BOSTON — A patient in Canada contracted a multiclass resistant strain of HIV-1 despite long-term adherence to pre-exposure prophylaxis, according to data presented at CROI 2016.
The case is the first to demonstrate failure with Truvada (emtricitabine/tenofovir disoproxil fumarate, Gilead Sciences; FTC/TDF), which is associated with nearly 100% (95% CI, 86-100) HIV prevention efficacy, according to presenter David C. Knox, MD, HIV primary care provider at the Maple Leaf Medical Clinic in Toronto.
“Failure of PrEP in this case was likely due to the transmission of a PrEP-resistant, multiclass resistant strain of HIV-1,” Knox said during a presentation.
Knox’s patient, a man aged 43 years, initiated FTC/TDF in April 2013. The patient underwent seven nonreactive, fourth-generation HIV screening tests before HIV antigens were detected in May 2015. Two to 6 weeks before the reactive test, the patient reported multiple acts of anal receptive sex with casual male partners without the use of condoms.
HIV serology was repeated 7 days later and revealed a low p24 antigen concentration just below the limit of a positive result. In light of possible baseline nucleoside reverse transcriptase inhibitor (NRTI) mutations and resistance, the patient was assigned Prezista (darunavir, Janssen) with Norvir (ritonavir, AbbVie), or DRV/r, and Isentress (raltegravir, Merck).
“At this point, as the treating provider, I became concerned that this could be a true breakthrough HIV infection in the context of PrEP because my patient was adamant that he’d been adherent to his PrEP over the preceding 24 months,” Knox said.
Knox and colleagues launched an investigation to confirm whether the patient was adherent to PrEP. They collected pharmacy dispensing records for FTC/TDF and performed liquid chromatography-mass spectrometry (LC-MS) on a plasma sample collected during the initial reactive test to examine TDF and FTC concentrations. The researchers also collected dried blood spots (DBS) on day 16 to evaluate tenofovir diphosphate (TVF-DP) concentrations.
Pharmacy records showed timely prescription refills, and DBS testing revealed a TVF-DP concentration level of 2,297 fmol/punch, suggesting that PrEP was consistently utilized during the time of seroconversion.
“The DBS-observed TFV-DP concentrations were substantially greater than the expected concentrations for 20 days of therapy with TDF/FTC,” Knox said. “This suggests that there were substantial amounts of TFV-DP in the patient’s red blood cells in the 1 to 3 months prior, which would have overlapped with the patient’s clinical and laboratory seroconversion. Previous literature has demonstrated that dried blood spot concentrations of only 700 fmol/punch have been associated with protection from HIV.”
Initial results of LC-MS were inconclusive; however, repeat screening with a more sensitive assay showed there was 150 ng/mL of TDF, Knox said. FTC was above the quantification limit.
Standard and deep sequencing revealed the virus was a CCR5-tropic clade B HIV-1 strain with mutations resistant to NRTIs (41L, 67G, 69D, 70R, 184V and 215E), non-nucleoside reverse-transcriptase inhibitors (181C) and integrase strand transfer inhibitors (INSTIs; 51Y, 92Q).
“The baseline NNRTI and INSTI mutations suggest this was a case of transmitted rather than acquired resistance,” Knox said. “Importantly, the presence of the 215E mutation, which is a revertant of the 215 Y/F mutation, is known to evolve in the absence of NRTIs, and is a commonly reported transmitted mutation. So, its presence also supports the conclusion that this is a case of transmitted resistance.”
Knox and colleagues concluded that the patient’s resistance profile indicated that he was exposed to the virus from someone who was failing a Stribild (elvitegravir/cobicistat/FTC/TDF, Gilead Sciences) regimen.
“The clinical history, pharmacy records, the LC-MS results consistent with recent dosing and the dried blood spots consistent with long-term dosing of FTC/TDF suggest that HIV infection is, in fact, possible despite adherence to oral daily PrEP,” Knox said.
He added that the findings have clinical implications for the future of HIV treatment and prevention, and suggested that physicians increase baseline resistance testing to integrase-based regimens, which are included in five of six new Department of Health and Human Services-recommended regimens for treatment-naive patients.
“The ability to study rare events that occur during PrEP treatment has to be balanced with the feasibility of storing HIV nonreactive samples for potential future analysis,” he said. “As we look toward how PrEP may evolve in the future, it’s important to understand how breakthrough infections today and baseline resistance to the integrase class may impact the efficacy of PrEP options available to us in the future.” – by Stephanie Viguers
Knox DC, et al. Abstract 169aLB. Presented at: Conference on Retroviruses and Opportunistic Infections; Feb. 22-25, 2016; Boston.
Disclosure: Knox reports serving as a consultant for Merck and ViiV Healthcare, and receiving funding from Gilead Sciences.