In 1991, the first case of lactic acidosis, a life-threatening condition, was reported in an HIV-positive man who was in a Phase 1 clinical trial of didanosine.59 Subsequently, it became clear that didanosine, AZT, and stavudine (especially when combined with didanosine) were the culprits.60,61 In January 2001, the FDA issued a warning about lactic acidosis and concomitant use of stavudine and didanosine in pregnant and postpartum women and recommended that the combination be avoided unless no other options were available. In February 2002, another life-threatening side effect, ascending neuromuscular weakness, was linked with lactic acidosis related to use of stavudine both alone and in combination with didanosine.62
With HAB guidance, grantees quickly implemented pharmacogenomic testing. Providers could use a genetic test to prevent a potentially deadly side effect and to keep a valuable drug in the armamentarium. Although abacavir was safe and effective for many people, 4 to 5 percent of users suffered from a hypersensitivity reaction (HSR), usually within 9 to 11 days after starting the drug. It was especially concerning that HSR symptoms overlapped with those of common viral infections.63 Researchers made two key discoveries: They found that a genetic variation involved with immune system function, HLA-B57, was associated with HSR and that genetic testing for HLA-B57 could predict abacavir hypersensitivity.64,65,66 Once again, science was rapidly integrated into clinical care. The January 2008 guidelines added a recommendation for HLA-B57 screening prior to abacavir use, and AETCs immediately disseminated the recommendation in slide sets and the Spring 2008 HIV Meds Quarterly Research Brief.67,68
“We had to talk about side effects and complications of antiretroviral therapy so people knew what to look out for. It was our job to be up on the literature,” says Frank. The severity of these side effects and the urgency of medical interventions required to treat them underscored the importance of rapid information dissemination, a hallmark of the Ryan White HIV/AIDS Program.
Although the benefits of HAART were clearly demonstrated, they came with a price: People had to contend with inconvenient dosing schedules, food requirements, and side effects. Adherence was crucial because skipping doses could lead to drug resistance and, ultimately, to treatment failure.
The recommended approach for treating HIV was to “hit early, and hit hard.” The first HIV treatment guidelines recommended that HIV treatment be started in patients with “<500 CD4+ T cells/mm3 or >10,000 branched DNA or 20,000 reverse transcription polymerase chain reaction copies of HIV RNA/mL” given patient willingness and readiness to initiate treatment.69 “We didn’t realize back then that we were developing an environment for people to develop terrible cross-resistance,” says Travieso Palow. “We gave people one new drug at a time, as they came out. We didn’t know any better. Even with the new drugs, people were still dying. We were throwing everything but the kitchen sink at people.”
Unfortunately, clinicians began to notice that HIV drugs were not working for some of their patients. Patients who had been heavily pretreated with NRTIs before PIs and NNRTIs were available had developed drug resistance.70,71 Years of trying to keep people alive by treating them with a single drug or by adding new drugs as they came along made it difficult to construct effective regimens, which required at least two active drugs.72,73 People were developing resistance to a single drug or even to an entire class of drugs (called “cross-resistance”) after using only one of them.