Advances and Challenges in Antiretroviral Therapy for HIV/AIDS

Since HIV was first isolated in 1983, it has claimed nearly 50 million lives and impacted millions more worldwide. Yet over four decades, antiretroviral therapy (ART)—combining drugs to block HIV replication—has transformed HIV from a fatal disease to a manageable chronic condition. Today, ART is recommended for all people living with HIV (PLWH) by the World Health Organization (WHO), regardless of their CD4 cell count or clinical stage. But while progress is undeniable, ending the HIV epidemic requires addressing persistent gaps in treatment access, efficacy, and long-term health.

Ruo-Jing Bai, Li-Li Dai, and Hao Wu—researchers from the Center for Infectious Diseases at Beijing Youan Hospital and Beijing Key Laboratory for HIV/AIDS Research—explore these advances and challenges in a 2020 study published in the Chinese Medical Journal. Their work highlights how ART has evolved, where it falls short, and what’s next for HIV care.

Rapid-Start ART and the “U=U” Revolution

A key strategy to accelerate progress toward the Joint United Nations Programme on HIV/AIDS (UNAIDS) 90-90-90 targets—90% of PLWH diagnosed, 90% on treatment, 90% virally suppressed—is rapid-start ART, which initiates treatment as early as the day of diagnosis. This approach not only improves health outcomes for PLWH but also slows transmission: the “U=U” (Undetectable = Untransmittable) campaign, launched in 2016, confirms that people with undetectable viral loads cannot pass HIV sexually to partners.

Rapid-start (including same-day ART) is now used in low-, middle-, and high-income countries. However, the authors caution that evidence for universal rapid start is still limited. Context matters: same-day ART may not be right for everyone, and messaging around U=U must clarify it applies only to sexual transmission (not breastfeeding or needle sharing) and does not prevent other STIs.

Novel Drugs: Longer-Lasting, More Tolerable, and Resistance-Fighting

Today, the U.S. Food and Drug Administration (FDA) has approved over 30 ART drugs and 10 combination products. Most first-line regimens use an integrase strand transfer inhibitor (INSTI)—like dolutegravir (DTG) or bictegravir—paired with two nucleoside reverse transcriptase inhibitors (NRTIs). These INSTIs are preferred for their strong resistance protection, mild side effects, and no need for “boosters” (extra drugs to enhance efficacy).

But researchers are pushing further to solve ART’s biggest pain points: daily pill burden and drug resistance. New classes of drugs show promise:

Capsid assembly (CA) inhibitors: GS-6207, a once-monthly injectable, blocks HIV’s ability to replicate and enter cell nuclei. A single dose stays effective for 12+ weeks and works against drug-resistant HIV-1 and HIV-2.
Maturation inhibitors (MIs): GSK3532795 (formerly BMS-955176) stops HIV from making mature, infectious particles. Data from the 2019 Conference on Retroviruses and Opportunistic Infections (CROI) show strong antiviral activity at daily doses of 50–200 mg.
Nucleoside reverse transcriptase translocation inhibitors (NRTTIs): Islatravir (MK-8591) is a first-in-class drug that blocks HIV’s genetic replication and stops DNA chain growth. It’s 100x more potent than older NRTIs and works against resistant strains—making it a candidate for long-acting implants for pre-exposure prophylaxis (PrEP).
Long-acting (LA) drugs: Albuvirtide (ABT), a fusion inhibitor approved in China in 2018, has a 12-day half-life (vs. 3.8 hours for older fusion inhibitor T20). LA injectables and implants could help people who struggle with daily pills.

Other advances include broadly neutralizing antibodies (bnAbs)—like PGT121—which target HIV’s outer envelope and neutralize 60–70% of global strains, and attachment inhibitors (e.g., fostemsavir) for people with multi-drug-resistant HIV.

Two-Drug Regimens: Simplifying Treatment Without Sacrificing Efficacy

Traditional ART uses three drugs, but two-drug regimens (2DRs) are gaining traction for their lower cost and fewer side effects. Guidelines now recommend regimens like DTG + lamivudine (3TC) or darunavir/ritonavir (DRV/r) + raltegravir (RAL) for select patients—e.g., those who can’t take tenofovir or abacavir. A monthly injectable 2DR (cabotegravir + rilpivirine) has been shown to be safe and effective for maintenance therapy, with patients reporting higher satisfaction than daily pills.

But 2DRs aren’t for everyone. They’re less effective for people co-infected with hepatitis B (HBV), and there’s no data on their use in pregnancy, tuberculosis (TB) co-infection, or kidney disease.

Persistent Challenges: Resistance, Adherence, and Long-Term Health

For all its progress, ART faces major hurdles:

Resistance: Drug-induced or transmitted resistance can render ART ineffective.
Adherence: Daily pills are hard for many to maintain—especially in low-resource settings.
Drug interactions: ART can clash with other medications (e.g., for TB or heart disease).
Non-AIDS morbidity: As PLWH live longer, conditions like obesity, diabetes, and cardiovascular disease are rising. INSTIs like DTG have been linked to excessive weight gain, and neural-tube defects in babies born to women taking DTG during pregnancy require more research.

The Quest for a Functional Cure

Even with perfect ART adherence, HIV hides in “latent” reservoirs—cells where the virus lies dormant. If ART stops, the virus rebounds quickly. A functional cure—sustained viral suppression without daily pills—would be transformative. Researchers are exploring:

“Kick and kill”: Drugs that “kick” latent HIV out of cells so the immune system can “kill” infected cells.
Gene therapy: Editing immune cells to resist HIV (like the “Berlin Patient,” the only person cured of HIV).
bnAb combinations: Pairing long-acting antibodies with LA drugs to suppress HIV for months without pills.

The Path Forward

ART has come a long way, but ending the HIV epidemic requires more than better drugs—it needs equitable access to treatment, improved adherence support, and continued research into curative therapies. As the authors note, “Before a cure arrives, future research must focus on making ART more effective, safer, more convenient, and accessible to all PLWH.”

The original study was published in the Chinese Medical Journal (2020;133:2775–2777) by Ruo-Jing Bai, Li-Li Dai, and Hao Wu.

doi.org/10.1097/CM9.0000000000001226

Was this helpful?

0 / 0