Another possible case of PrEP 'breakthrough' infection reported

Poor prescribing and monitoring make it impossible to tell if this is a fourth case of PrEP failure

A presentation at the recent 25th Conference on Retroviruses and Opportunistic Infections (CROI 2018) describes what appears to be another case of infection with HIV in someone consistently taking pre-exposure prophylaxis (PrEP). However, a lack of monitoring and a failure to give the subject an HIV test around the time he experienced what may have been HIV seroconversion symptoms means that it is difficult to be 100% certain that this is a case of PrEP failure.

Two cases were presented in 2016 of people who were infected with drug-resistant virus despite taking PrEP, one in Toronto and one in New York.  A third case from Amsterdam in 2017 did not involve drug-resistant HIV.

In this case, because of lack of monitoring, it is impossible to say whether the patient caught HIV that was already resistant to the PrEP drugs tenofovir and emtricitabine, or whether resistance developed as a result of his staying on PrEP for a month after suspected symptoms of acute HIV infection were seen.

Glossary

seroconversion

The transition period from infection with HIV to the detectable presence of HIV antibodies in the blood. When seroconversion occurs (usually within a few weeks of infection), the result of an HIV antibody test changes from HIV negative to HIV positive. Seroconversion may be accompanied with flu-like symptoms.

 

acute infection

The very first few weeks of infection, until the body has created antibodies against the infection. During acute HIV infection, HIV is highly infectious because the virus is multiplying at a very rapid rate. The symptoms of acute HIV infection can include fever, rash, chills, headache, fatigue, nausea, diarrhoea, sore throat, night sweats, appetite loss, mouth ulcers, swollen lymph nodes, muscle and joint aches – all of them symptoms of an acute inflammation (immune reaction).

retrospective study

A type of longitudinal study in which information is collected on what has previously happened to people - for example, by reviewing their medical notes or by interviewing them about past events. 

boosting agent

Booster drugs are used to ‘boost’ the effects of protease inhibitors and some other antiretrovirals. Adding a small dose of a booster drug to an antiretroviral makes the liver break down the primary drug more slowly, which means that it stays in the body for longer times or at higher levels. Without the boosting agent, the prescribed dose of the primary drug would be ineffective.

drug resistance

A drug-resistant HIV strain is one which is less susceptible to the effects of one or more anti-HIV drugs because of an accumulation of HIV mutations in its genotype. Resistance can be the result of a poor adherence to treatment or of transmission of an already resistant virus.

The case features the first time that analysis of tenofovir levels in hair have been used to establish retrospectively that the person infected had been consistently taking PrEP over the time he is thought to have been infected.

The case involved a 34-year-old gay man from North Carolina and was presented by Joshua Thaden of the University of North Carolina, which has long hosted a key HIV clinic and research centre – it was one of the first clinics in the world to offer protease inhibitors in the 1990s.

The patient concerned had a negative HIV test in December 2015, and started taking PrEP in February 2016. He insists that he had no sexual contacts between those two dates. After three months, in May 2016, he decided to stop taking PrEP as he said he didn’t think he was at risk, but resumed against two months later in July 2016.

This is all taken from the patient’s retrospective account of his PrEP history. Although he was told he should attend at the end of his first and third month of PrEP for HIV testing and monitoring, he was given not just one month’s prescription but one month with eleven refill notes – so essentially a year’s worth of PrEP at once. He was not contacted when he failed to turn up for his monitoring appointments. So until January 2017, which is as far back as direct measurements of PrEP in his hair can go, we only have the patient’s assurance that he took PrEP regularly every day from July 2016 onwards.

The patient stayed on PrEP until April 2017. In March 2017 he came down with symptoms suggestive of HIV seroconversion illness – namely fever and muscle ache.  However, HIV seroconversion symptoms are notoriously unspecific. The patient was given a test for influenza A and B at this point, but it is impossible to rule out that his symptoms could have been due to another viral infection. If he had been tested for HIV at this point, acute HIV infection might have been detected.

He did test HIV positive when he came back for a test in April 2017 – having spent at least another month on PrEP with HIV infection. At this point his viral load was 27,000 copies/ml – typical of a ‘steady state’ infection rather than acute HIV, when viral load is usually higher.

He was also tested for PrEP drug levels, which were found to be adequate, and for HIV drug resistance. He turned out to have K65R and M184V, the two signature resistance mutations against tenofovir and emtricitabine. He also had K103N, which is the most common resistance mutation to the first-generation non-nucleoside reverse transcriptase inhibitors (NNRTI) drugs efavirenz and nevirapine.

He was put on an initial antiretroviral therapy regimen of rilpivirine, dolutegravir and boosted darunavir and quickly became virally suppressed, with the darunavir being withdrawn from his treatment in July 2017.

Because the patient had gone unmonitored for so long, it was decided to analyse tenofovir levels in his hair. These showed that he had tenofovir levels consistent with seven-day-a-week dosing between 15 January 2017 and 15 April, when he stopped PrEP. But measurements cannot go back beyond that,

The researchers think that the most likely scenario is that he was infected with a virus with at least the K103N NNRTI mutation in March 2017. But were the signature PrEP resistance mutations also in the virus he acquired, or did they develop as a result of him staying on PrEP for a month – or more, if he actually caught HIV earlier – while HIV positive?

On the one hand, infection with HIV with both K65R and M184V is very rare, as confirmed by another presentation from Seattle at this conference (see this article), but these mutations can develop relatively easily if someone stays on PrEP while HIV positive. The researchers therefore think this is the most likely scenario.

But if his virus only had K103N when he was infected, this brings up the troubling possibility that this is the second case of PrEP breakthrough by HIV that has no prior resistance to PrEP. We will probably never know, because the chance to catch his infection in the process of it happening was missed in this case.

References

Thaden JT et al. Seroconversion on PrEP: a protocol for untangling adherence vs. resistance failure. 25th Conference on Retroviruses and Opportunistic Infections (CROI 2018), Boston, abstract 1041, 2018.

View the abstract on the conference website.

Download the presentation poster (PDF) from the conference website.

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