Antiretroviral treatment has transformed HIV infection from an almost uniformly fatal infection into a manageable chronic condition. Starting daily antiretroviral therapy as soon as possible after diagnosis and staying on treatment are essential for keeping HIV under control, which benefits individual health and prevents HIV transmission to others. NIAID-supported research has played a key role in optimizing antiretroviral drug regimens and in establishing the importance of early treatment and strict adherence.
The choice of an antiretroviral drug regimen depends on a variety of factors, including results of drug resistance testing, other health conditions that the person may have, and possible side effects of the medications. Today, triple-drug therapy remains the standard. For people living with HIV in the United States, most first-line regimens include two nucleoside reverse transcriptase inhibitors (NRTIs) plus an integrase inhibitor or protease inhibitor. Learn more about Antiretroviral Drug Discovery and Development.
Earlier antiretroviral regimens consisted of multiple pills that had to be taken at intervals throughout the day and often caused unwanted side effects. Continued research has reduced the pill burden and decreased the side effects of antiretroviral therapy, making it easier for people to properly adhere to and thus benefit from the therapy. View an infographic comparing antiretroviral therapy in the 1990s and today.
NIAID-supported research also has provided clear-cut scientific evidence supporting current recommendations that all people diagnosed with HIV begin treatment as soon as possible. Together, results from a trifecta of key studies―SMART, HPTN 052, and START―conclusively demonstrated that starting antiretroviral treatment promptly after HIV diagnosis, and continuing it without interruption, protects the health of the infected individual while preventing HIV transmission to uninfected sexual partners.
In addition to supporting scientific research, NIAID has played a critical role in developing HIV treatment guidelines for health care providers. Today, NIAID scientists play leadership roles on panels that review new evidence and update the U.S. Department of Health and Human Services HIV treatment guidelines as needed.
What to Start: Optimizing Antiretroviral Drug Regimens
NIAID-supported research comparing different treatment regimens has helped optimize antiretroviral drug combinations. Following the emergence of highly active antiretroviral therapy in the late 1990s, major questions that researchers sought to answer included which and how many drug classes to combine and how many drugs to use.
Two key NIAID-supported studies—CPCRA 058 FIRST and ACTG 384—showed that three-drug cocktails containing medications from two classes were better than regimens containing more drugs and more classes. The CPCRA 058 FIRST results suggested that initial treatment with a two-class regimen (two NRTIs plus a non-nucleoside reverse transcriptase inhibitor [NNRTI] or a protease inhibitor), but not with a three-class regimen (protease inhibitor plus NNRTI plus NRTI), is a good strategy for long-term antiretroviral management. ACTG 384 found that a three-drug combination of the NRTIs AZT and 3TC plus the NNRTI efavirenz was superior to five other drug combinations tested, including four-drug triple-class regimens.
Other research has focused on developing regimens that may limit adverse drug effects. Some trials have assessed “NRTI-sparing” regimens that omit NRTIs, which are associated with unpleasant side effects. For example, the ACTG 5142 study found that a combination of an NNRTI and a protease inhibitor was similarly effective at suppressing HIV as two NRTI-containing regimens in people who had not received previous treatment for HIV. However, researchers observed development of more drug resistance among the participants taking the NRTI-sparing regimen. Later, the ACTG A5241 study found that people with drug-resistant HIV can achieve viral suppression without incorporating NRTIs into their regimen.
Recent research has focused on determining whether HIV can be successfully controlled with fewer than three antiretroviral drugs. The ACTG A5353 study and the PADDLE study are evaluating how well a two-drug combination of the integrase inhibitor dolutegravir and the NRTI lamivudine will suppress HIV in people who have not previously taken antiretroviral therapy. Other studies are evaluating strategies in which an intensive “lead-in” phase with several drugs is followed by a “maintenance” phase with dolutegravir alone.
When to Start: Research Supports Early Initiation of Antiretroviral Therapy
Current U.S. HIV treatment guidelines and guidelines from the World Health Organization recommend that all people diagnosed with HIV begin antiretroviral therapy as soon as possible, regardless of their CD4+ cell count, a measure of immune system health. While past guidelines recommended waiting until a person’s CD4+ count dipped below a certain threshold, NIAID-supported research has offered clear-cut scientific evidence to support the benefits of early initiation of antiretroviral treatment for all people living with HIV.
Findings from the NIH-supported Multicenter AIDS Cohort Study (MACS) published in the late 1990s established that lower viral load and higher CD4+ cell counts are associated with lower risk of progression to AIDS and death. Since then, numerous research collaborations have evaluated the risk of antiretroviral drug toxicity versus the benefit of HIV suppression.
Findings from a large NIAID-funded international trial known as SMART, reported in 2006, demonstrated that the benefits of therapy far outweighed the risks of toxic effects. Between 2009 and 2011, several independent analyses also indicated that early initiation of therapy was beneficial.
In 2015, findings from the landmark NIAID-funded START study offered concrete scientific evidence to support the current recommendations to begin treatment as soon as possible after diagnosis. The study conclusively showed that starting antiretroviral therapy early, without waiting for CD4+ cell counts to decline, prevented serious AIDS-related events such as AIDS-related cancers, serious non-AIDS-related events, and death. The researchers tracked multiple non-AIDS-related events, including cardiovascular disease, end-stage kidney disease, liver disease, non-AIDS-related cancers, and deaths not attributable to AIDS. Overall, the risk of serious AIDS events, serious non-AIDS events, or death was reduced by 57 percent among those who received early treatment compared to those who started treatment after their CD4+ cell counts had declined below a certain threshold.
The results from this trifecta of key studies—SMART, HPTN 052, and START—underscore the importance of prompt initiation of antiretroviral therapy for the health of people with HIV, aligning these benefits with the public health benefit of early treatment to prevent HIV transmission. Read more about Treatment as HIV Prevention.
Staying on Treatment: Adherence Leads to Durable Viral Suppression
Strict adherence to antiretroviral therapy―taking drugs daily as prescribed―is essential for achieving and maintaining HIV suppression, which leads to improved health and quality of life. In addition, when antiretroviral therapy keeps HIV fully suppressed, the risk that the treated individual will sexually transmit the virus to an HIV-negative partner is negligible. Loss of viral suppression as a consequence of non-adherence to antiretroviral therapy may lead to the emergence of drug-resistant HIV variants and loss of future HIV treatment options.
In the past, scientists assessed treatment interruption strategies, in which people would take planned breaks from their daily antiretroviral therapy. In 2006, NIAID halted the SMART study after results showed that patients receiving episodic antiretroviral treatment had twice the rate of disease progression as those receiving continuous treatment. Moreover, the risk of severe side effects from the drugs did not differ significantly between the two participant groups, and cardiovascular effects were actually more common in the episodic treatment group. The landmark SMART findings proved that continuous treatment works better than a “drug conservation strategy,” in which antiretrovirals are given only when a person’s CD4+ cell count—a key measure of immune system health—drops below a certain threshold.
A number of factors can influence adherence to daily antiretroviral therapy, including characteristics of the prescribed regimen. Simple, once-daily regimens with few side effects or toxicities are associated with higher levels of adherence. NIAID-supported research has contributed to optimizing antiretroviral therapy, reducing the number of pills needed, decreasing the side effects, and determining the best drug combinations. NIAID continues to work to improve HIV treatment, including the development of long-acting therapies that may serve as alternatives to daily treatment. To learn more about these efforts, see Future Directions for HIV Treatment Research.
Guidelines for Health Care Providers
HHS publishes a series of guidelines to provide health care practitioners in the United States with HIV care and treatment recommendations based on current scientific knowledge. These guidelines are developed by panels composed of representatives from federal agencies, including NIAID, and clinicians and community members across the country, and the panels review new evidence and update recommendations when needed. The guidelines address antiretroviral treatment for adults and adolescents, pediatric antiretroviral treatment, use of antiretroviral drugs in pregnant women for maternal health and to reduce the risk of perinatal transmission, and treatment and prevention of opportunistic infections. For a complete list of these guidelines, as well as options to download PDF versions, slide sets, and related documents, see AIDSinfo’s Clinical Guidelines Portal.
NIAID has played a pivotal role in the development of HIV treatment guidelines. The first antiretroviral therapy guidelines were published in 1993 by an independent panel of experts convened by NIAID. These science-based recommendations described clinical scenarios for people with HIV and offered antiretroviral therapy suggestions. Within a few years, official federal guidelines for HIV treatment followed. In 1996, HHS and the Henry J. Kaiser Family Foundation convened a panel to develop guidelines for clinical management of adults and adolescents with HIV infection. Co-chaired by NIAID Director Anthony S. Fauci, M.D., this panel comprised federal, private sector, and academic experts, as well as representatives of AIDS interest groups and health policy groups. The first national guidelines, outlining the use of antiretroviral therapy in adults and adolescents, were issued in 1998. Today, NIAID scientists play key leadership roles on the current panel that reviews and updates the guidelines as needed.