Antiretroviral Treatment of HIV Infection

ByEdward R. Cachay, MD, MAS, University of California, San Diego School of Medicine
Reviewed/Revised May 2024
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Because disease-related complications can occur in untreated patients with high CD4 counts and because less toxic medications have been developed, treatment with antiretroviral therapy (ART) is now recommended for all patients. The benefits of ART outweigh the risks in every patient group and setting that has been carefully studied.

ART aims to

  • Reduce the plasma HIV RNA level to undetectable (ie, < 20 to 50 copies/mL)

  • Restore the CD4 count to a normal level (immune restoration or reconstitution)

ART can usually achieve its goals if patients take their medications > 95% of the time.

If treatment fails, drug susceptibility (resistance) assays can determine the susceptibility of the dominant HIV strain to all available medications. Genotype assays may also be helpful.

Many patients with HIV infection are taking complex regimens involving multiple pills. With the availability of new co-formulated HIV drugs, many patients could benefit from simplification of their ART regimen, guided by HIV DNA archive genotype testing.

(See also Treatment in Human Immunodeficiency Virus [HIV] Infection.)

Classes of antiretrovirals

Multiple classes of antiretrovirals are used in ART. Two classes inhibit HIV entry, and the others inhibit one of the 3 HIV enzymes needed to replicate inside human cells; 3 classes inhibit reverse transcriptase by blocking its RNA-dependent and DNA-dependent DNA polymerase activity.

  • Nucleoside reverse transcriptase inhibitors (NRTIs) are phosphorylated to active metabolites that compete for incorporation into viral DNA. They inhibit the HIV reverse transcriptase enzyme competitively and terminate synthesis of DNA chains.

  • Nucleotide reverse transcriptase inhibitors (nRTIs) competitively inhibit the HIV reverse transcriptase enzyme, as do NRTIs, but do not require initial phosphorylation.

  • Non-nucleoside reverse transcriptase inhibitors (NNRTIs) bind directly to the reverse transcriptase enzyme.

  • Protease inhibitors (PIs) inhibit the viral protease enzyme that is crucial to maturation of immature HIV virions after they bud from host cells.

  • Entry inhibitors (EIs), sometimes called fusion inhibitors, interfere with the binding of HIV to CD4+ receptors and chemokine co-receptors; this binding is required for HIV to enter cells. For example, CCR-5 inhibitors block the CCR-5 receptor.

  • Post-attachment inhibitors bind to the CD4 receptor and prevent HIV (that also binds to the CD4 receptor) from entering the cell.

  • Integrase strand transfer inhibitors prevent HIV DNA from being integrated into human DNA.

  • Attachment inhibitors bind directly to the viral envelope glycoprotein 120 (gp120), close to the CD4+ binding site, which prohibits the conformational change necessary for initial interaction between the virus and the surface receptors on CD4 cells, thereby preventing attachment and subsequent entry into host T cells and other immune cells.

  • Capsid inhibitors interfere with the protein shell (HIV capsid) that protects HIV's genetic material and enzymes required for replication.

Antiretroviral regimens

Combinations of 2, 3, or 4 medications from different classes are usually necessary to fully suppress replication of wild-type HIV. The specific drugs are chosen based on the following:

  • Anticipated adverse effects

  • Simplicity of regimen

  • Concomitant conditions (eg, hepatic or renal dysfunction)

  • Other drugs being taken (to avoid drug interactions)

To maximize adherence, clinicians should choose an affordable, well-tolerated regimen that uses once/day (preferable) or twice-a-day dosing. Guidelines from expert panels for initiating, selecting, switching, and interrupting therapy and special issues concerning treatment of women and children change regularly and are updated on the U.S. Department of Health and Human Services website, HIVinfo.NIH.gov.

Tablets containing fixed combinations of ≥ 2 medications are now widely used to simplify regimens and improve adherence.

Adverse effects with combination tablets are the same as those for the individual drugs included.

Intramuscular injectable long-acting medications

Drug interactions

Interactions between antiretrovirals may increase or decrease efficacy.

Conversely, combining certain antiretrovirals (eg, ZDV and stavudine [d4T]) may decrease the efficacy of each medication. However, these combinations are not used in clinical practice anymore.

Combining medications often increases the risk that either medication will have an adverse effect. Possible mechanisms include the following:

  • Hepatic metabolism of PIs by cytochrome P-450: The result is decreased metabolism (and increased levels) of other medications.

can enhance metabolism of PIs and NNRTIs and thus decrease plasma PI and NNRTI levels. Thus, interactions should always be checked before any new medication is started (see Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents: Drug-Drug Interactions).

Adverse effects of antiretrovirals

Antiretrovirals can have serious adverse effects. Some of these effects, notably anemia, hepatitis, renal insufficiency, pancreatitis, and glucose intolerance, can be detected by blood tests before they cause symptoms. Patients should be screened regularly, both clinically and with appropriate laboratory testing (complete blood count; blood tests for hyperglycemia, hyperlipidemia, hepatic and pancreatic damage, and renal function; urinalysis), especially after new drugs are started or unexplained symptoms develop.

Metabolic effects consist of interrelated syndromes of fat redistribution, hyperlipidemia, and insulin resistance. Subcutaneous fat is commonly redistributed from the face and extremities to the trunk, neck, breasts, and abdomen—a cosmetic effect (called lipodystrophy) that can stigmatize and distress patients. Treating the resulting deep facial grooves with injected collagen or polylactic acid can be beneficial.

Weight gain, central obesity, hyperlipidemia, and insulin resistance, which together constitute the metabolic syndrome, increase the risk of myocardial infarction, stroke, and dementia.

Mechanisms for metabolic effects appear to be multiple; one is mitochondrial toxicity. Risk of metabolic effects (highest with PIs) and mitochondrial toxicity (highest with NRTIs) varies by medication class and within medication classes (eg, among NRTIs, highest with d4T).

Metabolic effects are dose-dependent and often begin in the first 1 to 2 years of treatment. Lactic acidosis is uncommon but can be lethal.

Nonalcoholic fatty liver disease is being increasingly recognized among patients with HIV. Certain early-generation ART medications caused steatosis, and as their use decreased, incidence of steatosis decreased. Nonetheless, even with newer-generation ART drugs, there appears to be a risk of steatosis.

Long-term effects and optimal management of metabolic effects are unclear. Lipid-lowering medications (statins) and insulin-sensitizing medications (glitazones) may help. Patients should be counseled about maintaining a healthy diet and regular physical activity as ways to help promote health. (See also the recommendations of the HIV Medicine Association of the Infectious Diseases Society of America and the Adult AIDS Clinical Trials Group: Guidelines for the Evaluation and Management of Dyslipidemia in HIV-infected Adults Receiving Antiretroviral Therapy.)

Bone complications of ART include asymptomatic osteopenia and osteoporosis, which are common. Uncommonly, osteonecrosis of large joints such as the hip and shoulder causes severe joint pain and dysfunction. Mechanisms of bone complications are poorly understood.

Lipodystrophy (Lipoatrophy) in HIV
Lipodystrophy (Lipoatrophy) in HIV (1)
Lipodystrophy (Lipoatrophy) in HIV (1)

    These images show clinical signs of lipodystrophy and lipoatrophy. The left panel shows the accumulation of fat tissue in the posterior cervical areas known as “buffalo hump” (red arrow). The right panel shows increased abdominal fat. The abdominal fat that people with HIV experience is deep inside the organ cavity (visceral fat). The right panel also shows the loss of fat under the skin in the arms and legs, known as lipoatrophy.

... read more

Image courtesy of Dr. Edward R. Cachay.

Lipodystrophy (Lipoatrophy) in HIV (2)
Lipodystrophy (Lipoatrophy) in HIV (2)

    With use of antiretroviral medications, body fat can be redistributed from the face and extremities (left panel) to the trunk, breasts, and abdomen (center panel) and neck (right panel).

... read more

© Springer Science+Business Media

Immune reconstitution inflammatory syndrome (IRIS)

Patients beginning ART sometimes deteriorate clinically, even though HIV levels in their blood are suppressed and their CD4 count increases, because of an immune reaction to subclinical opportunistic infections or to residual microbial antigens after successful treatment of opportunistic infections (see immune reconstitution inflammatory syndrome for a more detailed discussion).

Interruption of antiretroviral therapy

Pearls & Pitfalls

More Information

The following English-language resources may be useful. Please note that THE MANUAL is not responsible for the content of these resources.

  1. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents: Drug-Drug Interactions

  2. Primary Care Guidelines for the Management of Persons Infected with Human Immunodeficiency Virus: 2020 Update by the HIV Medicine Association of the Infectious Diseases Society of America: Evidence-based guidelines for the management of people infected with HIV

Drugs Mentioned In This Article
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