What are the key principles in managing HIV infection?
First of all, there is no evidence that people infected with HIV can be cured by the currently available therapies. In fact, individuals who are treated for years and are repeatedly found to have no virus in their blood 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 lamivudine (Epivir, 3TC),emtricitabine (Emtriva, FTC), and the drugs in the class of nonnucleoside analogue reverse transcriptase inhibitors (NNRTI) such asnevirapine (Viramune, NVP), delavirdine(Rescriptor, DLV), and efavirenz (Sustiva, EFV). Thus, if these drugs are used as part of a combination of drugs that does 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 aszidovudine (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. Factors to consider before starting antiviral therapy
One of the most controversial areas in the management of HIV disease is deciding the best time to start antiviral treatment. Clearly, therapy during the mildly symptomatic stage of the disease delays progression to AIDS, and treating individuals with AIDS postpones death. Consequently, most experts have long agreed that patients who have experienced complications of HIV disease, such as oral thrush (yeast infection in the mouth), chronic unexplained diarrhea, fevers, weight loss, opportunistic infections, or dementia (for example, forgetfulness) should be started on antiviral treatment even if the symptoms are mild. In patients who do not have symptoms, however, there is more uncertainty. Most recommendations for this group are based on the predictors of clinical progression, such as the number of CD4 cells. One can envision that as treatments become easier to take, better tolerated, and increasingly effective, therapy will begin to be started earlier in the course of infection. When to start antiviral therapy
Guidelines for starting antiviral therapy have been proposed by panels of experts from several groups including the DHHS and IAS-USA. They recommend treating all patients who have symptoms and those who have CD4 cell counts of less than 350 cells per mm3. Recent data supporting even earlier initiation of therapy includes analyses of groups of patients followed over time. Although the data is imperfect, a recent study showed 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, there is growing evidence that currently used treatments are usually very well tolerated and effective in suppressing viral load. Guidelines will continue to change with time, but for now, the emphasis should be on discussing all of the potential benefits and risks of therapy and deciding when is best for each individual. Regardless, all agree that HIV is generally a slowly progressive disease, and therapy rarely needs to be started abruptly. Therefore, there usually is time for each patient to carefully consider options prior to starting 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 thatdepression, feelings of isolation, substance abuse, and side effects of the antiviral drugs can all be associated with the failure to follow the treatment program. 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.hivatis.org. The most recent IAS-USA guidelines were published in the Journal of the American Medical Association (JAMA) in the summer of 2008. 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 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 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 (Isentress, RAL) 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.
Nucleoside and nucleotide analogue reverse transcriptase inhibitors
NRTIs block an enzyme of the HIV called reverse transcriptase that allows HIV to infect human cells, particularly CD4 T 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 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. Usual dosing schedule and meal restrictions for NRTIs
|
ZDV |
d4T |
ddl |
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 |
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 food.
Nonnucleoside analogue reverse transcriptase inhibitors
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 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 | 100 |
| Schedule |
1 twice/day
(start with 1 once/day
for first 14 days) | 2 thrice/day | 1 once/day | 2 twice/day |
Meal restrictions |
None |
None |
Avoid high-fat meals |
After meals |
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), and
- 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 | 21twice/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 RTV3once/day | 24twice/day | 8005once/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 |
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 was recently approved for use in combination therapy in treatment-experienced patients with drug-resistant virus 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" 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 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.
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 in development. 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.
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 able to tolerate currently available agents. The most promising new drugs at this time are those in existing classes, such as a new integrase inhibitor, CCR5 antagonist, and NNRTI.
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 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.
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 provider. 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 mm3and 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.
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 with IDV and ATV and increased blood bilirubin levels 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. 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.
Integrase inhibitor
RAL has not been strongly linked to any specific side effect in clinical trials. However, there have been some cases of muscle problems that need 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.
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 100-fold 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
Viral load increasing 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.
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 provider in advance to establish the best strategy for safely accomplishing this.
