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

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What are the key principles in managing HIV infection?

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First of all, there is no evidence that people infected with HIV can be cured by the currently available therapies, although research related to curing people of infection will be discussed later. Nevertheless, in general, those who are treated for years and are repeatedly found to have no virus in their blood by standard viral load assays will experience a prompt rebound in the number of viral particles when therapy is discontinued. Consequently, the decision to start therapy must balance the risk versus the benefits of treatment. The risks of therapy include the short- and long-term side effects of the drugs, described in subsequent sections, as well as the possibility that the virus will become resistant to the therapy which can limit options for future treatment.

A major reason that resistance develops is the patient's failure to correctly follow the prescribed treatment, for example, by not taking the medications at the correct time. If virus remains detectable on any given regimen, resistance eventually will develop. Indeed, with certain drugs, resistance may develop in a matter of weeks, such as with the nucleoside reverse transcriptase inhibitors (NRTIs) lamivudine (Epivir, 3TC), emtricitabine (Emtriva, FTC), the drugs in the class of nonnucleoside analogue reverse transcriptase inhibitors (NNRTI) such as nevirapine (Viramune, NVP), delavirdine (Rescriptor, DLV), efavirenz (Sustiva, EFV), and rilpivirine (Edurant, RPV), as well as the integrase strand transfer inhibitors (InSTIs) such as raltegravir (Isentress, RAL) and elvitegravir (EVG), the latter currently only available as part of a combination with other agents (Stibild, QUAD). Thus, if these drugs are used as part of a combination of agents that do not suppress the viral load to undetectable levels, resistance will develop rapidly and the treatment will lose its effectiveness. In contrast, HIV becomes resistant to certain other drugs, such as zidovudine (Retrovir, AZT), stavudine (Zerit, D4T), and protease inhibitors (PIs), over months. In fact, for some PIs whose effects are enhanced by giving them in combination with the PI ritonavir (Norvir, RTV) to delay their clearance by the body, resistance appears to be markedly delayed. These drugs are discussed in more detail in subsequent sections, but it is important to note that when resistance develops to one drug, it often results in resistance to other related drugs, so-called cross-resistance. Nevertheless, HIV-infected individuals must realize that antiviral therapy can be and typically is very effective. This is the case even in those who have a low CD4 cell count and advanced disease, as long as drug resistance has not developed.

What factors should be considered before starting antiviral therapy?

One of the biggest questions related to the management of HIV disease is the optimal time to start antiviral treatment. There is very strong data demonstrating that therapy is appropriate for those with low CD4 cells (for example, <350 cells/mm3) as well as in those with even mild symptoms of disease such as oral thrush, as well as chronic unexplained diarrhea, fever, weight loss, opportunistic infections, or dementia (for example, forgetfulness). For asymptomatic patients with CD4 cells greater than 350 cells/mm3, there has traditionally been more uncertainty as to whether therapy should be routinely recommended outside of select situations where treatment has for years been recommended regardless of CD4 cells, such as individuals who are pregnant in order to prevent transmission of HIV to the baby or who have HIV-associated renal disease or chronic hepatitis B infection where the antiviral treatment for HIV also treats the hepatitis virus. Specific considerations related to the rationale for earlier initiation of therapy, including starting therapy in all patients regardless of CD4 cell count, are discussed below. Regardless, prior to initiating antiviral therapy, everything possible should be done to ensure that the patient is committed to the treatment, able to adhere to the regimen, and will follow up with his or her health care professional to assess whether medications are tolerated and working.

When should antiviral therapy be started?

Guidelines for starting antiviral therapy have been proposed by panels of experts from several groups, including the DHHS (http://www.aidsinfo.nih.gov) and IAS-USA. For several years, these guidelines have recommended treating all patients who have symptoms of HIV infection as well as those who have CD4 cell counts of less than 350 cells/mm3. Recent data supporting even earlier initiation of therapy includes analyses of groups of patients followed over time. Although the data is imperfect, there are now several studies that suggest that outcomes are better amongst those who start when CD4 cells drop to below 500 cells/mm3, and at least one study, but not others, showing that those who started treatment with CD4 cells greater than 500 cells per mm3 actually were less likely to die than those who did not start treatment until their CD4 cells declined to less than 500 cells/mm3. In addition, there is increasing evidence that ongoing viral replication, even in the setting of high CD4 cells may be associated with damage to the brain, kidneys, heart, and possibly even liver. Along with these studies arguing for earlier treatment, new regimens are increasingly easy to take, including a growing number of one-pill-per-day options and growing evidence that currently used treatments are very well tolerated and effective in suppressing viral load. Another compelling argument that can now be made for early therapy is the ability to reduce the risk of transmission to uninfected partners. A relatively recent study called HPTN 052 demonstrated that amongst couples where one person is HIV-infected and the other is not, those that were on antiretroviral therapy were 96% less likely to transmit HIV to their uninfected partner than those not on treatment. Finally, there is now a large study that is specifically studying whether starting treatment with CD4 cells greater than 550 cells/mm3 results in better outcomes than those who defer treatment until CD4 cells are less than 350 cells/mm3. Based upon consideration of all these factors, current United States guidelines are now recommending that all HIV-infected individuals who are prepared to commit to treatment receive therapy regardless of CD4 cell count or symptoms of disease, much as is done for most infectious diseases for which there is effective therapy. It is worth noting that these recommendations for universal treatment of HIV-infected patients have not been adopted by all countries and may be limited by resources available for antiviral treatment.

Before starting treatment, patients must be aware of the short- and long-term side effects of the drugs, including the fact that some long-term complications may not be known. Patients also need to realize that therapy is a long-term commitment and requires consistent adherence to the drugs. In addition, clinicians and patients should recognize that depression, feelings of isolation, substance abuse, and side effects of the antiviral drugs can all be associated with the failure to follow the treatment program.

What is the 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 2012.

Antiviral treatment options have primarily included combinations of two NRTIs, often referred to as "nucs," and one PI, typically with a low dose of RTV, a PI used at low doses to increase the level of the principle PI being used, so called "boosting." Alternative, preferred options include the use of two NRTIs with a NNRTI, the latter often called "non-nucs." Some of these NNRTI-containing combinations are simpler to take than PI-containing combinations and tend to have different side effects. NRTIs can also be combined with the InSTIs RAL or EVG, the latter as part of a fixed-dose combination pill that also includes a new pharmacologic boosting agent called cobicistat (COBI) with very good viral suppression and tolerability.

What are 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 (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, 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 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 such a reaction. In fact, when available, it is now the standard of care to perform this test prior to initiation of ABC.

What are the 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 a day 1 twice a day
2 (100) twice a day or
1 (400) once a day
1 thrice a day 1 (150) twice a day or 1(300) once a day 1 twice a day or 2 once a day 1 once a day 1 once a 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. Certain combinations of drugs in this class should generally be avoided, including d4T with ZDV or ddI; 3TC with FTC; and TDF with ddI.

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 the recently approved 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




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.

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 was shown to be very effective and well tolerated but not as good at suppressing plasma HIV RNA as EFV, particularly amongst those that started therapy with higher HIV RNA levels, for example, >100,000 copies/mL. It is currently recommended only for those starting therapy for the first time and have HIV RNA levels <100,000 copies/mL.

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 new InSTI, EVG, known as Stribild (also referred to as the QUAD). 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 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 new InSTI under development.

What are 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.

What is a 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 and naïve 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. What is unique 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 assays. 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 dosed 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.

What is an integrase strand transfer inhibitor?

The first available drug in this class is RAL which is very potent at suppressing HIV in all patients who have never been on this drug or others in the class. It was initially 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. As noted above, a second drug in this class, EVG was recently approved for use as first-line therapy as part of the fixed-dose combination pill of TDF/FTC/COBI/EVG. This drug is well tolerated and given as one pill per day, but unlike RAL does need to be taken with food, has interactions with other drugs, so must be used with caution in those on multiple medications and there is an effect on measures of kidney function so it should not be used in individuals with moderate to severe underlying kidney disease. EVG is also being considered as a stand alone medication that can be given outside of the fixed-dose combination pill, including for those with drug resistant virus that want to create a new regimen with an InSTI other than RAL.

Usual dosing schedule and meal restrictions for InSTIs

  RAL EVG1
Dose in each pill (mg) 200 150
Schedule 1 twice a day 1 per day
Meal restrictions None With food

RAL, raltegravir; EVG, elvitegravir.

1Currently, it is only approved as part of the fixed-dose combination pill of EVG (150 mg)/COBI (150 mg)/FTC (200 mg)/TDF (300 mg). Currently, it is being reviewed as single pill that can be given along with pharmacologic boosting agents, such as COBI or RTV in other HIV-infected patient populations.

What drugs are 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 to certain individuals with approval of the FDA. In particular, these drugs are used in individuals no longer responding or able to tolerate currently available agents. As noted above, drugs likely to be approved in the near future will include EVG as a stand-alone pill, separate from the QUAD for those who are treatment experienced. Similarly, COBI, the pharmacologic booster as a stand-alone pill, separate from the QUAD for use in combination with select PIs. The FDA is currently reviewing data from several large studies of a new InSTI, DTG for both those starting therapies for the first time and those with drug-resistant virus. This drug can be given once daily, has limited drug-drug interactions, and does not require pharmacologic boosting. Initial data suggests that it is very well tolerated and effective against some viruses that have developed resistance to other InSTIs. Like COBI, this drug does influence measures of renal function, so, while not specifically toxic to the kidney, will need to be used with caution in those with moderate to severe kidney impairment.

What are side effects of HIV therapy?

There are many potential side effects associated with antiviral therapies. The most common ones for each class of drug are summarized in readily available product information. Some specific toxicities are summarized by class below.

NRTIs

Most NRTIs can cause mild nausea and loose stools. In general, these symptoms resolve with time.

ZDV has been associated with decreased production of blood cells by the bone marrow, most often causing anemia, and occasionally hyperpigmentation (most often of the nails).

D4T can damage nerves and cause peripheral neuropathy, a neurological condition with numbness and/or tingling of the feet and hands, and inflammation of the pancreas (pancreatitis) that causes nausea, vomiting, and mid upper abdominal pain.

DDI also causes pancreatitis and, to a lesser extent, peripheral neuropathy. Peripheral neuropathy can become permanent and painful, and pancreatitis can be life-threatening if therapy is not discontinued. The drug ddC also is associated with peripheral neuropathy as well as oral ulcers.

ABC can cause a hypersensitivity reaction during the first two to six weeks of therapy in approximately 5% of individuals. The hypersensitivity reaction most often causes fever and other symptoms, such as muscle aches, nausea, diarrhea, rash, or cough. The symptoms generally get worse with each dose of ABC and, if suspected, therapy must be discontinued and never restarted for fear of developing a life-threatening reaction. There is now a simple blood test (HLA-B*5701) that can be performed to determine whether a patient is at risk for developing the hypersensitivity reaction. If the test is positive, the patient should never receive this medication.

TDF is generally well tolerated although there may be rare kidney damage and may have a greater impact on reducing bone density than other agents.

FTC is also well tolerated except for the occasional development of hyperpigmentation, most often on the palms and soles. This hyperpigmentation occurs more frequently in people of color.

Although all NRTIs can be associated with lactic acidosis (a serious condition in which lactic acid accumulates in the blood), it may occur more often with some drugs, such as d4T. Although this complication of treatment is rare, it can be severe and life-threatening. Early symptoms of lactic acidosis are nausea, fatigue, and sometimes shortness of breath. Lactic acidosis needs to be watched for and, if suspected, requires that therapy be discontinued until symptoms and laboratory test abnormalities resolve.

There has been a great deal of attention given to the more recently identified problem of "lipodystrophy." Individuals suffering from this syndrome can be categorized as having lipohypertrophy (fat accumulation) syndromes, such as the "buffalo hump" on the back of the neck, breast enlargement, or increased abdominal girth. Others primarily suffer from lipoatrophy with fat loss under the skin with complaints of prominent veins on the arms and legs, sunken cheeks, and decreased gluteal (buttock) size. These syndromes appear to be related to multiple factors, including, but not limited to, drug therapy. The NRTIs appear to be most closely linked to lipoatrophy, in particular D4T and to a lesser extent ZDV. In fact, some studies have suggested slow accumulation of fat in those who modify the NRTI component of their regimen. Some NRTIs also have been linked to elevation in lipid (fat) levels in the blood. While switching therapy is always a consideration in those experiencing potential drug-related toxicity, this should only be done under the careful supervision of an experienced HIV provider.

NNRTIs

The most common side effect associated with NNRTIs is a rash, typically occurring during the first weeks of therapy. This is most common in individuals treated with NVP. In this case, the overall risk of rash is reduced if therapy is started as a single, 200 mg NVP pill once per day during the first two weeks before increasing to the full dose of 200 mg twice per day. If the rash is mild, therapy usually can be continued if antihistamines are given, and if the rash resolves, treatment with the NNRTI can be continued. If the rash is severe, associated with liver inflammation or blisters, changes in the mouth or around the eyes, or with high fevers, therapy with the NNRTI usually needs to be discontinued. Decisions regarding continuing or stopping treatment need to be made with the primary care professional. In some patients, NVP can cause a severe allergic reaction characterized by fever, rash, and severe liver inflammation. Recent data suggests that the groups at the greatest risk for the severe reaction are those with stronger immune systems, such as HIV-uninfected people given this treatment after an exposure to HIV, women with CD4+ T cells >250 cells per mm3 and men with CD4+ T cells >400 cells per mm3. There is also likely to be increased risk in pregnant women and individuals with other underlying liver diseases. Consequently, NVP probably should not be used in any of these groups, or if used, used with caution. In addition, whenever NVP is started, liver tests that are markers for liver inflammation should be monitored at regular intervals during the first several months of treatment.

Side effects associated with EFV are mostly dizziness, confusion, fatigue, and vivid dreams. These tend to be most prominent during the first weeks of therapy and then often decrease in severity. It is generally recommended that EFV be taken at bedtime so that the patient is asleep during the time dizziness and confusion may be most severe. It is also noteworthy that there may be an increased risk of depression associated with the use of this drug, and it should be used with caution in those with poorly managed depression. Rash and liver inflammation can occur with both EFV and DLV, and these drugs may also be linked to abnormalities of lipids in the blood.

The most common side effect reported with the most recently approved NNRTI, ETR, is rash and it was generally mild and rarely required that medications needed to be stopped.

All of the NNRTIs are associated with important drug-drug interactions so must be used with caution in patients on other medications. There are numerous resources available to patients on these medications to make sure that they do not adversely interact with other HIV or non HIV-related drugs.

PIs

There are currently nine approved PIs that all have distinct toxicities. The most common side effects associated with these drugs are nausea and diarrhea, which occur more often with some PIs than others. For example, diarrhea is more common with NFV than other PIs but can occur with any and all drugs in this class. Many of the drugs in this class also increase blood lipid levels, some more than others with ATV and possibly DRV appearing to have less effect on lipids than other drugs in the class. Other unique toxicities associated with various PIs are kidney stones, kidney damage and increases in blood bilirubin levels and potentially jaundice with IDV and ATV. Some of these drugs also have been associated with elevations in blood sugar levels and bleeding in hemophiliacs. Finally, little is known regarding the role these drugs may play in the development of lipodystrophy.

Most PIs are associated with important drug-drug interactions so must be used with caution in patients on other medications. There are numerous resources available to patients on these medications to make sure that they do not adversely interact with other HIV or non HIV-related drugs.

Fusion inhibitors

The only drug in this class is T-20, which is administered as a twice-daily subcutaneous injection. The most common side effect is redness and pain at the site of injection. Rarely, infection can occur at the injection site. There also are reports of generalized allergic reactions.

CCR5 antagonist

Although there were some early concerns of liver inflammation for drugs in this class, MVC appeared to be well tolerated in clinical trials without any specific toxicities attributable to the drug. However, it is a new drug in a new class and the first to actually target the cell. For these reasons, longer follow-up from clinical trials and those followed in the clinic will be very important for assessing the overall safety of the drug. There are important drug-drug interactions with MVC, so it too must be used with caution in patients on other medications.

Integrase strand transfer inhibitors

RAL has not been strongly linked to any specific side effect in clinical trials. However, there have been some cases of muscle problems and of increasing depression that needs to be watched for when starting this or any new medications. As with all new medications, more data will come from extended follow-up of patients in the clinic and in clinical trials. EVG appears to be well tolerated when used as the fixed-dose combination of QUAD, with the anticipated effect on measures of kidney function, most likely related to the COBI component of the regimen, many complicated drug-drug interactions and modest effects on blood lipids.

Monitoring antiviral therapy

The goals of antiviral therapy are to enhance immunity and delay or prevent clinical advancement to symptomatic disease without inducing important side effects or selecting for drug-resistant virus. Currently, the best marker of a drug's activity is a decrease in the viral load.

Ideally, prior to initiating treatment, the viral load and the CD4 cell count should be checked and the viral load test then repeated after approximately four weeks of treatment. If the patient is beginning a regimen that includes two to three drugs for which the patient's virus does not appear to be resistant, it is expected that the amount of virus should decrease by at least hundredfold during this interval. The ultimate goal is for the viral load to decrease to undetectable levels which should occur by approximately 24 weeks. Those that are not having an appropriate response to therapy need to be questioned to make sure that they are taking their medications correctly, and if not, why. If the viral load is not going to undetectable levels and the patient is taking the medications correctly, then it is likely that there is a resistant virus to some of the medications. Drug-resistance testing then should be performed and the patient managed as described in the next section.

What happens if the patient's viral load increases while on HIV therapy?

If the patient does suppress their virus to undetectable levels on antiviral therapy but then develops detectable virus, several things should be considered. First, it must be established that the patient is taking the medications correctly. If they are missing doses, then every effort must be made to understand why this is happening and correct the situation, if possible. If the poor adherence is a result of drug side effects, efforts should be directed toward managing the side effects or changing to a better-tolerated regimen. If poor adherence is occurring because of the medication schedule of dosing, new strategies should be discussed such as placing medications in a pillbox, associating the dosing with certain daily activities such as tooth brushing, or possibly changing the regimen. Finally, if the reason for poor adherence is depression, substance abuse, or another personal issue, these issues need to be addressed and managed.

It is important to remember that sometimes, for reasons not entirely understood, the viral load can briefly increase. Unexpected increases, therefore, necessitate repeated testing of the viral load before any clinical decisions are made. If, however, the viral load is continually detected despite proper adherence to the prescribed therapy, serious consideration must be given to the possibility that the virus has become resistant to one or more of the medications being given. There is now an abundance of data showing that the use of drug-resistance tests can improve the response to a follow-up regimen. Testing can be used to determine if an individual's HIV has become resistant to one or more of the drugs that are being taken. There are currently two main types of resistance tests available in the clinic: one that is called a genotype and the other a phenotype assay. The former looks for mutations in the virus and the latter the actual amount of drug it takes to block infection by the patient's virus. The genotype test is very helpful in those being screened for the presence of resistant virus prior to initiating treatment and those experiencing viral rebound on one of their first treatment regimens. The phenotype test is particularly useful in those who are highly treatment experienced and have substantial amounts of drug resistance. The information derived from these tests, along with a tropism test will ultimately tell the provider which of the many approved drugs are likely to be fully active against the specific patient's virus. Using this information, the goal is to include at least two and ideally three fully active drugs in the next regimen in order to optimize the chances of suppressing the viral load to undetectable levels.

What are the risks of missing doses or stopping antiviral therapy?

It is strongly advised that individuals on an antiviral regimen not miss any doses of their medications. Unfortunately, life is such that doses often are missed. Reasons for missing doses range from just forgetting to take the medication, leaving town without the medication, or because of a medical emergency, such as the need for urgent surgery. For example, after an appendectomy for acute appendicitis, a patient may not be able to take oral medication for up to several days. When a dose is missed, the patient should contact his or her physician without delay to discuss the course of action. The options in this situation are to take the missed doses immediately or simply resume the drugs with the next scheduled dose.

Although every missed dose increases the chance that the virus will develop resistance to the drugs, a single missed dose should not be cause for alarm. On the contrary, it is an opportunity to learn from the experience and determine why it happened, if it is likely to happen again, and what can be done to minimize missing future doses. Furthermore, if a patient cannot resume medication for a limited time, such as in a medical emergency, there still is no cause for alarm. In this circumstance, the patient should work with their HIV provider to restart therapy as soon as is feasible. Stopping antivirals is associated with some risks of developing drug resistance, and those who wish to stop therapy for any one of a number of reasons should discuss this with their health care professional in advance to establish the best strategy for safely accomplishing this.

Medically Reviewed by a Doctor on 4/3/2013

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