Antiretroviral Therapy (ART) in Treatment-Naive Patients With HIV Infection 

The CD4 count is an important indicator of immune function and also guides antiretroviral therapy (ART) in patients with human immunodeficiency virus (HIV) infection.[1] ART improves survival and reduces complications related to acquired immunodeficiency syndrome (AIDS). It also helps to reduce inflammation and other complications associated with HIV infection and to reduce HIV transmission.[2] The benefits of ART also include decreased morbidity and mortality.[3]

The current recommendation is that all patients with HIV infection undergo ART regardless of CD4 counts to reduce the morbidity and mortality associated with HIV infection.

Recent studies

Two large randomized controlled trials (Strategic Timing of Antiretroviral Therapy [START][4] and TEMPERANO[5] ) evaluated the optimal time to initiate ART, and both demonstrated about a 50% reduction in morbidity and mortality among HIV-infected individuals with CD4 counts more than 500 cells/µL randomized to receive ART immediately versus delaying initiation of ART. Based on the START and TEMPRANO findings, the Panel on Antiretroviral Guidelines for Adults and Adolescents (the Panel) has increased the strength and evidence rating for the recommendation on initiating ART to AI for all HIV-infected patients, regardless of CD4 count.

An AI rating is defined as a strong recommendation with high-quality evidence (ie, one or more randomized trials with clinical outcomes and/or validated laboratory endpoints).

An ART regimen for treatment-naive patients generally consists of two nucleoside reverse transcriptase inhibitors (NRTIs) in combination with a third active ART drug from one of three drug classes: an integrase strand transfer inhibitor (INSTI), a non-nucleoside reverse transcriptase inhibitor (NNRTI), or a protease inhibitor (PI) with a pharmacokinetic enhancer (ie, cobicistat or ritonavir).[2, 6]

When the CD4 cell count is < 200 cells/µL, patients are at a greater risk for life-threatening, AIDS-defining, opportunistic infections.[7]

Clinical trials have shown that early antiretroviral therapy (ART) in patients with a CD4 count < 200 cells/µL improves survival and delays disease progression compared with delayed ART.[8]

When discussing starting ART, physicians should inform patients that data on the clinical benefit of starting treatment at a CD4 count >500 cells/µL are variable; it is not strong for individual health, but it clearly reduces transmission.[2]

Increased urgency for ART

While antiretroviral therapy (ART) is recommended for all patients with HIV infection, the following conditions increase the urgency to initiate therapy:[2]

• Pregnancy
• AIDS-defining conditions
• Acute opportunistic infections
• Lower CD4 counts (eg, < 200 cells/µL)
• Rapidly declining CD4 counts (eg, >100 cells/µL decrease per year)
• Higher viral loads (eg, >100,000 copies/mL)
• HIV-associated nephropathy (HIVAN)
• Acute/early HIV infection
• HIV/hepatitis B virus coinfection
• HIV/hepatitis C virus coinfection

Special considerations when selecting initial therapy

Therapy should be individualized and based on factors such as the following:

• Comorbid conditions (eg, cardiovascular disease, chemical dependency, liver disease, psychiatric disease, renal diseases, tuberculosis)
• Potential adverse drug effects
• Potential drug interactions with other medications
• Pregnancy or pregnancy potential
• Results of genotypic drug-resistance testing
• Gender and pretreatment CD4 count if considering nevirapine (NVP)
• HLA-B*5701 testing if considering abacavir (ABC)
• Coreceptor tropism assay if considering maraviroc (MVC)
• Patient adherence potential
• Convenience (eg, pill burden, dosing frequency, food and fluid considerations)

Preferred regimens have favorable tolerability and toxicity profiles, are clinically effective, and are characterized by ease of use. An antiretroviral therapy (ART) regimen generally consists of 2 NRTIs (one of which is FTC or 3TC) plus an INSTI, NNRTI, or a pharmacokinetic-enhanced PI (ie, PI administered with cobicistat or ritonavir). Note that FTC or 3TC may be used interchangeably in the regimens listed that are not fixed-dose combination products. Regimens that include abacavir are only for patients who are HLA-B*5701 negative.[2]

Integrase strand transfer inhibitor (INSTI)–based regimens 

See the list below:

• Dolutegravir (DTG) / abacavir (ABC) / lamivudine (3TC) - Available as fixed-dose formulation (Triumeq)
• Dolutegravir (DTG) plus tenofovir disoproxil fumarate (TDF) / emtricitabine (FTC)
• Elvitegravir (EVG) / cobicistat (c) / tenofovir alafenamide (TAF) / emtricitabine (FTC) - Only for patients with a pre-ART creatinine clearance (CrCl) ≥30 mL/min; available as a fixed-dose formulation (Genvoya)
• Elvitegravir (EVG) / cobicistat (c) / tenofovir disoproxil fumarate (TDF) / emtricitabine (FTC) - Only for patients with a pre-ART CrCl ≥70 mL/min; available as a fixed-dose formulation (Stribild)
• Raltegravir (RAL) plus tenofovir disoproxil fumarate (TDF) / emtricitabine (FTC)

Protease inhibitor–based regimen

See the list below:

• Darunavir (DRV) / ritonavir (RTV) plus tenofovir disoproxil fumarate (TDF) / emtricitabine (FTC)

Regimens that are effective and tolerable, but that have potential disadvantages when compared with the preferred regimens listed above, have limitations for use in certain patient populations, or have less supporting data from randomized clinical trials. An alternative regimen may be the preferred regimen for some patients.[2]

Nonnucleoside reverse transcriptase inhibitor (NNRTI)–based regimens

See the list below:

• Efavirenz (EFV) / tenofovir disoproxil fumarate (TDF) / emtricitabine (FTC)
• Rilpivirine (RPV) / tenofovir disoproxil fumarate (TDF) / emtricitabine (FTC)

Protease inhibitor–based regimens

See the list below:

• Atazanavir (ATV) / cobicistat (c) plus tenofovir disoproxil fumarate (TDF) / emtricitabine (FTC)
• Atazanavir (ATV) / ritonavir (r) plus tenofovir disoproxil fumarate (TDF) / emtricitabine (FTC)
• Dolutegravir (DRV) / cobicistat (c) plus abacavir (ABC) / lamivudine (3TC)
• Dolutegravir (DRV) / ritonavir (r) plus abacavir (ABC) / lamivudine (3TC)
• Dolutegravir (DRV) / cobicistat (c) plus tenofovir disoproxil fumarate (TDF) / emtricitabine (FTC)

Acceptable regimens are not as efficacious as the preferred or alternative regimens. Moreover, additional definitive data are needed for these recommendations.[2]

Integrase strand transfer inhibitor (INSTI)–based regimen

See the list below:

• Raltegravir (RAL) plus abacavir (ABC) / lamivudine (3TC)

Non-nucleoside reverse transcriptase inhibitor (NNRTI)–based regimen

See the list below:

• Efavirenz (EFV) plus abacavir (ABC) / lamivudine (3TC)

Protease inhibitor–based regimens

See the list below:

• Atazanavir (ATV) / cobicistat (c) plus abacavir (ABC) / lamivudine (3TC)
• Atazanavir (ATV) / ritonavir (r) plus abacavir (ABC) / lamivudine (3TC)
• Lopinavir (LPV) / ritonavir (r) plus abacavir (ABC) / lamivudine (3TC)
• Lopinavir (LPV) / ritonavir (r) plus tenofovir disoproxil fumarate (TDF) / emtricitabine (FTC)

Other regimens when tenofovir disoproxil fumarate (TDF) or abacavir (ABC) cannot be used

See the list below:

• Dolutegravir (DRV) / ritonavir (r) plus raltegravir (RAL)
• Lopinavir (LPV) / ritonavir (r) plus lamivudine (3TC)