Human Immunodeficiency Virus (HIV, AIDS) (cont.)

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What are nonnucleoside analogue reverse transcriptase inhibitors?

Like NRTIs, NNRTIs block the reverse transcriptase enzyme, preventing uninfected cells from becoming infected.

NNRTIs include NVP, DLV, EFV, etravirine (Intelence, ETR), and RPV. ETR was developed specifically to be an option for patients who have developed resistance to the earlier drugs in the class. NVP, DLV, EFV, and RPV are typically used with two NRTIs, and ETR is primarily being used as part of regimens for those with a history of different types of treatment to which they have developed resistance.

For people without a history of drug resistance, there are now two effective fixed-dose combination pills that include TDF plus FTC with either EFV or RPV, both as a single pill that can be taken once per day. The combination with RPV (Complera) was shown to be very effective and well tolerated but not as good at suppressing plasma HIV RNA as the combination with EFV (Atripla), particularly amongst those who started therapy with higher HIV RNA levels (for example, >100,000 copies/mL). It is currently recommended only for those that have HIV RNA levels of <100,000 copies/mL.

Usual dosing schedule and meal restrictions for NNRTIs
  NVP DLV EFV ETR RPV
Dose in
each pill (mg)
200 200 600 200 50
Schedule 1 twice a day
(start with 1 once a day
for first 14 days)
2 thrice/day 1 once a day 1 once a day 1 once a day
Meal restrictions None None Avoid high-fat meals After meals With meals
NVP, nevirapine; DLV, delavirdine; EFV, efavirenz; ETR, etravirine; RPV, rilpivirine.

What are protease inhibitors?

PIs block the action of an HIV enzyme called protease that allows HIV to produce infectious copies of itself within HIV-infected human cells. Thus, blocking protease prevents HIV in already-infected cells from producing HIV that can infect other, not yet infected cells.

PIs include

  • saquinavir (SQV), which comes as the hard gel capsule Invirase (INV),
  • ritonavir (Norvir, RTV),
  • indinavir (Crixivan, IDV),
  • nelfinavir (Viracept, NFV),
  • fosamprenavir (Lexiva, FPV),
  • lopinavir/ritonavir (Kaletra, LPV/r),
  • atazanavir (Reyataz, ATV),
  • tipranavir (Aptivus, TPV),
  • darunavir (Prezista, DRV).

Each of these drugs has been shown to effectively reduce the viral load when used in combination with other active drugs.

Usual dosing schedule and meal restrictions for PIs
  SQV+ IDV NFV FPV LPV/r ATV TPV DRV
Dose in each pill (mg) 500 400 625 700 200/50 200 or 300 250 400 or 600
Schedule 21 twice a day 2 every 8 hours 2 twice a day 2 twice a day or with RTV2 2 twice a day or 4 once a day 2 (200) or 1 (300) with RTV3 once a day 24 twice a day 8005 once a day or 600 twice a day with RTV given with each dose5
Meal restrictions With large meals 1 hour before or 2 hours after meals, or with low-fat meals With meals None With meals With meals With meals With meals
SQV, saquinavir; IDV, indinavir; NFV, nelfinavir; FPV, fosamprenavir; LPV/r, lopinavir plus ritonavir; ATV, atazanavir; TPV, tipranavir; DRV, darunavir.

1Administered with RTV at a dose of 100 mg twice a day.

2FPV can be given without RTV in patients without resistance to PIs or at a dose of 1,400 mg once daily with either 100 mg or 200 mg of RTV once daily. In treatment-experienced patients, FPV is given at a dose of 700 mg twice daily with RTV 100 mg twice daily.

3ATV can be given alone at a dose of 400 mg once daily or at a dose of 300 mg once daily with RTV 100 mg once/daily.

4TPV is always given at a dose of 500 mg twice/daily with RTV 200 mg twice daily.

5DRV can be given to those with a history of drug resistance at a dose of 600 mg twice daily with 100 mg RTV twice daily. For those without resistance, it can be given at a dose of 800 mg (two 400 mg tablets or a single 800 mg tablet) with 100 mg RTV once daily.

Although RTV is approved for treatment of HIV-infected patients at a dose of 600 mg twice daily, it is virtually never used at this dose because of severe side effects. Because of this, it is not included in the above table. However, PIs are frequently dosed with low doses of RTV. RTV delays the clearance of the other drugs from the system, making them easier to take and more effective. The dose of RTV varies depending upon which drugs it is being taken with and how it is being administered. The only PI that is not substantially affected by RTV is NFV.

LPV/r comes coformulated as Kaletra while all other RTV-containing regimens require taking RTV along with the other PI. In the case of TPV, RTV must be given as 200 mg with each dose of TPV twice per day. In contrast, ATV can be given without RTV at a dose of two 200 mg capsules once daily or 300 mg with 100 mg RTV once daily. The latter should always be used in PI-experienced subjects and when used in combination with TDF or NNRTIs which can reduce the drug levels of ATV. Similarly, FPV is also used differently in PI-naïve and experienced individuals. In treatment-naïve individuals, it can be given as two 700 mg tablets twice daily or two 700 mg tablets (1,400 mg total) with either 100 or 200 mg RTV, all once daily. In treatment-experienced patients, or when used with NNRTIs, it should be given as one 700 mg tablet with 100 mg RTV, both twice daily. The most recently approved of the PIs is DRV which was initially used exclusively in treatment-experienced patients with drug-resistant virus. In this setting, it is given as 600 mg with 100 mg RTV, both given twice daily. More recently, DRV was approved for those who have never been treated before given at a dose of 800 mg once daily with 100 mg of RTV once daily.

A new pharmacologic enhancing agent, COBI has recently been studied as an alternative to RTV. It is approved as part of the fixed-dose combination pill that includes TDF/FTC/COBI and the InSTI, EVG, known as Stribild. It has also been studied as an alternative boosting agent with ATV and DRV and is currently being reviewed by the United States FDA for this purpose where it may someday even offer the advantage of being combined into a single pill with the select PIs to further simplify dosing of this type of regimen.

There are now three approved combination pills that allow for a full regimen to be taken as a single pill once per day. This includes the following NRTI plus third drug combinations:

  • TDF/FTC/EFV (300/200/600 mg) as Atripla
  • TDF/FTC/RPV (300/200/25 mg) as Complera
  • TDF/FTC/EVG/COBI (300/200/150/150 mg) as Stribild

It is anticipated that a fourth such pill will soon be under review by the FDA, the combination of ABC/3TC and dolutegravir (DTG) at (600/300/50 mg), the latter being a recently approved InSTI.

Medically Reviewed by a Doctor on 8/5/2014

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