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. 2022 Dec 13;226(12):2170-2180.
doi: 10.1093/infdis/jiac415.

HIV RNA Screening Reduces Integrase Strand Transfer Inhibitor Resistance Risk in Persons Receiving Long-Acting Cabotegravir for HIV Prevention

Susan H Eshleman  1 , Jessica M Fogel  1 , Elias K Halvas  2 , Estelle Piwowar-Manning  1 , Mark A Marzinke  1   3 , Ryan Kofron  4 , Zhe Wang  5 , John Mellors  2 , Marybeth McCauley  6 , Alex R Rinehart  7 , Marty St Clair  7 , Adeola Adeyeye  8 , Juan C Hinojosa  9 , Robinson Cabello  10 , Keren Middelkoop  11 , Brett Hanscom  5 , Myron S Cohen  12 , Beatriz Grinsztejn  13 , Raphael J Landovitz  14 ; HPTN 083 Study Team
Collaborators, Affiliations

HIV RNA Screening Reduces Integrase Strand Transfer Inhibitor Resistance Risk in Persons Receiving Long-Acting Cabotegravir for HIV Prevention

Susan H Eshleman et al. J Infect Dis. .

Abstract

Background: The HPTN 083 trial demonstrated that long-acting cabotegravir (CAB-LA) was superior to tenofovir-disoproxil fumarate/emtricitabine for human immunodeficiency virus (HIV) preexposure prophylaxis (PrEP). Integrase strand transfer inhibitor (INSTI) resistance-associated mutations (RAMs) were detected in some participants with HIV infection. We used a low viral load INSTI genotyping assay to evaluate the timing of emergence of INSTI RAMs and assessed whether HIV screening with a sensitive RNA assay would have detected HIV infection before INSTI resistance emerged.

Methods: Single-genome sequencing to detect INSTI RAMs was performed for samples with viral loads <500 copies/mL from 5 participants with previously identified INSTI RAMs and 2 with no prior genotyping results.

Results: Major INSTI RAMs were detected in all 7 cases. HIV RNA testing identified infection before major INSTI RAMs emerged in 4 cases and before additional major INSTI RAMs accumulated in 1 case. Most INSTI RAMs were detected early when the viral load was low and CAB concentration was high.

Conclusions: When using CAB-LA PrEP, earlier detection of HIV infection with a sensitive RNA assay may allow for earlier treatment initiation with the potential to reduce INSTI resistance risk. Further studies are needed to evaluate the value and feasibility of HIV RNA testing with CAB-LA PrEP.

Keywords: HIV; HPTN; INSTI; PrEP; cabotegravir; injectable; integrase; prevention; resistance.

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Conflict of interest statement

Potential conflicts of interest. R. J. L. has served on scientific advisory boards for Merck and has received honoraria from Roche and Janssen. A. R. and M. S. C. are employees of ViiV Healthcare. J. W. M. is a consultant to Gilead Sciences, owns shares of Abound Bio, Inc, and share options in Infectious Disease Connect. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

Figures

Figure 1.
Figure 1.
Study cohort and summary of findings. The top box shows the number of persons enrolled and the person-years of follow-up for the CAB arm of HPTN 083. The second box shows the number of HIV infections identified in the blinded phase of the study and the annual incidence of HIV infection in the CAB arm [1]. The third box shows the number of participants evaluated in this report. The fourth box shows how many participants had major INSTI RAMs detected at any study visit, among the 16 CAB cases analyzed to date; this box also shows the breakdown of cases by case type (baseline, oral phase, injection phase). The lower row of boxes shows the number of cases and break down of cases by case type with major INSTI RAMs at the first visit where the site detected infection based on results from HIV rapid tests and an instrumented HIV antigen/antibody test (first site positive visit) and at the first HIV positive visit. Abbreviations: Ab, antibody; Ag, antigen; c/mL, copies per mL; CAB, cabotegravir; HIV, human immunodeficiency virus; INSTI, integrase strand transfer inhibitor; RAM, resistance-associated mutation; VL, viral load.
Figure 2.
Figure 2.
Case summary: baseline infection (case A2). Key events and laboratory results for participant A2. A case description is provided in Supplementary File 2. Red line indicates the first HIV positive visit; blue line indicates the first site positive visit; bracket shows the number of days between these 2 visits. Green lines indicate CAB injections. The X-axis indicates the number of weeks since the first HIV-positive test result, the left Y-axis indicates viral load, and the right Y axis indicates CAB concentration. Horizontal lines indicate CAB cutoffs (1.33 µg/mL = 8 × PA-IC90; 0.664 µg/mL = 4 × PA-IC90; 0.166 µg/mL = 1 × A-IC90; BLQ <0.025 µg/mL). A target concentration >8 × PA-IC90 was used to interpret drug concentrations. Results from retrospective testing performed at the HIV Prevention Trials Network Laboratory Center are shown above the graph: + reactive or positive test result, − nonreactive or negative test result. Viral load values are shown (HIV RNA copies/mL). HIV genotyping results are shown at the top; results from the low viral load single-genome integrase sequencing (low VL SGS-IN) assay are highlighted. All INSTI RAMs are shown; major INSTI RAMs are bolded. Abbreviations: Ag/Ab, antigen/antibody test; BLQ, below limit of quantification; CAB, cabotegravir; HIV, human immunodeficiency virus; INSTI, integrase strand transfer inhibitor; PA-IC90, in vitro protein-adjusted 90% CAB inhibitory concentration; WT, wild type.
Figure 3.
Figure 3.
Case summaries: oral-phase infections (cases C1 and C3). Results for participants who acquired HIV infection while receiving oral cabotegravir: (A) case C1, and (B) case C3. Key features of the figure are as in Figure 2. Viral load values <40 indicate that HIV RNA was detected below the lower limit of quantification. One viral load result was obtained with a single-copy RNA assay (asterisk, case C3). Abbreviations: Ag/Ab, antigen/antibody test; BLQ, below limit of quantification; CAB, cabotegravir; EFV, efavirenz; FTC,emtricitabine; HIV, human immunodeficiency virus; IND, indeterminate; ND, not detected; TDF, tenofovir disoproxil fumarate; WT, wild type.
Figure 4.
Figure 4.
Case summaries: injection-phase infections (cases D1–D4). Key events and laboratory results for participants who acquired HIV infection while receiving CAB injections: (A) case D1, (B) case D2, (C) case D3, and (D) case D4. Key features of the figure are as in Figure 2. Viral load values <40 indicate that HIV RNA was detected below the lower limit of quantification. One viral load result was obtained with a single-copy RNA assay (asterisk, case D2). The nonnucleoside reverse transcriptase inhibitor resistance mutation, K103N, is shown in blue text (case D3). Abbreviations: Ag/Ab, antigen/antibody test; BLQ, below limit of quantification; CAB, cabotegravir; DRVc, darunavir/cobicistat; DRVr, darunavir/ritonavir; EFV, efavirenz; FTC, emtricitabine; HIV, human immunodeficiency virus; IND, indeterminate; ND, not detected; PEP, postexposure prophylaxis; TAF, tenofovir alafenamide; TDF, tenofovir disoproxil fumarate.
Figure 4.
Figure 4.
Case summaries: injection-phase infections (cases D1–D4). Key events and laboratory results for participants who acquired HIV infection while receiving CAB injections: (A) case D1, (B) case D2, (C) case D3, and (D) case D4. Key features of the figure are as in Figure 2. Viral load values <40 indicate that HIV RNA was detected below the lower limit of quantification. One viral load result was obtained with a single-copy RNA assay (asterisk, case D2). The nonnucleoside reverse transcriptase inhibitor resistance mutation, K103N, is shown in blue text (case D3). Abbreviations: Ag/Ab, antigen/antibody test; BLQ, below limit of quantification; CAB, cabotegravir; DRVc, darunavir/cobicistat; DRVr, darunavir/ritonavir; EFV, efavirenz; FTC, emtricitabine; HIV, human immunodeficiency virus; IND, indeterminate; ND, not detected; PEP, postexposure prophylaxis; TAF, tenofovir alafenamide; TDF, tenofovir disoproxil fumarate.
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