Antiretroviral Drug Discovery and Development

For more than three decades, NIAID has fostered and promoted development of antiretroviral therapies that have transformed HIV infection from an almost uniformly fatal infection into a manageable chronic condition. In the 1980s, the average life expectancy following an AIDS diagnosis was approximately one year. Today, with combination antiretroviral drug treatments started early in the course of HIV infection, people living with HIV can expect a near-normal lifespan. Watch then NIAID Director Anthony S. Fauci, M.D., reflect on advances in HIV treatment.

NIAID plays a role in many stages of the antiretroviral drug discovery and development process. The search for new drugs remains a priority due to the development of resistance against existing drugs and the unwanted side effects associated with some current drugs. NIAID supports basic research to identify novel strategies to prevent HIV from taking hold and replicating in the body, as well as preclinical research to formulate antiretroviral drugs that can be tested in people.

NIAID also helps advance clinical drug development. NIAID today supports the largest networks of HIV therapeutic clinical trial units in the world, including the Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections (ACTG), the International Network for Strategic Initiatives in Global HIV Trials (INSIGHT), and the International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) network. Learn more about pediatric HIV treatment research.

In addition to drug discovery, NIAID-supported research has contributed to optimizing antiretroviral therapy by reducing the number of pills needed, decreasing side effects, and determining the best drug combinations. NIAID-supported research also has provided clear-cut scientific evidence supporting current recommendations that all people diagnosed with HIV begin treatment immediately. Read more about Starting and Staying on Antiretroviral Treatment.

AZT: The First Drug to Treat HIV Infection

Scientists funded by NIH’s National Cancer Institute (NCI) first developed azidothymidine (AZT) in 1964 as a potential cancer therapy. AZT proved ineffective against cancer and was shelved, but in the 1980s, it was included in an NCI screening program to identify drugs to treat HIV/AIDS. In the laboratory, AZT suppressed HIV replication without damaging normal cells, and the British pharmaceutical company Burroughs Wellcome funded a clinical trial to evaluate the drug in people with AIDS. Used alone, AZT decreased deaths and opportunistic infections, albeit with serious adverse effects. In March 1987, AZT became the first drug to gain approval from the U.S. Food and Drug Administration for treating AIDS. AZT, also referred to as zidovudine, belongs to a class of drugs known as nucleoside reverse transcriptase inhibitors, or NRTIs.

The ACTG, established in 1987, quickly began work to build on this discovery. The ACTG 016 clinical trial established a lower therapeutic dosage of AZT, helping to reduce some of the drug’s serious side effects. The pivotal ACTG 019 trial investigated whether it was beneficial to put people living with HIV on AZT before their infections progressed to AIDS. ACTG 019 showed that AZT effectively delayed the onset of AIDS in asymptomatic people with HIV, marking the first demonstration of a treatment for HIV infection.

Accelerating Antiretroviral Drug Development

Established in the early years of the HIV/AIDS pandemic, the NIAID-supported National Cooperative Drug Discovery Group Program for the Treatment of AIDS (NCDDG-AIDS) provided a framework for scientists from academia, industry, and government to collaborate on research related to the identification and development of new drugs. NIAID-supported researchers developed cell culture and biochemical test systems that allowed researchers to more easily screen drug candidates, and NIAID also played a key role in the development of animal models for preclinical testing.

In the early 1990s, additional NRTI drugs gained FDA approval. The development of AZT and other NRTIs showed that treating HIV was possible, and these drugs paved the way for discovery and development of new generations of antiretroviral drugs.

While the earliest antiretroviral agents were developed before many HIV diagnostics were available in the clinic, the development of laboratory tests to measure viral load and CD4+ cell count greatly accelerated progress in drug development. Viral load describes the amount of HIV in the blood. Typically, the higher the viral load, the faster the CD4+ cell count—an indicator of how well the immune system is working—will fall. These advances made it possible for researchers to use lab test results, viral load measurements in particular, to assess how well an investigational antiretroviral agent worked. This approach required drug trials to last roughly 6 months, whereas relying solely on clinical indicators, such as progression to AIDS or death, ordinarily required trials to last years before a result was available.

The Advent of Combination Therapy

The limitations of single-drug treatment regimens quickly became apparent. HIV replicates swiftly and is prone to errors each time it does. These errors, or mutations, cause small changes in the virus. HIV variants with mutations that confer resistance to an antiretroviral drug can evolve rapidly. In some people taking AZT alone, drug resistance developed in a matter of days. Scientists thus tested whether combining drugs would make it difficult for the virus to become resistant to all the drugs simultaneously.

In the early 1990s, data from an NIAID-funded study of AZT in combination with another NRTI drug called dideoxycytidine (ddC), or zalcitabine, showed that this two-drug therapy was more effective than AZT alone, raising hopes about the use of combination therapy in treating HIV/AIDS.

Results from the ACTG 175 trial, announced in 1995, showed that two-drug combinations were superior to AZT alone in preventing decline in CD4+ cell count or death. The trial also showed that antiretroviral therapy reduced the risk of death in people with asymptomatic, intermediate-stage disease. 

Around the same time, another NIAID-supported trial called CPCRA 007 assessed combination therapy for  people with more advanced HIV, the majority of whom had previously been treated with AZT. This study was conducted by the NIAID-supported Terry Beirn Community Programs for Clinical Research on AIDS (CPRCA), a network of community-based health care providers who integrated scientific research into primary care that later became part of the INSIGHT network.

CPCRA investigators found that two-drug therapy had no significant benefit over AZT alone in slowing disease progression or death in this patient group. However, among CPCRA 007 participants with little or no prior AZT use, combination therapy was more effective than AZT alone.

The results of ACTG 175 and CPCRA 007, as well as other studies, indicated that prior antiretroviral experience can profoundly influence the effectiveness of some treatments, underscoring the importance of careful planning in the use of antiretroviral drugs.

Durable HIV Suppression with Triple-Drug Therapy 

While the effects of two-NRTI therapy were better than those of single-drug therapy for many people with HIV, they were of limited duration. A major advance came in 1996, when researchers found that triple-drug therapy could durably suppress HIV replication to minimal levels, while creating a high genetic barrier against development of drug resistance.

The possibility and success of triple-drug therapy, also called highly active antiretroviral therapy, or HAART, was partially due to the appearance of a new antiretroviral drug class—the protease inhibitors. In December 1995, saquinavir became the first protease inhibitor to receive FDA approval. In 1996, results from an NIAID-sponsored trial showed that a three-drug regimen of saquinavir, ddC, and AZT was more effective than two-drug therapy with ddC and AZT.

One of the key studies demonstrating the efficacy of triple-drug therapy was ACTG 320, also supported by NIAID. This study found that a three-drug combination of the protease inhibitor indinavir and two NRTIs reduced viral loads to very low levels for up to one year in people who had previously been taking single-drug therapy. ACTG 320 also showed that adding at least two new drugs when switching therapy is more effective than adding a single new drug.

With HAART, which combines drugs from at least two different classes, many patients saw the amount of HIV in their blood drop to undetectable levels. But while HAART was lifesaving, the early regimens were far from perfect. The side effects were burdensome, and the daily dosing was complex. Certain drugs had to be taken in combination at different intervals throughout the day, some with food and some without. The complexity made it difficult for people to adhere to the regimens long-term.

Identifying New Classes of Antiretroviral Drugs

To address the complexity of antiretroviral regimens, drug toxicities, and the issue of drug resistance, NIAID supports research aimed at novel formulations and development of drugs that work by different mechanisms and target various steps in the HIV replication process. Currently, more than 30 antiretroviral drugs are available, including several fixed-dose combinations, which contain two or more medications from one or more drug classes in a single tablet. Today, many people control their HIV by taking as little as one pill once a day. Access an infographic comparing antiretroviral therapy in the 1990s and today

The mid-1990s marked the emergence of another new class of antiretroviral drugs called non-nucleoside reverse transcriptase inhibitors or NNRTIs. Because they are cheaper and easier to produce than protease inhibitors, they helped scale up antiretroviral therapy in resource-limited settings.

Identification of novel drug targets has played a key role in discovery and development of new antiretroviral drug classes. For example, since the 1980s, scientists have known that a molecule called CD4 is the primary receptor for HIV on immune cells. In the mid-1990s, NIAID scientists reported the discovery of a co-receptor called CXCR4, which is required for entry of certain HIV strains into immune cells. This discovery inspired researchers to look for other co-receptors. A number of research groups, including NIAID scientists, determined that a different receptor called CCR5 is actually the primary co-receptor used by HIV to infect immune cells. This work laid the foundation for the development of the CCR5-blocking drug maraviroc, which received FDA approval in 2007.

Another major antiretroviral drug class emerged in 2007, with FDA approval of the integrase inhibitor raltegravir. Raltegravir quickly became a valued component for combination antiretroviral therapy, but HIV can follow several pathways to develop resistance to the drug. HIV variants resistant to raltegravir may also be resistant to elvitegravir, another first-generation integrase inhibitor.

Dolutegravir, which received FDA approval in 2013, is a second-generation integrase inhibitor that appears to have a high barrier to the development of HIV drug resistance. In clinical trials, dolutegravir was effective both for people living with HIV who had not previously taken HIV therapy and for people who were treatment-experienced, including those for whom first-generation integrase inhibitors were ineffective. Additional advantages of dolutegravir include convenient once-daily dosing, a good safety profile, and a relatively low production cost. Dolutegravir now is included in two of the first-line regimens that the U.S. Department of Health and Human Services medical practice guidelines recommend for adults with HIV, and it was recently added to World Health Organization guidelines as an alternative first-line agent for adults.

NIAID continues to support work to develop new antiretroviral drugs and new tools to improve HIV treatment, such as long-acting therapies that may serve as alternatives to daily antiretroviral therapy. Learn more about Future Directions for HIV Treatment Research.

For more information on FDA-approved antiretroviral drugs, see the AIDSinfo Drug Database.

View an AIDSinfo infographic showing a timeline of HIV drug approvals.

Download a PDF reference guide to drugs that fight HIV-1.

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