'Succumbing to exhaustion'

It's almost too minute and technical to believe. An unheralded tiny viral blip that was to signal the emergence of AZT resistance went unheeded. Harmless enough, it would seem. Then, in an unlikely chain reaction that borders on the complexity of nuclear fission, an Eagle scout of a pill taker ends up with resistance to two out of three drug classes. If David Barr can't make this treatment paradigm work, then we are all doomed. The reputation for ritonavir (in the lopinavir/r) and 3TC resistant mutants to be uniquely T-cell friendly will be brutally tested now. And tenofovir will finally get its day in the sun. Below, David tells it all: lock, stock and two smoking barrels.

A few months ago I had a viral breakthrough on my regimen, and I went off the drugs. I was tolerating the regimen without problem. It was the drug resistance that led me to stop. The regimen was no longer working and there seemed no harm in stopping while my doctor and I figured out what my next step would be. I thought that maybe my viral load would stabilize at a low level and my T-cells would stay up. If that were the case, I would stay off treatment and continue monitoring until there was a reason to start again. But that wasn't the case.

My lowest T-cell count was just before starting HAART in 1996, 180. I had taken AZT for a while in 1989, but stopped it. Before starting HAART, I was developing low level symptoms—fatigue, oral hairy leukoplakia, rashes, etc. My first regimen was Crixivan/ AZT/3TC. My baseline viral load was 325,000 and my T-cells were 180 when I started in 1996. I became undetectable in 6 weeks.

It took years for my T-cells to really start climbing, but I had a slow and steady rise until I hit about 800. I had some problems with fat redistribution and lipid levels. The fat redistribution seemed to level off after a while, but the lipid abnormalities continued.

My doctor convinced me to switch regimens in 2000 because of these side-effects. I was also interested in seeing what life would be like without a three-times-a-day Crixivan regimen. I switched to neviripine, d4T and abacavir. I had one blip of 150 right before going off the Crix regimen. but we didn't pay attention to it since I was switching anyway and my doctor felt it was an aberration. That was a mistake. Had we looked, we would have seen AZT resistance—and I would not have started abacavir. I went back to undetectable after starting the new regimen, but only for about 8 months, after which I started to have a detectable viral load. The AZT resistance quickly led to resistance to abacavir, which in turn put too much pressure on the neviripine. It was a real domino effect. My adherence had been excellent. (I wish I could say that about my exercise.)

I felt that by staying on meds I was only increasing my degree of drug resistance. I decided to stop therapy to re-assess what I should do next. Before stopping, I had a final viral load done (24,000) and T-cells (775). I also had a genotype and phenotype done. It showed I was resistant to: AZT, 3TC, d4T, abacavir, neviripine, and efavirenz. Because my T-cells were high, I wasn't worried about disease progression. I was uncomfortable about going off therapy and was extremely disappointed that after many years of success, my treatment strategies were now limited.

After 4 weeks off treatment my viral load had gone from 24,000 to 602,000; my T-cells from 775 to 430. I tested again about 3 weeks later and the results were pretty much the same. This was scary and disappointing and made me want to get back on treatment. I definitely experienced some symptoms from the high rise in viral load. I became feverish, achy, and very fatigued. It felt just like I did before starting HAART in 1996. After years of feeling well on medication, it was really scary and depressing to feel sick again. The bubble of feeling well was always artificial, but it wasn't any fun having it pierced.

I started my new regimen three days ago—Kaletra, 3TC, ddI EC, and tenofovir. Because I now have a good deal of nuke and non-nuke resistance, I felt that I needed a really potent regimen because after this one, it is going to be much harder for me to find a useful combination. If I can tolerate this regimen (and if tenofovir is a potent drug), this regimen should last a while. So far, my stomach is upset and I feel a bit woozy. Hopefully, this will subside as I get used to the ritonavir in the Kaletra. I am really worried that the fat redistribution and lipid problems are going to start progressing again.

I am really concerned and frightened of the side effects that may be associated with these drugs. But I also think that there is a lot of complaining about side effects that needs to be checked. In most cases, AIDS is much worse that the side effects we have seen most people develop. That is not true for everyone, of course, but I think it is true for most of us. Despite all the fears, we are not seeing people dropping dead of heart attacks all over the place.

I don't like the changes that have taken place in my body, but I am very willing to live with them over CMV, MAC, etc. If the changes in my body were more profound, I might feel differently. My triglycerides have been over 1,500 for a few years. I am constantly worried that some little twinge or irregular heart beat is the stroke or heart attack that I have been waiting for.

I think that people are understandably tired of taking their medication. I think we are tired of taking the pills, tired of having our lives structured by a pill regimen, tired of the side effects. Much of the talk and excitement about treatment interruptions seems to be about this to me. It is rarely based in science. It could be that strategies to pulse therapy over weeks or months may be effective, but we have no idea if that is true and should really wait for study results. Many people going on treatment interruptions at this point seem to be succumbing to exhaustion. I hope that they are still monitoring themselves closely. I hope that they are not forgetting that however bad the drugs may be, AIDS is worse.

I took a treatment interruption because I didn't know what else to do—not because I wanted to. What I really want is an AIDS holiday, not a drug holiday.

If the drugs are working for me, then the difficulties of taking them become my only real physical manifestation of AIDS. So that makes me want to stop taking the drugs. But what I really want to stop is thinking about AIDS. Once the drugs stopped working and my viral load came back and I started feeling sick, the threat of AIDS was back with a vengeance—and I wanted my pills. I think this treatment strategy is very, very fragile, and I am amazed it has worked for as long as it has in so many people. I don't want to take it for granted.

If some data come along that say I can pulse my therapy, great, but I won't do it until then. I am much more concerned with what happens when I have no drugs to take than I am with how soon I can stop taking them. When I stop taking these drugs, it will be because they are not helping me any more. And that means that something worse is going to happen to me than taking pills everyday. ¤

'Souped-up monotherapy'

When it comes to the management of a fatal infection like HIV, it has been argued that self-experimentation seldom leads to knowledge. Others in this fix are quick to point out that current approaches to treatment are all just one big experiment, anyway. Opposite ends of an authoritative continuum, it would appear: "Do nothing without solid clinical evidence to back it up"—and the hallowed imprimatur of some omniscient governing body, goes the thinking of the first camp. "Search out all there is to know, follow the heeding of your gut, and do what makes sense to you in order to stay well," the other. That the latter of the two approaches reverberates as the spirit in which the entire AIDS activist movement was born seems ridiculously self-evident. This TAGline editor is keen to include himself among the ranks of the provocative, the circumspect and the headstrong—and recounts his story here.

Like many people I know, I started antiretroviral therapy shortly after the Vancouver conference in the autumn of 1996. With T-cell counts that had see-sawed between 400 and 500 for nearly a decade, I'd always sort of been on the cusp of start/don't start. It was the three-years-to-eradication talk, which began early in the spring of 1996 and then reached its frenzied crescendo by late summer, that tipped the balance for me in favor of starting. After I'd taken my first dose I remember wandering the streets of the East Village, zombie-like, imagining the end of AIDS. Even if the big talk didn't pan out, at least I would give my immune system a break. And so that was the deal I made with myself: jump on the "It's the virus, stupid" bandwagon, see where it leads, give it a couple of years, then reassess the situation.

Contrary to the neatly organized stories of viral "set points," my viral load measurements had always been all over the map. Eighty thousand one month, a hundred and fifty the next; one hundred thousand in the spring, one hundred and eighty in the fall. Half a year of monthly DNCB paintings had appeared to bring my viral load down to 50,000 just before I started taking the pills. (No, there wasn't a control group.)

At that time there were only three protease inhibitors available. Ritonavir's reputation terrified me, and saquinavir seemed like protease-lite. Given the alternatives, indinavir seemed the safest bet. And I liked the twice a day schedule of d4T and 3TC, so that's where I began. Yet I under-estimated how intrusive the fasting requirements and thrice daily indinavir dosing would be in my life. I was obsessively compliant but was driving my boyfriend crazy. I lived my life by the ticking hands of the clock.

My viral load fell below 400 copies within a month. A few months later, when I changed doctors in order to gain access to the ultra-sensitive 50 copy assay, my virus was still detectable—and took nearly 6 months to go below 50. My T-cells never really budged; five or six hundred was the most I ever got.

A couple months into the combo my skin and lips began to harden, dry and crack—to the point where it was as if the skin from my elbows or heels had overgrown to the rest of my body. Under the sheets it was like sharing a bed with a pint-sized pachyderm. "The skin is the body's largest organ—and a window to the immune system," I remember my dermatologist friend telling me. If this is what Crixivan is doing to my skin, I mused, god only knows the effect it's having on my insides! My boyfriend urged me to jump ship. He'd been one of those ritonavir people who, incredibly, had suffered no ill effects at all, not even the first few weeks. "Only twice a day—and with food," he lobbied me to join him, but I declined.

Nelfinavir came along late that winter—and I jumped. What a relief it was to have no more fasting requirements. Even for an urban gay man living on the outer reaches of a Barbie doll six-pack culture, planning for a full stomach was much more exciting than contemplating its opposite. Apart from the early diarrhea and the chronic loose stools, nelfinavir was a veritable vacation compared to indinavir. Some months later I would talk with friends who had also made the switch. We shared stories of shitting our pants in the middle of Manhattan, no time to search out a toilet. (Imodium anyone?) Wasn't life on Viracept grand.

The year 1996 had not even come to a close when researchers began explaining why the Perelson/Ho predictions were a fantasy. Memory T-cells would pose a significant hurdle, as would the existence of viral reservoirs untouched by treatment. The Diamond team's assumption of 100% viral shut-down was also to prove naïve. As experiments at Hopkins, the NIH and UC-San Diego proceeded, the 3-year cure time line had been quickly extended to 60. The bandwagon, it seemed, had encountered an impasse.

In the spring of 1998, faithful to my earlier bargain with myself, I bid my triple combo farewell and opted for an experimental foray with a less intensive "maintenance therapy" regimen of ddI and hydroxyurea. ("High genetic barrier to resistance," and all that.) Never mind that the handful of such trials (ACTG 343, Trilège, ADAM) were not panning out. Most of them had been poorly designed, almost as if they had been set up to show failure. None of them had included hydroxyurea as part of the maintenance regimen. Little by little my viral load became detectable again. It plateaued at around 1,000 copies and remained there for many months.

Over the course of the past three years I have gone on and off my ddI/hydroxyurea bitherapy for increasing periods of time. First just a week, then two; later for a month, then longer. Each time I would test my viral load obsessively and go back on my souped-up monotherapy when the virus threatened to break out. Strangely, it always seemed to rise at a snail's pace. Emboldened, I began to take longer treatment breaks: two months, three months, five. But I'd grown complacent: my RNA results came back at 180,000; CD4s hadn't budged. I pulled the pills back out for a couple of months.

I am currently logging the progress of my longest time off therapy since this experiment began some five years ago. My March 2001 viral load, nine months off therapy, was a mere 12,000 copies; my CD4s, at 660, were higher than ever—even on the protease triple combo.

Of course, it's possible that with only a moderately high baseline viral load I hadn't needed a triple combo in the first place. (Remember though, back in 1996 a mere 20,000 copies was considered immediately life-threatening, thanks to the pip-squeak arriviste John Mellors and his poorly preserved plasma samples from the MACS.) Perhaps ddI/HU would have been sufficient from the start. My doctors and I conceded that possibility in a letter to the Lancet (3 October 1998, 352:1149). The dinitrochlorobenzene pre-treatment spree was omitted from the Lancet letter. Why risk the ridicule?

Now, of course, we learn there may be individual characteristics—genetic makeup—which pre-determine the course of one's HIV infection. Chemokine receptors mutations (e.g., CCR2, SDF-1) and HLA subtypes. I didn't even know what HLA was, and yet researchers now talk of "advantageous" and "disadvantageous" alleles. (see inset, page 3) With all the progress the field has made, it boggles the mind to think how much we still don't understand.

My physician friend in Berlin talks of how shamefully crude our methods are some fifteen years into HIV care. The fact that we are still relying on CD4 cell counts and plasma viral loads in 2001 seems absolutely barbaric to him. Will we, a year or two from now, be routinely measuring patients' viral diversity, the breadth of their CTL response, cytokine signaling and antigen presentation?

I performed my own maintenance therapy experiment because I was less afraid of developing resistance to ddI than to a protease inhibitor or a non-nuke. I also wanted to thumb my nose at an oligopolistic biomedical industrial complex that delights in the stranglehold it exercises over the AIDS research agenda.

Who knows what my counts will be when I test again in a few weeks. Maybe it will be time to haul out the Videx again. It's even possible that one day ddI's high but not nonexistent genetic barrier will be reached, and I'll have to re-think this entire strategy. For the time being, though, I will keep on experimenting, "N of 1" or not. Sometimes self-experimentation's all a guy's got. ¤

The human leukocyte antigens (HLAs) are also known as MHC (major histocompatiblity complex) or "self" molecules. They are genetically inherited proteins present on the surface of human cells. T and B cells recognize antigens only when "presented" to them next to an MHC ("self") molecule. There are two main types of HLA. Class I is divided into HLA A, B, C and are expressed by most human cells. Class I HLAs are involved in presenting antigen to CD8 cells, thus activating the CD8s. When CD8 cells recognize antigen presented by HLA class I, they kill the cell presenting it. In this way the CD8 cells destroy cells infected with viruses, including HIV. Genetic make-up of a person's HLA affects the rate of HIV disease progression.

Class II is divided into HLA DP, DQ, DR and are expressed by macrophages and dendritic cells. Class II is involved in presenting antigen to CD4 cells, thus activating CD4 cells. When CD4 cells recognize antigen presented by HLA class II, they secrete cytokines (e.g., IL-2, IL-4) which in turn stimulate further immune responses. Mass General's Bruce Walker, the godfather of structured treatment interruption in acute HIV infection, argues that the role of particular alleles in the loss of control in persons who experience viral breakthrough on antiretroviral therapy needs to be carefully studied. Similarly, he says it is important to determine whether early treatment of acute infection followed by STI "can ever result in durable control in someone with a 'disadvantageous allele.'" ¤