Diagnostic and therapeutic challenges for HIV infection under PrEP

Michael J. Peluso, University of California, San Francisco (USA), presented at the virtual CROI in March 2020 the largest case series to date of patients who developed early HIV infection under PrEP.

3 case types from an overlapping group were presented

Pre-exposure prophylaxis (PrEP) is highly effective in most cases. If PrEP and HIV infection overlap, it can be difficult to make a diagnosis. Michael J. Peluso, University of California, San Francisco (USA), presented at the virtual CROI in March 2020 the largest case series to date of patients who developed early HIV infection under PrEP.

Pre-exposure prophylaxis (PrEP) protects about 3 million people worldwide from HIV infection. It is very effective when used according to recommendations.

PrEP failure even with good adherence is rare, only 7 cases have been published worldwide. If PrEP is used in persons with undiagnosed HIV infection, i.e. overlapping, this can make it more difficult for detecting the viral antigens and delay the antibody response.

The UCSF Treat Acute HIV Study included 58 subjects at the median age of 30 years at the time of analysis. 87% were men who had sex with men (MSM). 34 subjects had not used PrEP, 13 had used PrEP but not at least 10 days before diagnosis. In 11 patients there was an overlap between PrEP and HIV detection.

In 5 of these 11 subjects PrEP had been initiated, but they then tested HIV positive. 6 patients developed HIV infection under PrEP. It could be observed that persons with overlapping PrEP and HIV infection had a low viral load and inconsistent test results. Peluso presented three typical test subjects from this overlapping group.

Case 1: Rapid resistance development

Case 1 was a 31-year-old man who had not previously used PrEP. Four days before PrEP began, he had sexual contact with an HIV-positive partner who thought he was suppressed. At the examination for the beginning of PrEP an antibody test was negative, he started PrEP with TDF/FTC. On day 7 of PrEP, pooled HIV RNA from the first test turned positive. The antigen-antibody test was also positive. The plasma HIV RNA was over 200 copies/ml. Genotyping revealed M1841 mutants. In order to determine whether the mutation was acquired or had only arisen in the patient, the sample from day 0 was genotyped and a wild-type virus was found here. This indicates that this resistance developed rapidly under PrEP with TDF/FTC.

"Often a freshly acquired HIV infection is detected as a result of a PrEP consultation," explained Peluso. Transmitted M184V/I resistance is rare, but it is known to be associated with PrEP failure. In this case, resistance developed very rapidly under TDF/FTC. By testing for plasma HIV RNA during PrEP or at baseline, one could additionally identify high-risk individuals with occult acute HIV infection.

Case 2: Overstrained PrEP

Case 2 was a 24-year-old man who had been using a PrEP for about 1 year and came to an inspection. 3 months earlier an antigen-antibody test had been negative. One month before the control he was sexually active for about 2 weeks, he had an estimated 45 partners within 2 weeks. At the control, he had a positive antibody-antigen test, a negative differentiation assay, and a positive plasma RNA detection. The test was repeated after one week and gave similar results. A quantitative RNA test with a limit of 20 copies/ml was negative. He remained on the PrEP and was included in the early HIV infection study. After one month the antigen-antibody test was negative and no plasma RNA was detectable. However, detailed examinations proved that he was infected. Antiretroviral therapy was initiated.

The problem, in this case, is that the extent of adherence was not known. Peluso defined it as a hypothesis-generated case: if the exposure level is very high, a PrEP might possibly protect less. In this case, sero-reversion occurred and special assays were required to confirm the diagnosis. In this case, the PrEP may have been overwhelmed by the man's numerous contacts, despite adherence. According to statistical models, more than 90 sexual contacts per month could overwhelm the PrEP.

Case 3: Infection under PrEP and PEP

Case 3 was a 54-year-old man who presented himself with a partner for an HIV test. He had been on PrEP for about a year. About two months earlier, an antibody-antigen test was negative. A month before the HIV test, he stopped taking PrEP because of infrequent sexual activity. However, five days before the HIV test he had sexual contact with a new partner. Two days before the test he started PrEP again. The partner had a positive HIV antigen-antibody test and a high viral load. The initial antigen-antibody test in the 54-year-old was negative, a quantitative RNA test showed less than 20 copies/ml. For clinical reasons, however, an antiretroviral therapy with three substances was started. He was included in the study and tested again a week later. Antibody tests were negative and plasma RNA was not detectable at a limit of 40 copies/ml. In further tests after 3 weeks, among other things, intact provirus and intact proviral DNA could be detected.

Initially, it was assumed that the patient had successfully fought the infection by PrEP for 72 hours and antiretroviral therapy for 5 days. This would be the earliest case of HIV therapy so far. However, HIV infection was not eliminated. A 72-hour window with post-exposure prophylaxis (PEP) consisting of two substances may not be sufficient to prevent the formation of an HIV reservoir.

Peluso recommended the following strategies for complex diagnosis and therapy in cases with HIV/PrEP overlap:

Peluso MJ, et al. Diagnostic and therapeutic challenges arise with early HIV infection on PrEP. Virtual CROI 2020, Abstract 140. https://www.croiconference.org/sessions/diagnostic-and-therapeutic-challenges-arise-early-hiv-infection-prep