PrEP Failure Case Shocks at Confab

PrEP dominated the news at the Conference on Retroviruses and Opportunistic Infections last week in Boston, including the report of a rare failure to prevent HIV in a man taking daily Truvada (tenofovir/emtricitabine).

Other sessions discussed PrEP-related challenges such as kidney and bone side effects and high rates of sexually transmitted infections.

According to the best estimates based on data from Truvada manufacturer Gilead Sciences and large PrEP programs - which admittedly are not very precise - some 40,000 to 50,000 people in the U.S. are now taking PrEP, the majority of them gay men. Last week, Canada and Israel approved tenofovir/emtricitabine for PrEP, joining France, South Africa, and Kenya.

"The uptake of PrEP has been similar to other technologies," Dr. Brad Hare, director of HIV care at Kaiser Permanente San Francisco, said at the conference. "Early adopters are like the people who wait outside the Apple store. The next wave comes from culture change - people's friends and neighbors use it and they wonder if it's right for them too. The late adopters don't know what an iPhone is."

PrEP Failure Case

The top headline coming out of CROI was a report on the final day of the conference about a gay man in Canada who became infected with a drug-resistant strain of HIV despite good adherence to PrEP.

"Becoming infected with a virus like this one with so much resistance is rare," Dr. Albert Liu, from the San Francisco Department of Public Health, told the Bay Area Reporter. "While it's important to know that these cases can happen, PrEP is still a very powerful tool that can help prevent new infections in our community."

Dr. David Knox, a physician at the Maple Leaf Medical Clinic in Toronto, reported that the 43-year-old man - who had an HIV-positive partner with undetectable viral load as well as casual sexual contacts - had been on Truvada PrEP for two years. He attended the clinic and was tested for HIV every three months, as recommended. Pharmacy records show he refilled his Truvada prescription regularly.

In April 2015 the man began having symptoms including fever and abdominal pain. Around this time a regularly scheduled HIV test revealed acute, or very recent, HIV infection. The same blood sample showed adequate levels of the drugs in Truvada, as did a dried blood spot test used to estimate drug levels over the past several weeks.

Genetic sequencing showed that the man's virus was completely resistant to emtricitabine and partially resistant to tenofovir. It also showed resistance to older nucleoside analogs, NNRTIs, and integrase inhibitors. Nevertheless, he was able to put together a regimen of antiretrovirals that still work, and he achieved undetectable viral load within a few weeks and is doing well, Knox reported.

This first documented case of apparent PrEP failure spurred much news coverage and discussion at the conference, with experts agreeing that it does not call into question the high effectiveness of PrEP.

The international iPrEx trial found that daily Truvada reduced the risk of HIV infection by 92 percent among gay men and transgender women with adequate drug levels, and no one who took Truvada at least four times a week in an open-label extension of the study became infected. Large PrEP programs like those at Kaiser in San Francisco and the San Francisco AIDS Foundation's Strut center have also seen no new infections among people taking PrEP consistently.

"A virus like this was not seen in tens of thousands of people who took PrEP in clinical trials and every indication is that such viruses are extremely rare," iPrEx researcher David Glidden, Ph.D., from UCSF told the B.A.R. "PrEP protection is extremely high, even if it is not 100 percent. Few technologies in medicine could live up to such a standard. PrEP remains the most powerful and rigorously tested HIV prevention tool ever developed."

Others agreed.

"It seems like we are holding PrEP to a higher standard than we do for other methods of protection against diseases that don't relate to sex - in particular sex among stigmatized people," concurred David Evans of Project Inform. "While we need to reiterate to people when they are prescribed PrEP that it is not foolproof, we should not revert to over-hyping Truvada's weaknesses."

Kidneys, Bones, and STIs

CROI featured a poster discussion session looking at research on kidney problems and high rates of sexually transmitted infections among people taking PrEP.

The tenofovir in Truvada has been used in HIV treatment for more than a decade and is generally considered safe, but it can cause kidney injury and bone loss in some people. PrEP clinical trials - which excluded people with pre-existing kidney impairment - did not reveal any notable kidney problems, but sometimes uncommon side effects only show up after many more people are using a drug.

Dr. Monica Gandhi, from UCSF, presented findings from a study of kidney function changes in the iPrEx trial. They found that creatinine clearance - a measure of the kidney's filtering capacity - decreased by less than 3 percent on average after starting Truvada, but people with the highest levels of tenofovir and emtricitabine in their hair samples had a 6 percent decline. Older people were more likely to see a clinically significant decrease in creatinine clearance, but this seldom happened among participants under age 40, even with daily dosing.

Liu's team presented a similar analysis of kidney function among participants in the PrEP Demo Project, which enrolled more than 500 gay and bisexual men and transgender women at health centers in San Francisco, Miami, and Washington, D.C. Here, creatinine clearance decreased?by about 3 percent during the first three months on Truvada, then remained stable through the end of the one-year study. Larger declines were associated with higher drug levels, older age, and reduced kidney function at study entry.

These studies show that Truvada PrEP is safe for most people, but impaired kidney function - usually mild or moderate - can occur in a small proportion, especially if they have other risk factors. The findings support the Centers for Disease Control and Prevention's Truvada PrEP guidelines, which recommend that creatinine clearance should be monitored at least every six months.

"Providers may want to consider additional monitoring for people who have lower kidney function before starting PrEP, particularly in older individuals," Liu told the B.A.R.

Conversely, Gandhi suggested at a CROI news conference that maybe less frequent monitoring could be considered for people under age 40 who have good kidney function when they start PrEP.

Bone loss is the other potentially worrisome side effect of Truvada. Researchers reported last year that young men in another PrEP demonstration project experienced a small amount of bone loss after starting Truvada. But Dr. Robert Grant from UCSF reported at CROI that in the iPrEx study spine and hip bone density recovered after stopping PrEP.

Another common concern is the high rates of sexually transmitted infections seen among PrEP users. There is little evidence that PrEP actually leads to an increase, but gay men at risk for HIV already have high STI rates, and PrEP users are likely already having, or wish to have, condomless sex.

Regular STI screening for people on PrEP encourages prompt diagnosis and treatment, which reduces onward transmission. The CDC's PrEP guidelines recommend STI testing at least every six months, though people should be seen every three months for HIV testing and prescription renewal.

Sarit Golub, Ph.D., of Hunter College, presented findings from the SPARK PrEP demonstration project at Callen-Lorde Community Health Center in New York City, where participants are tested for chlamydia, gonorrhea, and syphilis every three months.

At each follow-up visit between 11 and 21 percent of participants were diagnosed with STIs, and most did not have symptoms or a prior history that would have triggered screening if it were not done routinely on a schedule. Current CDC guidelines may miss a significant number of asymptomatic STIs among PrEP users, the researchers concluded, suggesting that STI screening may be warranted every three months.

Likewise, Liu's PrEP Demo Project team reported that about 40 percent of chlamydia cases, 30 percent of gonorrhea cases, and 20 percent of syphilis cases detected during quarterly screening would have been missed with biannual screening.

"Folks who are deciding to take PrEP need it," Golub stressed at the CROI news conference. "If there is an increase in STIs, it is outweighed by HIV protection."