In the early days of the human immunodeficiency virus (HIV) epidemic, there was little hope. HIV infection, when untreated, damages the immune system, making people with the virus more susceptible to other diseases. Over time, HIV infection progresses to acquired immunodeficiency syndrome (AIDS). The first approved treatment for HIV, azidothymidine (AZT), appeared in 1987. It was initially developed as an anti-cancer drug. Researchers tested AZT against HIV-infected animal cells in the lab. “When it got into the clinic, it seemed like a miracle,” said Dennis Liotta, a chemist at Emory University in Atlanta, Georgia. But the miracle was short-lived, prolonging lives by only a few months.
HIV, an RNA virus, must convert its RNA into DNA upon entering a human cell. This task is performed by reverse transcriptase (RT), the initial target for early HIV drugs. AZT and other nucleoside reverse transcriptase inhibitors (NRTIs) like didanosine, zalcitabine and stavudine followed. However, the virus quickly mutated, escaping these drugs and causing patients to relapse.
Advancements in Combination Therapy
By the mid-1990s, the fight against HIV advanced with the approval of protease inhibitors, starting with saquinavir in 1995. These drugs blocked the protease enzyme, preventing the virus from maturing. The introduction of combination therapies, or highly active antiretroviral therapies (HAART), in 1996 marked a significant leap. Combining RT inhibitors with protease inhibitors significantly reduced opportunistic infections and AIDS-related deaths.
Despite the benefits, the dosing of early combination therapies was challenging. Patients were required to take multiple medications daily. Missing doses led to sub-therapeutic levels, allowing resistant mutations to emerge. “That became a compliance nightmare,” said Liotta.
Game-Changing Discoveries
More effective and practical treatments became available in the late 1990s and early 2000s. Non-nucleoside reverse transcriptase inhibitors (NNRTIs) like nevirapine, delavirdine and efavirenz were introduced. These drugs inhibited RT by locking onto it, distorting its shape and slowing DNA synthesis.
In 2006, the approval of Atripla®, a combination of three RT inhibitors, marked an important treatment milestone. “That was a game-changer because we went from 15 or 20 pills in the mid-90s to taking one pill three times a day,” Liotta said.
The Rise of Integrase Inhibitors
The next breakthrough came with the development of integrase inhibitors. These drugs, starting with raltegravir in 2007 and followed by dolutegravir in 2013, prevented the virus from integrating its DNA into the host cell’s genome. These new treatments, combined with existing drug classes, simplified regimens further so patients could take one daily pill.
Ongoing Challenges and Innovations
Despite advancements, eradicating HIV remains elusive. The virus integrates its DNA into the host’s genome, creating proviruses that lie dormant in lymph nodes and other tissues. “The problem with HIV is that you need to ensure that you get rid of every infected cell,” said Rafick-Pierre Sekaly, a researcher at Emory University.
Scientists are exploring various strategies, including CRISPR gene editing and modifying patients’ T cells to target infected cells. Early trials show promise, but significant challenges remain.
Viral Control
Today, combination treatment can often help most people with HIV reduce their viral load within six months to a controlled level, and it is possible to reduce viral load to undetectable levels. One standard treatment combines antivirals, an integrase inhibitor and a NRTI in a single daily pill. Injectable combination treatments are also available, offering once-monthly or bi-monthly dosing.
The Quest for a Cure
Research toward potential cures continues, guided by advances in understanding and technology. Although stem cell transplantation is not approved for HIV, it is used for people with life-threatening cancer. Three people who received stem cell transplants are considered cured of the disease. The first, Timothy Brown, received two stem cell transplants to treat leukemia in 2006. He received stem cells from a donor with a rare genetic mutation that blocks HIV infection. In addition, there are several cases of sustained HIV control after stopping treatment. Liotta and Sekaly are optimistic. “I don’t think we will have a cure in the next five years, but we are heading in the right direction,” said Sekaly.
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