Starting and Staying on Antiretroviral Treatment

Antiretroviral treatment has transformed HIV infection from an almost uniformly fatal illness 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.

Early antiretroviral treatment 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. Learn more about Antiretroviral Drug Discovery and Development.

Today, triple-drug therapy remains the standard. 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.

NIAID-supported research 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 person living with HIV while preventing transmission of the virus to sexual partners.

In addition to supporting scientific research, NIAID has played a critical role in developing guidelines to provide health care practitioners in the United States with HIV care and treatment recommendations based on current scientific knowledge. 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 regimen comprising three drugs from two classes, but not with a three-class regimen, is a good strategy for long-term antiretroviral management. ACTG 384 found that a three-drug combination comprising two nucleoside reverse transcriptase inhibitors (NRTIs) and one non-nucleoside reverse transcriptase inhibitor (NNRTI) was superior to five other drug combinations tested, including four-drug, three-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 living with drug-resistant HIV can achieve viral suppression without incorporating NRTIs into their regimen.

Research also has aimed to determine whether HIV can be successfully controlled with fewer than three antiretroviral drugs. A two-drug regimen received FDA approval in 2017 to treat adults living with HIV whose virus has been suppressed on a stable antiretroviral treatment regimen for at least six months. Researchers currently are evaluating how well two-drug combinations can suppress HIV in people who have not previously taken antiretroviral therapy.

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. 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, without waiting for CD4+ cell counts to decline. Overall, the risk of serious AIDS events, serious non-AIDS events, or death was reduced by 57 percent among START participants who received early treatment compared to those who started treatment after their CD4+ cell counts had declined below a certain threshold.

The results from SMART and START, together with those from the large NIAID-supported HPTN 052 clinical trial, underscore the importance of prompt initiation of antiretroviral therapy for the health of people living 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: The Benefits of Durable Viral Suppression

Strict adherence to antiretroviral therapy―taking drugs daily as prescribed―is essential for reducing viral load (the amount of HIV in the blood) to an undetectable level, which improves health and prevents transmission to others. People living with HIV who achieve and maintain a durably undetectable viral load have effectively no risk of transmitting the virus to a sexual partner. Read more in NIAID's fact sheet 10 Things to Know About HIV Suppression.

In the past, scientists assessed treatment interruption strategies, in which people would take planned breaks from 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 clearly demonstrated the benefits of continuous treatment.

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 continues to work to improve HIV treatment and to develop long-acting therapies that may serve as alternatives to daily treatment. To learn more about these efforts, see Future Directions for HIV Treatment Research.

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