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.
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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
991
Block randomization (1:1) to pre-ART OLA testing or OLA testing after 12mo on ART
Coptic Hospital
Maseno, Kenya
Coptic Hospital
Nairobi, Kenya
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
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
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
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
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. \[Chung et al. Lancet HIV 2020; 7: e104-12\]
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Time frame: 15 months
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
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
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