Guidelines on HIV treatment

HIV treatment recommendations

The advent of antiretroviral treatment (ART) in the mid-1990s revolutionised the management and prognosis of HIV¹.

The goal of HIV treatment is to suppress viral load to undetectable levels, preserve or improve immune function and, consequently, reduce the risk of opportunistic infections and cancers commonly associated with HIV while simultaneously preventing viral transmission^2,3.

ART is recommended for all people living with HIV, regardless of CD4 count. Genotypic resistance testing should not delay treatment initiation^3-5. The aim of treatment is to reduce associated morbidity and mortality and improve quality of life, ideally achieving an undetectable viral load, which prevents sexual transmission of the virus^3-5.

The latest European AIDS Clinical Society (EACS) guidelines define virological response to treatment as follows⁶:

• Virological suppression: HIV viral load (HIV-RNA) below 50 copies/mL for at least 6 months³
• Virological failure:
  • Incomplete suppression: Generally, HIV-RNA above 50 copies/mL at 6 months after commencing an initial course of ART, although the guidelines note suppression may be delayed in people with very high baseline levels (>100,000 copies/mL)³
  • Virological rebound: HIV-RNA above 50 copies/mL in a person with previously undetectable HIV-RNA³

The US guidelines, from the Department of Health and Human Services (DHHS), are similar but use an HIV-RNA threshold of 200 copies/mL for incomplete response and rebound⁴. They also include a separate category for virological failure, defined as the inability to either achieve or maintain HIV-RNA below 200 copies/mL.

The US guidelines contain two additional definitions:

• Virological blip: An isolated detectable HIV-RNA level in a person with otherwise suppressed HIV-RNA⁴
• Low-level viraemia: Detectable HIV-RNA level below 200 copies/mL⁴

There are many key areas for clinicians to consider when talking to people with HIV prior to initiation of therapy (Figure 1).

Figure 1. What to review prior to initiation of antiretroviral therapy^4-6.

International guidelines recommend that ART is initiated as soon as possible after HIV diagnosis and genotypic resistance testing should not delay treatment initiation^4-6.

The eight different classes of HIV treatments are⁴:

• nucleoside reverse transcriptase inhibitors (NRTIs)
• protease inhibitors (PIs)
• non-nucleoside reverse transcriptase inhibitors (NNRTIs)
• fusion inhibitors
• CCR5 coreceptor antagonists (entry inhibitors)
• integrase strand transfer inhibitors (INSTIs)
• entry inhibitors (gp120 attachment inhibitor and CD4 post-attachment inhibitor)
• capsid inhibitors (lenacapavir – approved in the USA and Europe in 2022)

The key considerations when choosing an ART regimen should be⁴:

• virologic efficacy
• toxicity
• pill burden
• dosing frequency
• drug–drug interactions
• comorbidities
• access
• cost
• drug resistance

Potential first-line ART regimens for a treatment-naive patient generally consist of two NRTIs in combination with an INSTI, NNRTI or boosted PI^4-6.

NRTIs currently recommended in guidelines are^4-6:

• lamivudine
• abacavir
• emtricitabine
• tenofovir

Recommended INSTIs are^4-6:

• bictegravir
• dolutegravir
• elvitegravir
• raltegravir
• cabotegravir

Recommended NNRTIs are^4-6:

• doravirine
• efavirenz
• rilpivirine

Recommended PIs are^4-6:

• atazanavir
• darunavir

For many PIs, adequate plasma levels cannot be achieved without coadministration of a booster (P450 CYP3A inhibitor)⁷.

For people who have achieved viral suppression with a daily oral regimen, a long-acting injectable regimen (cabotegravir plus rilpivirine) is approved for injection every 2 months in Europe and monthly or bimonthly in the USA^6,8. Lenacapavir, a twice-yearly subcutaneous injection for multi-drug resistant HIV, has also been approved⁹.

The NRTI abacavir is contraindicated in people who are HLA-B*5701-positive. Even if HLA-B*5701-negative, counselling on the risk of hypersensitivity reaction (HSR) is critical^4,6. Abacavir should be used with caution or avoided in persons with a high CVD risk^4,6.

There is a need to screen for potential barriers to ART adherence, including depression, stigma, cultural or social reasons, cognitive impairment, harmful alcohol use or recreational drug use, and discuss these with patients^4,5

Considerations in special populations

Children

For children diagnosed with HIV, the World Health Organization (WHO) recommends three first-line regimens⁵:

• Two nucleoside reverse transcriptase inhibitors (NRTIs) plus dolutegravir
• Two NRTIs plus lopinavir/ritonavir
• Two NRTIs plus a non-nucleoside reverse transcriptase inhibitor (NNRTI)

For infants, the US Department of Health and Human Services panel on treatment of HIV during pregnancy and prevention of perinatal transmission recommend the following antiretroviral regimens¹⁷:

• Antiretroviral prophylaxis: Administration of one or more antiretroviral drugs
• Presumptive HIV therapy: Administration of a three-drug antiretroviral regimen
• HIV therapy: administration of a three-drug antiretroviral regimen at treatment doses (i.e., ART)

Adolescents

Adolescents can broadly be divided into two groups: (1) those who acquired HIV when they were very young, via vertical transmission, and are therefore more likely to have received ART treatment previously, and (2) those who acquired HIV more recently as teenagers⁴. It is key to consider an adolescent’s readiness to begin and adhere to treatment, and support is essential to reduce the likelihood of non-adherence. Teenagers who have recently acquired HIV should start ART as early as possible to reduce the risk of complications, mortality and HIV transmission⁴.

Older people

Raised markers of immune activation and inflammation may be associated with both chronic HIV infection and ageing⁴. Early treatment may be particularly important in newly diagnosed older people, partly because of less effective immune recovery and an increased risk of serious non-AIDS events. The Department of Health and Human Services (DHHS) guidelines provide specific recommendations regarding which drugs to start in older adults based on the individual’s characteristics, medical conditions and other medications. It is important to consider that those with comorbidities may require additional drug-based interventions, which could make therapeutic management more complex⁴. This is applicable not only to those who develop HIV in older age, but also to those living with HIV who develop comorbidities with ageing⁴.

People with substance use disorders

Substance use disorders among people with HIV have been estimated to have a prevalence of 48%, are more common in younger and male patients¹⁸, and are known to contribute to poor health outcomes⁴. Individuals should be screened for substance use disorders as part of clinical care. Ongoing substance use is not a contraindication to ART, and it is important to consider potential barriers to treatment adherence and comorbidities that could have an impact; for example, advanced liver disease and potential drug–drug interactions⁴.

People with coinfections and comorbidities

Other factors that may complicate treatment should be taken into consideration. These include coinfections with hepatitis B or C virus, or tuberculosis, which should be screened for and factored into initial ART selection or treatment modifications⁴. Comorbid conditions including cardiovascular, renal or liver disease, conditions affecting bone density, psychiatric illnesses or neurological diseases may require an assessment of potential polypharmacy that will affect initial or ongoing ART. These conditions are more likely in older people with HIV and tend to increase with age and duration of HIV infection⁴.

Treatment recommendations for special populations are summarised in Figure 2. 

Figure 2. Considerations in special populations⁴. ART, antiretroviral therapy.

Drug–drug interactions

Drug–drug interactions (DDIs) are relatively common with antiretroviral drugs¹⁹. This can result in increased or decreased drug exposure. In turn, this may increase the frequency and/or severity of toxicities or affect the therapeutic response to treatment. Not all DDIs are of clinical significance. There is a distinction to be made between the interaction itself and its relevance in terms of potentially influencing drug levels or having an effect on the individual¹⁹.

As DDIs are common, it is important to consider any additional medications, including over-the-counter and home remedies, being taken by people with HIV undergoing antiretroviral therapies (ART)

The Liverpool website for HIV drug interactions is a useful resource20. Established in 1999 by members of the Department of Pharmacology, University of Liverpool, the drug interactions website is freely available to healthcare professionals, patients and those undertaking research.

More information can be found in the World Health Organization, Department of Health and Human Services, and European AIDS Clinical Society guidelines^3-5.