Clinicians and patients face many challenges associated with antiretroviral therapy (ART). These include making decisions about when to start therapy, what regimen to start, when to change medications, and how to switch if a regimen is failing. Although clinical research guides the selection of antiretroviral (ARV) regimens, it is important to remember that the best regimen for any patient is the regimen that individual is willing and able to take. No regimen, no matter how potent, will be effective if the patient does not take it properly. Adherence to ART is one of the most important predictors of treatment efficacy. Although many factors may interfere with proper adherence to ART, adverse reactions to the medications are among the most important. In one trial, patients experiencing adverse events were 13 times less likely than those not experiencing adverse events to have the highest levels (95-100%) of adherence. Monitoring and managing adverse reactions to ARVs are crucial to establishing a successful HIV regimen.
Although adverse reactions are common and often predictable, their management must be individualized. Several factors will affect the management of adverse reactions, including comorbid conditions, the patient's other current medications, the availability of alternative medications, and the patient's history of medication intolerance. In some cases, the patient's report of the severity of adverse effects can be inconsistent with the clinical interpretation (i.e., some patients may overemphasize symptoms, whereas others underemphasize them), and this must be considered when determining the management of adverse reactions.
Using a case-based approach, this chapter suggests strategies for the evaluation and management of adverse effects, and it reviews several of the most commonly noted adverse effects in patients starting an ARV regimen. It is not intended as a comprehensive guide to adverse effects. For detailed information regarding assessment of symptoms, see the complaint-specific chapters found in section Common Complaints of this manual. For information on common adverse reactions to ARV agents and to medications used to prevent and treat opportunistic infections, see chapter Antiretroviral Therapy and the Antiretroviral Reference Tables in this manual. In each case of suspected medication adverse effects, the patient should be evaluated for other possible causes of the symptoms. Consultation with an HIV expert can help in determining the best management strategy when symptoms may have multiple and overlapping causes.
A pregnant woman presents 3 weeks after starting a new ARV regimen. She complains of fatigue, nausea, and rash. Her current ARV medications are nevirapine (NVP) plus a fixed-dose combination of zidovudine (ZDV) and lamivudine (3TC) (i.e., Combivir). This was selected on the basis of her pregnancy, her preferences, and her past treatment history. She also is taking trimethoprim-sulfamethoxazole (TMP-SMX) as prophylaxis against PCP. Although she reports that she had not missed any doses of her medications and she likes the low pill burden of this regimen, she does not want to continue because she has been feeling so sick that she cannot adequately care for her children. She is asking to stop her ARV therapy because of "too many side effects."
The patient should be evaluated in the clinic for her complaints about adverse effects.
The following are suggestions for this evaluation; they are not intended to be a complete review of the workup and management of each symptom or objective finding. For more-detailed information, refer to the complaint-specific chapters of this manual, as noted above.
Vital signs: Fever may indicate a hypersensitivity reaction (HSR) or acute hepatitis attributable to medications, or an immune reconstitution inflammatory syndrome in relation to an opportunistic infection in the setting of early ART therapy. See chapter Fever for a more complete discussion about fever workup and considerations. Tachycardia or hypotension may suggest anemia, HSR, dehydration, infection, or another illness.
Physical examination: Pay special attention to the skin (rash, pallor), mucous membranes, and liver (enlargement or tenderness). Positive physical examination findings should be evaluated for severity and extent of involvement.
Laboratory tests: Check the complete blood count when monitoring drugs that may cause bone marrow toxicity (e.g., anemia, neutropenia). Perform a complete metabolic panel including electrolytes and liver function tests (LFTs). If the history suggests pancreatitis, evaluate amylase and lipase.
Other studies: Perform as indicated by symptoms and examination (e.g., chest X-ray if respiratory symptoms are present).
Step 1: Clarify the patient's reports of adverse reactions by requesting the following information for each symptom the patient describes:
- Characterize the symptoms by asking about severity, onset, timing, and frequency. It is helpful to have the patient describe whether the symptoms have been improving or worsening over time.
- Ask whether the patient has tried any remedies to alleviate the symptoms and whether they were helpful.
- Explore how the patient is currently taking the regimen. Closed-end questions (e.g., "What are your current medications?" "How often do you take them?" "How many pills of each medicine do you take?" and "Do you take your medicines with or without food?") can be helpful in determining whether the patient has been taking medications correctly. Incorrect administration of medications (e.g., taking higher dosages than recommended) can lead to adverse effects and often is overlooked by providers.
Step 2: Assess the severity of the reaction against the need to continue the current regimen. For this assessment, it is important to have an understanding of the relative availability of alternative ARV regimens. Also try to determine the patient's risks of adverse reactions to specific medications. A review of the patient's clinical status, treatment history, resistance tests, and other testing is important.
- Most adverse effects are self-limited and mild-to-moderate in severity. With supportive care, patients often are able to continue their current medications. This is particularly true with regard to gastrointestinal symptoms (e.g., nausea, vomiting, bloating, diarrhea). Supportive care for gastrointestinal adverse effects includes reminding the patient to take medications with food (if appropriate), suggesting the use of symptomatic remedies (e.g., ginger-containing beverages or foods to relieve nausea [see "Nausea," below]), and prescribing medications such as antiemetics or antidiarrheals if needed. Other symptoms that can be monitored carefully with supportive care include fatigue, malaise, mild rashes, abdominal pain, and bloating.
- More severe reactions often require discontinuation of the offending medication. These include fever, liver function abnormalities, rash with mucous membrane involvement, or severe systemic symptoms.
- Determining which medication in a multidrug regimen is causing the reaction is often challenging because it is common for patients to concurrently take several medications with overlapping toxicities.
- Some patient factors affect the risk of particular adverse drug effects. For example, patients with higher CD4 cell counts at the time that nevirapine is initiated have a greater risk of hepatotoxicity (specifically, women with CD4 counts of >250 cells/µL or men with CD4 counts of >400 cells/µL), and patients with the HLA-B*5701 allele have higher rates of abacavir HSR. In patients with these risk factors, these drugs should be avoided.
- It is important to consider the possibility that non-ARV medications in the patient's regimen could be causing the adverse effects. This could include medications given as prophylaxis (or treatment) for opportunistic infections (e.g., TMP-SMX), or medications to treat other comorbidities. Even with patients who have been on other non-ARV medications for months or years, initiation of a new ARV regimen (e.g., one with potent hepatic CYP 450 inhibition or induction effects) may alter serum levels of these other medications (see chapter Drug-Drug Interactions with HIV-Related Medications). For example, an increase in anxiety symptoms after starting a new ARV regimen could be attributable to altered drug concentrations of a chronic antidepressant or antianxiety medicine caused by an ARV, not to the new ARV medications themselves.
- The threshold for stopping a medication depends in part on the availability of alternative agents for the individual patient. Some patients have limited alternatives because their virus is resistant to other ARVs or because they have not tolerated certain ARVs in the past. For patients who develop significant adverse effects when starting their first ARV regimen, consider substituting alternative ARV medications (chosen with efficacy considerations in mind) that are better tolerated as early as possible to prevent nonadherence arising from a desire to avoid the adverse effects. For these situations, single-drug substitutions often improve tolerance and make it more likely that long-term viral suppression will be achieved.
- Some patients may refuse to attempt symptomatic treatment or to make substitutions in the ARV regimen. Although treatment interruptions generally should be avoided, in certain situations it may be best to discontinue all ARVs and return to an adherence-readiness assessment (see chapter Adherence) to determine when to restart ART and what medications to restart (see chapter Antiretroviral Therapy).
Gathering Additional Subjective and Objective Information
For the patient who reported nausea, fatigue, and rash 3 weeks after starting nevirapine and ZDV/3TC (Combivir) (see above), additional history, physical examination, and laboratory work yielded the following information:
- Nausea: This has been present since she started ART 3 weeks ago. She has had difficulty taking the ARVs with food, because of nausea. No actual vomiting or other abdominal pain has occurred. She has not tried any remedies. The nausea is not worsening and perhaps has improved slightly over the past few days.
- Fatigue: This has been present since she started ARVs 3 weeks ago. She is able to exercise and perform normal daily activities.
- Vital signs: Normal, with no fever or signs of hemodynamic changes.
- Skin: Skin and conjunctival pallor is noted, along with mild-to-moderate maculopapular rash on the trunk, back, and extremities. These are associated with slight itching, but no pain. No mucous membrane involvement is noted. The rash has been present for 6 days, with slight improvement over the past day.
- Abdomen: Nontender, with normal liver size.
- Complete blood count: Normal, except for a slight increase in mean corpuscular volume (MCV), probably from ZDV therapy and not indicating macrocytic anemia.
- LFTs: Normal.
- Pretreatment laboratory results: CD4 count of 190 cells/µL, HLA-B*5701 negative.
Assessing Availability of Alternative Regimens
A clarified ARV history yielded the following information. The patient took ZDV for 5 months during another pregnancy a few years ago, and she recalls similar feelings of nausea and fatigue that caused her distress at the time. She was able to continue ZDV through the end of her pregnancy. She has taken several ritonavir-boosted protease inhibitors briefly in the past; she did not tolerate these and subsequently has refused treatment with protease inhibitors. The resistance test done prior to initiation of ART shows no significant ARV resistance. She has no comorbidities. The patient has a number of treatment options, but these may be limited by tolerance issues (e.g., protease inhibitor intolerance).
The patient's symptoms are mild and are most likely related to starting ARV therapy, although pregnance also can have associated nausea and fatigue. The laboratory evaluation does not reveal significant abnormalities (e.g., anemia, transaminitis). In particular, the symptoms, signs, and laboratory work are not consistent with HSR, hepatotoxicity, or other serious adverse effects. Thus, no additional workup is needed at this time. Careful monitoring is important because, if symptoms do not improve over the next few days, the patient should have a more extensive workup for other possible causes of the symptoms. If other causes of her symptoms are ruled out and she is unable to tolerate supportive care, alternative ARV medications (e.g., tenofovir, abacavir, an integrase inhibitor, or perhaps an unboosted protease inhibitor) could be substituted for medications in her current regimen, keeping in mind the need to maintain efficacy of the overall regimen and the recommendations for ART in pregnancy (see chapter Reducing Maternal-Infant HIV Transmission).
A suggested treatment plan for the mild adverse effects exhibited by the patient described above is as follows:
Fatigue is a common adverse effect among patients who are starting ART. It is usually self-limited, and, with reassurance that symptoms should improve over a few weeks, most patients are able to continue their regimens without any changes. If fatigue does not resolve within the first weeks of treatment, it is important to rule out other causes of fatigue, including depression. For ZDV-containing regimens, clinicians should rule out ZDV-induced anemia, especially when patients are taking other medications that can cause bone marrow toxicity (e.g., TMP-SMX). Some patients experience fatigue from ZDV even without anemia. If fatigue persists for several weeks or becomes debilitating, and other causes are ruled out, consider replacing ZDV in this regimen. Patients taking regimens containing efavirenz also may complain of fatigue. With efavirenz, the fatigue often is related to sleep disturbances and other central nervous system (CNS) effects of this medication. Efavirenz-related CNS adverse effects, including fatigue, are likely to resolve over a period of days to weeks. Toxicities can be minimized by ensuring that patients take efavirenz on an empty stomach (1 hour before or 2 hours after eating). (See chapter Fatigue.)
Nausea is another common adverse effect described by patients starting a new ARV regimen. As with fatigue, it usually is self-limited, and patients without other systemic symptoms, acute hepatitis, HSR, or pancreatitis usually can continue their regimens. Supportive care often helps patients to continue their regimens. For example, patients should take their medications with food, unless contraindicated for the ARV. Small, frequent snacks may be helpful for patients with significant nausea. Clinical trials have suggested that ginger extract may relieve nausea symptoms. Patients can take ginger (available in a variety of forms, including ginger ale, tea, cookies, and candies) or antiemetics.
Among the medications that the patient described above is taking, ZDV is the most likely culprit to cause persistent nausea. If nausea symptoms continue for several weeks despite taking the ARVs with food, using ginger, or taking other antiemetics, and if other underlying causes are ruled out, consider replacing ZDV in this regimen. (See chapter Nausea and Vomiting.)
Rash is a common adverse effect of certain ARVs and many other medications. It may present with a wide range of severity, as follows:
- Mild rash with no other related symptoms, resolving over the course of days or weeks
- Moderate rash, may be accompanied by systemic symptoms (e.g., fever, liver function abnormalities, myalgias)
- Life-threatening rashes (e.g., Stevens-Johnson syndrome, toxic epidermal necrolysis) associated with pain, mucous membrane involvement, fever, liver function changes, and myalgias
If a patient is taking two or more medications that have rash as a possible adverse effect, it may be difficult to determine which medicine is the most likely cause of the rash. In the case of the patient described above, the rash most likely is related to one of two medications. Her rash currently is mild, but drug rash can range from mild to severe and life-threatening (including Stevens-Johnson syndrome).
- Mild nevirapine rash: usually a self-limited reaction that can be treated symptomatically
- Moderate to severe nevirapine rash, with or without hepatitis: requires discontinuation of nevirapine
- TMP-SMX reaction: may be mild or severe, and onset may be delayed
- Other reactions: can be caused by other medications, by immune reconstitution inflammatory effects, contact dermatitis, folliculitis, and other causes
If the clinician discontinues all of the suspect medications and the rash resolves, the patient will be relieved, but the clinician will not be able to determine which medication caused the rash. In cases of mild rash, it is reasonable to try to identify the offending agent by discontinuing one medication at a time (a substitution should be made for a discontinued ARV, to maintain regimen potency). This situation would require careful clinical judgment or consultation with an expert regarding the advantages or disadvantages of discontinuing each of the suspect medications.
Other Adverse Reactions
Patients may describe any number of adverse effects after starting new medications. Although some adverse effects are caused directly by the medications themselves, some symptoms may occur simply in the process of starting ART. The start of ART may precipitate a significant psychological shift in a patient's perception of self, in living with HIV infection, and in daily routine. In particular, patients who have kept their HIV infection distant from their "everyday" lives may notice significant psychological changes as they take medications every day, go to the pharmacy to pick up medications, and make frequent visits to the clinic for evaluation and laboratory work. Some patients become depressed upon realizing that the severity of their illness now requires them to be on treatment. These psychological adjustments can cause significant symptoms that should be assessed and managed in a manner similar to the way in which pharmacologic adverse reactions are managed.
These psychological effects can be considered "process" effects from starting ART rather than adverse effects of the ARV medications themselves. As with the self-limited adverse effects of early-stage ARV therapy, process effects should become more tolerable over time as the medication regimen becomes routine for the patient. One of the most common process effects is fatigue. Many patients hope that their ARV regimen will give them increased energy and health, and they become frustrated when they notice increasing fatigue after starting the regimen. These patients must be evaluated to rule out common adverse effects that contribute to fatigue (e.g., anemia, hepatitis, lactic acidosis). Equally important, especially for patients beginning a new regimen, symptoms of fatigue could indicate depression or signal that the "process" of taking medications is emotionally difficult. Counseling, peer support, and antidepressant medications can be used to treat this type of fatigue. Often, once patients realize that some of the goals of treatment are being achieved (e.g., the CD4 cell count increases, the HIV viral load becomes undetectable, or symptoms of HIV infection resolve), they recognize the benefits of ARV medications, and their fatigue or other adverse symptoms associated with the process of starting the regimen may lessen.
This discussion has focused on the adverse reactions to ARV medications that patients are most likely to describe as they start a new regimen. Patients and providers also need to consider counseling about and management of long-term toxicities such as lipodystrophy, renal dysfunction, peripheral neuropathy, cardiac disease, diabetes, and dyslipidemia. As these long-term toxicities continue to challenge providers and patients alike, clinical trials and expert guidelines will provide support and information.
Clinicians are encouraged to report adverse reactions to medications to the U.S. Food and Drug Administration (FDA) MedWatch program by telephone at 800-FDA-1088, via fax at 800-FDA-0178, via the Internet at www.fda.gov/Safety/MedWatch/HowToReport/, or by mail at MedWatch HF-2, FDA, 5600 Fishers Lane, Rockville, MD 20857.
- All medications have potential to cause adverse reactions, which are defined as negative, unintended effects of medication use.
- Advise patients to report any adverse reaction to their medical care provider as soon as possible.
- Before starting a new medication, medical care providers or pharmacists should counsel patients about the most common adverse effects and about any remedies that are available to minimize the severity of those effects.
- Advise patients to talk to their provider or pharmacist before starting any new medications (including over-the-counter medications and herbs) because some drugs may interact with ARVs or other medications and can increase side effects or cause unwanted reactions.
- Nausea is one of the most common adverse effects. Counsel patients that nausea can be minimized by taking medications with food (if indicated, as some medications should be taken on an empty stomach) or by using ginger-based food or beverages (e.g., ginger ale, tea, cookies). If these measures do not work, patients should talk with their medical care provider; they may need medications to treat the symptoms.
- Counsel patients that they should not stop taking any medications unless instructed to do so by their medical care provider.
- Calmy A, Hirschel B, Cooper DA, et al. A new era of antiretroviral drug toxicity. Antivir Ther. 2009;14(2):165-79.
- Ickovics JR, Cameron A, Zackin R, et al. Consequences and determinants of adherence to antiretroviral medication: results from Adult AIDS Clinical Trials Group protocol 370. Antivir Ther. 2002 Sep;7(3):185-93.
- Montessori V, Press N, Harris M, et al. Adverse effects of antiretroviral therapy for HIV infection. CMAJ. 2004 Jan 20;170(2):229-38.
- Panel on Antiretroviral Guidelines for Adults and Adolescents. Table 13: Antiretroviral Therapy-Associated Common and/or Severe Adverse Effects. In: Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. Department of Health and Human Services. Accessed December 1, 2013
- Roca B. Adverse drug reactions to antiretroviral medication. Front Biosci. 2009 Jan;14:1785-92.