HIV PrEP program shows an ~43-72% protection rate!

[DarklingAlice]

I love it when my phone wakes me up with good news ^_^

Just a couple of days ago Oniya and I briefly discussed the high mutation rate of HIV as one of the many factors preventing a cure for the disease. I also pointed out that said variability makes it difficult to have faith in a traditional vaccination being discovered.

This is a disease that has multiple methods (including its hyper-variable regions) to evade any kind of immune control or cure. The natural conclusion seems to be that we need to look for alternate routes of inhibition. We need to find a way to never let the virus take hold and that needs to be accomplished through non-immune system (or rather not wholly immune system) pathways.

The first and most effective methods we have to do this are responsible sexual practices and condom use and responsible practices with injectable drugs. Unfortunately, the reality of the situation seems to be showing that this will never happen. There are too many uncontrollable factors (e.g. rape) for any purely behavioral solution to be as effective as it would need to be.

Fortunately, we have other options:

NIAID sponsored the study, also known as iPrEx, through a grant to the J. David Gladstone Institutes, a non-profit independent research organization affiliated with the University of California at San Francisco. Additional study funding was provided by the Bill & Melinda Gates Foundation. Gilead Sciences, based in Foster City, Calif., donated the study drug.

Led by study chair Robert M. Grant, M.D., of the Gladstone Institute of Virology and Immunology, and study co-chair Javier R. Lama, M.D., of Investigaciones Medicas en Salud, a Peruvian-based research organization, the iPrEx study enrolled a total of 2,499 men who have sex with men and transgendered women who have sex with men. All participants were at least 18 years old and HIV-negative at time of enrollment. The study, which began in June 2007, was conducted at 11 sites in Brazil, Ecuador, Peru, South Africa, Thailand and the United States.

The study participants were randomly assigned to receive either a daily antiretroviral tablet containing combination emtricitabine (FTC 200 milligrams) and tenofovir (TDF 300 milligrams), known by the brand name Truvada, or a placebo pill. Before enrollment, all participants received detailed information about the possible risks and benefits of participating in the trial. Once enrolled, they were evaluated for HIV infection monthly for the duration of their participation in the study. The average enrollment was 1.2 years. In addition, all participants were routinely counseled about safe sex practices and provided condoms and treatment for other sexually transmitted infections.

In the final analysis, 100 cases of HIV infection occurred among participants in the iPrEx study. Of those, 36 HIV infections occurred among the 1,251 participants who received the antiretroviral therapy compared with 64 HIV infections among the 1,248 participants who received the placebo. This level of effectiveness in reducing the risk of HIV infection, 43.8 percent, is statistically significant. Furthermore, the drug’s ability to reduce the risk of HIV acquisition was greater among those volunteers who were more adherent to the daily drug regimen. Participants who took the drug on 50 percent or more days as measured by pill count, bottle count and self reporting experienced 50.2 percent fewer HIV infections. Those who took the drug on 90 percent or more days had 72.8 percent fewer HIV infections.

The researchers concluded that consistent with earlier, smaller studies leading up to this trial, Truvada appeared to be safe and well-tolerated for its use in the iPrEx study. Side effects were mild and infrequent and included a small number of participants with transient nausea and mild elevations in creatinine, a naturally occurring molecule filtered by the kidneys. These elevations resolved spontaneously or with discontinuation of the drug. Additionally, very little drug resistance occurred with no instances of tenofovir resistance and three cases of emtricitabine resistance (one participant in the placebo group; two participants in the active drug group). The two cases of emtricitabine in the active drug group occurred among individuals who were in the stages of acute HIV infection at the time of enrollment, but who tested negative for HIV. Both groups of study participants reported a decrease in the number of sexual partners and increased condom use.

“The iPrEx study provides important evidence that PrEP works to reduce HIV infection risk among gay and bisexual men,” says Dr. Grant. “The need for new HIV prevention methods is critical. PrEP, in combination with other prevention methods, such as HIV testing, counseling and consistent condom use, could represent a major step forward for efforts to control the global epidemic.”

Correct and consistent condom use and a reduced number of sexual partners remain the most effective ways for gay and bisexual men to protect against HIV infection.

“A variety of expert and community advisory groups at the federal, state and local levels are looking closely at the study data and will move forward in a deliberative and measured way over the coming months to determine whether and how these findings should be incorporated into ongoing HIV prevention programs,” says Howard K. Koh, M.D., assistant secretary for health at the U.S. Department of Health and Human Services.

Participants in the iPrEx study are being informed of the results and counseled on the need to continue safe sex practices. Individuals who acquired HIV infection during the study were referred to appropriate medical care. Investigators will conduct a follow-on study in which all HIV-negative iPrEx participants will be offered the combination drug for 18 months. That study, which will begin in 2011, is designed to provide additional information about the drug’s long-term effectiveness and safety as well as participant risk behavior and pill-taking practices.

I am going to give the article a thorough read over today and will add to this if anything else crops up. My first observations are:
---The problem with any pill taking regimen is making people take their pills. That's the difference between the 43% protection rate and the 72% in the title. There just isn't a good way to control patient behavior even if they have been properly educated in what to do (e.g. antibiotics is a good parallel case).
---Emtricitabine and Tenofovir are both NRTIs. While there is nothing wrong with that in theory as both drugs are unique enough that a single resistance mutation is unlikely to arise against both simultaneously, it might be nice to see a more broad spectrum form of regulation targeting multiple parts of the retroviral life cycle.
---Not sure what the mass media will make of this. Remember: Not a cure. Not a sure fire prevention method. Yet very promising progress in a new direction.

NIAID News Report on the Study
Editorial in this month's NEJM
The NEJM Article

EDIT: to add a link to Elizabeth Pisani's usual insightful commentary

[Oniya]

Considering where the NRTI has its effect (in the actual replication of the viral nucleic acid sequence), I have trouble thinking of a way it could evolve a resistance to it.  I would think that it would have to come up with a way of replicating that doesn't involve DNA/RNA.

Very promising research indeed.

[Pumpkin Seeds]

I think most people would be surprised to find out how effective the treatment regime is for HIV.  When I was doing my clinicals at a HOP clinic, many of those that were compliant with their treatments had undetectable levels of the virus.  This means that under scrutiny the viral load was so low as not to show up on a normal screening.  The multi-drug combinations work at multiple parts of the virus to prevent infection of the cell, reproduction of the virus and attachment to other cells.  That this multi-point attack can now be taken with only one or two pills is improving compliance as well.  The side effects can be a little troublesome but there is a variety of medications now.  While a cure or vaccine is probably not in the near future.  A far cry from the days of when HIV was a death sentence.

[DarklingAlice]

Considering where the NRTI has its effect (in the actual replication of the viral nucleic acid sequence), I have trouble thinking of a way it could evolve a resistance to it.  I would think that it would have to come up with a way of replicating that doesn't involve DNA/RNA.

The simplest way to put this is that NRTI's are a wrench in the works. NRTI stands for Nucleotide or Nucleoside Reverse Transcriptase Inhibitor. Reverse transcriptase attempts to incorporate an NRTI into the growing DNA chain and essentially stalls out, creating an abortive transcript. However, reverse transcriptase is capable of mutating to avoid incorporating the NRTI's, and indeed NRTI use induces an obvious selective pressure to do so. The reason two are used simultaneously in this study is that the odds of the same reverse transcriptase mutating to avoid both of them are lower than the odds of it mutating to avoid just one.

However, as the study shows, such mutations occurred even in their relatively small sample population. This is the reason why the most commonly used treatment for HIV today is HAART or Highly Active Anti Retroviral Therapy, consisting of two NRTIs and a protease inhibitor used in conjunction to target two separate points in the retroviral life cycle.