February 13, 2016
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Human Immunodeficiency Virus (HIV) (cont.)

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What is the initial therapy for HIV?

In the United States, guidelines for using antiviral therapy have been developed and are updated on a regular basis by an expert panel assembled by the DHHS, the IAS-USA panel, and others. The DHHS guidelines are available at http://www.aidsinfo.nih.gov. The most recent IAS-USA guidelines were published in the Journal of the American Medical Association (JAMA) in the summer of 2014 and will soon be updated.

Antiviral treatment options have primarily included combinations of two NRTIs, often referred to as "nucs," and a third drug, typically being a boosted PI, a NNRTI, often called "non-nucs, and InSTIs such as RAL, EVG or dolutegravir (Tivicay, DTG). Many of these drugs are available in fixed-dose combinations and now five options as single-tablet regimens.

What are nucleoside and nucleotide analogue reverse transcriptase inhibitors (NRTIs)?

NRTIs block an enzyme of the human immunodeficiency virus called reverse transcriptase that allows HIV to infect human cells, particularly CD4 cells or lymphocytes. Reverse transcriptase converts HIV genetic material, which is RNA, into human genetic material, which is DNA. The human-like DNA of HIV then becomes part of the infected person's own cells, allowing the cell to produce RNA copies of the HIV that can then go on to attack other not yet infected cells. Thus, blocking reverse transcriptase prevents HIV from taking over (infecting) human cells.

In general, most antiviral regimens for HIV disease contain a backbone of at least two NRTIs. The NRTIs include zidovudine (Retrovir, ZDV), stavudine (Zerit, d4T), didanosine (Videx, ddI), zalcitabine (HIVIDddC), 3TC, FTC, abacavir (Ziagen, ABC), or tenofovir disoproxil fumarate (Viread, TDF). The NRTIs FTC and 3TC are highly related compounds and, although data is somewhat limited, most experts agree that they probably can be used interchangeably. That said, many combinations of NRTIs can be used together, with current guidelines generally recommending the fixed-dose combination of TDF with FTC (Truvada) or, in select regimens or as an alternative, the fixed-dose combination of ABC/3TC (Epzicom). ABC has been associated with severe allergic reactions in approximately 5% of patients. Recent studies have shown that a blood test (HLA-B*5701) can be performed to determine who is at risk for this reaction so that the drug can be avoided in these individuals and be used in others with greater confidence that there will not be such a reaction. In fact, when available, it is now the standard of care to perform this test prior to initiation of ABC. The main side effects associated with TDF are reduced kidney function and bone density.

What are the usual dosing schedule and meal restrictions for NRTIs?

ZDVd4TddIddC3TCABCTDFFTC
ZDV, zidovudine; d4T, stavudine; ddI, didanosine; ddC, zalcitabine; 3TC, lamivudine; ABC, abacavir; TDF, tenofovir; FTC, emtricitabine.
Dose in each pill (mg)30030 or 40100 or 4000.75150 or 300300300200
Schedule1 twice a day1 twice a day
2 (100) twice a day or
1 (400) once a day
1 thrice a day1 (150) twice a day or 1 (300) once a day1 twice a day or 2 once a day1 once a day1 once a day
Meal restrictionsNoneNone
30 minutes before or 60 minutes after a meal
NoneNoneNoneNoneNone

The following are available fixed-dose combination pills of NRTIs:

  • ZDV/3TC (300 mg/150 mg) as Combivir; one twice per day
  • ZDV/3TC/ABC (300 mg/150 mg/300 mg) as Trizivir; one twice per day
  • ABC/3TC (600 mg/300 mg) as Epzicom; one per day
  • TDF/FTC (300 mg/200 mg) as Truvada; one per day

These are standard doses for average-sized adults, and dosing may vary depending upon the weight of a patient. Certain combinations of drugs in this class should generally be avoided, including d4T with ZDV or ddI, 3TC with FTC, and TDF with ddI.

A new formulation of TDF called tenofovir alafenamide (TAF) is being developed in existing fixed-dose combinations that currently include TDF; this includes TAF/FTC/EVG/COBI (Genvoya) (25/200/150/150 mg). Studies are under way looking at TAF/FTC (25/200 mg) and TAF/FTC/RPV (25/200/25 mg). The new formulation of tenofovir results in lower plasma levels and higher intracellular concentrations of the active drug. Data to date suggests that compared to TDF-containing regimens this form is equally effective with less adverse effects on bone mineral density and possibly on the kidneys.

What are nonnucleoside analogue reverse transcriptase inhibitors (NNRTIs)?

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

NNRTIs include NVP, DLV, EFV, 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.

Usual dosing schedule and meal restrictions for NNRTIs
NVPDLVEFVETRRPV
NVP, nevirapine; DLV, delavirdine; EFV, efavirenz; ETR, etravirine; RPV, rilpivirine.
Dose in
each pill (mg)
20020060020050
Schedule1 twice a day
(start with 1 once a day
for first 14 days)
2 thrice/day1 once a day1 twice a day1 once a day
Meal restrictionsNoneNoneAvoid high-fat mealsAfter mealsWith meals

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 the viral load as the combination with EFV (Atripla), particularly amongst those who started therapy with higher viral loads and lower CD4 cell counts (for example, >100,000 copies/mL and <200 cells/mm3, respectively). It is currently recommended only for those that have viral load levels of <100,000 copies/mL and CD4 cell counts greater than 200 cells/mm3.

Medically Reviewed by a Doctor on 12/17/2015

Source: MedicineNet.com
http://www.medicinenet.com/human_immunodeficiency_virus_hiv/article.htm

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