Human Subject: An Investigational Memoir

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5. QID

“La meilleure théorie est celle qui a été vérifiée par le plus grand nombre de faits.”

During my teenage years, I thought sex was disgusting, scary, decadent, and a waste of time. Then I tried it. Then I tried to have as much of it as I could. Between the ages of 19 and 28, I had sex, mainly of the unprotected variety, with 16 men (no women). Call me promiscuous; call me young and foolish; call it the pre-AIDS era. For whatever reason, I did not place a high value on avoiding sexually transmitted diseases.

Actually they were “venereal diseases” back then. The name was changed ostensibly to make the meaning clearer to those with no knowledge of Latin, but I think it was just a case of wanting to substitute a new term for a stigmatized one (like calling an increase in the war effort a surge instead of an escalation). After a couple of decades “STD” had acquired its own stigma, so now the official name is STI—sexually transmitted infection. It won’t be long before that, too, is relegated to the hall of shame, because, let’s face it: Whatever you call the diseases, people will always associate them with behaviors that are socially frowned-on or at least irresponsible. I wonder why the same kind of stigma doesn’t attach to lung cancer, since it’s also a disease that most victims could avoid if they adopted healthier habits.

When I was 26, I started having some minor genital infections that seemed impossible to cure completely. I theorized that I’d gotten this persistent illness from a guy named Richard, so one friend of mine called it “Riccardus recurrus.” The intermittent outbreaks were annoying, but I didn't give them a lot of thought.

Aside from sporadic genital sores and an occasional low-grade fever, I only noticed one other symptom. A hypersensitivity that stopped short of pain, but was more unpleasant than tingling, would begin in my lower spine and extend gradually to my left ankle. This sensation would usually last for a couple of days. Meanwhile, other parts of that leg were completely numb. Fearing (or hoping) that I had some rare neurological disorder, I went to see a neurologist. When he couldn't find anything wrong with me, I figured I must have a disease that was rarely seen in civilized parts of the world.

So I was getting these three unusual symptoms—low-grade fever, left-leg discomfort, and genital lesions—for about 20 years without ever noticing that they always occurred within a couple of days of each other. Then I finally got a symptom that couldn't be ignored: a large, itchy, red welt that would appear every few months on my left buttock. At first I thought it was a recurring insect or spider bite, but that really made no sense. Only an obsessive-compulsive and extremely hardy creature would have kept biting me in just that one spot and at all times of the year.

I can’t remember exactly when or how I made the connection, but eventually I learned enough about genital herpes to link the appearance of the red bump with the other symptoms I'd been having. So, decades after being infected, I was finally diagnosed with herpes simplex virus, type 2. (Type 1, best known for causing cold sores, can also cause genital herpes, but HSV-1 is much less likely than HSV-2 to cause repeated genital outbreaks.)

At least I wasn't alone. According to the CDC (http://www.cdc.gov/std/Herpes/STDFact-Herpes.htm), the number of Americans with genital herpes increased by about 30 percent between the time I was infected and the time I was diagnosed. I had assumed that most people aren't as slow on the uptake as I am when it comes to figuring out that there's something wrong with them, but according to the American Social Health Association (http://www.ashastd.org/learn/learn_statistics.cfm), up to 90 percent of people infected with HSV-2 don't even know they have it. Of course, that’s mainly because you can have absolutely no symptoms when infected with the virus.

It takes a clever virus to fool its hosts into obliviously transmitting it. HSV-2 is particularly adept at assuring itself a long and infectious life. It works like most viruses, commandeering your body's cells and turning them into virus-producing factories. Then it lies dormant in a host cell for months or years at a time, just waiting for you to let down your defenses enough so that it can go back into action. If you're lucky, the virus stays dormant most of the time, only flaring up during times of stress. But here's the really clever twist: Even when you aren't having an active infection, your body can be “shedding” the virus.

During its inactive periods, HSV-2 resides in the lumbosacral dorsal root ganglion, a tissue mass containing sensory neurons at the base of the spine. These nerve cells are some of the largest cells in the body, so herpes has plenty of room to stretch out. In this ganglionic green room, the virus naps until it gets its cue to reactivate.

There are six other herpesviruses that affect humans. One of those, varicella zoster (VZV), causes chickenpox, also known as varicella. In keeping with the herpetic protocol, VZV hangs around after you've recovered from chickenpox, hoping that you'll lose the immunity you got from having the disease. Some adults who had chickenpox as a child do lose enough immunity so that VZV is reactivated (usually after age 50) to cause the painful disease known as shingles, or herpes zoster. Here are some facts about shingles:

In 1995 an effective varicella vaccine became available. Now it's recommended for all infants and for older children who haven't had chickenpox. After it was introduced, the incidence of chickenpox steadily declined, but this was balanced by an increase in the rate of shingles cases. Why? Because we're rarely exposed these days to children with chickenpox, which would help to boost our immunity to the virus. (Edmunds & Brisson, 2002).

In 2005 Merck & Co. began testing a shingles vaccine in older adults. The vaccine, which was more potent than the one used to prevent chickenpox, successfully decreased the incidence of shingles. For those who got the disease despite being vaccinated, the symptoms were less severe, and patients were less likely to get PHN. In 2006 the FDA approved the vaccine, Zostavax, for people 60 and older.

Developing a vaccine for HSV-2 has been a little trickier. In 2002 a vaccine was tested and found to prevent the disease in about 75 percent of women who had neither type 1 nor type 2 herpes simples. The vaccine was a lot less effective in men, and it didn’t work well for women who had antibodies to both HSV-1 and HSV-2. Currently there’s another study in progress to test the vaccine in about 7500 women, ages 18 to 30, who have no antibodies to either variety of herpes simplex. (This may be harder than it sounds, because between 50 and 80 percent of the population has

It's estimated that one in four women is infected with genital HSV-2. That's about 25 percent more than the number of men who are infected. The discrepancy is probably due to the fact that transmission occurs more frequently in the man-to-woman direction than the reverse. Having a vaccine that works for most women should help to level the playing field, so to speak.

When I was first diagnosed, I got a prescription for Zovirax (acyclovir) ointment to apply when I had outbreaks of the disease. That worked for a while, but never very well. Once you've reached the stage where you have a full-blown itchy welt, the virus pretty much has a mind of its own. (It's hard not to attribute human reasoning ability to such a successful pathogen.)

Next I tried oral antiviral drugs, both acyclovir and Famvir (famciclovir). The idea was to start taking the medication when I first felt the malaise and tingling that preceded the lesion. This technique worked briefly, until the virus developed a tolerance for the drugs.

The most effective herpes treatments are those that continuously interfere with the virus's ability to replicate. This form of treatment is called suppressive therapy, and all three common anti-herpes drugs have been proven effective at it (Lebrun-Vignes et al., 2007). Only one, however, has so far been shown to reduce the chance of transmitting the disease. This isn't because anyone tested the effectiveness of all three drugs. It's because GlaxoSmithKline, the makers of Valtrex (valacyclovir), funded a study that showed their drug works, and then they made sure the results were well publicized. The other two drugs are generic, so no one had any incentive to prove that they were just as effective in preventing viral shedding.

I had seen the reports touting the benefits of Valtrex, but it wasn't on the drug formulary for my HMO, and it was prohibitively expensive. Instead I got a prescription for daily acyclovir. I was convinced that if someone would just compare the two drugs, acyclovir would prove to be equally effective in preventing viral shedding and transmission. The following winter, as I was launching my career as a human subject, I learned that someone was indeed conducting such a comparison.


The herpes research clinic, which was affiliated with Big U and which I’ll therefore call UniVir, had little in common with the for-profit PsychoPharm. One major difference was that the herpes researchers got no funding for this study from any pharmaceutical company. One goal of the research was to show that another drug was just as effective as Valtrex in preventing viral shedding; it would not have been in the best interests of GlaxoSmithKline's shareholders to fund such a study. Therefore, the research clinic had to purchase all of the study medications with its own funds.

This was a “crossover” study, meaning that both drugs would be tested on all participants. First I would be randomly assigned to receive one medication or the other. After seven weeks, there was a seven-day washout week, during which no medication would be taken. Then, for the final seven weeks, I would take the other study drug. (All these sevens gave the study a strangely Biblical quality.)

At the screening visit I met with a nurse practitioner, Donna, who would be my main contact over the course of the study. Her title on the consent form was Healthcare Specialist. In addition to taking my vital signs and a tube of blood, she explained in scrupulous detail what I would be expected to do during the study:

The swabbing would definitely be the most burdensome part. It would pretty much preclude leaving home for more than a few hours at a time, although I would get a nifty insulated lunch bag, with accompanying freezable cold packs, just in case I ever got a job. How clever to disguise these medical paraphernalia as lunch, I thought. In a pinch one could even put some actual food in with the swabs, vials, and labels.

For all this inconvenience, Donna told me, I would receive $300. I would also get to keep the lunch bag. How could I resist such a deal?

After I'd signed the consent form, we made an appointment for me to return at a later date to begin the study. If for some reason my blood work didn't check out (if I had the wrong kind of herpes, or no herpes, or HIV), they would let me know.

On my return visit I learned that I had indeed qualified (HSV-2 positive, HIV negative), so Donna gave me more in-depth instructions and a brief physical exam. When she took my blood pressure, she told me that variations in BP aren't significant as long as they’re within a certain range. She also told me that the method used (mechanical versus electronic) and the amount of pressure exerted by the cuff can affect the results.

When she measured my height, I was surprised that I had shrunk half an inch in the few short weeks since Lisa had measured me. A few days later, when I had my screening for the depression study, I was 5-foot-2 again. I figured that this was because Donna's method wasn't as accurate as the one used at PsychoPharm. Apparently some research protocols don't specify the method to use when taking vital signs or measurements, but some do. The Wyeth/PsychoPharm protocol dictated exactly which device to use for getting blood pressure; presumably it also specified a particular type of scale.

After the physical, it was time for a not-so-dry run of the swabbing procedure. I’ll spare you the gruesome details, but at one point we were required to wait a full minute before moving on to the next step in the swabbing sequence. Donna tried to pass the time by asking me about my employment situation. My small-talk skills are deficient in even the most relaxed circumstances. Sitting naked on an examining table, being quizzed about the sensitive subject of unemployment, I answered in a nervous, rambling sentence, ending with the most personal disclosure: “ . . . participating in research studies, and writing about the experience.”

At that point I emitted a nervous laugh, which would have been fine if I hadn't simultaneously emitted a burst of flatulence, right in poor Donna's face. She leapt back, in case there was more to it than just hot air. There wasn't, but the lapse in etiquette was embarrassing enough for me. It also apparently distracted Donna from my last statement, because over the course of the next 15 weeks she never asked about my writing.

When the minute was up, I finished swabbing and, after getting comments from Donna on my technique (“you're being too dainty”), placed the swab in a small plastic vial. As instructed, I tried to break the stem against the rim of the container so that only the tip remained in the vial. This was about as easy as breaking a green twig. To put it delicately—oh, heck, there’s no way to be delicate about this—the stem of the swab had soaked up enough vaginal secretions to make it behave just like one of those Q-tip stems that bend but won’t break. With Donna’s encouragement, I finally managed to snap off the stem, and then I screwed a green cap on the vial, just as I would do four times a day for the next 15 weeks.

Swabbing supplies I made an appointment to return at the same time two weeks later, and I was given all the paraphernalia I would need for the first two weeks of the study: several dozen little screw-top vials containing a buffer solution, about an equal number of swabs, and several sheets of self-stick labels. The labels were preprinted with my code name and the description “Genital Mix"; there was a space for the date and time, which I would record before sticking the label on the vial. (The labels were about five millimeters wider than the circumference of the vial, so it was always a challenge to affix them without obscuring some of the pertinent information.) I also got a chart called a Symptom Diary on which to record data for each day, including any symptoms I experienced, when I took the medication, and whether or not I had performed each of the four daily swabbings. And of course I got the stylish black insulated lunch bag to carry all my new toys.

On the daily diary there was a box called “Sex,” which I was to mark if I'd had sex prior to the swabbing. I pictured the researchers comparing how sexually active their subjects were, and perhaps betting at the start of each subject’s participation on how much sex he or she would have. Maybe they would even award prizes for copious copulation. With my highly competitive nature, I was motivated to have as much sex as possible during the course of the study.

Back home, it took me a few days to develop an efficient swabbing routine. Then I decided that maybe I should read the printed instructions. It turned out that there were a couple of things I was doing wrong. For one thing, I was sure Donna had told me to insert the swab, leave it in for a minute, and then rotate it before removing. The instructions clearly said to rotate upon insertion, then wait 60 seconds, then remove. I revised my procedure accordingly, figuring that I had misremembered what Donna had said. The instructions also said to wash my hands before swabbing. I wasn’t about to wash both before and after, so instead I tried to keep my hands from getting contaminated while swabbing. This rarely worked, so I sometimes used a hand sanitizer before putting the sample in the fridge; at other times I just said to heck with sanitation and opened the fridge with a contaminated hand. Swabbing trash

I was slightly dismayed by the amount of trash I had to generate for the study. Each swab came in a protective paper wrapper, and only the tip was saved in the vial of buffer solution. Of course this isn't really much waste compared to the vast number of single-use items discarded in other health-care settings. The ECGs I had for the depression study involved the use of disposable electrodes, which are pretty substantial objects. And you can be sure that nobody washes and reuses those screw-top urine specimen jars.

Unlike in the depression study, I wasn't required to have a washout period to get my current drug out of my system. Instead I switched right over from twice-daily acyclovir (800 mg total) to once-daily Valtrex (500 mg). A few days after the switch, I started experiencing vague inklings of a herpes outbreak. But that recurrence never actually occurred. I suspect that the vague inklings were due to heightened anxiety, which was easily explained: The beginning of the herpes study corresponded with my Paxil washout period.

After two weeks I returned to trade my full box of vile vials for a new set of supplies. I also had to show Donna my swabbing technique, so that she could be sure I was doing it right. This time, fortunately, she wasn’t subjected to a gaseous assault. And she was quite complimentary of my performance, although I wasn’t getting as much of the “juicy stuff” as I should. I promised that in the future I would be more thorough.

When I confessed to her that for the first few days I'd been swabbing incorrectly, i.e., rotating the swab just before removing it, she said, “Really? I thought that was how you were supposed to do it.”

This lack of knowledge on the part of an investigator was disconcerting, and I would soon learn that it was disconcertingly common. Protocols aren’t always followed, instructions are sometimes ambiguous, and subjects are unreliable sources of information about their own symptoms. Worst of all, the investigators I encountered didn’t seem bothered by any of these issues. The more time I spent as a research subject, the less confidence I had in the results of any studies. For the moment, however, I still felt that I was engaged in a worthwhile and honorable pursuit.

Donna told me that so far only two people had completed the study, and two others were currently enrolled. At least one had dropped out, unable to handle the routine of swabbing four times a day (or, as a doctor might abbreviate it, “qid”). Since the goal was to run 62 subjects eventually, and the study had been in progress for nearly six months, I wondered whether the data I contributed would ever make it into a valid study. When I expressed my concerns a few weeks later, Donna told me that two more people had enrolled, and she assured me that the data would all be used, no matter how few people completed the study.

She may have meant that UniVir’s data could be combined with data from other studies in what’s called a meta-analysis. This is a technique of statistical analysis that uses the results of many studies to measure the effectiveness of a particular treatment. It has some drawbacks, and the reliability depends a lot on the design of the individual studies. I would think that for this particular study it would be hard to do a meta-analysis, because there weren’t any comparable studies being done. At least that was my understanding as a mostly ignorant participant.

My doubts reminded me of people (myself included, I confess) who won't vote for a political candidate if that person has very little chance of getting elected. At some point you just have to do the good, conscientious thing and not worry about whether your vote—or, in this case, your “genital mix"—will make a difference.

I’ve always considered myself a fairly competent person and a valuable employee. Now that my only real job was participating in research, I wondered if any other study subjects, particularly the full-time guinea pigs, ever asked researchers to provide them with references or letters of recommendation. “Jane Doe was a very conscientious and compliant subject. She always showed up on time for appointments, she took all the medications we gave her, and she never complained about the treatment she got or the paltry payment.” I wondered if having such a letter in hand would move one to the head of the line in the screening process.

For now I wasn't too concerned about being eligible for another study. I pretty much had my hands and other body parts full with the two I was already in. But I'm one of life's perfection-seeking “maximizers”: No matter how much I like a job or living situation, I'm always in the market for something more or better.


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