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A third class of HIV drugs that target another fragment of HIV's chemistry emerged while all this was happening. Doctors and patients began mixing up three-drug cocktails, zeroing in on one that reduced virus counts in the blood to undetectable levels. Today's HIV drugs target nucleosides, nucleotides, and three other classes of enzymes (transcriptase, protease, and integrase); "fusion" or "entry" inhibitors bind to glycoproteins in ways that stop the virus from prying its way into our cells. For now, at least, we have enough HIV drugs and cocktails to ensure that the HIV virus is no longer a nearly automatic death sentence for people with access to modern medicine.
The Dawn of Precision Molecular Medicine
The HIV drugs that followed AZT were the beneficiaries of two major loopholes in the federal drug law created soon after HIV surfaced. The rapid arrival of these precisely targeted HIV drugs heralded a new paradigm for how modern molecular medicine creates safe and effective treatment regimens.
Although not framed in these terms, the loopholes got the FDA fairly close to what might be called toolkit licensing: License a drug not as an antidote to clinical symptoms but as a molecular scalpel or suture, and let doctors take it from there. Doctors prescribe the drug to patients whose disorder presents the target that the drug is known to hit, perhaps in combination with other drugs directed at other targets. They work out the connections between molecular and clinical effects on their own, one patient at a time. The FDA-approved label plays little if any role.
Enacted in 1983, the Orphan Drug Act took the first significant step toward toolkit licensing. The original idea was to help resurrect "orphan drugs," those dropped by pharmaceutical companies because too few patients needed them. But the law ended up covering other drugs that addressed rare and currently untreatable diseases. It directed the FDA to be very flexible when licensing such drugs, basing approvals on the strength of favorable case reports, animal models, or even in vitro studies when no good animal model existed.
While the FDA was relying on a fungus to help rush AZT through Washington, the agency was also drafting its "accelerated approval" rule, which was finalized in late 1992, then codified and somewhat expanded by Congress in 1997. When the disease is sufficiently serious and available treatments are inadequate, a new drug can get to market by demonstrating that it does indeed produce its intended molecular-scale effect or, more generally, produces favorable changes in what the FDA calls "biomarkers" or "surrogate end points."
Biomarkers and other surrogates allow the FDA to make a first call about the drug's efficacy much earlier, without waiting for clinical effects to surface and persist for some arbitrary period of time. The FDA must be persuaded that the microscopic changes are connected to the clinical symptoms, but "reasonably likely" will suffice. These truncated front-end trials need not resolve concerns about how the drug's performance might be affected by many aspects of genetic or lifestyle diversity; "differences in response among subsets of the population," in FDA parlance, may be addressed later. So too may open-ended questions about distant side effects. The manufacturer must still complete controlled trials, but it does so after the drug is licensed-and thus does so after, or in tandem with, the wider use of the drug by unblinded physicians who can investigate why the drug works in some patients but not others. The FDA rescinds the license if things don't pan out.
Almost all of the early HIV- and AIDS-related drugs were designated as orphans. Most were rushed through the FDA under the accelerated approval rule. And almost all were widely prescribed off label.
HIV's endless mutability-and the arrival of targeted drugs that were licensed quickly, largely on the strength of low-level effects-left doctors in charge of working out the molecular details that determine how to combine drugs into the cocktail that produces the best clinical outcome for the individual patient. We have since learned how that process unfolded and where it ends: It has unfolded remarkably well, and it doesn't end.
A couple of dozen HIV drugs have been approved worldwide; they are typically used in about 10 fairly standard cocktails. The efficacy of each cocktail depends on which strain launched the infection and how it has evolved inside the patient. Different forms of the disease predominate in different countries; the strains also track gender, sexual practices, needle use habits, and other factors, including the variations in human genes that give different individuals more or less inborn resistance to the infection.
When HIV is viewed from the treatment perspective, we see that medicine is now dealing with at least a dozen different diseases, each forever poised to mutate into some new, untreatable form. Treatments work best when the doctor selects just the right trio of scalpels from the molecular tool kit. Choosing them isn't easy, because so many different variables come into play. Until recently, trial and error played a large role. The doctor started with one mix, monitored viral loads and other biomarkers in the patient's bloodstream, and adjusted the treatment accordingly.
Monitoring and adjusting on the fly remain essential, but the process is now often guided by sophisticated analytical engines fueled by huge collections of patient records, including data on HIV genotypes, treatment histories, and responses, along with patient age, gender, race, and route of infection entry. Patient genotypes are certain to be added soon.
As of late 2011, the largest such engine-the one that powers Europe's EuResist network-was using data from 49,000 patients involving 130,000 treatment regimens associated with 1.2 million records of viral genetic sequences, viral loads, and white blood cell counts. When presented with 25 actual case histories that weren't already in its database, EuResist beat nine out of 10 international experts in predicting how well the treatments would perform.
Here, then, we have a medical world that stands Washington's old regulatory science on its head. Whatever we may call it up here, there is in fact no single disease down there, and the disease down there tomorrow will be different from today's. We have treatments that work, but no single HIV drug can honestly be called "safe" or "effective." All have nasty side effects, and when they are used one at a time, each may fail the individual patient-and endanger others by helping to breed a new drug-resistant strain of the virus.
The FDA has licensed or at least tentatively approved at least eight cocktails. Controlled clinical trials were completed before most of the later-developed drugs were licensed, and once it was clear that only cocktails worked, new drugs had to be tested as part of a cocktail from the get go. But nobody even bothered to pretend that when the FDA licensed them, it had in hand what the federal drug law still requires: "substantial evidence" about how the cocktails would perform when they met any substantial fraction of all the variations in HIV and patient chemistry that they might encounter in the future.