Antiretroviral therapy (ART) has transformed HIV from a near-certain death sentence into a manageable chronic condition. Since the introduction of combination ART in the mid-1990s, HIV-related deaths have plummeted, and people living with HIV can now expect to live nearly as long as people without HIV — provided they have access to treatment and take it consistently. This guide explains how ART works, the different classes of antiretroviral drugs, and why early treatment is so important.
What Is Antiretroviral Therapy?
Antiretroviral therapy (ART) refers to the use of a combination of antiretroviral drugs to treat HIV infection. The term "antiretroviral" refers to the fact that HIV is a retrovirus — a type of virus that uses an enzyme called reverse transcriptase to convert its RNA genome into DNA. Antiretroviral drugs work by targeting various stages of the HIV replication cycle, preventing the virus from reproducing and spreading throughout the body.
Modern ART typically involves a combination of two or three drugs from two or more different drug classes. This combination approach — sometimes called "highly active antiretroviral therapy" or HAART — is used because HIV can quickly develop resistance to a single drug, but it is much harder for the virus to simultaneously develop resistance to multiple drugs with different mechanisms of action.
The NIH's guidelines for the use of antiretroviral agents in adults and adolescents are the authoritative resource for HIV treatment recommendations in the United States.
Classes of Antiretroviral Drugs
There are currently seven major classes of antiretroviral drugs, each targeting a different step in the HIV replication cycle:
1. Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NRTIs)
NRTIs were the first class of antiretroviral drugs developed and remain a cornerstone of most ART regimens. They work by mimicking the building blocks of DNA, causing HIV's reverse transcriptase enzyme to incorporate them into the viral DNA chain — which then terminates the chain and prevents further replication.
Common NRTIs include tenofovir (TDF or TAF), emtricitabine (FTC), lamivudine (3TC), and abacavir (ABC). Many modern ART regimens combine two NRTIs in a single pill, such as Truvada (TDF/FTC) or Epzicom (ABC/3TC).
2. Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
NNRTIs also target reverse transcriptase, but they work differently from NRTIs — they bind directly to the enzyme and change its shape, preventing it from functioning. Common NNRTIs include efavirenz (EFV), rilpivirine (RPV), and doravirine (DOR).
3. Protease Inhibitors (PIs)
Protease inhibitors block HIV's protease enzyme, which is needed to cut long chains of HIV proteins into the individual proteins that make up a new HIV particle. Without functional protease, HIV produces immature, non-infectious viral particles. Common PIs include darunavir (DRV) and atazanavir (ATV), which are typically boosted with ritonavir (RTV) or cobicistat (COBI) to increase their effectiveness.
4. Integrase Strand Transfer Inhibitors (INSTIs)
INSTIs block HIV's integrase enzyme, which is needed to insert the viral DNA into the host cell's genome. Without integration, HIV cannot establish a permanent infection. INSTIs are now the preferred first-line drug class for most people starting ART because of their high efficacy, tolerability, and high barrier to resistance. Common INSTIs include dolutegravir (DTG), bictegravir (BIC), and raltegravir (RAL).
5. Fusion Inhibitors
Fusion inhibitors prevent HIV from entering CD4 cells by blocking the fusion of the viral envelope with the cell membrane. The only FDA-approved fusion inhibitor is enfuvirtide (T-20, brand name Fuzeon), which is given by injection and is typically reserved for people with drug-resistant HIV.
6. CCR5 Antagonists
CCR5 antagonists block the CCR5 co-receptor on CD4 cells, which most strains of HIV use to enter the cell. Maraviroc (MVC, brand name Selzentry) is the only approved CCR5 antagonist. It requires a tropism test before use to confirm that a person's HIV uses the CCR5 co-receptor.
7. Attachment Inhibitors and Post-Attachment Inhibitors
Newer drug classes include attachment inhibitors (fostemsavir/Rukobia) and post-attachment inhibitors (ibalizumab/Trogarzo), which are used for people with highly drug-resistant HIV who have limited treatment options.
Current Recommended ART Regimens
The NIH guidelines recommend several preferred first-line ART regimens for treatment-naive adults. As of 2024, the preferred regimens are:
- Bictegravir/tenofovir alafenamide/emtricitabine (BIC/TAF/FTC, brand name Biktarvy) — A single-tablet regimen taken once daily; highly effective with a high barrier to resistance
- Dolutegravir/abacavir/lamivudine (DTG/ABC/3TC, brand name Triumeq) — A single-tablet regimen; requires HLA-B*5701 testing before use due to risk of abacavir hypersensitivity
- Dolutegravir + tenofovir alafenamide/emtricitabine (DTG + TAF/FTC) — Two pills taken once daily
- Dolutegravir + tenofovir disoproxil fumarate/emtricitabine (DTG + TDF/FTC) — Two pills taken once daily
Long-acting injectable ART is also now available. Cabotegravir + rilpivirine (CAB + RPV, brand names Cabenuva) is given as two injections once monthly or every two months, offering an alternative to daily oral therapy for people who are virologically suppressed.
When to Start ART
Current guidelines recommend that ART be started as soon as possible after HIV diagnosis, regardless of CD4 count. This recommendation is based on strong evidence that early treatment leads to better health outcomes and reduces the risk of HIV transmission. The Strategic Timing of Antiretroviral Treatment (START) trial, published in the New England Journal of Medicine in 2015, definitively showed that immediate ART was superior to deferred ART in preventing serious illness and death.
Goals of ART
The primary goals of ART are:
- Viral suppression: Reducing the viral load to undetectable levels (typically defined as less than 20–50 copies/mL of blood)
- Immune reconstitution: Allowing the CD4 count to recover to normal or near-normal levels
- Prevention of transmission: An undetectable viral load means the person cannot sexually transmit HIV (U=U)
- Long-term health: Preventing AIDS-defining illnesses, reducing non-AIDS comorbidities, and enabling a normal life expectancy
Adherence: The Key to Success
ART only works if it is taken consistently as prescribed. Missing doses can allow HIV to replicate, potentially leading to drug resistance and treatment failure. Modern ART regimens are designed to be as simple as possible — many are single-tablet, once-daily regimens — to make adherence easier.
If you are struggling with adherence, talk to your healthcare provider. There are many strategies and support services available, including pill organizers, reminder apps, and adherence counseling. The Ryan White HIV/AIDS Program provides support services to help people with HIV stay in care and adhere to treatment.
Conclusion
Antiretroviral therapy is one of the great success stories of modern medicine. With ART, HIV has been transformed from a fatal disease to a manageable chronic condition. The key to success is early diagnosis, prompt initiation of treatment, and consistent adherence. If you are living with HIV and not yet on treatment, talk to your healthcare provider today — starting ART is the most important thing you can do for your health and the health of your partners.