Acute Side Effects from Antiretroviral Medication

thanks for tuning in to my presentation today my name is Dave Hoshi I'm a clinical professor at Iowa State University and today I'm going to be presenting on the acute side effects from antiretroviral medication and it seems like almost every day we are exposed to literature whether it's in the lay press or in the medical literature about drug adverse effects and because drug adverse effects are a major limiting factor in achieving therapeutic outcomes regardless of the disease state as providers we really need to effectively balance that relationship between tolerability of drug regimens and achieving therapeutic outcomes and that's what I really hope to focus on today and hope that you come away with is is identifying these acute side effects from antiretrovirals usually what we see in the first few months be following this presentation up with a with another one on the chronic side effects so I have no relationships or financial ties I need to disclose even though I sometimes wish they did have financial ties but anyway again what I really want for you to get out of out of this presentation today is not only to identify these adverse effects from medications but is to develop appropriate management strategies as some of it may be as simple as as riding the storm out and others may be more severe course of treatment needing ICU admission or IV therapy so with that the most common common adverse drug effects that we see our gastrointestinal dermatological CNS in nature so those are the ones we're really going to focus on today but before I get to those specific conditions I wanted to talk briefly about general adverse drug effects from antiretrovirals it is still the number one reason why patients switch regimens whether they need to discontinue or start something new or have a drug substitution the intolerance that some patients have or the sensitivity that some patients have these medications can be very severe despite the fact that side effects have declined to the severity of side effects have declined with the newer agents that have been introduced over the nest past decade when compared to medications used back in the 80s and 90s the other positive feature of adverse effects is that we are seeing few of them because we are starting patients soon or on therapy meaning we're starting patients on higher cd4 cells cd4 cell counts then what we use to and when patients have low cd4 count specifically lower than 200 they may be at a greater risk of developing an iris or immune reconstitution inflammatory syndrome where where the immune system as its restoring itself is wreaking havoc on the body and it may be difficult to tease out whether there's an acute adverse effect of the drug or there's something else like an iris going on additionally we may see higher rates of adverse effects in other patient populations on that that are necessarily accounted for from clinical studies those being specifically women and older pop and older patients women have higher rates of rashes ototoxicity lactic acidosis where older patients may also be a bit more sensitive to some of the drug side effects and not really have the compensatory mechanisms to adjust for some of those side effects and and lastly many medications will have overlapping side effects or toxicities between the anti retrovirals or with other conditions for example although a single drug may have a five or ten percent likelihood of causing a rash or causing nausea when added to other medications that cause rashes or nausea it can have almost an additive effect and then trying to decipher which medication causes on that effect can be more difficult and finally when patients have other disease stage such as the use of alcohol or hepatitis on some of these adverse effects may be a bit more pronounced as well so the the emphasis or the focus point of this presentation is really the take-home points of how you can educate your patients about what to expect for potential side-effects and how to manage those side effects to get them adjusted to new therapy because nobody likes to start and stop medications so with that really providing tools to your patients can help can help them achieve good their outcomes the gastrointestinal side effects tend to be the most common problem seen with antiretroviral therapy and of that diarrhea is probably the most common and when we looked at the spectrum of diarrhea in in patients with HIV it can happen from the onset and acute acute seroconversion to late stage AIDS and can also be caused by antiretroviral medications and the e ology of all these all these effects can be quite problematic or problematic to decipher and what I mean by that is a patient may have may have progressed progressed immune deficiency and because of the depletion or the viral replication with the intent within the intestinal tract and the involvement of the cd4 cells within the intestinal tract may be having diarrhea from that then when antiretrovirals are added those can aggravate or irritate the intestinal tract leading to more diarrhea and can be difficult to decipher what the true underlying cause is so with that keep in mind when evaluating patients that it's a full spectrum of the the diarrhea is related to the full spectrum of the disease from acute infection because of that there's also differences in severity patients may have a mild presentation with only you know mild loose stools to severe presentation with six to seven watery explosive episodes of diarrhea day and the thing to really take away in deducing on whether or not it's a drug-related side effect is first of all is the on timing associated with the introduction of the agent these drugs can have adverse effects within a few days and it's most commonly associated with a protease inhibitor class of medication the low pinon via ritonavir combinations has greater propensity to cause diarrhea when looked at or when compared to daru nevere or atazanavir boosted regimens now if you look at the common denominator and all those are those combinations right on a Viera is still one of the biggest contributing factors and when you look at some of the rates of diarrhea it can be as high as 25% however a lot of those original doses were four to five times higher than what we actually use today so certainly keep that in mind and lastly there's also some post marketing data that suggests relative Eeyore may be associated with some mild diarrhea as well now assuming that all of the causes have been have been accounted for and that the diarrhea is associated to drug therapy or associated with drug therapy management of this can be as simple as emphasizing or edging the educating the patient to take the medications properly some patients will take them with or without food but lessening diarrhea the most part can be achieved by taking medications with food the only exception to this would be would be a favor ins and if a brands based regimens should be taken on an empty stomach as taking them within with food can increase absorption too much also assessing hydration status of the patient if they have if they're having severe watery diarrhea and are not able to keep up with their hydration status that should be assessed as well as far as management of the diarrhea mild diarrhea a lot of the time can be can be taken care of by over-the-counter agents such as loperamide or imodium bulk forming agents such as Metamucil there's also some data to suggest that oat bran tablets can help as well and finally calcium tablets such as tums has been shown to reduce frequency of diarrhea if if those do not work then access to person medications such as lomotil or – oxalate atropine can be can be used and and then also a well call has some some good data to support its use in treatment of diarrhea induced by anti retrovirals and because of that it also may help with cholesterol which sometimes can be a can be a significant barrier in patients with with HIV other GI ha complaints seen with anti retrovirals include nausea and vomiting and these are side effects listed in every class of medications so again there may be additive effects or overlapping toxicities that really need to be taken into account and it's seen you know when you utilize all medications or medications from different classes so the P is or the protease inhibitors are more notorious of causing nausea and vomiting than your nucleoside reverse transcriptase inhibitors and to a much lesser degree your n NRT eyes and your integrase inhibitors can cause some nausea and vomiting but much less likely so as far as nausea as previously mentioned medications more or less can be taken with or without food again if average is the only exception favron should be taken on an empty stomach and so you can minimize the side effects by taking them with food another approach is by taking the medications at bedtime if patients are having mild nausea they sometimes can sleep through that if they take their medications at bedtime but if patients continue to have nausea on despite you know all of these lifestyle changes the use of antiemetic medication can be used safely compazine or pro quo Terezin are inexpensive and effective and sometimes patients may need something a little bit more potent something along the lines of ondansetron or so Fran can certainly do the trick as well and then lastly with nausea if weight loss is an issue the use of certain appetite stimulants can certainly be employed and and whether your state supports the medical marijuana or the use of Marinol or in a banal that can sometimes help with nausea as well as increased appetite now something that's a bit more severe is vomiting and for a couple reasons one vomiting certainly can lead to dehydration and other electrolyte abnormalities however if a patient vomits soon after taking their medication the medication may not be absorbed if it doesn't get absorbed and it can't then it can have its clinical effect therefore vomiting needs to be addressed more acutely and more aggressively and with that similar approaches of use of antiemetic medications can be employed but in severe cases cases patients may need to have their medication switch to a different to a different antiretroviral so that so that they can overcome that vomiting now general rule of thumb is that to allow 15 to 20 minutes for medications to absorb after they're swallowed so if a patient vomits usually within 15 minutes they should be reduced but anything greater than 15 or 30 minutes usually is adequate enough time for patients to absorb the medication a Patou toxicity is probably the the largest biggest concern from a gastrointestinal standpoint and panel toxicity from anti retrovirals is probably the most severe complication and historically HIV meds have been notorious for causing some of these problems and actually carried a lot of black box warnings now of all the agents are out there nevirapine a nevirapine carries the largest risk in the nnr t eyes it's often associated with with rashes or hypersensitivity symptoms and those should be addressed very very quickly as the rash may coincide with with the pyro toxicity and subsets of patients have been identified for a greater risk of toxicity those include treatment naive women with cd4 cd4 cells greater than 250 and men with cd4 counts greater than 400 so it's generally recommended to avoid the use of nevirapine in patients with elevated cd4 counts another way to reduce the risk of hepatic toxicity is to titrate the dose initially over on the first two weeks of therapy by giving 200 milligrams once a day then increasing to 200 milligrams twice a day or switching the patient to an extended-release formulation of 400 milligrams once a day patients on protease inhibitors can also carry a bit of a risk of toxicity seen through the through the channels of drug-induced hepatitis or a paddock decompensation and but more specifically one that is seen on a much more frequent basis is is jaundice from atazanavir due to hyperbilirubinemia so it's very common to see patients have elevated bilirubin levels and and generally generally letting patients float up to up to and around bilirubin levels of four but once they start getting elevated above that or symptomatic patients really need to be switched to a different antiretroviral a nucleoside reverse transcriptase inhibitors have an association more so with the older agents as opposed to the newer agents however be very careful in patients who are Co infected with hepatitis B so if you remove some of these agents that do have antiviral activity against hepatitis B if you remove that you may get a flare of your hepatitis B during that time so that needs to be considered in patients Co infected with hepatitis B so general approach or management to have a Patou toxicity again any type of abdominal pain with elevated liver function test should be addressed promptly and drugs should be high on the differential list so whether or not you need to discontinue antiretroviral therapy or switch it really needs to be discussed in those risks and benefits weighed out and lastly asymptomatic hyperbilirubinemia it's perfectly fine to let patients run between two and three however once they start getting up in three and four really should be really should be examined for switching and therapy so let's transition over to dermatological effects and and dermatological tations are common across the spectrum of the disease and again it can sometimes be difficult to differentiate between infections immune reconstitution syndrome adverse drug effects and the other run-of-the-mill skin conditions unrelated to HIV so again having a good relationship with dermatologists can greatly help can greatly help you in your valuation of skin reactions but let's look at a few of the the most common um first off are non-nucleoside reverse transcriptase inhibitors skin rashes are extremely common within this class of agents and and with that the spectrum includes minor singly or feminist lesions all the way up to Stevens Johnson syndrome and in this for the most part is seen usually within the first six weeks liver function tests are usually elevated during this time as well so those should be jointly examined general treatment approach is that my reactions can be generally treated with antihistamines however for Stevens Johnson's were more severe reactions determining whether or not all agents first of all all agents should be removed if Stevens Johnson is suspected patients should be treated symptomatically and supportively whether that requires hospital administer hospital admission or closed outpatient monitoring and generally to minimize these side effects we really want to again dose escalate the nevirapine 200 milligrams a day for two weeks up to 400 thereafter 400 once a day or two I'll feei you'ii skin reactions from protease inhibitors are also common up to 10% of patients can develop rashes from protease inhibitors atazanavir de Runa Viren Foss imprimatur can all cause these rashes and the major problem that is seen is is in patients with that having history of a savant sulfonamide allergy and and in part these agents specifically de Revere has package labeling stating to be cautious and use with patients with a sulfonamide algae as there may be some cross sensitivity so just be careful with that but again there isn't anything unless it was a life-threatening hypersensitivity that you know otherwise patients can be closely monitored very rarely Stevens Johnson has been reported with protease inhibitors but extremely rare and then lastly with the nucleoside reverse transcriptase inhibitors that a back of the air is the most common drug associated with with rashes and and there's specific hypersensitivity reaction associated with back of ear that may include one of the symptoms as a diffuse maculopapular popular non paretic rash in addition to other symptoms can be head to toe on the palm surfaces and the thing to note is that it usually does occur in the first six weeks of therapy but has been known to pop up throughout therapy you know any time and because of this we can generally screen with with the HLA b5 701 test this is recommended by the DHHS guidelines that ain't patient projected of starting a back of your be screened with this test because if it is positive when the patient has a greater likelihood of developing this reaction if the patient does not have this genetic tat or does not have this genetic predisposition then they have a much lower likelihood or risk of developing this type of hypersensitivity and then lastly tune off of Ihram try site of beam inside ova dean may all cause mild mild skin reactions and lastly in respects to skin reactions immune reconstitution has to be taken into account in your differential if patients do develop certain skin reactions seen here is a patient after eight weeks of starting antiretroviral therapy developed herpes zoster as part of their immune reconstitution so patients who have extremely low cd4 cells as their immune system starts rebuilding itself you can see activation such as this so again keeping that in mind when you do see immune reconstitution that mild symptoms can generally be managed with NSAIDs and continuing antiretroviral therapy as opposed to severe symptoms which steroids may need to be employed now lastly are the CNS adverse effects that I want to emphasize and sort of differentiate these two into a couple categories general CNS effects as well as on neuro psych citing neuropsychiatric side effects so um so general run-of-the-mill adverse effects can be seen in all classes of antiretrovirals primarily with headache is the major complaint and and again these effects may be additive when when using agents from different classes and identifying the offending agent can certainly be difficult management of headache again assuming that all other causes such as such as toxoplasmosis meningitis all of the things have been ruled out in in as far as non medication causes treatment can range from OTC agents such as Tylenol other NSAIDs all the way up to stronger narcotics if the patient you know needs to try to stay on that therapy however sometimes if it's available switching switching regimens to find a less likely offending agent is an option as well however rarely comes to comes to that now neuropsychiatric side-effects are are seen predominantly from favorites and enough averin s– is a non-nucleoside reverse transcriptase inhibitor it is first-line dhhs guideline recommended agent in combination with an try side Amin and Tanaka veer the thing about this medication is it does cross the blood-brain barrier and can cause more CNS effects it can cause dizziness insomnia vivid dreams impaired concentration drowsiness and in this is usually seen in the first few days of initiating therapy peaks at about two weeks and then begins to taper after about two four weeks so patients really need to be supported through the first month of therapy when they start a triplet and um note there is risk of activating or reactivating underlying psychiatric problems in in HIV patients who are started on this medication so again really based on some of the available data it really should be argued that favron should not be initiated in patients who have either active uncontrolled psychiatric illness or severe sleep disorders so again patients with history of psychosis mania suicide ideation anxiety all of these can be worsened with therapy and needs to be if this agent is going to be selected these patients need to be actively monitored and closely monitored and have a plan in place should some of these symptoms begin to rise so to tie it all together in respects to first-line dhhs guideline recommended regimens you know favron based regimens you really need to be cautious about the cns effects have just discussed as well as rashes that may present at as a nevere when used in combination with ritonavir can cause nausea rash Donnell discomfort as well as the elevated bilirubin darou nevere when used in combination with ritonavir can cause diarrhea nausea potential sulfonamide rash so be careful of that the nucleoside reverse transcriptase inhibitor backbone of ten avi random Trice Ida beam can cause headache fatigue nausea and lastly ritonavir which is used boost atazanavir guru nevere can cause nausea and diarrhea as well as have some additive effects finally remember that these acute side effects are common but many will resolve as therapy continues so really being able to identify and differentiate these acute effects these cue side effects is is a is a really key clinical tool and and also being able to identify patients who may be at higher risk for adverse effects again such as female patients older patients patients with other comorbidities and really emphasize focusing on an appropriate regimen will help you again lessen the likelihood of adverse outcomes and and finally through the use of education appropriate follow-up constant contact and providing tools to your patients can overcome these problems and really help ensure therapy best therapeutic outcomes for your patients so good luck and thank you

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