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Treatment-naive patients have more antiretroviral therapy alternatives than treatment-experienced individuals.

People who have never received treatment for a certain illness are considered treatment-naïve for that particular condition. In the field of sexually transmitted infections, this word most commonly refers to HIV-positive patients who have never received antiretroviral medication for their illness.

The current treatment guidelines for treatment-naive individuals include the use of regimens such as:

• Nucleoside (and nucleotide) reverse transcriptase inhibitors (NRTIs)
• Nonnucleoside reverse transcriptase inhibitor (NNRTI)
• Ritonavir-boosted protease inhibitor (PI)
• Integrase strand transfer inhibitor (INSTI)

NRTIs

1. Tenofovir–emtricitabine:
   • Tenofovir is a prodrug which means it is converted into its active form in the body. The two active metabolites of tenofovir are tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide (TAF). Tenofovir-diphosphate is the intracellular, pharmacologically active molecule that is active against the hepatitis B virus. TDF and TAF are combined with emtricitabine and a variety of third agents.
   • Tenofovir disoproxil fumarate-emtricitabine is well tolerated, and several well-designed trials have indicated that when combined with a range of other third agents, this combination is efficient in decreasing HIV RNA. TDF is linked to renal toxicity and should be avoided in individuals with impaired kidney function.
   • Tenofovir alafenamide-emtricitabine is more efficient than tenofovir disoproxil fumarate-emtricitabine and has better renal and bone safety. Unlike TDF, TAF can be given to the majority of individuals with moderately impaired kidney function.
   • TAF is more associated with weight gain than TDF. However, this may be due to the cause that TDF affects the suppressing of weight rather than a direct outcome of TAF. TAF is also known for its drug interactions, so it is usually avoided in individuals who are on specific drugs, such as rifamycin and certain anticonvulsants.
2. Abacavir–lamivudine:
   • Abacavir-lamivudine is another extensively used NRTI combination. Abacavir is not recommended for people who have certain genes (HLA-B*5701) that increase sensitivity to the drug and the risk of experiencing an abacavir hypersensitivity response.
   • Although abacavir is less toxic to the kidneys and bones than TDF, there are concerns regarding its usage in individuals with high virus loads and those with or at risk of cardiovascular disease.

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NNRTI

NNRTIs are often used in conjunction with a tenofovir-containing NRTI combination. The most widely used medicines for treatment-naive patients are efavirenz, rilpivirine, and Doravirine.

1. Efavirenz:
   • For many years, efavirenz was the chosen third agent. However, it is now considered an alternate agent. Efavirenz has a high risk of adverse effects such as neurologic and mental side effects including headache, confusion, and forgetfulness.
2. Rilpivirine:
   • Rilpivirine is well tolerated and favors a good lipid profile. However, it is restricted to individuals with a baseline viral load of 100,000 copies/mL and a CD4 count of 200 cells/µL. Furthermore, rilpivirine must be taken with a meal, and the use of rilpivirine with proton pump inhibitors is not recommended.
3. Doravirine:
   • Doravirine is the newest NNRTI approved for use in the United States. It has fewer negative effects on the central nervous system than efavirenz and better lipid profiles than both efavirenz and darunavir/ritonavir. However, there has been little experience with this agent, and it has never been compared with INSTIs. It is often chosen as the third agent for the majority of patients.

PIs

PIs are usually given in conjunction with a nucleoside combination although they can be used as part of a nucleoside-sparing/limiting regimen. PIs should be used in conjunction with a boosting agent such as ritonavir or cobicistat. Although both boosted darunavir and boosted atazanavir are efficacious as a first-line treatment when combined with nucleoside analogs, boosted darunavir is often favored because it is more well-tolerated.

Hyperglycemia, diabetes, and hyperlipidemia are some adverse effects of PIs. Furthermore, the requirement for pharmacological boosting may lead to substantial medication interactions. However, because PIs have a high barrier to resistance, they are occasionally recommended for patients who take their drugs on an irregular basis.

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INSTI

INSTIs dolutegravir or bictegravir are included in one of the preferred regimens for the majority of patients. These agents are well tolerated; however, they may cause more weight gain than other agents. Weight increase among INSTI patients was comparable between bictegravir and dolutegravir-based regimens.

In general, dolutegravir and bictegravir, as well as the first medicine in this family, raltegravir, have limited drug-drug and drug-food interactions. The INSTI elvitegravir must be administered with cobicistat, a pharmacokinetic boosting agent that dramatically increases medication interactions; as a result, it is no longer regarded as a recommended agent. However, all INSTIs interact with cation-containing substances such as calcium, iron, or magnesium, necessitating them to be taken several hours apart or, in some cases, coupled with meals. 

1. Raltegravir:
   • Raltegravir was in use since 2007. Hence, it has the most clinical experience among the INSTIs. It has the fewest drug-drug interactions among the drugs in this class. It can be given to treatment-naive individuals as one 400 mg pill two times a day (800 mg total daily dosage) or two 600 mg pills one time daily (1200 mg total daily dose). Raltegravir is not available as a single-pill regimen.
2. Elvitegravir:
   • Elvitegravir is available in two co-formulated single-pill formulations that include:
     • Elvitegravir-cobicistat-emtricitabine-tenofovir alafenamide
     • Elvitegravir-cobicistat-emtricitabine-tenofovir disoproxil fumarate 
   • The TDF-containing coformulation should only be used in patients with normal kidney function, whereas the TAF-containing formulation can be used in individuals with mild to moderate kidney disease.
3. Dolutegravir:
   • Dolutegravir is given one time a day for treatment-naive patients and is usually well tolerated. It is available as a co-formulated tablet such as:
     • Dolutegravir-abacavir-lamivudine
     • Dolutegravir-lamivudine
   • Dolutegravir resistance is extremely rare, even in the event of virologic failure, suggesting that it has a greater resistance barrier than raltegravir or elvitegravir. As a result, this drug is highly suited for people who require therapy before genotyping testing results are available.
   • Despite its numerous benefits, dolutegravir has been linked to higher weight gain than other drugs and may have more neuropsychiatric adverse effects than other INSTIs. Furthermore, it has more medication interactions than raltegravir such as with metformin and anti-epileptic drugs but significantly less than elvitegravir/cobicistat.
4. Bictegravir:
   • Bictegravir is a part of a single-pill, fixed-dose combination regimen, bictegravir-emtricitabine-tenofovir alafenamide. Clinical trials have not revealed any evidence of resistance to this regimen. Rifamycins and some antiarrhythmic medicines are examples of notable medication interactions. In terms of weight gain, bictegravir looks to be similar to dolutegravir.
5. Cabotegravir:
   • The newest integrase inhibitor, cabotegravir, was licensed for use with rilpivirine and is available in an oral and a long-acting injectable formulation; nonetheless, this medication should only be used in virologically suppressed patients switching regimens.

What are the goals of the antiretroviral therapy in naive patients?

Treatment selection and adjustment to achieve optimal response are essentially based on regular measurement of viral load (and, if necessary, resistance testing) and CD4 cell count. With the use of genotypic resistance testing of the HIV strains at the start of therapy and after treatment, failure is becoming increasingly common. 

Due to increasing transferred drug resistance (TDR), a PI-based regimen may be a preferable alternative for some individuals. Old ART combinations are being challenged by new combinations. However, there is presently insufficient evidence to advocate using the newer over the classic. Drug co-formulations and single-tablet regimens are rapidly becoming accessible, and their convenience may boost patient adherence to therapy.

Treatment-naive patients have more antiretroviral therapy alternatives than treatment-experienced individuals. This is because doctors are less or not concerned at all about the presence of resistance to one or more medications or drug classes. However, treatment varies in patients who are infected with HIV strains that are already resistant to one or more antiviral medications.

Antiretroviral treatment (ART) aims to minimize HIV-related morbidity and death (from both infectious and noninfectious causes), while also preventing HIV transmission to others. To accomplish and maintain these objectives, ART should result in the greatest possible suppression of HIV RNA. Suppression of plasma viral load below the detection limit of commercial tests also prevents drug-resistant mutations from being selected and allows for enhanced immunologic function (as measured by the CD4 cell count).