HIV Positive
Conditions
Keywords
Transmitted Drug Resistance
Brief summary
The investigators propose to gauge improvements in the rate of durable suppression of viral replication by ART when OLA is used to guide clinical decisions at the PEPFAR Coptic Hope Center in Kenya, and to determine the cost-effectiveness of implementing this strategy at Coptic Hope Center.
Detailed description
Durable suppression of HIV replication is critical to (1) improving the health of infected individuals, (2) to reducing HIV transmission to sexual partners and from mothers to their infants, and (3) to maintaining the effectiveness of the current 1st-line non-nucleoside reverse transcriptase inhibitors (NNRTI)- based ART. Across multiple trials, individuals with NNRTI-resistance, even at low-concentrations, have substantially greater virologic failure when treated with NVP- vs PI-ART. A cost-effective strategy is needed to detect and manage ARV-resistant HIV infections. A simple low-cost innovative assay the investigators developed and successfully transferred to Asian and African countries (oligonucleotide ligation assay (OLA)) can detect NNRTI+lamivudine (3TC) resistant HIV using reagents that costs \<$7.00/person. Furthermore, detection of NNRTI-resistance by OLA is highly (P\<0.001) associated with virologic failure of nevirapine (NVP)-ART in two retrospective studies; one of Thai women who had been previously randomized to single-dose NVP and the second of ARV-naïve Kenyan adults. The investigators hypothesize that implementation of OLA into routine care will allow Kenyan clinicians to appropriately target protease inhibitor (PI)-based ART and improve rates of durable suppression of viral replication, and thus improve CD4 cell gains and individuals' health, reduce the transmission of ARV-resistant HIV within the community, and maintain the utility of NNRTI-ART. In addition, the investigators hypothesize that programmatically OLA-guided ART will be more cost-efficient compared to the current strategy of empiric use of NNRTI-ART as initial treatment.
Interventions
OTHERPre-ART Oligonucleotide Assay (OLA)
Block randomization (1:1) to pre-ART OLA testing or OLA testing after 12mo on ART
Sponsors
Seattle Children's Hospital
University of Nairobi
University of Washington
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
2 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Confirmed HIV infection 2. \>2 years of age 3. Qualifying for 1st-line ART based on Kenyan Guidelines 4. Plan to reside in area for \>1 year 5. Adult patient or parent of minor agrees to study and provides informed consent
Exclusion criteria
1. Received ART previously from Hope Center 2. Ongoing ART 3. Plan to start 2nd-line ART
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Virologic Failure With OLA-guided ART vs. Standard of Care | 12 months | The primary endpoint will be a comparison of the rates of viral non-suppression \>400 copies/mL between study arms at 12 months |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Prevalence of TDR by Consensus Sequencing and OLA | 15 months | We did not analyze and report outcome of people with TDR, instead we reported pretreatment drug resistance (PDR) as this parameter could be determined but antiretroviral history was not reliably available. Thus, PDR is considered below in place of TDR. PDR was assessed by OLA and confirmed by consensus sequence or next-generation sequencing. |
| Estimates of Medical Resource Utilization During the One-year Trial Period | 15 months | Estimates of medical resource utilization during was not calculated. No data available (data on medical resource utilization was not collected during the one-year trial) |
| An Assessment of the Potential Long-term Cost-effectiveness of OLA-guided Testing Over a Patient's Lifetime | 15 months | This was not calculated as the model could not test for a period longer than 15 years due to computing limitations. |
| Determination of Whether Low-level ARV Resistance (<5%) Detected by PYRO But Not by OLA is Associated With Virologic Failure | 24 months | The prespecified outcomes of this study included differences in the rate of virologic failure over 24 months of efavirenz-based ART between participants by frequency of drug-resistant variants detected by next-generation sequencing at enrollment. Drug-resistance frequency was defined as the proportion of a nucleotide variant encoding a drug-resistant codon in specimens with at least 100 viral templates sequenced. Virologic failure was defined as plasma HIV RNA of at least 400 copies/ml in sequential specimens or at the final study visit in participants prescribed efavirenz-based ART. \[Milne et al. AIDS 2022 Nov 15;36(14):1949-1958\] |
| The Difference in Virologic Failure Among Participants With Transmitted Drug-resistance (TDR) ≥10% Associated With Use of OLA-guided ART vs. SOC | 15 months | We did not analyze and report outcome of people with TDR ≥10%, instead we reported pretreatment drug resistance (PDR) as this parameter could be determined but antiretroviral history was not reliably available. Thus, PDR ≥10% is considered below in place of TDR ≥10%. Chung et al. Lancet HIV 2020; 7: e104-12. |
| Difference in Virologic Failure in the Subgroup of Participants With Prior or Ongoing ART Use Associated With Use of OLA-guided ART vs. SOC | 15 months | The primary outcome was virologic failure defined as plasma HIV RNA of at least 400 copies per mL after initiation of antiretroviral therapy (ART). |
| Proportion of Subgroup With TDR With Virologic Failure by Randomization Arm | 15 months | We did not analyze and report outcome of people with TDR, instead we reported pretreatment drug resistance (PDR) as this parameter could be determined but antiretroviral history was not reliably available. Thus, PDR is considered below in place of TDR. The primary outcome for this analysis was the difference in virologic failure, defined as plasma HIV-1 RNA of at least 400 copies per mL following ART initiation, by PDR. \[Chung et al. Lancet HIV 2020; 7: e104-12\] |
Other
| Measure | Time frame | Description |
|---|---|---|
| Detection of Resistance Mutations at OLA Codons by OLA vs. Consensus Sequencing | Enrollment | Rates of pre-treatment drug resistance among all study participants in the study were assessed by OLA but not by consensus sequencing (CS) due to the high cost of sequencing the entire population. However, all mutations detected by OLA were confirmed by CS in Seattle, and if not detected by CS were confirmed by next generation Illumina sequencing. Participants with any indeterminate OLA results were also sequenced to determine the genotype at the indeterminate codon. |
| Descriptions of Technology Transfer of OLA to the Hope Center Laboratory, Including Intra- and Inter-assay the Reproducibility, and Discussion of Obstacles and Possible Solutions | 15 months | Technology transfer of OLA to the Hope Center Laboratory in Kenya is described, including intra- and inter-assay the reproducibility, and discussion of obstacles and possible solutions. Duarte et a. AIDS 2018, 32:2301-2308 |
| A Comparison of OLA Results Obtained Using DBS in Kenya to Retesting of Same Specimens With Input of Viral Templates Measured in Seattle | 15 months | DBS were not tested in Kenya and thus, the comparison of OLA results obtained using DBS in Kenya to retesting of same specimens with input of viral templates measured in Seattle was not evaluated. |
Countries
Kenya
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Pre-ART Oligonucleotide Assay (OLA) Pre-ART OLA will be tested for resistance at 5 pol codons conferring high-level resistance to NNRTI and 3TC (K103N, V106M, Y181C, G190A and M184V)
Pre-ART Oligonucleotide Assay (OLA): Block randomization (1:1) to pre-ART OLA testing or OLA testing after 12mo on ART | 492 |
| No OLA (Standard of Care [SOC]) The participants will receive standard of care as per Kenya guidelines but will be offered OLA resistance testing after 12 months | 495 |
| Total | 987 |
Baseline characteristics
| Characteristic | Pre-ART Oligonucleotide Assay (OLA) | No OLA (Standard of Care [SOC]) | Total |
|---|---|---|---|
| Age, Continuous | 38 years | 37 years | 37 years |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 492 Participants | 495 Participants | 987 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment Kenya | 492 participants | 495 participants | 987 participants |
| Sex: Female, Male Female | 320 Participants | 321 Participants | 641 Participants |
| Sex: Female, Male Male | 172 Participants | 174 Participants | 346 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 34 / 492 | 43 / 495 |
| other Total, other adverse events | 32 / 492 | 26 / 495 |
| serious Total, serious adverse events | 39 / 492 | 34 / 495 |
Outcome results
Primary
Number of Participants With Virologic Failure With OLA-guided ART vs. Standard of Care
The primary endpoint will be a comparison of the rates of viral non-suppression \>400 copies/mL between study arms at 12 months
Time frame: 12 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pre-ART Oligonucleotide Assay (OLA) | Number of Participants With Virologic Failure With OLA-guided ART vs. Standard of Care | 34 Participants |
| No OLA (Standard of Care [SOC]) | Number of Participants With Virologic Failure With OLA-guided ART vs. Standard of Care | 39 Participants |
Secondary
An Assessment of the Potential Long-term Cost-effectiveness of OLA-guided Testing Over a Patient's Lifetime
This was not calculated as the model could not test for a period longer than 15 years due to computing limitations.
Time frame: 15 months
Population: This was not calculated as the model could not test for a period longer than 15 years due to computing limitations.
Secondary
Determination of Whether Low-level ARV Resistance (<5%) Detected by PYRO But Not by OLA is Associated With Virologic Failure
The prespecified outcomes of this study included differences in the rate of virologic failure over 24 months of efavirenz-based ART between participants by frequency of drug-resistant variants detected by next-generation sequencing at enrollment. Drug-resistance frequency was defined as the proportion of a nucleotide variant encoding a drug-resistant codon in specimens with at least 100 viral templates sequenced. Virologic failure was defined as plasma HIV RNA of at least 400 copies/ml in sequential specimens or at the final study visit in participants prescribed efavirenz-based ART. \[Milne et al. AIDS 2022 Nov 15;36(14):1949-1958\]
Time frame: 24 months
Population: Analysis included 352 participants from Nairobi, including 332 with virologic suppression at month-12 of efavirenz-based ART who enrolled for a second year and 20 participants who experienced virologic failure by month-12 of efavirenz-based ART. Pretreatment drug-resistance was classified as: wild-type (0%), low-frequency (1-9%), high-frequency (10-100%). Virologic failure by month-24 of efavirenz-based ART, was compared between individuals with and without pretreatment drug-resistance.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Pre-ART Oligonucleotide Assay (OLA) | Determination of Whether Low-level ARV Resistance (<5%) Detected by PYRO But Not by OLA is Associated With Virologic Failure | Wild-type resistance | 301 Participants |
| Pre-ART Oligonucleotide Assay (OLA) | Determination of Whether Low-level ARV Resistance (<5%) Detected by PYRO But Not by OLA is Associated With Virologic Failure | Low-frequency resistance | 10 Participants |
| Pre-ART Oligonucleotide Assay (OLA) | Determination of Whether Low-level ARV Resistance (<5%) Detected by PYRO But Not by OLA is Associated With Virologic Failure | High-frequency resistance | 11 Participants |
| No OLA (Standard of Care [SOC]) | Determination of Whether Low-level ARV Resistance (<5%) Detected by PYRO But Not by OLA is Associated With Virologic Failure | Wild-type resistance | 20 Participants |
| No OLA (Standard of Care [SOC]) | Determination of Whether Low-level ARV Resistance (<5%) Detected by PYRO But Not by OLA is Associated With Virologic Failure | Low-frequency resistance | 5 Participants |
| No OLA (Standard of Care [SOC]) | Determination of Whether Low-level ARV Resistance (<5%) Detected by PYRO But Not by OLA is Associated With Virologic Failure | High-frequency resistance | 5 Participants |
Secondary
Difference in Virologic Failure in the Subgroup of Participants With Prior or Ongoing ART Use Associated With Use of OLA-guided ART vs. SOC
The primary outcome was virologic failure defined as plasma HIV RNA of at least 400 copies per mL after initiation of antiretroviral therapy (ART).
Time frame: 15 months
Population: The analysis population included only those participants that had prior or ongoing ART use (non-ARV naive) at randomization.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Pre-ART Oligonucleotide Assay (OLA) | Difference in Virologic Failure in the Subgroup of Participants With Prior or Ongoing ART Use Associated With Use of OLA-guided ART vs. SOC | Participants with pre-ART and virologic failure | 1 Participants |
| Pre-ART Oligonucleotide Assay (OLA) | Difference in Virologic Failure in the Subgroup of Participants With Prior or Ongoing ART Use Associated With Use of OLA-guided ART vs. SOC | Participants with pre-ART and no virologic failure | 31 Participants |
| No OLA (Standard of Care [SOC]) | Difference in Virologic Failure in the Subgroup of Participants With Prior or Ongoing ART Use Associated With Use of OLA-guided ART vs. SOC | Participants with pre-ART and virologic failure | 1 Participants |
| No OLA (Standard of Care [SOC]) | Difference in Virologic Failure in the Subgroup of Participants With Prior or Ongoing ART Use Associated With Use of OLA-guided ART vs. SOC | Participants with pre-ART and no virologic failure | 31 Participants |
Secondary
Estimates of Medical Resource Utilization During the One-year Trial Period
Estimates of medical resource utilization during was not calculated. No data available (data on medical resource utilization was not collected during the one-year trial)
Time frame: 15 months
Population: No data available (data on medical resource utilization was not collected).
Secondary
Prevalence of TDR by Consensus Sequencing and OLA
We did not analyze and report outcome of people with TDR, instead we reported pretreatment drug resistance (PDR) as this parameter could be determined but antiretroviral history was not reliably available. Thus, PDR is considered below in place of TDR. PDR was assessed by OLA and confirmed by consensus sequence or next-generation sequencing.
Time frame: 15 months
Population: WHO defines pretreatment HIV drug resistance (PDR) as DR that is detected in ARV drug-naive people initiating ART or people with prior ARV drug exposure initiating or reinitiating first-line ART. Thus, we did not report outcomes with TDR, instead we reported PDR as this could be determined but antiretroviral history was not available. Thus, PDR is reported in place of TDR.~This analysis included participants with PDR assessed by OLA and confirmed by consensus sequencing by study arm.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Pre-ART Oligonucleotide Assay (OLA) | Prevalence of TDR by Consensus Sequencing and OLA | Participants with PDR | 51 Participants |
| Pre-ART Oligonucleotide Assay (OLA) | Prevalence of TDR by Consensus Sequencing and OLA | Participants without PDR | 441 Participants |
| No OLA (Standard of Care [SOC]) | Prevalence of TDR by Consensus Sequencing and OLA | Participants with PDR | 42 Participants |
| No OLA (Standard of Care [SOC]) | Prevalence of TDR by Consensus Sequencing and OLA | Participants without PDR | 453 Participants |
Secondary
Proportion of Subgroup With TDR With Virologic Failure by Randomization Arm
We did not analyze and report outcome of people with TDR, instead we reported pretreatment drug resistance (PDR) as this parameter could be determined but antiretroviral history was not reliably available. Thus, PDR is considered below in place of TDR. The primary outcome for this analysis was the difference in virologic failure, defined as plasma HIV-1 RNA of at least 400 copies per mL following ART initiation, by PDR. \[Chung et al. Lancet HIV 2020; 7: e104-12\]
Time frame: 15 months
Population: WHO defines pretreatment HIV drug resistance (PDR) as DR that is detected in ARV drug-naive people initiating ART or people with prior ARV drug exposure initiating or reinitiating first-line ART. Thus, we did not report outcomes with TDR, instead we reported PDR as this could be determined but antiretroviral history was not available. Thus, PDR is reported in place of TDR.~The population included the subgroup of participants with PDR in each study arm.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Pre-ART Oligonucleotide Assay (OLA) | Proportion of Subgroup With TDR With Virologic Failure by Randomization Arm | Participants with PDR and virologic failure | 5 Participants |
| Pre-ART Oligonucleotide Assay (OLA) | Proportion of Subgroup With TDR With Virologic Failure by Randomization Arm | Participants with PDR and no virologic failure | 30 Participants |
| No OLA (Standard of Care [SOC]) | Proportion of Subgroup With TDR With Virologic Failure by Randomization Arm | Participants with PDR and virologic failure | 13 Participants |
| No OLA (Standard of Care [SOC]) | Proportion of Subgroup With TDR With Virologic Failure by Randomization Arm | Participants with PDR and no virologic failure | 13 Participants |
Secondary
The Difference in Virologic Failure Among Participants With Transmitted Drug-resistance (TDR) ≥10% Associated With Use of OLA-guided ART vs. SOC
We did not analyze and report outcome of people with TDR ≥10%, instead we reported pretreatment drug resistance (PDR) as this parameter could be determined but antiretroviral history was not reliably available. Thus, PDR ≥10% is considered below in place of TDR ≥10%. Chung et al. Lancet HIV 2020; 7: e104-12.
Time frame: 15 months
Population: WHO defines pretreatment HIV drug resistance (PDR) as DR that is detected in ARV drug-naive people initiating ART or people with prior ARV drug exposure initiating or reinitiating first-line ART. PDR is either transmitted or acquired drug resistance, or both. Thus, we did not report outcomes with TDR, instead we reported PDR as this could be determined but antiretroviral history was not available. Thus, PDR is reported in place of TDR. This included participants with PDR ≥10% at randomization.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Pre-ART Oligonucleotide Assay (OLA) | The Difference in Virologic Failure Among Participants With Transmitted Drug-resistance (TDR) ≥10% Associated With Use of OLA-guided ART vs. SOC | Participants with PDR and virologic failure | 5 Participants |
| Pre-ART Oligonucleotide Assay (OLA) | The Difference in Virologic Failure Among Participants With Transmitted Drug-resistance (TDR) ≥10% Associated With Use of OLA-guided ART vs. SOC | Participants with PDR and no virologic failure | 30 Participants |
| No OLA (Standard of Care [SOC]) | The Difference in Virologic Failure Among Participants With Transmitted Drug-resistance (TDR) ≥10% Associated With Use of OLA-guided ART vs. SOC | Participants with PDR and virologic failure | 13 Participants |
| No OLA (Standard of Care [SOC]) | The Difference in Virologic Failure Among Participants With Transmitted Drug-resistance (TDR) ≥10% Associated With Use of OLA-guided ART vs. SOC | Participants with PDR and no virologic failure | 13 Participants |
Other Pre-specified
A Comparison of OLA Results Obtained Using DBS in Kenya to Retesting of Same Specimens With Input of Viral Templates Measured in Seattle
DBS were not tested in Kenya and thus, the comparison of OLA results obtained using DBS in Kenya to retesting of same specimens with input of viral templates measured in Seattle was not evaluated.
Time frame: 15 months
Population: DBS were not tested in Kenya.
Other Pre-specified
Descriptions of Technology Transfer of OLA to the Hope Center Laboratory, Including Intra- and Inter-assay the Reproducibility, and Discussion of Obstacles and Possible Solutions
Technology transfer of OLA to the Hope Center Laboratory in Kenya is described, including intra- and inter-assay the reproducibility, and discussion of obstacles and possible solutions. Duarte et a. AIDS 2018, 32:2301-2308
Time frame: 15 months
Population: Technology transfer to Kenya is described, including quality control measures and a discussion of issues.~Duarte et a. AIDS 2018, 32:2301-2308
Other Pre-specified
Detection of Resistance Mutations at OLA Codons by OLA vs. Consensus Sequencing
Rates of pre-treatment drug resistance among all study participants in the study were assessed by OLA but not by consensus sequencing (CS) due to the high cost of sequencing the entire population. However, all mutations detected by OLA were confirmed by CS in Seattle, and if not detected by CS were confirmed by next generation Illumina sequencing. Participants with any indeterminate OLA results were also sequenced to determine the genotype at the indeterminate codon.
Time frame: Enrollment
Population: Among the subgroup of enrollment samples with both OLA and CS testing, we compared mutation detection by each method at OLA codons and assessed mutations at non-OLA codons detected by CS. Only mutations with Stanford HIVDR Program drug resistance mutation scores ≥10 were included.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Pre-ART Oligonucleotide Assay (OLA) | Detection of Resistance Mutations at OLA Codons by OLA vs. Consensus Sequencing | G190A | 16 Participants |
| Pre-ART Oligonucleotide Assay (OLA) | Detection of Resistance Mutations at OLA Codons by OLA vs. Consensus Sequencing | K103N | 69 Participants |
| Pre-ART Oligonucleotide Assay (OLA) | Detection of Resistance Mutations at OLA Codons by OLA vs. Consensus Sequencing | Y181C | 19 Participants |
| Pre-ART Oligonucleotide Assay (OLA) | Detection of Resistance Mutations at OLA Codons by OLA vs. Consensus Sequencing | K65R | 9 Participants |
| Pre-ART Oligonucleotide Assay (OLA) | Detection of Resistance Mutations at OLA Codons by OLA vs. Consensus Sequencing | M184V | 16 Participants |
| Pre-ART Oligonucleotide Assay (OLA) | Detection of Resistance Mutations at OLA Codons by OLA vs. Consensus Sequencing | Not detected | 346 Participants |
| No OLA (Standard of Care [SOC]) | Detection of Resistance Mutations at OLA Codons by OLA vs. Consensus Sequencing | M184V | 8 Participants |
| No OLA (Standard of Care [SOC]) | Detection of Resistance Mutations at OLA Codons by OLA vs. Consensus Sequencing | G190A | 9 Participants |
| No OLA (Standard of Care [SOC]) | Detection of Resistance Mutations at OLA Codons by OLA vs. Consensus Sequencing | K65R | 8 Participants |
| No OLA (Standard of Care [SOC]) | Detection of Resistance Mutations at OLA Codons by OLA vs. Consensus Sequencing | K103N | 44 Participants |
| No OLA (Standard of Care [SOC]) | Detection of Resistance Mutations at OLA Codons by OLA vs. Consensus Sequencing | Not detected | 392 Participants |
| No OLA (Standard of Care [SOC]) | Detection of Resistance Mutations at OLA Codons by OLA vs. Consensus Sequencing | Y181C | 14 Participants |