Population: All Arm A participants who experienced KS progression and entered Step 2 to initiate delayed ET.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A: ART Alone or With Delayed ET | Cumulative Incidence of KS Response After Initiation of Delayed Etoposide in Arm A | 62.57 cumulative events per 100 participants |
Secondary
Kaposi Sarcoma (KS) Status at Week 96 Compared to Study Entry
KS status is a composite, categorical outcome, ordered from worst to best as E1 (Failure: KS PD, initiation of an alternate KS treatment, or no follow-up at Week 96 including death and missed visit), E2 (Stable: in follow-up at Week 96 with no KS progression nor response and without initiation of an alternate KS treatment) and E3 (Response: in follow-up at Week 96, with KS PR or CR and without initiation of an alternate KS treatment). Alternate KS treatment was defined as chemotherapy agent other than ET or other treatment triggered by worsening KS. KS outcome status (PD, stable, PR or CR) compared to study entry was evaluated at Week 96 based on clinical assessment of KS cutaneous lesions (count, character and marker lesion area), oral KS, visceral KS and tumor-associated edema and as described in the publications (Krown et al 1989, Cianfrocca et al 2002). Data on initiation of alternate KS treatment, loss to follow-up and deaths are from entry through Week 96.
Time frame: Entry through Week 96.
Population: All eligible participants who initiated study treatment and had Study Week 96 data potential (i.e. participants enrolled at least 93 weeks prior to the date when the DSMB's recommendation to close the study became public).
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm A: ART Alone or With Delayed ET | Kaposi Sarcoma (KS) Status at Week 96 Compared to Study Entry | E1 (Failure) | 33 Participants |
| Arm A: ART Alone or With Delayed ET | Kaposi Sarcoma (KS) Status at Week 96 Compared to Study Entry | E2 (Stable) | 4 Participants |
| Arm A: ART Alone or With Delayed ET | Kaposi Sarcoma (KS) Status at Week 96 Compared to Study Entry | E3 (Response) | 21 Participants |
| Arm B: ART With Immediate ET | Kaposi Sarcoma (KS) Status at Week 96 Compared to Study Entry | E1 (Failure) | 33 Participants |
| Arm B: ART With Immediate ET | Kaposi Sarcoma (KS) Status at Week 96 Compared to Study Entry | E2 (Stable) | 0 Participants |
| Arm B: ART With Immediate ET | Kaposi Sarcoma (KS) Status at Week 96 Compared to Study Entry | E3 (Response) | 28 Participants |
Secondary
KS Complete Response at Week 48 Compared to Study Entry
KS complete response (CR) compared to study entry based on clinical assessment of KS cutaneous lesions (count, character and marker lesion area), oral KS, visceral KS and tumor-associated edema and as described in the publications (Krown et al 1989, Cianfrocca et al 2002).
Time frame: Entry and Week 48
Population: All eligible participants who initiated study treatment and had Study Week 48 data potential (i.e. participants enrolled at least 45 weeks prior to the date when the DSMB's recommendation to close the study became public) who had Week 48 KS exam performed and had not initiated alternate KS treatment before Week 48.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm A: ART Alone or With Delayed ET | KS Complete Response at Week 48 Compared to Study Entry | KS CR at Week 48 | 3 Participants |
| Arm A: ART Alone or With Delayed ET | KS Complete Response at Week 48 Compared to Study Entry | No KS CR at Week 48 | 55 Participants |
| Arm B: ART With Immediate ET | KS Complete Response at Week 48 Compared to Study Entry | KS CR at Week 48 | 4 Participants |
| Arm B: ART With Immediate ET | KS Complete Response at Week 48 Compared to Study Entry | No KS CR at Week 48 | 39 Participants |
Secondary
KS Complete Response at Week 96 Compared to Study Entry
KS complete response (CR) compared to study entry based on clinical assessment of KS cutaneous lesions (count, character and marker lesion area), oral KS, visceral KS and tumor-associated edema and as described in the publications (Krown et al 1989, Cianfrocca et al 2002).
Time frame: Entry and Week 96
Population: All eligible participants who initiated study treatment and had Study Week 96 data potential (i.e. participants enrolled at least 93 weeks prior to the date when the DSMB's recommendation to close the study became public) who had Week 96 KS exam performed and had not initiated alternate KS treatment before Week 96.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm A: ART Alone or With Delayed ET | KS Complete Response at Week 96 Compared to Study Entry | KS CR at Week 96 | 2 Participants |
| Arm A: ART Alone or With Delayed ET | KS Complete Response at Week 96 Compared to Study Entry | No KS CR at Week 96 | 33 Participants |
| Arm B: ART With Immediate ET | KS Complete Response at Week 96 Compared to Study Entry | KS CR at Week 96 | 4 Participants |
| Arm B: ART With Immediate ET | KS Complete Response at Week 96 Compared to Study Entry | No KS CR at Week 96 | 26 Participants |
Secondary
KS Partial or Complete Response at Week 48 Compared to Study Entry
KS partial response (PR) or complete response (CR) compared to study entry based on clinical assessment of KS cutaneous lesions (count, character and marker lesion area), oral KS, visceral KS and tumor-associated edema and as described in the publications (Krown et al 1989, Cianfrocca et al 2002).
Time frame: Entry and Week 48
Population: All eligible participants who initiated study treatment and had Study Week 48 data potential (i.e. participants enrolled at least 45 weeks prior to the date when the DSMB's recommendation to close the study became public) who had Week 48 KS exam performed and had not initiated alternate KS treatment before Week 48.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm A: ART Alone or With Delayed ET | KS Partial or Complete Response at Week 48 Compared to Study Entry | Week 48: KS PR or CR | 24 Participants |
| Arm A: ART Alone or With Delayed ET | KS Partial or Complete Response at Week 48 Compared to Study Entry | Week 48: no KS PR or CR | 34 Participants |
| Arm B: ART With Immediate ET | KS Partial or Complete Response at Week 48 Compared to Study Entry | Week 48: KS PR or CR | 27 Participants |
| Arm B: ART With Immediate ET | KS Partial or Complete Response at Week 48 Compared to Study Entry | Week 48: no KS PR or CR | 16 Participants |
Secondary
KS Partial or Complete Response at Week 96 Compared to Study Entry
KS partial response (PR) or complete response (CR) compared to study entry based on clinical assessment of KS cutaneous lesions (count, character and marker lesion area), oral KS, visceral KS and tumor-associated edema and as described in the publications (Krown et al 1989, Cianfrocca et al 2002).
Time frame: Entry and Week 96
Population: All eligible participants who initiated study treatment and had Study Week 96 data potential (i.e. participants enrolled at least 93 weeks prior to the date when the DSMB's recommendation to close the study became public) who had Week 96 KS exam performed and had not initiated alternate KS treatment before Week 96.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm A: ART Alone or With Delayed ET | KS Partial or Complete Response at Week 96 Compared to Study Entry | KS PR or CR at Week 96 | 21 Participants |
| Arm A: ART Alone or With Delayed ET | KS Partial or Complete Response at Week 96 Compared to Study Entry | No KS PR or CR at Week 96 | 14 Participants |
| Arm B: ART With Immediate ET | KS Partial or Complete Response at Week 96 Compared to Study Entry | KS PR or CR at Week 96 | 28 Participants |
| Arm B: ART With Immediate ET | KS Partial or Complete Response at Week 96 Compared to Study Entry | No KS PR or CR at Week 96 | 2 Participants |
Secondary
KS Partial Response at Week 48 Compared to Study Entry
KS partial response (PR) compared to study entry based on clinical assessment of KS cutaneous lesions (count, character and marker lesion area), oral KS, visceral KS and tumor-associated edema and as described in the publications (Krown et al 1989, Cianfrocca et al 2002).
Time frame: Entry and Week 48
Population: All eligible participants who initiated study treatment and had Study Week 48 data potential (i.e. participants enrolled at least 45 weeks prior to the date when the DSMB's recommendation to close the study became public) who had Week 48 KS exam performed and had not initiated alternate KS treatment before Week 48.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm A: ART Alone or With Delayed ET | KS Partial Response at Week 48 Compared to Study Entry | KS PR at Week 48 | 21 Participants |
| Arm A: ART Alone or With Delayed ET | KS Partial Response at Week 48 Compared to Study Entry | No KS PR at Week 48 | 37 Participants |
| Arm B: ART With Immediate ET | KS Partial Response at Week 48 Compared to Study Entry | KS PR at Week 48 | 23 Participants |
| Arm B: ART With Immediate ET | KS Partial Response at Week 48 Compared to Study Entry | No KS PR at Week 48 | 20 Participants |
Secondary
KS Partial Response at Week 96 Compared to Study Entry
KS partial response (PR) compared to study entry based on clinical assessment of KS cutaneous lesions (count, character and marker lesion area), oral KS, visceral KS and tumor-associated edema and as described in the publications (Krown et al 1989, Cianfrocca et al 2002).
Time frame: Entry and Week 96
Population: All eligible participants who initiated study treatment and had Study Week 96 data potential (i.e. participants enrolled at least 93 weeks prior to the date when the DSMB's recommendation to close the study became public) who had Week 96 KS exam performed and had not initiated alternate KS treatment before Week 96.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm A: ART Alone or With Delayed ET | KS Partial Response at Week 96 Compared to Study Entry | KS PR at Week 96 | 19 Participants |
| Arm A: ART Alone or With Delayed ET | KS Partial Response at Week 96 Compared to Study Entry | No KS PR at Week 96 | 16 Participants |
| Arm B: ART With Immediate ET | KS Partial Response at Week 96 Compared to Study Entry | KS PR at Week 96 | 24 Participants |
| Arm B: ART With Immediate ET | KS Partial Response at Week 96 Compared to Study Entry | No KS PR at Week 96 | 6 Participants |
Secondary
KS Progressive Disease at Week 48 Compared to Study Entry
KS progressive disease (PD) compared to study entry based on clinical assessment of KS cutaneous lesions (count, character and marker lesion area), oral KS, visceral KS and tumor-associated edema and as described in the publications (Krown et al 1989, Cianfrocca et al 2002).
Time frame: Entry and Week 48
Population: All eligible participants who initiated study treatment and had Study Week 48 data potential (i.e. participants enrolled at least 45 weeks prior to the date when the DSMB's recommendation to close the study became public) who had Week 48 KS exam performed and had not initiated alternate KS treatment before Week 48.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm A: ART Alone or With Delayed ET | KS Progressive Disease at Week 48 Compared to Study Entry | KS PD at Week 48 | 21 Participants |
| Arm A: ART Alone or With Delayed ET | KS Progressive Disease at Week 48 Compared to Study Entry | No KS PD at Week 48 | 37 Participants |
| Arm B: ART With Immediate ET | KS Progressive Disease at Week 48 Compared to Study Entry | No KS PD at Week 48 | 36 Participants |
| Arm B: ART With Immediate ET | KS Progressive Disease at Week 48 Compared to Study Entry | KS PD at Week 48 | 7 Participants |
Secondary
KS Progressive Disease at Week 96 Compared to Study Entry
KS progressive disease (PD) compared to study entry based on clinical assessment of KS cutaneous lesions (count, character and marker lesion area), oral KS, visceral KS and tumor-associated edema and as described in the publications (Krown et al 1989, Cianfrocca et al 2002).
Time frame: Entry and Week 96
Population: All eligible participants who initiated study treatment and had Study Week 96 data potential (i.e. participants enrolled at least 93 weeks prior to the date when the DSMB's recommendation to close the study became public) who had Week 96 KS exam performed and had not initiated alternate KS treatment before Week 96.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm A: ART Alone or With Delayed ET | KS Progressive Disease at Week 96 Compared to Study Entry | KS PD at Week 96 | 10 Participants |
| Arm A: ART Alone or With Delayed ET | KS Progressive Disease at Week 96 Compared to Study Entry | No KS PD at Week 96 | 25 Participants |
| Arm B: ART With Immediate ET | KS Progressive Disease at Week 96 Compared to Study Entry | KS PD at Week 96 | 2 Participants |
| Arm B: ART With Immediate ET | KS Progressive Disease at Week 96 Compared to Study Entry | No KS PD at Week 96 | 28 Participants |
Secondary
Number of Participants With Grade 3 or Higher Adverse Events
Number of participants who experienced an AE (sign/symptom or laboratory abnormality) of Grade 3 or higher. The AEs were graded by the clinicians according to the Division of AIDS (DAIDS) AE Grading Table (see reference in the Protocol Section) as follows: Grade 1=Mild, Grade 2=Moderate, Grade 3=Severe, Grade 4=Potentially Life-Threatening.
Time frame: From study treatment dispensation through up to Week 96, until long-term follow-up began in Step 3 or until study discontinuation.
Population: All eligible participants who initiated study treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm A: ART Alone or With Delayed ET | Number of Participants With Grade 3 or Higher Adverse Events | 47 Participants |
| Arm B: ART With Immediate ET | Number of Participants With Grade 3 or Higher Adverse Events | 42 Participants |
Secondary
Percentage of Participants With ARV Dose Modification
ARV dose modifications were reported as temporarily held, prematurely discontinued and increased. The percentage of participants who experienced each dose modification is provided in the data table below. The categories are not mutually exclusive. A participant may have experienced multiple dose modifications and may be counted in more than one category. Each participant is counted at most once within category.
Time frame: From treatment dispensation to Week 96
Population: All eligible participants who initiated study treatment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm A: ART Alone or With Delayed ET | Percentage of Participants With ARV Dose Modification | Temporarily held | 7.4 percentage of participants |
| Arm A: ART Alone or With Delayed ET | Percentage of Participants With ARV Dose Modification | Prematurely discontinued | 26.6 percentage of participants |
| Arm A: ART Alone or With Delayed ET | Percentage of Participants With ARV Dose Modification | Increased | 1.1 percentage of participants |
| Arm B: ART With Immediate ET | Percentage of Participants With ARV Dose Modification | Temporarily held | 11.5 percentage of participants |
| Arm B: ART With Immediate ET | Percentage of Participants With ARV Dose Modification | Prematurely discontinued | 21.9 percentage of participants |
| Arm B: ART With Immediate ET | Percentage of Participants With ARV Dose Modification | Increased | 0 percentage of participants |
Secondary
Percentage of Participants With Etoposide Dose Modification
Etoposide (ET) was administered for a maximum of 8 cycles (16 weeks) from study entry (Arm B) or from Step 2 entry (Arm A). Dose modifications were reported as temporarily held, resumed at a different dose, deferred, prematurely discontinued and underdosed. The percentage of participants who experienced each dose modification is provided in the data table below. The categories are not mutually exclusive. A participant may have experienced multiple dose modifications and may be counted in more than one category. Each participant is counted at most once within category.
Time frame: From ET dispensation to ET discontinuation (total duration of ET was up to 16 weeks)
Population: All eligible participants who initiated study treatment. Arm A participants are limited to those who entered Step 2 to initiate delayed ET.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm A: ART Alone or With Delayed ET | Percentage of Participants With Etoposide Dose Modification | Resumed at a different dose | 15.6 percentage of participants |
| Arm A: ART Alone or With Delayed ET | Percentage of Participants With Etoposide Dose Modification | Discontinued | 6.3 percentage of participants |
| Arm A: ART Alone or With Delayed ET | Percentage of Participants With Etoposide Dose Modification | Deferred | 37.5 percentage of participants |
| Arm A: ART Alone or With Delayed ET | Percentage of Participants With Etoposide Dose Modification | Underdosed | 0 percentage of participants |
| Arm A: ART Alone or With Delayed ET | Percentage of Participants With Etoposide Dose Modification | Temporarily held | 0 percentage of participants |
| Arm B: ART With Immediate ET | Percentage of Participants With Etoposide Dose Modification | Underdosed | 1.0 percentage of participants |
| Arm B: ART With Immediate ET | Percentage of Participants With Etoposide Dose Modification | Temporarily held | 5.2 percentage of participants |
| Arm B: ART With Immediate ET | Percentage of Participants With Etoposide Dose Modification | Resumed at a different dose | 9.4 percentage of participants |
| Arm B: ART With Immediate ET | Percentage of Participants With Etoposide Dose Modification | Deferred | 24.0 percentage of participants |
| Arm B: ART With Immediate ET | Percentage of Participants With Etoposide Dose Modification | Discontinued | 10.4 percentage of participants |
Secondary
Percentage of Participants With HIV-1 RNA Suppression
HIV-1 RNA suppression was defined as plasma HIV-1 RNA \<400 copies/mL. Only Arm A participants could enter Step 2 to initiate delayed ET.
Time frame: Entry and Weeks 12, 24, 32, 48, 72, 96; Step 2 entry and Weeks 12, 24, 32, 48 and 72.
Population: All eligible participants who initiated study treatment and had HIV-1 RNA results available at the specific visit. HIV-1 RNA testing was done locally using Abbott RealTime HIV-1 Test or Roche AmpliPrep/Taqman HIV-1 Test. Only Arm A participants could enter Step 2 to initiate delayed ET.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm A: ART Alone or With Delayed ET | Percentage of Participants With HIV-1 RNA Suppression | Step 2 Week 72: HIV-1 RNA suppression | 100.0 percentage of participants |
| Arm A: ART Alone or With Delayed ET | Percentage of Participants With HIV-1 RNA Suppression | Week 96: HIV-1 RNA suppression | 92.9 percentage of participants |
| Arm A: ART Alone or With Delayed ET | Percentage of Participants With HIV-1 RNA Suppression | Step 2 entry: HIV-1 RNA suppression | 93.3 percentage of participants |
| Arm A: ART Alone or With Delayed ET | Percentage of Participants With HIV-1 RNA Suppression | Step 2 Week 12: HIV-1 RNA suppression | 100.0 percentage of participants |
| Arm A: ART Alone or With Delayed ET | Percentage of Participants With HIV-1 RNA Suppression | Step 2 Week 24: HIV-1 RNA suppression | 95.8 percentage of participants |
| Arm A: ART Alone or With Delayed ET | Percentage of Participants With HIV-1 RNA Suppression | Step 2 Week 32: HIV-1 RNA suppression | 96.0 percentage of participants |
| Arm A: ART Alone or With Delayed ET | Percentage of Participants With HIV-1 RNA Suppression | Step 2 Week 48: HIV-1 RNA suppression | 100.0 percentage of participants |
| Arm A: ART Alone or With Delayed ET | Percentage of Participants With HIV-1 RNA Suppression | Entry: HIV-1 RNA suppression | 4.3 percentage of participants |
| Arm A: ART Alone or With Delayed ET | Percentage of Participants With HIV-1 RNA Suppression | Week 12: HIV-1 RNA suppression | 90.3 percentage of participants |
| Arm A: ART Alone or With Delayed ET | Percentage of Participants With HIV-1 RNA Suppression | Week 24: HIV-1 RNA suppression | 94.5 percentage of participants |
| Arm A: ART Alone or With Delayed ET | Percentage of Participants With HIV-1 RNA Suppression | Week 32: HIV-1 RNA suppression | 92.0 percentage of participants |
| Arm A: ART Alone or With Delayed ET | Percentage of Participants With HIV-1 RNA Suppression | Week 48: HIV-1 RNA suppression | 95.3 percentage of participants |
| Arm A: ART Alone or With Delayed ET | Percentage of Participants With HIV-1 RNA Suppression | Week 72: HIV-1 RNA suppression | 91.2 percentage of participants |
| Arm B: ART With Immediate ET | Percentage of Participants With HIV-1 RNA Suppression | Entry: HIV-1 RNA suppression | 4.2 percentage of participants |
| Arm B: ART With Immediate ET | Percentage of Participants With HIV-1 RNA Suppression | Week 72: HIV-1 RNA suppression | 96.6 percentage of participants |
| Arm B: ART With Immediate ET | Percentage of Participants With HIV-1 RNA Suppression | Week 12: HIV-1 RNA suppression | 90.6 percentage of participants |
| Arm B: ART With Immediate ET | Percentage of Participants With HIV-1 RNA Suppression | Week 48: HIV-1 RNA suppression | 98.6 percentage of participants |
| Arm B: ART With Immediate ET | Percentage of Participants With HIV-1 RNA Suppression | Week 24: HIV-1 RNA suppression | 97.5 percentage of participants |
| Arm B: ART With Immediate ET | Percentage of Participants With HIV-1 RNA Suppression | Week 96: HIV-1 RNA suppression | 93.8 percentage of participants |
| Arm B: ART With Immediate ET | Percentage of Participants With HIV-1 RNA Suppression | Week 32: HIV-1 RNA suppression | 94.7 percentage of participants |
Secondary
Premature Study Discontinuation by Week 48
Premature study discontinuation by Week 48 due to any reason, including death.
Time frame: Entry through Week 48
Population: All eligible participants who initiated study treatment and had Study Week 48 data potential (i.e. participants enrolled at least 45 weeks prior to the date when the DSMB's recommendation to close the study became public).
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm A: ART Alone or With Delayed ET | Premature Study Discontinuation by Week 48 | Premature study discontinuation by Week 48 | 13 Participants |
| Arm A: ART Alone or With Delayed ET | Premature Study Discontinuation by Week 48 | No premature study discontinuation by Week 48 | 67 Participants |
| Arm B: ART With Immediate ET | Premature Study Discontinuation by Week 48 | Premature study discontinuation by Week 48 | 11 Participants |
| Arm B: ART With Immediate ET | Premature Study Discontinuation by Week 48 | No premature study discontinuation by Week 48 | 72 Participants |
Secondary
Premature Study Discontinuation by Week 96
Premature study discontinuation by Week 96 due to any reason, including death.
Time frame: Entry through Week 96
Population: All eligible participants who initiated study treatment and had Study Week 96 data potential (i.e. participants enrolled at least 93 weeks prior to the date when the DSMB's recommendation to close the study became public).
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm A: ART Alone or With Delayed ET | Premature Study Discontinuation by Week 96 | Premature study discontinuation by Week 96 | 14 Participants |
| Arm A: ART Alone or With Delayed ET | Premature Study Discontinuation by Week 96 | No premature study discontinuation by Week 96 | 44 Participants |
| Arm B: ART With Immediate ET | Premature Study Discontinuation by Week 96 | Premature study discontinuation by Week 96 | 10 Participants |
| Arm B: ART With Immediate ET | Premature Study Discontinuation by Week 96 | No premature study discontinuation by Week 96 | 51 Participants |