PREP-HYPE OR HOPE

PREP: Hope or Hype?
George M. Carter, 12/18/10

Recently, the press was buzzing with the news that a new study has shown that the use of the two-drug combo known as Truvada (a mix of tenofovir and emtricitabine (FTC-TDF), nucleoside analogue drugs), can reduce the risk of becoming HIV infected. The study was published in the New England Journal of Medicine which if you click on this sentence you can get that copy and the Supplemental to it.

The researchers looked at 2,499 gay men and intersex transgenders, mostly in Lima and Iquitos, Peru, but also at sites in Ecuador, Brazil, Thailand, South Africa, and the United States (San Francisco and Boston). Participants were randomized to receive either the drug or a placebo. In addition, and this is very important, participants were also involved in a very vigorous program of counseling, clinical care and access to condoms.

The excitement of the study's results arose from the finding that among the participants that received drugs, the RELATIVE risk of becoming infected was reduced by 44%. Indeed, in a sub-analysis of the drug arm, the few people that took the drug consistently had a reduction of 92%, as NIAID's director, Tony Fauci was reported crowing about in the New York Times. (See FN1.)

Sounds great, eh? Just take a pill and all is well! While it is scientifically encouraging that chemoprophylaxis can reduce the risk of infection, there are some significant caveats.

Let's take a step back. Where are we in the world? Well, according to the UN, the world has something like 33.3 MILLION men, women and children living with HIV disease. Of these, about 5.2 million are receiving antiretroviral (ARV) therapy. Yet estimates are that RIGHT THIS VERY MINUTE, some 10 to 15 million of these people need ARV due to their CD4 count or clinical condition. (The higher number reflects thinking that ARV therapy should start earlier, say between 350-500 CD4 count).

Yet those HIV+ who need treatment NOW do not have access to Gilead's Truvada or any generic thereof--or any ARV therapy. Yet somehow, money is going to magically appear to make this drug available to at-risk individuals in the developing world? This seems implausible at best. Indeed, will scarce funds be funneled AWAY from extant prevention and treatment programs and into the coffers of Gilead? Or was this research just a matter of using developing nation's people as guinea pigs? Worse, Michel Sidibe recently noted that there is an ENORMOUS struggle to maintain adequate supplies of medicine (including but not limited to ARV) for the people who currently do receive ARV (Science 2010;330(6009):1301).

The study itself bears some scrutiny. Several issues arose, including the risk of resistance developing. While it seemed limited, the study sites were largely populated by people who do not have access to FTC-TDF. Further, the study was designed to stop once a certain number of infections were seen and this seemed to have happened rather quickly. Thus, by week 96, only 343 of 384 participants made quarterly site visits in the active treatment arm (331 of 378 in the placebo arm), down from 1075/1194 and 1098/1203 at week 12. While something like 10% of people missed their visit in each arm, the total numbers saw a steady and steep decline. This may be relevant insofar as the cumulative probability of becoming HIV-infected, while lower in the FTC-TDF arm than the placebo from about week 24 to week 72, began to narrow as time went on, as is depicted in figure 2 on page 8. Does this indicate that the putative benefit wanes over time? And with numbers dropping off so rapidly, it is impossible to effectively assess the issues of resistance and toxicity.

Another caveat, only about half the participants took their pills consistently. While this pointed to the possibility of the treatment being more effective among people who are strongly adherent (including to condoms), this also represents a significant challenge. If the drugs DO work as advertised (and a second confirmatory study is necessary), they must be used every single day. AND in the context of periodic visits to a clinic for testing, follow-up, counseling and condom distribution.

Most of these studies that toss around huge numbers assess relative risk as opposed to absolute risk. It's not so complicated. They looked at a total of 2499 participants 1251 in the FTC-TDF arm and 1248 in the placebo arm. There were a total of 110 infections in the study, but 10 appeared to have been seroconversions at the start of the trial, so the study authors used a modified intent-to-treat that ignored those 10. (Intent-to-treat is a statistical measure to assess data based on the initial treatment intent, "not on the treatment eventually administered.")

So there were 100 infections over a median of 1.2 years on the drugs: 36 in the drug arm and 64 in the placebo arm. The 44% we hear about is the difference of 100-36/64 or 44%. But another way to look at it is the ABSOLUTE RISK. That is, 36 out of 1251 people in the drug arm became HIV+ over a median of 1.2 years. The calculation of 36/1251 yields about 2.87% risk of becoming infected on the drugs, but that is a rough estimate. On placebo, 64/1248 would be 5.1% or an absolute risk reduction of 2.2%/year. According to lead author, Robert Grant: The annual incidence was 3.86 in the placebo group and 2.16 in the FTC/TDF group. (This was during an email exchange with Dr. Grant prior to a conference call with Dr. Grant and others on 12/3/10.)

This is a pretty marginal absolute risk and places the findings in a more stark context. According to Dr. Grant, to prevent one infection, you have to treat 45 people at unsustainable and enormous cost (see the Summary Points below). Even then, the treatment may induce significant toxicities or develop drug reistance over time.

Look at it this way. Say you are an HIV-negative gay man. You ask your doctor to prescribe Truvada. She agrees. You must then take it every single day. You must be able to pay for it. You must be able to tolerate the unintended weight loss and nausea that a significant number of participants experienced (see FN2). You must face the risks of bone destruction over time and the slight risk of lactic acidosis. You must use condoms still. And after a year, your chance of becoming HIV infected will have been lessened by 1.7% than had you not taken the drug and done all those things we know can drastically reduce the risk of infection.

Let's look at it another way. Let's use the same metric of relative risk reduction: perhaps it helps to clarify by looking at truly SUCCESSFUL forms of chemoprophylaxis. Pneumocystis jirovecii (formerly carinii) pneumonia (PCP) is a significant cause of morbidity (illness) and mortality (death) among people with HIV, especially when the CD4 count plunges below 200. A two-drug combination known as Bactrim or Septra (trimethoprim-sulfamethoxazole) is given to prevent PCP from developing when the CD4 count is low. According to one meta-analysis of the drug, the drug reduces the risk of infection by 92%! (See Green et al., Cochrane Database Syst Rev. 2007 Jul 18;(3):CD005590). Contrast this with the much more costly, toxic and largely unavailable drug with its 44% relative risk reduction and the results are not so exciting.

My biggest fear is to the extent any program is rolled out, it will be at the enormous loss of funds for prevention and treatment programs that are already struggling with woefully inadequate resources. There is NO QUESTION that prevention and treatment operate TOGETHER and must be pursued more vigorously. Currently, the Obama administration is not putting adequate funding or resources into either the national or international situation, preferring instead to offer tax breaks to the extremely wealthy, continue two wars and satisfy corporate needs for intellectual property rights over human life.

Nonetheless, should that situation shift and further funding be available to concentrate on providing more comprehensive treatment for all people with HIV, robust prevention programs are vital. These must incorporate counseling, local community development and strengthening, free access to quality condoms and lubricants, access to clean needles and to robust harm reduction programs, the option to be safely circumcisized (a one-time procedure that is of low cost). Once all that is in play in each locality, then MAYBE this form of PREP could have some small role to play among a carefully targeted group of high-risk individuals who can sustain good adherence. And this is ONLY true if in the developing world, the treatment is no more than $0.10/day, let alone the crippling up to $15,000 per patient per year cost that Gilead arbitrarily and capriciously soaks Americans and other westerners for. But even then, it is an extremely limited role. And even then, sufficient people-power--physicians, clinicians, nurses, outreach workers and others--will be necessary to assure that ongoing use doesn't rot their bones or blow out their kidneys.

I've summarized some of my thoughts below.

SUMMARY POINTS:

At least 24 Million HIV+ NEED ARV NOW and cannot get it (given WHO's 2013 recommendation for people with HIV on treatment when CD4 falls below 500). How are we supposed to figure out how to pay for PREP when we haven't figured out how to pay for ARV to prevent HIV+ people from DYING OUTRIGHT?

Any program for PREP using these drugs must include the kind of intensive counseling, condom distribution and community building seen in this study; funds must not be diverted from prevention and treatment programs simply to enrich Gilead. Any rollout must be preceded by funding and developing prevention AND treatment programs at LEAST as vigorous as that seen in iprex and this must include needle access and drug treatment programs BEFORE any initiation of drug use among high risk individuals. A baseline of robust prevention (not "abstinence only" nonsense) is essential.

Annual toxicities are cumulative -- will they worsen over time? Especially kidney trouble among Africans and African Americans? Osteopenia and lactic acidosis risks?

The cost: It will require treating at least 45 people over a year to prevent one infection: economies of scale notwithstanding, from some source or another a minimum of $146/pt/year * 44 patients or US$6,570 to prevent one infection per year or in the places where Gilead happily charges whatever they want, we'll give a mid-range $12,000/pt/year * 45 = US$540,000/pt/year to prevent a single infection. And that is just the (arbitrary and vicious) cost of the DRUG! A QALY analysis of physician, nurse and outreach time and costs will add substantially to that per patient cost. (Click this sentence to review a fascinating example of a condom distribution program in Louisiana.)

Resistance developing to the drugs is likely; how much will develop is unclear. Given that the most likely use of PREP will be among the "wealthy" who have insurance, such at risk gay men generally live in communities where there is access to ARV and they are therefore more likely to encounter an HIV+ individual with virus resistant to FTC-TDF who may pass that virus on more successfully if they have detectable viral load. Thus, resistance remains a worry.

At the end of the day, Gilead, with the aid of our tax dollars to NIAID, essentially got a new "off-label" indication for a brand new market: HIV-negative (insured/rich) gay men. Barring some genuine good faith efforts on their part to provide these medicines at vastly reduced prices, it seems exceedingly unlikely that this tool will be used ANYWHERE but among those that can afford the exorbitant prices demanded by Gilead. Meanwhile, millions of men, women and children face early death due to untreated HIV infection. And I am very sad to say, it would appear that the amazing, brave volunteers in these studies in the developing world were merely used as guinea pigs for that profiteering. (Stay tuned for the January edition of Vanity Fair for an in-depth report on the brutal, extortionist use of people in developing nations by pharma to maximize profits. When intellectual property rights are distorted into meaning profits are greater than human life, this is simply economic genocide.)

I would be DELIGHTED to be proven wrong.

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FN1 - While the substudy above seems to suggest that higher adherence dramatically reduced the RELATIVE risk further, this is not necessarily a scientifically valid conclusion. Doing a subanalysis of the treatment arm and pulling information is really a bit of statistical legerdemain that is not sanctioned as a legitimate result. While it may turn out to be true, at the moment we can only best judge by the intent-to-treat analysis. Indeed, you could take a subset of the placebo armÑsay up to 96% of that arm and say that 100% of them remained HIV-negative.

FN2 - 20 patients (2%) treatment arm vs 9 (<1%) in the placebo arm for nausea and 27 patients (2%) treatment arm vs 14 (1%) in the placebo arm for unintentional weight loss. Interesting to note that here Òabsolute riskÓ is what is evaluated, not relative risk, when it comes to adverse events. A relative risk would be on the order of a 100% increased risk of adverse events of grade 2 or worse.