Initial therapy for HIV

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 2010.

Antiviral treatment options have primarily included combinations of two nucleoside analogue reverse transcriptase inhibitors (NRTI), often referred to as “nucs,” and one PI, typically with a low dose of Ritonavir, a PI used at low doses to increase the level of the principle PI being used, so called “boosting.”

Alternative, options include the use of two NRTIs with a nonnucleoside analogue reverse transcriptase inhibitor (NNRTI), the latter often called “non-nucs.” These NNRTI-containing combinations generally are easier to take than PI-containing combinations and tend to have different side effects. Recently, NRTIs were combined with the integrase inhibitor raltegravir with very good viral suppression and tolerability. This novel combination has now been approved by the Food and Drug Administration as another treatment option for those initiating therapy for the first time and is considered along with NNRTIs and PIs as one of the preferred options.

Nucleoside and nucleotide analogue reverse transcriptase inhibitors

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 or infecting human cells.

In general, most antiviral regimens for HIV disease contain a backbone of at least two NRTIs. The NRTIs include ZDV, d4T, ddI, zalcitabine (HIVID, ddC), 3TC, FTC, abacavir (Ziagen, ABC), or TDF. The NRTIs FTC and 3TC are highly related compounds and most experts agree that they probably can be used interchangeably. Many combinations of NRTIs can be used together, with current guidelines generally recommending the fixed-dose combination of TDF with FTC with alternatives being the fixed-dose combinations of ABC/3TC or ZDV/3TC. Other options would include ddI plus 3TC or FTC. ABC has been associated with severe allergic reaction 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 allergic reaction.

Usual dosing schedule and meal restrictions for NRTIs

	ZDV	d4T	ddI	ddC	3TC	ABC	TDF	FTC
Dose in each pill (mg)	300	30 or 40	100 or 400	0.75	150 or 300	300	300	200
Schedule	1 twice/day	1 twice/day	2 (100) twice/day or 1 (400) once/day	1 thrice/day	1 (150) twice/day or 1(300) once/day	1 twice/day or 2 once/day	1 once/day	1 once/day
Meal restrictions	None	None	30 minutes before or 60 minutes after a meal	None	None	None	None	None

ZDV, zidovudine; d4T, stavudine; ddI, didanosine; ddC, zalcitabine; 3TC, lamivudine; ABC, abacavir; TDF, tenofovir; FTC, emtricitabine.

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. When TDF is taken with ddI, the standard ddI dose should be reduced to 250 mg per day and can be taken with meals.

Nonnucleoside analogue reverse transcriptase inhibitors(NNRTI s)

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

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

Usual dosing schedule and meal restrictions for NNRTIs

	NVP	DLV	EFV	ETR
Dose in each pill (mg)	200	200	600	200
Schedule	1 twice/day (start with 1 once/day for first 14 days)	2 (three times)/day	1 once/day	1 once/day
Meal restrictions	None	None	Avoid high-fat meals	After meals

NVP, nevirapine; DLV, delavirdine; EFV, efavirenz; ETR, etravirine.

For people without a history of drug resistance, there is a very effective fixed-dose combination pill that includes TDF with FTC and EFV as a single pill that can be taken once per day.

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/day	2 every 8 hours	2 twice/day	2 twice/day or with RTV2	2 twice/day or 4 once/day	2 (200) or 1 (300) with RTV3 once/day	24 twice/day	8005 once/day or 600 twice/day
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/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) 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 two 400 mg tablets (800 mg total) once daily with 100 mg of RTV once daily.

Fusion inhibitors:

A fusion inhibitor blocks an early step in the viral life cycle. Enfuvirtide (Fuzeon, T-20) attaches to the envelope surrounding the virus and prevents it from entering the CD4 cells. This prevents the infection of CD4 cells by HIV. T-20 is the first approved drug in this class. It is given as a twice daily subcutaneous injection (90 mg). It is used primarily in individuals who have developed resistance to other classes of drugs in order to create a new potent combination. Like all other antivirals, it is most useful in those taking other active drugs at the same time in order to optimize the chance of getting viral loads to undetectable levels and to prevent the development of drug resistance.

CCR5 antagonist:

The first available drug in this class is called maraviroc (Selzentry, MVC), which is now approved for use in combination therapy in treatment-experienced patients who do not have detectable CXCR4-using virus as determined by a tropism assay. This is a unique drug in a new class that blocks viral entry by interacting with the CCR5 molecule on the surface of the CD4 cell. It is known that HIV first binds to the CD4 molecule on the surface of CD4 cells and then connects with the CCR5 or CXCR4 molecule. Only after this second step is the virus able to enter the cell. The CCR5 antagonist prevents viruses that use CCR5 from getting into the cell. The   unique thing about this drug compared to others is that 20%-50% of patients have viruses that are able to use the CXCR4 receptor. In these cases, CCR5 antagonists do not appear to be active at suppressing virus. Therefore, in order to know if the drug will work for a given patient, a new test needs to be performed, the so called “tropism” assay. This test will tell the provider and patient whether there is virus that uses CXCR4, in which case the patient would not be a candidate for MVC, or if they only have viruses that use CCR5, in which case MVC should be an active drug. Without tropism results, it is impossible to know whether MVC will be an active drug for a given patient.

MVC is typically given at either 300 mg or 150 mg twice daily, depending upon what other drugs it is given with. If the patient is taking any RTV, then they would usually receive the 150 mg dose. If RTV is not being used as part of the regimen, they would generally receive the 300 mg dose and sometimes even higher if it is being used with drugs like ETR. HIV providers are aware that whenever using any anti-HIV medications attention must be given to possible drug interactions.

Integrase inhibitor:

The first available drug in this class is RAL and represents a new drug in a new class that appears to be very potent at suppressing HIV in all patients who have never been on this drug or other integrase inhibitors. Initially, it was approved for treatment-experienced patients with drug-resistant virus. It is also now approved for those starting therapy for the first time. The approved dose of RAL is 400 mg twice daily.

Drugs in development:

There are many drugs currently in development that may simplify therapy and provide important options for those who have developed extensive drug resistance. Drugs that show promise in early clinical trials are often made available by the manufacturer with approval of the Food and Drug Administration (FDA), to certain individuals. In particular, these drugs are used in individuals no longer responding or are not able to tolerate currently available agents. The most promising new drugs in the advanced stages of development are those in existing classes, such as new integrase inhibitors, and a new NNRTI.