In 1995, the treatment landscape for HIV was bleak. The only medications approved by the Food and Drug Administration (FDA) belonged to a class of drugs called nucleoside reverse transcriptase inhibitors (NRTIs), which included AZT, ddI and d4T. Although NRTIs could halt HIV replication and slow  HIV disease progression, they weren’t strong enough on their own—or even when paired up—to stop the virus from developing resistance in a matter of weeks or months. But in late 1995, the FDA approved Roche’s Invirase (saquinavir), kicking off the protease inhibitor revolution and ushering in the era of combination therapy for HIV. Abbot’s Norvir (ritonovir) was approved next. On March 13, 1996, the FDA approved Merck’s Crixivan (indinavir sulfate), the third drug in the protease inhibitor category.

When paired with two NRTIs, protease inhibitors suppressed HIV to undetectable levels for long periods of time.  Protease inhibitors and NRTIs disrupt the HIV replication process at two different points.

Crixivan was approved with record speed, according to The New York Times. Facing pressure from Congress to hasten drug approvals, the FDA approved it a mere 42 days after Merck submitted its application.

Based on early trials, Crixivan appeared to be the most effective of the three protease inhibitors to hit the market in the late ’90s. It reduced the amount of detectable virus in the blood by 90% to 98% when used in combination with NRTIs. Crixivan was also sold for about 30% less than the other protease inhibitors.

But Crixivan wasn’t easy to manage: It had to be refrigerated, and people with HIV had to take it every eight hours without food. Like other protease inhibitor, the drug often caused diarrhea so forceful that people couldn’t make it to the bathroom in time. POZ founder Sean Strub told The New York Times that this aspect of taking the drug was “the most humiliating thing I’ve ever dealt with since being positive.” In the same article, treatment activist Spencer Cox (who diedin 2012) joked that the drug’s prescribing instructions should advise users to always carry an extra pair of underwear.

Additionally, Crixivan and other protease inhibitors soon came to be associated with unsightly and uncomfortable fat deposits on the midriff (“Crix belly”) or shoulders (“buffalo hump”) often accompanied by a conspicuous loss of normal fat in the face and limbs. These side effects became telltale signs of living with HIV and would prove to be generally irreversible without cosmetic surgery. (Later research, however, revealed that loss of face and limb fat was actually a side effect of older NRTIs.)

What’s more, as a component of the early HIV combination regimens, or “cocktails,” Crixivan sometimes failed as people with HIV developed resistance to the drug, especially if they had already developed resistance to the NRTIs with which Crixivan was used.

Nonetheless, regimens with Crixivan were still the most powerful weapon against HIV up to that point. Indeed, in 1996, AIDS-related deaths in New York City dropped 30%. For the first time since their diagnosis, many people living with HIV allowed themselves to contemplate a future. After maxing out her credit cards believing she was going to die, Michelle Lopez, who found out she was living with HIV in 1991, told the Times, “I…have a bit more hope…. I feel now as if I’m going to be able to see [my son] graduate from college.

In the 21st century, as one breakthrough after another led to ever more powerful and easier-to-take HIV regimens, often formulated into one pill (and now long-term injectables), Crixivan faded from use. Many longtime survivors of HIV have ugly memories of its debilitating and disfiguring side effects. But Crixivan played a huge role in HIV’s evolution from an almost certain killer to a chronic manageable illness. From 1996 to 2000, AIDS deaths in the United States declined dramatically. It would take longer for such declines to be seen throughout the world—and only after AIDS activists shifted their focus to make sure that new drugs such as Crixivan, which had been a game changer in the United States and Europe, were available in less wealthy nations in other parts of the world, including Africa.