In the 2022 Conference on Retroviruses and Opportunistic Infections (CROI), Dr. Susan Eshleman from the School of Medicine of John Hopkins University, Baltimore of the United States (US), presented a study on human immunodeficiency virus (HIV) screening using ribonucleic acid (RNA) assays in patients receiving long-acting injectable cabotegravir (CAB-LA) for pre-exposure prophylaxis (PrEP), and its implications on clinical practice.¹

The superiority of CAB-LA over oral tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) in HIV prevention was demonstrated in the HPTN 084 and HPTN 084 trials.¹ The US Food and Drug Administration (FDA) approved CAB-LA for reducing the risk of HIV sexual transmission, since these trials showed that CAB suppressed viral replication and delayed antibody production in breakthrough infections.¹ In this setting, rapid test and antigen/antibody (Ag/Ab) assays may fail to detect the infection, while supplemental Ab tests may test negative for many months, and HIV RNA levels often remain low or undetectable for long periods.¹ Therefore, a delayed HIV detection would result in delayed initiation of antiretroviral theory (ART), the emergence of integrase strand transfer inhibitor (INSTI) resistance, and the potential effect on personal health or continued HIV transmission.¹

In this study, a low viral load (VL) INSTI genotyping assay was used to evaluate the timing of INSTI resistance emergence and assess whether earlier HIV detection using sensitive RNA assays would reduce its risk.¹

Prior testing in the HPTN 083 CAB arm included 16 HIV infections among 2,282 enrolled patients.¹ Genotyping was performed in samples with VL >500c/mL.¹ Of the 16 cases, 5 had INSTI resistance, and 2 had no results due to low VL at all visits. These 6 cases were discussed during this study presentation.¹

In the current study, single genome sequencing assay was used for qualitative RNA test positive samples with VL <500c/mL.¹ Participants had an optional 5-week oral lead-in period before CAB-LA injection followed by CAB concentration monitoring. They also had HIV testing using qualitative RNA followed by rapid and Ag/Ab tests.¹

In the first case, the participant had an undetectable HIV infection using RNA in the study enrollment but a detection was found 60 days later, after receiving oral CAB and 1 CAB injection.¹ Moreover, major INSTI resistance was detected at the first site positive visit, and low VL genotyping detected these mutations at earlier visits.¹ In this case, using RNA tests for HIV screening close to the time of CAB initiation would have allowed earlier initiation of ART before CAB administration.¹

In the second case, the site detected HIV infection 47 days after the first HIV-positive visit.¹ This participant had 2 CAB injections during this period and major INSTI resistance was detected at the first site positive visit, with 1 of them being detected a few weeks earlier.¹ In the third case, HIV was detected 4 months after the first HIV-positive visit, and the participant had nucleoside reverse transcriptase inhibitor (NRTI) resistance and major INSTI resistance mutations at the first HIV-positive visit.¹ In these 2 cases, HIV screening using RNA tests would have allowed the earlier initiation of ART before the detection of major INSTI resistance-associated mutations (RAMs).¹

In the forth case, the infection was detected 45 days after the first HIV-positive visit with major INSITI resistance mutations detected a few months later.¹ Additionally, in the fifth case, the site detected the HIV infection 3-4 months after the first HIV-positive visit, and genotyping results were not obtained due to VL <500c/mL.¹ In these 2 cases, ART could have been initiated before additional major INSTI RAMs were detected with the use of an RNA test for HIV screening.¹

In the last case, HIV infection was detected more than 3 months after the first HIV-positive visit, and genotyping was also not obtained due to low VL.¹ The impact of screening using RNA tests could not be assessed due to the lack of genotyping results near the time of HIV infection.¹

The study results showed that in 5 out of 7 cases, major INSTI RAMs were not only detected in high VL “breakthrough” samples, but in low VL as well.¹ Screening using RNA assay would have been able to detect infection before a major INSTI RAM was detected (4 cases), or before additional major INSTI RAMs accumulated (2 cases).¹

In conclusion, the use of sensitive RNA assay for HIV screening can help identify infections earlier, allowing earlier ART initiation and a lower risk of INSTI resistance.+ These findings supported the information listed in the US package insert and the recent US Centers for Disease Control and Prevention (CDC) guidance on HIV testing in the setting of CAB-LA for PrEP.¹ Moreover, none of the participants was started on an INSTI-based ART regimen due to the lack of data on its use in infections occurring with CAB for PrEP.¹ Because of high proven efficacy, CAB-LA should be considered for HIV PrEP even when HIV RNA screening is not readily available.¹