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Second case report of PrEP failure due to drug-resistant virus
Roger Pebody, 2016-10-18 22:10:00
A PrEP user in New York City has become HIV positive with
virus that is resistant to Truvada and
other antiretroviral drugs, the HIV Research for Prevention (HIVR4P 2016) conference in Chicago heard today. This
is only the second such case that has been reported, highlighting the rarity
but not the impossibility of HIV infections in people who adhere to their PrEP (pre-exposure prophylaxis)
The man appears to have acquired HIV from a casual male
partner who had virus with multiple resistance mutations, including some which
conferred resistance to tenofovir disoproxil fumarate and emtricitabine, the
components of Truvada. The man who
acquired HIV reported not using condoms when taking the insertive (‘top’) role
with two casual partners while he was using PrEP.
While he also had condomless sex with his primary partner,
who is HIV positive and has an undetectable viral load, phylogenetic testing
showed that there was no relationship between his virus and that of his primary
partner. He must have acquired HIV from outside the couple.
Howard Grossman said that the case involved a gay man in his
early twenties who had tested HIV negative multiple times before beginning PrEP
on January 1 2016. While the man had previously used condoms with his
HIV-positive partner, he did not do so after he began PrEP.
In the middle of February and at the end of March the couple
had threesomes with two different casual partners. Each time, the PrEP user had
insertive anal intercourse without a condom with the casual partner. He did not
have receptive intercourse.
The man missed a scheduled follow-up visit but did attend an appointment at the beginning of May. On that occasion, the 4th generation (antibody
and p24 antigen) HIV diagnostic test was reactive, as was the nucleic acid
amplification test (NAAT), which is a viral load-type test that directly detects
the genetic material of HIV.
However, the conventional RNA test used for viral load was
not reactive – in other words it did not pick up any signal of infection.
Moreover when tests were repeated two and five weeks later, they were reactive
but indicated an undetectable viral load. This is unusual during early HIV
infection and made the situation more difficult to interpret, said Dr Grossman.
Both the man and his partner insisted that he had been 100%
adherent to PrEP. In addition, testing of dried blood spots and of hair samples
in early June showed drug levels that were consistent with good adherence to Truvada in the previous 30-60 days, in
other words in April and May. However, this is after the period in which the man reported sex with casual
partners. There are no objective, biological data to assess the man’s adherence
in February and March.
Rather than this being a case of PrEP failure due to lapses
in adherence, it appears to be due to the transmitted virus having multiple mutations,
including those conferring resistance to the components of Truvada. Resistance testing showed that the man’s virus has
resistance against most nucleoside reverse transcriptase inhibitors (NRTIs, the
backbone of HIV treatment) as well as several non-nucleoside reverse
transcriptase inhibitors (NNRTIs).
Due to mutations K65R and M184V, there is high-level
resistance to tenofovir disoproxil fumarate, emtricitabine, lamivudine, abacavir
and didanosine. The mutations K103S, E138Q and Y188L confer high-level
resistance to efavirenz, rilpivirine and nevirapine. Thirteen other mutations
As a result, the man was provided with an intensive drug
regimen, adding the integrase inhibitor dolutegravir and the protease inhibitor
darunavir, boosted with cobicistat, alongside the existing Truvada. Grossman said that maintaining the tenofovir and emtricitabine
was likely to be better than not having a nucleoside element at all.
The man is doing well on this treatment and he has
maintained an undetectable viral load.
Phylogenetic analysis showed that the viral strains of the
man and those of his HIV-positive primary partner were unrelated. The man is
likely to have acquired HIV from one of the casual partners; it is plausible
that this man would have been in acute infection with a high viral load
“The patient became infected with a multidrug-resistant
HIV-1 variant despite adherence to tenofovir and emtricitabine as PrEP,” concluded
The case has some similarities with the
first case report of PrEP failure, reported earlier this year. That also
involved the acquisition of HIV that was resistant to multiple drugs.
Grossman told a press conference that there is no reason to
think that Truvada PrEP would protect
against viruses that are already resistant to its component drugs. However he said
that such cases of resistance are extremely rare. Very few people with newly
acquired HIV have transmitted resistance to tenofovir and emtricitabine
(resistance to other drugs that are not used as PrEP is more common).
He also said that two reports of infection in the context of
perhaps 100,000 people having taken PrEP represented a very low failure rate.
What else can we learn from the case? Grossman noted that
the man only reported taking the insertive role with his casual partners.
There’s a “myth in the community” that “tops don’t get HIV”, he said, which
this case challenged.
He also noted the difficulty of interpeting the lab results
in the case. Both conventional viral load tests and the Multispot HIV 1/2 test
(used to distinguish between HIV-1 and HIV-2 infections) failed to pick up the
new infection. Grossman called on the expertise and laboratory capacity of Martin
Markowitz of the Aaron Diamond AIDS Research Center and of Robert Grant of the
University of California, to help manage the case. There need to be ways for frontline PrEP providers who are dealing with unusual cases to access these kind
of resources, he said.