New Antiviral Research and the "Receding" Bottleneck
One irony in the push to license ddI and ddC is that, long before the drugs were approved, the hopes of researchers, doctors, and activists had moved well beyond the infertile terrain of the
nucleoside analogues. Officially, the research establishment continued to tout the potential virtues of combination therapy with the nucleosides and to promote the goal of turning AIDS into a "chronic manageable illness," though increasingly it appeared that the announcement in Montreal of its advent had been more than a little premature. Activists were less sanguine about the pace of progress. By the time of the San Francisco conference in 1990, ACT UP/New York had concluded: "This year, the hopes of many in the AIDS communities have reached a low ebb. It is clear to all that anti-HIV agents such as AZT, ddC and ddI will not, in any conceivable combination, stop the progression of HIV infection—at most, for those who are lucky, they will significantly slow it."
Writing in Outweek in 1990, New York activist Larry Kramer put the position in his own inimitably vituperative style. He accused researchers like Margaret Fischl and Paul Volberding of having "pumped AZT down the throats of AIDS patients like they were Strasbourg geese being fattened up for the kill." Kramer averred: "AIDS is not a manageable disease, and there is nothing at present that makes me think that it is going to be a manageable disease in my lifetime or the lifetime of the other 20 million HIV infected. ANYONE WHO TELLS YOU OTHERWISE IS A LIAR ."
ACT UP/New York's Treatment & Data Committee analyzed the predicament in the 1990 update of its AIDS Treatment Research Agenda , distributed at the San Francisco conference. The ACTG was concentrating its resources on "massive Phase II trials,of stop-gap first generation nucleoside analogues," to the exclusion of just about everything else. Hardly any compounds were in Phase I trials, even though dozens were known to act against HIV in vitro (the report listed sixty of them, along with many immune therapies, anti-infectives, and other drugs that awaited testing). Given the backlog, and given the ACTG's apparent priorities, the emergence of a new generation of antiviral treatments was necessarily years away. In that sense, the problem was no longer the FDA, the Treatment & Data Committee concluded. "As activists make increasing headway with regulators, the bottleneck in AIDS drug development seems to recede towards the beginning of the process, when compounds are taken from test tube and animal studies and administered to humans for the first time." Mixed metaphor though it may have been, this notion of the "receding bottleneck" served to orient treatment activists in the years to come.
For patients, the pace of AIDS antiviral research was measured in
relation to their own life expectancy; but researchers, whose point of reference was the rate of scientific progress for other diseases, found the advance of knowledge both swift and encouraging. "We have learned more about the AIDS virus than any other virus that affects humans," Dr. William Haseltine told New York Times reporter Gina Kolata in late 1990, reciting what had become almost a mantra in AIDS research circles. "Molecular biologists and drug development experts have climbed rapidly from a valley of despair to a peak of expectation in their struggle to combat the AIDS virus," wrote Kolata, focusing on a recent publication in Science by NCI scientists Hiroaki, Yarchoan, and Broder that identified "13 major chinks in [the virus's] armor, each one of which may in time yield to therapeutic attack." "There really is a large and growing menu" of ways to interrupt the cycle of viral replication, Broder told Kolata: "I think it's a very important time."
John James agreed there was room for "cautious" optimism, especially with regard to three promising sets of "designer drugs" that were farthest along in development. First, there were new drugs that acted at the same point in the virus's replication cycle (reverse transcription) as AZT, ddC, and ddI but didn't belong to the dideoxynucleoside family. These so-called non-nucleoside reverse-transcriptase inhibitors included the "L drugs" made by Merck (formally labeled "L-697, 661" and "L-697, 639") and a drug called nevirapine developed by Boehringer Ingelheim Pharmaceuticals.
Second, Hoffman-LaRoche had been developing a "tat inhibitor," which was designed to block the protein produced by the viral gene called tat . This protein, required for the replication of HIV, acted "downstream" of reverse transcriptase in the replication cycle; it was responsible for "transactivation," a speeding-up of the manufacture of the new viral particle. In vitro, the tat inhibitor was synergistic with AZT, meaning that the drugs might conceivably be given in combination to deliver a one-two punch against the virus. Unlike the reverse transcriptase inhibitors, a tat inhibitor would, in theory, work against chronically infected cells such as macrophages; such cells behave abnormally but are not killed by the virus. In addition, some believed that a tat drug also showed promise against Kaposi's sarcoma. Finally, Hoffman-LaRoche's drug seemed particularly promising because it was chemically related to diazepam (Valium), a well-known drug that had already been used extensively in humans.
The third exciting set of compounds, still under development, were called protease (or proteinase) inhibitors. These drugs would block the
action of a different enzyme, protease, that plays a role at yet a later stage in the viral life cycle. After being assembled, the newly produced virus that buds from the infected cell is in an immature state; the protease enzyme then processes the genetic material to complete the virus's development. Only at that point does the new virus become infectious. In the presence of a protease inhibitor, therefore, the new virus released into the bloodstream would be harmless, incapable of infecting other cells. At least, that was the theory being pursued by a number of pharmaceutical companies, including Hoffman-LaRoche.
These were the practical applications of the intense scrutiny of HIV by molecular biologists; one problem, however, was that scientific knowledge about the virus far outstripped an understanding of the immunopathogenesis of AIDS in the human body—that is, how the virus directly or indirectly contributed to the eventual collapse of immune functioning. As David Baltimore and Mark Feinberg wrote in an editorial in the New England Journal of Medicine toward the end of 1989: "Humans are genetically heterogeneous, lead idiosyncratic lives, and become infected through a number of routes, and important practical and ethical considerations constrain clinical experimentation. As a result, we are rapidly learning about the role of each of HIV's approximately 10,000 nucleotides, but remain largely ignorant of rudimentary aspects of the processes underlying the development of AIDS in humans." It was believed at the time, on the basis of blood work done with cohort studies, that there were three stages to "HIV disease." First, soon after infection with the virus, there was an initial stage of acute infection marked by a high viral load in the blood, a strong antibody response, and in many cases, symptoms such as a low-grade fever and swollen lymph glands. Then a long, middle stage of "latency" would set in, during which the viral load measurable in the blood was relatively low but the T-cell count gradually declined. In most cases this was succeeded—eventually—by a final stage of crisis, coincident with the onset of opportunistic infections (and, usually, a T-cell count below two hundred per cubic millimeter), in which the viral load once again became high. Increasingly it was also becoming apparent that "latency" was a misnomer, because although the infected person was outwardly healthy, and although the virus might indeed be dormant in some infected cells, the process of viral replication continued throughout the middle stage.
The implication of this clinical picture was that the infected person's immune system initially succeeded in controlling the infection and keeping the virus in check, but over time lost that ability quite
dramatically—for reasons that were not at all well understood, though hypotheses certainly abounded. Some, like Luc Montagnier, argued that simultaneous infection with other agents ("cofactors") speeded up the process of immune breakdown. Others pointed to syncytia formation (the clumping together of infected T cells) or to abnormalities with cytokines (the proteins released by immune system cells that signal other immune cells) or to autoimmune mechanisms. These competing hypotheses sometimes led to contradictory implications for treatment strategies. For example, researchers such as Jonas Salk were working on a "therapeutic vaccine" designed to bolster the immune response in people already infected with HIV; but those who believed that HIV progression was a result of "overactivation" of the immune system feared that such a therapy might actually make the infection progress faster. Clearly, in the absence of a good working knowledge of pathogenesis, it was difficult to elaborate a coherent therapeutic approach that aimed at preventing the development of AIDS and not just the replication of the virus.