Clinical Manual for Management of the HIV-Infected Adult
2006 Edition

Section 4: Complications of Antiretroviral Therapy

Adverse Reactions to HIV Medications

Background

Clinicians and patients face many challenges associated with antiretroviral (ARV) therapy. These include decisions about when to start therapy, what regimen to start with, when to change medications, and how to switch if a regimen is failing. Although clinical research should guide the selection of ARV regimens, it is important to remember that the best regimen for any individual patient is the regimen he or she 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 ARV therapy is one of the most important predictors of treatment efficacy. Although many factors may interfere with adherence to ARV therapy, adverse reactions to the medications are among the most important. In one trial, patients with adverse events were 13 times less likely than those without adverse events to have 95-100% 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 regimens, and the patient's history of medication intolerance. In addition, the patient's report of severity can be inconsistent with the clinical interpretation (ie, some patients may overemphasize symptoms, whereas others underemphasize symptoms), and this must be considered when determining the management of adverse reactions.

This chapter reviews some of the most common adverse effects noted as patients start an ARV regimen and suggests strategies for the management of adverse effects. 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 5 of this manual. For information on common adverse reactions to ARV agents and to medications used to prevent and treat opportunistic infections, see Section 10 of this manual. Consultation with an HIV expert also can help in determining the best management when symptoms may have multiple and overlapping causes. Finally, in each case of suspected medication adverse effects, the patient should be evaluated for other possible causes of his or her symptoms.

S: Subjective

A patient presents 2 weeks after starting her new ARV regimen complaining of fatigue, nausea, and rash. Her current ARV medications include a combination of zidovudine (ZDV), lamivudine (3TC), and abacavir (ABC) (ie, Trizivir)-and nevirapine (NVP). She has continued her prophylactic medications, which include trimethoprim-sulfamethoxazole (TMP-SMX) and fluconazole. 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.

O: Objective

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), acute hepatitis, or immune reconstitution syndrome related to starting ARV medications. See chapter Fever for a more complete discussion about fever workup and considerations. Tachycardia or hypotension may suggest anemia, HSR, dehydration, 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: Complete blood count is important when monitoring drugs that may cause bone marrow toxicity (eg, anemia, neutropenia). Perform a complete metabolic panel including electrolytes and liver function tests (LFTs). If the history suggests pancreatitis, evaluate amylase or lipase.
• Other studies: Perform as indicated by symptoms and examination (eg, chest x-ray if respiratory symptoms are present).

A: Assessment

Step 1: Clarify reports of adverse reactions by requesting the following information for each symptom the patient describes:

• Characterize the symptoms by asking about severity, onset, and frequency. It is also helpful to have the patient describe whether the symptom(s) have been improving or worsening over time.
• Ask whether the patient has tried any remedies to alleviate the symptom(s) and whether they were helpful.
• Explore how the patient is currently taking the regimen. Open-ended questions such as: "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 (eg, taking higher dosages than recommended) can lead to adverse effects and is often overlooked by providers.

Step 2: Assess the severity of the reaction against the need to continue the current regimen. An understanding about the relative availability of alternative ARV regimens is important in this assessment.

• 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 for gastrointestinal symptoms (eg, nausea, vomiting, bloating). Supportive care for gastrointestinal adverse effects includes reminding the patient to take medications with food (if appropriate), suggesting the use of ginger-containing beverages or foods to relieve symptoms (see "Nausea" below), and prescribing antiemetics 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, LFT abnormalities, or severe systemic symptoms. Determining which of the medications is causing the reaction is often challenging, because patients are commonly taking several medications with overlapping toxicities.
• The threshold for stopping a medication depends in part on the availability of alternative agents for any given patient. Some patients have limited alternatives because their virus is resistant to other ARV agents (eg, patients on salvage ARV regimens). For other patients, alternatives are limited by past adverse effects. For patients who develop significant adverse effects when starting their first ARV regimen, substituting alternative ARV medications that are better tolerated should be considered as early as possible during therapy to avoid nonadherence due to adverse effects. For these situations, single-drug substitutions often improve tolerance and achieve long-term viral suppression.
• Some patients may refuse to attempt supportive care and refuse to continue treatment. In these situations, it may be best to discontinue all ARV medications and return to an adherence-readiness assessment (see chapter Adherence) to determine when to restart medications and what medications to restart (see chapter Antiretroviral Therapy).

Clarified Subjective and Objective Information

For the patient who reported nausea, fatigue, and rash 2 weeks after starting ZDV/3TC/ABC (Trizivir) and NVP (see above), additional history, physical examination, and laboratory work yielded the following information:

• Nausea: This was present since she started ARVs 2 weeks ago. She has had difficulty taking medications 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 was present since she started ARVs 2 weeks ago. She is able to exercise and perform normal daily activities.
• Vital signs: Normal; 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 4 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.

Availability of Alternative Regimens

A clarified ARV history yielded the following information. The patient took ZDV alone for 3 months a few years ago, during one of her pregnancies, and 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. Otherwise, the patient is ARV naive and has many treatment options.

Assessment and Conclusion

The patient's symptoms are mild and are most likely related to starting ARV therapy. 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 various symptoms. If other causes of her symptoms are ruled out and she is unable to tolerate supportive care, alternative ARV medications (eg, didanosine, tenofovir, protease inhibitors) can be substituted for medications in her current regimen. Given her ARV history, substitutions are likely to be effective.

P: Plan

Following is a suggested treatment plan for the mild adverse effects exhibited by the patient described above:

Fatigue

Fatigue is a common adverse effect among patients who are starting ARV therapy. 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, practitioners should rule out ZDV-induced anemia, especially when patients are also taking other medications that can cause bone marrow toxicity (eg, 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. (See also chapter Fatigue.)

Nausea

Nausea is another common adverse effect described by patients starting a new ARV regimen. Like fatigue, it is usually self-limited, and patients without other systemic symptoms, acute hepatitis, or pancreatitis usually can continue their regimens. Supportive care is often helpful, however, in allowing patients to continue their ARVs. For example, patients should take their medications with food. Small, frequent snacks may be helpful for patients with significant nausea that prevents substantial meals. Clinical trials have suggested that ginger extract may relieve nausea symptoms. Patients can take ginger in a variety of forms, including ginger ale, tea, cookies, and candies. Among the medications that the current patient is taking, ZDV is the most likely culprit to cause persistent nausea. If nausea symptoms persist for several weeks despite taking medications with food, using ginger, or taking other antiemetics, and if other underlying causes are ruled out, consider replacing ZDV in this regimen. (See also chapter Nausea and Vomiting.)

Rash

Rash is a common adverse effect of certain ARVs and many other medications. It may present with a wide range of severity:

• Mild rash occurs with no other related symptoms and resolves over days or weeks.
• Moderate rash may be accompanied by systemic symptoms (eg, fever, LFT abnormalities, myalgias).
• Life-threatening rashes (eg, Stevens-Johnson syndrome) associated with pain, mucous membrane involvement, fever, LFT changes, and myalgias.

If a patient is taking 2 or more medications that have rash as a possible adverse effect, it may be difficult to determine which of the medicines is the most likely cause of the rash. In the case of the patient described above, rash may be related to the following:

• Mild ABC rash: Usually a self-limited reaction that can be treated symptomatically
• Moderate to severe ABC HSR: Resolution of symptoms requires discontinuation of ABC, but repeat challenge can be life threatening (see below for more details)
• Mild NVP rash: Usually a self-limited reaction that can be treated symptomatically
• Moderate to severe NVP rash accompanied by hepatitis: Requires discontinuation of NVP
• Mild TMP-SMX reaction: Either delayed or part of an immune reconstitution reaction
• Other reactions: Can be caused by other medications, contact dermatitis, folliculitis, immune reactivation or reconstitution effect 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 medication by discontinuing 1 medication at a time (generally, a substitution should be made for the discontinued ARV). This situation would require careful clinical judgment or consultation with an expert regarding the advantages or disadvantages of discontinuing each of the suspect medications.

Abacavir hypersensitivity reactions

Abacavir hypersensitivity reactions are a common cause of rash. The initial symptoms of possible ABC HSR are not life threatening, and it is important to try to distinguish true ABC HSR from isolated rash (without other hypersensitivity symptoms), self-limited adverse medication effects, or other illness (eg, influenza). This is often best accomplished by asking a patient who complains of mild gastrointestinal symptoms with or without rash to continue taking all medications while being monitored closely. Careful assessment of symptoms for a few days should clarify whether symptoms are lessening (indicating self-limited effects) or worsening (suggesting ABC HSR). The pattern of symptom onset is also helpful. For patients with ABC HSR, symptoms usually begin after 10 days of therapy and worsen approximately 30-60 minutes after each ABC dose administration. When ABC is discontinued because of suspected HSR, patients should never be rechallenged. Initial flulike symptoms are uncomfortable for patients, but not life threatening. If, however, ABC is discontinued when HSR symptoms are present and is then restarted, life-threatening HSRs may occur.

Clinicians should report ABC HSRs to the following agencies:

• Abacavir Hypersensitivity Reaction Registry at Glaxo Wellcome at 1-800-270-0425
• FDA MedWatch program by telephone at 800-FDA-1088, via fax at 800-FDA-0178, via the Internet at http://www.fda.gov/medwatch/report/hcp.htm, or by mail at MedWatch HF-2, FDA, 5600 Fishers Lane, Rockville, MD 20857

Other Adverse Reactions

Patients may describe any number of adverse effects after starting new medications. Although some adverse effects are directly caused by the medications themselves, some symptoms may occur simply in the process of starting ARVs. The start of ARV therapy 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 internal 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 changes can cause significant symptoms that should be assessed and managed similarly to the pharmacologic adverse reactions.

These psychological effects can be considered "process" effects from starting ARVs, rather than adverse effects of the medications themselves. As with the self-limited adverse effects of early 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 (eg, 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 some of the goals of treatment (eg, the CD4 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.

Clinicians are encouraged to report adverse reactions to medications to the FDA MedWatch program by telephone at 800-FDA-1088, via fax at 800-FDA-0178, via the Internet at http://www.fda.gov/medwatch/report/hcp.htm, or by mail at MedWatch HF-2, FDA, 5600 Fishers Lane, Rockville, MD 20857.

Patient Education

• All medications have potential to cause adverse reactions, which are defined as negative, unintended effects of medication use.
• Patients should be advised to report any adverse reaction to their medical care provider as soon as possible.
• Before starting a new medication, patients should be counseled by their medical care provider or pharmacist about the most common adverse effects and about any remedies available to minimize the severity of those effects.
• Nausea is one of the most common adverse effects. Nausea can be minimized by taking medications with food (if indicated, some medications should be taken on an empty stomach) or using ginger-based food or beverages (eg, 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.
• Patients should not stop taking any medications unless instructed to do so by their medical care provider.

References

• 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.
• U.S. Department of Health and Human Services. Table 17a: Potentially Life-Threatening and Serious Adverse Events. In: Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. May 4, 2006. Available online at aidsinfo.nih.gov/Guidelines/GuidelineDetail.aspx?GuidelineID=7.
• U.S. Department of Health and Human Services. Table 17c: Adverse Effects Compromising Quality of Life and/or with Potential Impact on Medication Adherence. In: Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. May 4, 2006. Available online at aidsinfo.nih.gov/Guidelines/GuidelineDetail.aspx?GuidelineID=7.
• U.S. Department of Health and Human Services. Table 19: Adverse Drug Reactions and Related "Black Box Warnings" in Product Labeling for Antiretroviral Agents. In: Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. May 4, 2006. Available online at aidsinfo.nih.gov/Guidelines/GuidelineDetail.aspx?GuidelineID=7.