Back HIV Prevention Pre-exposure (PrEP) CROI 2017: Unique Case of PrEP Failure Without Drug Resistance Reported in Amsterdam

CROI 2017: Unique Case of PrEP Failure Without Drug Resistance Reported in Amsterdam


HIV pre-exposure prophylaxis (PrEP) appears to be nearly 100% effective if taken consistently. However, among tens of thousands of cases of PrEP preventing HIV, there have been a few reports of people who acquired HIV despite high adherence to PrEP and adequate drug levels, including one reported in a poster at the Conference on Retroviruses and Opportunistic Infections (CROI 2017) last week in Seattle.

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The most fully documented case of tenofovir DF/emtricitabine (Truvada) PrEP failure was reported a year ago at CROI 2016 in Boston. In that case, the most likely explanation of why PrEP had not worked was that the person concerned had met someone with a strain of HIV with an unusual pattern of drug resistance that overcame PrEP.

Yesterday, however, CROI 2017 participants heard about a case in which someone in a PrEP demonstration study caught a strain of HIV with no drug resistance, despite documented high drug levels.

The Case


The case involved a 50-year old gay man who enrolled in the PrEP demonstration project in Amsterdam. He tested HIV negative at months 1, 3, and 6 after starting PrEP.

At month 6, in March 2016, he also provided a dried blood spot sample for the purposes of testing drug levels. Dried blood spot testing reveals intracellular drug levels and is a good guide to adherence in the past 30 days. His levels were considerably in excess of the 4-doses-a-week level needed to prevent HIV infection, indicating good adherence. Dried blood spot testing rules out the “"white coat effect," i.e., adherence being recorded as high because the person had taken their PrEP only 1 or 2 days before their appointment.

On May 24, 2016, about 6 weeks after his 6-month visit, the trial participant came to the clinic complaining of fever and of difficulty in urination and urethral inflammation. He was given an HIV test at this point, and tested HIV-positive. Another dried blood spot test was done, and this also revealed average to high PrEP drug levels, indicating good adherence during the previous 30 days. At this point PrEP was stopped.

Interestingly, the man was HIV antibody-positive but not antigen-positive. This means that the HIV proteins (antigens) that normally show up in the blood after infection -- usually sooner than antibodies -- were absent. Samples taken from both blood cells and from rectal tissues could not detect any cellular HIV RNA or integrated DNA. A Western Blot test, which detects both HIV proteins and antibodies, showed one very weak reaction to the HIV gp160 envelope protein. The man also had no detectable HIV viral load at this point or when he was tested a week later.

Two weeks after that, in a test carried out on June 15, the man had developed an HIV viral load of 20,000 copies/mL. A week later the results came back to the clinic and he was offered and started antiretroviral therapy. A confirmatory test at that point found a viral load of over 1 million. Because the results of resistance tests were not yet available, he was started on a quadruple therapy regimen of Truvada, boosted darunavir (Prezista), and dolutegravir (Tivicay), and his viral load was undetectable after 1 month.

When his resistance test did come back, it was found his HIV had no drug resistance mutations at all, not even minority ones. He was switched to Triumeq (abacavir/lamivudine/dolutegravir) and remains well with undetectable virus.

Puzzle and Hypotheses

So what happened here? This is the first case that offers evidence that appears to show that on rare occasions PrEP may not work against non-drug resistant HIV. talked to Elske Hoornenborg, who leads AMPrEP, and Godelieve de Bree, who works at the Amsterdam Academic Medical Centre and is involved in the man's HIV care.

It is possible that the man had a lapse in PrEP use immediately after his 6-month visit that did not show up in the 8-month dried blood spot test, but he maintains he had full adherence and there is absolutely no sign of any lapse.

A clue may lie in the fact that the man had a lot of high-risk sex, even for someone enrolling in a PrEP trial. During his first 7 months in the study he averaged 56 anal sex partners per month and about 30 episodes of condomless sex a month. He averaged 16 days per month when he had condomless sex and on those days averaged 3.7 partners.

"This PrEP user came to the study saying he had no doubt he would acquire HIV unless he went on PrEP," said Hoornenborg. "He was highly educated and knew exactly what the risks were but did not feel he was able to change his sexual risk pattern, so took action by applying for the study."

The man did have "chemsex" and took mephedrone, GHB/GBL, ketamine, cocaine, and amphetamine, and admitted to injecting ketamine twice but insisted he used sterile needles. He had 2 episodes of rectal gonorrhea and 1 of rectal chlamydia in his first 7 months on PrEP. He did not contract hepatitis C and was vaccinated against hepatitis B.

De Bree has a hypothesis. "This is speculative, but oral PrEP works by stopping HIV getting into the bloodstream and reaching the lymph nodes," she said. "Short-lived infections may be happening within the cells of the gut mucosa which can even stimulate an immune response, but which never get any further because the PrEP stops them at that point. It is perhaps just a matter of statistics that very occasionally, one infection slips through."

She added that some people have considerably lower levels of emtricitabine  in their gut tissues than they do in their blood, which could affect PrEP efficacy. Something might have happened in this person that affected their tissue levels of PrEP drugs temporarily.

There are mysteries to this case, however. The lack of HIV antigens and viral load in the first few weeks after infection can be explained by the individual being on PrEP, which would tend to suppress HIV replication even if it did not suppress infection. The lack of resistance also suggests that PrEP suppressed HIV before it could reach the levels at which resistance would have developed. Drug resistance would develop after infection if viral replication was not suppressed.

But in that case, how did the man develop antibodies to HIV? Antibodies only develop if HIV antigens are stimulating the immune system somewhere, and are sometimes lost, or never develop, in studies where people are treated extremely early. There must have been a point after infection at which HIV antigens were circulating at high enough levels to generate antibodies. It can be hypothesized that local priming with HIV in the gut -- which is an area rich in lymphocytes -- has led to the development of antibodies. There are people who have been exposed to HIV who, although remaining uninfected, develop an HIV-specific immune response.

The man's seroconversion illness symptoms are atypical too; difficulty with urination is not a common symptom and suggests very localized inflammation in the genital tract or prostate. This could also suggest an aberrant immune response that may have facilitated HIV infection, though all this is speculative.

Whatever the mechanisms, this case does look like the first case of infection with non-resistant HIV despite consistent adherence to PrEP.



E Hoornenborg and GJ de Bree. Acute infection with a wild-type HIV-1 virus in a PrEP user with high TDF levels. Conference on Retroviruses and Opportunistic Infections. Seattle, February 13-16, 2017. Abstract 953.