Coverage of 2007 IAS
(International AIDS Society)

July 2007, Sydney, Australia

Back to the Future?

July 23, 2007

The question of when is the best time to start anti-HIV therapy was a key story Monday at the International AIDS Society’s Conference on HIV, Pathogenesis, Treatment and Prevention in Sydney, Australia. There were two plenary sessions devoted to the early treatment of HIV disease and how new data could or should affect treatment guidelines. This article will look at the issue at hand and the presentations that addressed aspects of it.

It is difficult to imagine a more important unanswered question than when to start HIV drug treatment. While the question seems quite simple, answering it poses several formidable scientific hurdles which have yet to be overcome. The best way to answer important medical questions is through a randomized clinical trial. One way to address the when-to-start (WTS) question would be to randomly assign different groups of people to start taking HIV drugs based on some criteria, like CD4 T cell count or viral load. Researchers would then follow the groups over some period of time, gathering information on their health status, and compare the groups at the end.

A sizable and influential group of people have been calling for just such a study, and for good reason. To date this important decision has been guided by a mix of anecdotal information, non-randomized cohort studies and expert opinion. All of these methods give useful information, but none are as solid or reliable as a randomized, prospective clinical trial.

Lately the call for a WTS trial has gotten louder. Why? First, there’s growing confidence in using anti-HIV drugs. The introduction of more convenient, durable and less damaging drugs lessens the anxiety of exposing large numbers of people to them for extensive periods of time in a research setting. Also, as anti-HIV therapy is made more widely available throughout the world, the answer to this fundamental question gains even greater importance to more people.

However, not all are convinced that such a study is feasible now or maybe ever. To truly answer this question, a study would have to be long-term and would need to involve a large number of people. At the end of the study—likely seven or more years from when it is designed—would the answers given still be relevant? Few question the importance of the question, but significant questions remain about the possibility of truly answering it.

The first session in Sydney to touch on this topic was a well attended, interactive titled, ‘New Data and International Antiretroviral Treatment Guidelines.’ Sprinkled in to the three presentations were opportunities for audience members to vote on questions posed to them by the speakers. The votes were placed on small electronic devices handed out to the audience and tallied immediately. In all there were three presentations, each focused on a series of case studies. The overriding theme was how to incorporate new data into individual treatment decisions and broad guidelines.

The new data largely fall into two categories: new drugs and advances in understanding of HIV pathogenesis (how HIV causes disease). The years 2006–2008 is likely to been seen as one of the most productive periods in HIV drug development. The approval or Prezista (darunavir) along with the anticipated approvals of Selzentry (maraviroc), Isentress (raltegravir, MK-0518) and etravirine (TMC-125) have opened up the possibility of full viral suppression for many people with heavily drug-resistant HIV.

This is also the post-SMART Study era. The SMART study found, quite unexpectedly that people on continuous anti-HIV drug therapy had a lower risk of heart and kidney disease and cancer than people taking intermittent HIV drug therapy. Taken alongside the growing body of evidence (including data presented elsewhere at this meeting) that immune activation, caused or worsened by uncontrolled HIV replication, may underlie a significant amount of illness in people with HIV. These results have led to re-examining the cost-benefit analysis of HIV drug treatment. Put another way, while we are right to focus on the toxicities of HIV drugs, we should not underestimate the toxicity of HIV itself.

Complicating matters is cost. The more potent, durable, convenient drugs that are standard of care in the developed world are not widely used in the developing world. The most common HIV drug regimen used in Africa, accounting for about 60% of prescriptions according to one presenter today, is a generic, fixed-dose combination of Viramune (nevirapine), Epivir (lamivudine, 3TC) and Zerit (stavudine,d4T). Of these three drugs, only Epivir is a leading drug used in richer countries, while Viramune is a lesser used alternative to Sustiva (efavirenz). Zerit has fallen almost totally out of use due to medium and long-term toxicities. According to one presenter, the cost of switching out the NRTIs to the preferred Viread (tenofovir) and Emtriva (emtricitibine) would raise the cost of treatment 3 to 5 times.

Not surprisingly, no consensus emerged on how best to use these new drugs, or new understandings of pathogenesis. There was a general desire to use the newer drugs more often, but no plan for how to accomplish that.

Dr. Anthony Fauci chaired the later session, titled, ‘Treatment of Early HIV Disease.’ Opening by declaring this an opportune time to raise the question of early treatment, Dr. Fauci pointed to the same data on new drugs and pathogenesis as drivers of this question.

The first presenter, Dr. Yves Levy reiterated the now familiar story of immune activation. He presented data showing that markers of chronic inflammation were an accurate predictor of the risk of disease progression, independent of viral load. The field of immune activation is relatively young, and most of the data are from animal studies. With a slide titled, ‘The War is Won with the First Battle,’ he detailed the importance of both early events in HIV infection and the effect that starting therapy at different CD4 counts had on clinical outcomes. Looking at cohort studies, he showed that gains in CD4 count after starting anti-HIV drugs level off after a couple of years, leaving many people who start HAART with a less than ideal immune recovery. He also pointed out that people with higher CD4 counts (above 350) still have higher death rates than HIV negatives, but that the difference almost disappears when looking a people who have maintained CD4 counts above 500 for 7 or more years.

Dr. Jim Neaton detailed the changing patterns in HIV disease and death, away from the traditional AIDS-defining opportunistic infections toward serious non-AIDS diseases like heart disease, lung cancer and diabetes. For example looking at results from the CASCADE cohort, before 1997 (when HAART became widely available) around half of the deaths in this group were from AIDS-related illnesses, mostly opportunistic infections. After 1997 only 28% of deaths were from AIDS-related causes. Looking at the HOPS cohort, he showed that among people who started HAART with CD4 counts below 200, 60% of deaths were from AIDS-related causes, compared to around half that number for people who started with CD4 counts above 200.

A particularly interesting aspect of his talk was on the use of ‘biomarkers.’ Looking again at the SMART data, Dr. Neaton presented data on a marker of coagulation, called D Dimer (used to help diagnose deep vein thrombosis and other heart complications) as a powerful predictor of HIV disease progression. At the start of the study, he showed that people with HIV tended to have higher D Dimer levels than normal. He also showed a significant effect of starting HAART on D Dimer levels, which also translated into a lower risk of disease progression for people on HAART.

In a presentation titled, “Is Early Treatment Feasible in Resource Limited Settings?”, Paula Munderi spoke of the advances seen in Uganda using a conservative model for starting therapy. There, HIV drugs were offered when CD4+ cell counts fall below 200 or there are serious AIDS-related signs or symptoms. Even when starting therapy after considerable disease progression, the results were remarkable. Using this rule for starting therapy, treatment reduced the death rate 20-fold compared to that seen before the introduction of HAART. Most deaths happened in the first year of treatment, and rates were higher in people with CD4 counts below 50. With such a high apparent success rate, many would ask “what is the point of starting treatment much earlier?” A great deal of money could be saved using this approach since people would be on therapy for fewer years. Similarly, it would delay the risk of drug side effects.

While most of the researchers and doctors working in the developed world are debating the relative benefits of starting HAART with CD4 counts of 350 or above, Munderi is most concerned with what to do with people with CD4 counts between 350–200. The issue of limited resources must be addressed constantly in developing nations like Uganda.

Julio Montaner of British Columbia then posed the provocative question of how much would the expanded use of HIV drug treatment could contribute to HIV prevention. While not talked about much, there’s a general consensus—backed by some data—that anti-HIV drug treatment lowers the risk of HIV transmission. There were three lines of evidence presented. First he presented the steep decline in mother-to-child transmission rates seen after anti-HIV therapy—where rates of MTC transmission were lowered by over 80%. Next, he presented data on infection rates in discordant couples (where one partner is positive and one is negative). Studies showed an 8.6% infection rate among couples where HAART wasn’t used, compared to 0% in couples where HAART was used. Finally, he presented data showing a steep initial decline in HIV infection rates in British Columbia that followed the widespread introduction of anti-HIV drug therapy. That decline leveled off at around the same time as the rate of using anti-HIV drugs.

He proposed a study that would begin with a concerted outreach effort to identify and offer treatment to the estimated half of British Columbians who the current guidelines would recommend treatment for but who aren’t currently on therapy. They would then follow the HIV infection rate and see if the wider use of HIV drugs led to a further decline in HIV infection rates. This strategy of ‘treatment as prevention’ is controversial. The speaker emphasized that this strategy was to go alongside existing prevention efforts, not as a substitution for them.

The final presentation, from Dr. Fred Gordon, of the Insight Clinical Trials network, asked the question ‘Is an Early Treatment Study Important Now?’ Dr. Gordon presented a timeline showing an evolution of concern in the AIDS epidemic. In the earliest days the focus was on opportunistic infections. This shifted to concern about the complications of therapy, like lipodystrophy, liver problems and the risk of heart disease. Now he claims the focus should be on serious non-AIDS related illnesses. Dr. Gordon proposed looking at the asymptomatic, chronic phase of HIV disease as a period of increasing risk of serious non-AIDS related illness. He supported this by showing lower rates of serious non-AIDS related illnesses at all CD4 levels for people on HAART.

He finished by laying out plans for the START trial. The plan is to enroll 3,000 people with HIV who have never taken anti-HIV drugs. Half will be randomized to start therapy when their CD4 count reaches 500, the other half at 350. The researchers will compare both AIDS and non-AIDS related health outcomes, along with quality of life, drug resistance, adherence and so on—in short, a “when to start” trial.

When to Start a “When to Start” (WTS) Trial?
During the earlier session, two prominent HIV researchers were asked if they thought a WTS trial should be done. The first said, sort of sheepishly, that he didn’t think so. He argued that such a study would need to be so big and go on for so long, that by the time it was done the information gleaned was likely to be out of date. The second researcher took the position that the answer will never be known until it is studied, so it should be studied.

The first question from the audience came from Mark Harrington of the Treatment Action Group. He addressed Dr. Fauci, reminding him that 10 years ago he had asked for a WTS trial, and would he support one now? On one hand here we are a decade later, and still no gold-standard, randomized, prospective study to answer the question. But what if we had done this study back in 1997? What kind of information would it give today to help drive treatment recommendations and decisions? Would the toxicity and limited effectiveness of the drugs available at that time give us an answer that would only be relevant for those drugs? Could the answer be reasonably applied to a very different set of medications in use 10 years later? Many of the drugs likely to have been used in a WTS trial in 1997 are not widely used today, at least not in the developed world. If we assume that many of the drugs in wide use today will have fallen out of favor in 2017 and replaced by even less toxic and more potent drugs, would we still want to invest in a large, long-term WTS trial?

It is a simple question, with no simple answers. Another audience member reminded everyone that the switch from traditional AIDS-defining to non-AIDS illnesses hasn’t happened in much of the developing world. When much of the world isn’t able to offer HIV drugs until people’s CD4 counts have fallen below 200, how useful is a study comparing 350 to 500?

In the US and the rest of the developed world, there appears to be a pendulum shift underway toward earlier treatment. This is happening without the benefit of a prospective, randomized WTS trial. It is unlikely to wait until one is finished. While researchers, doctors and activists hammer out the complex issues underlying the idea of a WTS trial, individual treatment decisions and broad treatment guidelines will go on much as they have.

The data presented today and the discussions they generated reflect a couple of important realities. First, everyone would like to have results from a prospective, randomized WTS trial, but not everyone thinks one is feasible now, or perhaps ever. Second, the gaps in treatment access throughout the world make this issue both more important and more difficult to gain useful insights into.

It was with some disappointment then that Dr. Fauci was widely quoted discouraging people from discussing the idea of curing HIV infection (for more information on this, read Proof of Concept Study May Point to a Cure). While there’s little doubt that the prospects for curing this disease in the immediate future aren’t particularly bright—and the scientific challenges remain formidable—the prospects today are better than they’ve ever been and getting better every year. It is really the only goal worth fighting for. The history of AIDS treatment activism has taught many lessons, none more important than ‘you only get what you demand.’ Project Inform will continue to work for, and demand, a cure.