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

The treatment of human immunodeficiency virus (HIV) infection with combination antiretroviral therapy (ART) has changed human immunodeficiency virus (HIV) infection from a terminal illness to a chronic, managable disease with a life expectancy approaching that of the general population. ^[1]  Most persons living with HIV/AIDS (PLWHA) can experience a long, healthy life if given appropriate treatment. 

The CD4 count is an important indicator of immune function and also guides ART in patients with HIV infection. ^[2] 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. ^{[3, 4]} The benefits of ART also include decreased morbidity and mortality. ^[5] The goal of ART is to reduce the HIV viral load (RNA PCR) below the level of detection by commercial assays. Viral supression allows for immunologic improvement (as measured by CD4 counts), prevents the selection of drug-resistance mutation, and decreases HIV transmission to others. Two large observational studies of serodiscordant couples revealed that PLWHA who consistently take ART and maintain undetectable HIV viral loads do not transmit HIV to their sexual partners. ^[6]

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

Two large randomized controlled trials (Strategic Timing of Antiretroviral Therapy [START] ^[7] and TEMPERANO ^[8] ) evaluated the optimal time to initiate ART, and both demonstrated a significant 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) 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).

Although more than 25 antiretroviral medications are available from 6 major classes, an ART regimen for treatment-naive patients generally consists of 2 nucleoside reverse transcriptase inhibitors (NRTIs) in combination with a third active ART drug from 1 of 3 drug classes: an integrase strand transfer inhibitor (INSTI), a non-nucleoside reverse transcriptase inhibitor (NNRTI), or a protease inhibitor (PI) with a pharmacologic enhancer (ie, cobicistat or ritonavir). ^{[3, 9]}  Data also support the use of 2-drug INSTI + NRTI in certain situations. 

It is important to obtain testing for drug resistance and hepatitis co-infection before intitiation of ART, as these results can impact choice of regimen. However, ART initiation does not need to be delayed until the results of these tests are known. If the NRTI abacavir (ABC) is considered as part of treatment, HLA-B*5701 must be obtained and ABC only prescribed if the patient is negative for this haplotype, as persons who are positive are at risk for a potentially serious hypersensitivity reaction to the drug. 

In the setting of transmitted drug resistance, the choice of antiretroviral therapy should be tailored according the the results of resistance (typically genotype) testing.

Please see HIV Infection and AIDS.

CD4 counts provide a good asessment of innate immunity via T cells in patients infected with HIV. These counts are followed regularly over time to evaluate the response to anteretroviral therapy as well as to guide initiation of prophylactic antibiotics for oportunistic infections. When the CD4 cell count is < 200 cells/µL, patients are at a greater risk for life-threatening, AIDS-defining, opportunistic infections. ^[10]

ART is recommended to all persons living with HIV as it reduces both morbiity and mortality and prevents the transmission of HIV to others. ^{[8, 11]}

Increased urgency for ART

While antiretroviral therapy (ART) is recommended for all patients with HIV infection, one rare possible exeption to the rule is elite controllers who have no progression of HIV disease (indicated by preserved CD4 cell counts and undetectable viral load) despite being off antiretroviral therapy. Elite controllers may still exhibit higher markers of inflammation and theoretically benefit from ART inititation. Elite controllers who are not intiated on ART should still be closely monitored for decrease in CD4 cells, loss of viral suppression, and complications of HIV infection. ^[12]

The following conditions if concurrently present in HIV patients increase the urgency to initiate therapy ^[3] :

• 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, osteoporosis, tuberculosis, viral hepatitis)
• Potential adverse drug effects.
• Potential drug interactions with other medications
• Pregnancy or pregnancy potential should be evaluated. Bictegravir, tenofovir alafenamide and cobicistat should be avoided during pregnancy and conception as there is limited data to support their use. 
• Results of genotypic drug-resistance testing
• Gender and pretreatment CD4 count if considering nevirapine (NVP) which is contraindicated in women with CD4 count >250 cells /uL and men with CD4 count >400 cells /uL.
• HLA-B*5701 testing if considering abacavir (ABC)
• Patient adherence potential
• Convenience (eg, pill burden, dosing frequency, food and fluid considerations)
• Drug availability and cost

When to delay Initiation of therapy:

Certain opportunistic infections (as well as malignancies and autoimmune disorders) may clinically worsen with the initiation of ART, a condition known as immune reconstitution inflammatory syndrome (IRIS). In most situations, rapid initiation and maintenance of ART results in improved clincial outcomes and survival, despite the transient paradoxical clincial response. ^[12]  The major exception to this is cryptococcal meningitis, in which clinical outcomes and survival are improved by delaying ART initiation during the initial induction phase of antifungal treatment. ^{[13, 14]}

The other opportunistic infections where delay of ART initiation may be beneficial are tuberculous meningitis and coccidiodal meningitis. The benefit of ART delay has not be definitively established in these situations, and consultation with a specialist experienced with these conditions is recommended. In patients who have been started on treatment for pulmonary tuberculosis, ART initition may be delayed briefly during the initial phase of antituberculous therapy only if the CD4 count is >50 cells/uL. For patients with pulmonary tuberculosis in whom the CD4 count is < 50 cells/uL, ART should be intiated as soon as possible, preferably within the first 2 weeks of antituberculous therapy, to improve both morbidity and mortality. ^[15]

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 Emtricitabine (FTC) or Lamivudine (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. In patients who are co-infected with Hepatitis B, the choice of regimen should include two NRTIs that are active against both HIV and HBV, ie, tenofovir disoproxil fumarate (TDF) or tenofovir alafenamide (TAF) plus emtricitabine (FTC) or lamivudine (3TC). Regimens that include abacavir should be prescribed only to patients who are HLA-B*5701 negative, in order to prevent a hypersensitivity reaction to the drug. ^[3]

Integrase strand transfer inhibitor (INSTI)–based regimens 

Both the US Department of Health and Human Services (DHHS) and the International Antiviral Society-USA panel (IAS-USA) recomend starting treatment-naive patients on an integrase strand transfer inhibitor (INSTI) containing regimen in most situations. Fixed dose combination tablets are availabe to decrease pill burden and improve adherence. 

• Bictegravir (BIC)/tenofovir alafenamide (TAF)/emtricitabine (FTC) - Available as fixed-dose formulation (Biktarvy). 
• Dolutegravir (DTG) plus either tenofovir alafenamide (TAF)/emtricitabine (FTC) or  tenofovir disoproxil fumarate (TDF) / emtricitabine (FTC)  Note,  ​tenofovir alafenamide(TAF) has less risk for renal toxicity and bone mineral density loss and is preferred over  tenofovir disoproxil fumarate (TDF) in patients who have significant risk factors for these conditions. 
• Dolutegravir (DTG) / abacavir (ABC) / lamivudine (3TC) - Available as fixed-dose formulation (Triumeq) - ONLY if HLA-B*B5701 negative, NOT recommended if Hepatitis B co-infected
• Dolutegravir (DTG) / lamivudine (3TC)- Available as fixed-dose formulation (Dovato) - NOT recommended as initial ART if viral load >500,000 copies/mL, if Hepatitis B co-infected, or in rapid-start setting (i.e., prior to results of HIV genotypic testing, HIV viral load, and HBV testing are known.) 

Protease Inhibitor–based regimen

Although INSTI regimens are generally preferred, the use of a PI-containing regimen should be considered in the setting of INSTI resistance, certain drug interaction concerns (eg, a patient taking over 1gm of daily metformin), or concerns for poor medication adherence. These regimens have multiple potential drug interactions that should be considered when prescribing. 

• Darunavir (DRV) / cobicistat (COBI) / tenofovir alafenamide (TAF) / emtricitabine (FTC) -  Available as fixed-dose formuation (Symtuza). 

Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI)–based regimen

Once widely-used, NNRTI-regimens have generally out of favor as initial ART regimens due to increased risk for side effects and lower genetic barrier to resistance. However, these regimens have fewer drug interactions with medications used to treat tuberculosis, and now that generic formulations are available, may be significantly less costly than some other regimens. 

• Efavirenz (EFV) / tenofovir disoproxil fumarate (TDF) / emtricitabine (FTC) -available as fixed-dosed combination
• Alternatively, Efavirenz (EFV) plus tenofovir disoproxil fumarate (TDF) /lamivudine (3TC)

ART is recommended for all persons with HIV, and there is data to support starting ART as soon as possible following diagnosis to prevent complications of HIV, to reduce morbidity and mortality, and prevent transmission of HIV to others.

Laboratory testing for resistance (HIV genotype) should be obtained prior to the initiation of ART; however, initiation of ART can be prescribed before genotype and HLA B+5701 test results are available. In this setting, certain regimens are preferred for their relatively high genetic barrier to resistance, treatment of HBV co-infection, and no need for HLA screening. 

• Bictegravir (BIC)/tenofovir alafenamide (TAF)/emtricitabine(FTC)  - Available as fixed-dose formulation (Biktarvy)
• Dolutegravir (DTG) plus either tenofovir alafenamide(TAF)/emtricitabine(FTC) or  tenofovir disoproxil fumarate (TDF) / emtricitabine (FTC)-- see information re: TAF vs TDF above
• Boosted  Darunavir (DRV) + (TAF or TDF) + (FTC or 3TC) - available as fixed-dose formulation (Symtuza) or by component drugs. Pharmacologic booster agent can be either ritonovir or cobicistat. 

Injectable ART is now available for patients who prefer not to take oral therapy; however, the US Food and Drug Administration only has approved the treatment in persons who are already virally suppressed on ART for switching therapy. The NNRTI /INSTI combination of riliviprine/cabotegravir (Cabenuva) was initially approved as a 28 day oral lead-in dosage, followed by intramuscular injections administered in a healthcare setting every month. A higher-dose every 2-month dosing regimen has since been approved (following 2 initial monthly injections) and the oral lead-in dosing is now optional.