COMMENTARY

Updated NYSDOH AIDS Institute Guideline on Selecting an Initial ART Regimen

Samuel T. Merrick, MD

Disclosures

December 15, 2017

The Medical Care Criteria Committee of the New York State Department of Health AIDS Institute has recently released an important update to its guideline, Selecting an Initial ART Regimen.[1] The guideline presents current recommendations for preferred and alternative antiretroviral (ART) regimens for use in adult ART-naive patients who are not pregnant. In addition to recommended regimens, the guideline includes a detailed roadmap to assist clinicians in determining which of the many efficacious regimens might best be suited for an individual based on comorbidities, pretreatment laboratory values, concomitant medications, and lifestyle preferences.

When and What to Start Now Resolved

The question of when in the course of HIV disease to start ART has been contentious since 1990, when zidovudine was approved. Now, with the results of the START and TEMPRANO studies,[2,3] the question of when to start therapy—immediately upon diagnosis of HIV—has been resolved for all but a very small group of so-called elite controllers. (Elite controllers are people living with HIV and not using ART, who remain at or near undetectable viral load levels with a normal immune system.)

The question of which regimen to initiate in ART-naive patients has been almost as controversial. However, with the tremendous improvements in tolerance and convenience that have been made over the last 20 years, that decision is now more straightforward than it has been since ART was first introduced.

Clear Advantages to Lower Pill Burden

Data show better outcomes, as measured by adherence and virologic suppression, with a lower pill burden and once-daily versus twice-daily dosing.[4,5,6] With several single-tablet regimens (STRs) and several dual-drug fixed-dose combinations (FDCs) now available, most patients can be started on once-daily therapy.

In addition to the integrase strand transfer inhibitors (INSTIs) dolutegravir (DTG) and elvitegravir (EVG), the US Food and Drug Administration recently approved a new formulation of raltegravir (RAL), called raltegravir HD (RAL HD). This new formulation, which is designed for higher bioavailability, when taken once daily is noninferior to the old version of twice-daily RAL.[7]

An advantage of STRs over multitablet regimens is the lower likelihood of selective nonadherence, a problem that occurs when patients run out of one drug but continue with a partial regimen, thus running the risk of developing drug-resistant mutations.

A disadvantage of STRs is that they cannot be adjusted to accommodate impaired renal or hepatic function; however, use of the individual components with the appropriate dose adjustments can still allow for once-daily dosing in most situations.

Recommended Initial ART Regimens

The committee recommends a minimum of three drugs from two different classes for initial ART, with a nucleoside/nucleotide reverse transcriptase inhibitor backbone and an INSTI as the third drug.

Alternative regimens include darunavir (DRV) with a pharmacokinetic (PK) booster—with cobicistat (COBI), as an FDC, or with ritonavir (RTV)—or the non-nucleoside reverse transcriptase inhibitor (NNRTI) rilpivirine (RPV) as options for the third drug. Renal and bone mineral density data from randomized trials comparing tenofovir alafenamide (TAF) with tenofovir disoproxil fumarate (TDF) in both naive and previously suppressed patients support the choice of TAF over the older TDF when possible.[8,9,10] All of the studies using TAF in boosted regimens used the 10-mg dose, which is not commercially available in the United States. Although PK data suggest that TAF dosed at 25 mg is safe with boosted protease inhibitors, this committee does not yet recommend using the approved TAF 25 mg/emtricitabine (FTC) combination with boosted regimens. If this combination is prescribed, it should be done with caution in patients who have a creatinine clearance <50 mL/min. Although TAF is preferred, TDF remains a safe and efficacious alternative in patients with adequate renal function.

Rationale for Regimen Choices

The guideline also addresses Specific Factors to Consider and Discuss With Patients, Special Considerations for Comorbid Conditions, and Pre-ART Initiation Laboratory Testing to help clinicians formulate a rationale for choosing the best regimen for an individual patient. Below are two clinical scenarios that illustrate how to approach choosing an initial regimen.

Scenario 1. A patient with well-controlled diabetes who is being treated with metformin at the maximum recommended dose of 2000 mg daily and who is being treated for asthma with inhaled fluticasone propionate presents for ART initiation. The patient has a CD4 cell count of 290 cells/mm3, a viral load of 58,000 copies/mL, normal renal and hepatic function, and a genotype with no evidence of resistance. The patient asks for "one of the single-pill treatments." Of the preferred regimens, two contain DTG, which has significant drug interactions with metformin and should not be used in patients on doses higher than 1000 mg daily, and only one is a single pill.

The COBI in the TAF/FTC/COBI/EVG single-tablet regimen can raise levels of fluticasone propionate high enough to cause adrenal axis suppression. If the patient is willing to switch his inhaler to beclomethasone, then TAF/FTC/COBI/EVG would be a good choice.

TAF/FTC with RAL HD is also an option but requires three pills daily. Though it is a single tablet, the TAF/FTC/RPV regimen is identified as an alternative because it is less effective in patients with CD4 cell counts <200 cells/mm3 or viral loads >100,000 copies/mL, it is contraindicated when a patient is using a proton-pump inhibitor (PPI), and it requires dose separation even with commonly used histamine-2 receptor antagonists (H2RAs) such as ranitidine.

The patient reports no symptoms of reflux and has never required a PPI or H2RA and would prefer not to change the metformin dose for fear of requiring insulin. And with their asthma well-controlled, the patient would like to continue with the current inhaled steroid.

After discussion, the decision is made to initiate ART for this patient with TAF/FTC/RPV, even though it is an alternative regimen. This patient's CD4 cell count and viral load are in an acceptable range for use of this STR, which is the smallest pill and which allows the patient to continue all other medications without dose adjustment.

Scenario 2. A patient with a viral load of 150,000 copies/mL and CD4 cell count of 375 cells/mm3 presents for initiation of therapy. This patient, with a history of a myocardial infarction (MI) with subsequent atrial fibrillation and a creatinine clearance of 1.8 mg/dL, is taking apixaban 2.5 mg twice daily (dose-reduced for renal function) to prevent stroke and embolism. The patient is being treated with atorvastatin at the maximum dose to achieve lipid targets.

On baseline testing, the patient has a genotype with no evidence of resistance and is HLA B-5701 negative.

Apixaban can be dose-reduced by 50% when used with COBI or RTV; however, in patients already on a reduced dose based on age, body weight, or renal function, apixaban should not be coadministered. Therefore, although it would be possible to dose-reduce the atorvastatin by 50% to be compatible with RTV or COBI, these drugs should not be part of this patient's regimen.

Although the results are mixed, there have been signals in retrospective studies that suggest that patients at high risk for cardiovascular disease should avoid abacavir (ABC) if alternatives are available. Therefore, even though the patient is HLA B-5701 negative, given the history of MI, this may not be the best choice.[11,12] With a viral load >100,000 copies/mL, the patient cannot initiate therapy with TAF/FTC/RPV—although, once virologic suppression is achieved, this regimen could be used to simplify therapy. TAF/FTC with DTG or TAF/FTC with RAL HD are appropriate choices for this patient who chooses the former based on the lower pill count.

Benefits of Viral Suppression

ART is now recommended for all patients with HIV infection. Effective therapy is crucial for both the health of the individual with HIV infection and to reduce the risk for transmission, which supports the goal of ending the HIV epidemic. The New York State Department of Health and New York City Department of Mental Health and Hygiene, among many others, have endorsed the consensus statement from the Prevention Access Campaign that "U=U," or undetectable equals untransmittable.[13] Accumulated data over the last decade suggest that the risk for sexual transmission of HIV from someone who has a viral load below the limits of detection is negligible. The updated guideline provides the information necessary to make a careful and informed choice of initial therapy for patients of varying characteristics and preferences in order to achieve effective and durable viral suppression.

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