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Over the years, combination ART has optimized outcomes for HIV-positive pregnant women and their infants. The rate of MTCT has dropped to 1 to 2 percent.22 Combination ART also decreases premature births and maternal and infant mortality.23

Despite the breakthrough in prevention of MTCT, little could be done to prevent HIV progression in people already infected. Although AZT could prolong survival in symptomatic people who had already developed AIDS, it did not entirely halt disease progression, and efficacy waned as a result of drug resistance.24,25,26 Starting AZT earlier did not help. One large study reported that AZT use made no significant difference in rates of disease progression, illness, or death in asymptomatic people with CD4 cell counts below 500 cells/mm3, whereas others found short-term benefits but no ultimate difference in survival.27,28,29 “It was frustrating to see AZT work so well [for MTCT] but not for slowing down HIV progression,” recalls Laura Cheever, chief medical officer and deputy associate administrator of HAB.

Researchers were hoping that adding a second drug from the same class (called “dual nucleoside therapy”) would be more effective than single-drug therapy (called “monotherapy”). This approach initially showed promise in people with CD4 cell counts ranging from 200 to 500 cells/mm3. Combining AZT with another nucleoside reverse transcriptase inhibitor (NRTI) slowed disease progression and increased survival;30 however, combining NRTIs in people with AIDS who were pretreated with AZT made no difference in survival.31 Ultimately, it became clear that benefits of dual nucleoside therapy were not always durable and that combining two drugs from the same class did not prevent the emergence of drug resistance.32,33,34

Fortunately, advances in technology provided researchers with a new tool: HIV viral load (HIV RNA) testing. Researchers quickly discovered that changes in HIV RNA were predictive of changes in CD4 cell count, so HIV RNA testing could be used for two purposes: to predict disease progression (and, ultimately, risk of death) and to measure response to antiretroviral treatment.35

It was clear that suppressing HIV replication could delay disease progression and prolong survival, but a single class of drugs was insufficient: New weapons in the fight against HIV/AIDS were desperately needed. By 1994, AIDS had become the leading cause of death among people age 25 to 44, and 50,000 people in the United States had died from AIDS-related causes.36

1995: The HAART Era Begins: Preventing HIV Progression

Usually it takes years to get new medical advances out to the people who need it. But we were able to deliver HIV treatment as soon as the protease inhibitors were approved because Ryan White had been funding a system and had already built capacity to deliver multidisciplinary care. It’s not just medical technology; Ryan White put the spotlight on how care is delivered. It’s about culturally competent people that care, providing patient-centered, high quality treatment.

—Laura Cheever,
chief medical officer and deputy associate administrator of HAB

Despite many disappointments, researchers continued to be optimistic about ART; they were hoping that combinations of drugs targeting different steps of the HIV life cycle would be able to stop HIV replication, maintain viral suppression, and allow the immune system to recover.37 Frustration, despair, and rage finally began to give way to hope in late 1995, when saquinavir, an HIV protease inhibitor (PI) and the first drug from a new class, was approved by the U.S. Food and Drug Administration (FDA). In 1996, an HIV viral load test and three new drugs—two PIs and a non-nucleoside reverse transcriptase inhibitor (NNRTI)—were approved by the FDA (see Figure 1, Antiretroviral Drug Approvals by Class and Date). Clinicians finally had what they needed to fight HIV effectively. As Frank explains: “We thought that there was a latency period where nothing was happening with the virus. Finding out that HIV was making billions of copies changed our ideas about clinical management and contributed to the advent of HAART. We found out what the virus was doing, how to measure it, and how to suppress it.”

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