Effective symptom management is a critical skill for all HIV clinicians. Prior to the time when effective antiretroviral therapy became widely available in the developed world, symptom management focused on the palliation of irreversible complications of immune dysfunction. With current combination antiretroviral therapy, symptom management is more likely to address antiviral adverse effects, symptoms due to comorbid diseases (eg, hepatitis C and depression), and poorly understood complications of long-standing HIV disease (peripheral neuropathy, avascular necrosis, fatigue, and hypogonadism).
Thus, in an era of improved survival, the focus of symptom management has shifted to palliation of chronic symptoms, be they due to the disease itself, induced by medications, or secondary to associated conditions. Uncontrolled symptoms can result in poor adherence to medications, diminished quality of life, patient demoralization, and increased disease complications.(1-4)
Clinicians should inquire about symptoms at each visit. A standard three-question interview can effectively screen for new or persistent problems:
How are you doing with your adherence? (Patients may skip doses to avoid adverse effects.)
Are you having any adverse effects from your medications? (Patients may incorrectly or correctly ascribe a symptom to their medication; in either case the symptom should be addressed; see Case Example.)
How are you doing in general? (Patients may report specific symptoms, life stressors, substance use problems, or illness anxiety, all of which can compromise adherence.)
While some symptoms have straightforward explanations (eg, indinavir has been associated with the development of kidney stones), other symptoms remain poorly understood. These include minor cognitive dysfunction (which can persist or develop de novo in patients with chronic HIV suppression and immune reconstitution), peripheral nerve and spinal cord dysfunction, chronic pain (which is idiopathic in >10% of HIV patients with chronic pain), and insomnia. While CD4 and viral load markers predict opportunistic illness risk and HIV-related survival, they are not reliable markers for these poorly understood symptomatic complications.
Patients need to be encouraged to report symptoms and to be assured that their symptoms will thoroughly addressed, even if the etiology of the symptoms is not diagnosable.
The functional impact of symptoms must be assessed in order to gauge their significance. For example, many clinicians assume that the severity of diarrhea is best reflected by stool frequency or volume. For patients with diarrhea associated with protease inhibitors (PIs), urgency (and its feared consequence, fecal incontinence) determines whether the patient skips meals or PI doses, becomes homebound, or limits social activities. Similarly, a patient might have extensive sensory impairment on neurological exam but minimal balance or pain problems while another patient with neuropathy limited to the distal toes might be unable to stand or sleep because of "mild" peripheral neuropathy. Hence, when patients report symptoms, they should be asked how the specific symptom bothers them and whether it is interfering with any significant number of activities.
This chapter is a syndrome-based guide to the palliation of the more common symptoms experienced by people with HIV disease. In general, these symptoms are best palliated when a specific etiology is identified. For example, fatigue secondary to hypogonadism is readily reversed with androgen supplementation, and only partly compensated with stimulants. Conversely, many patients, particularly those with advanced AIDS, benefit from symptom relief even in the absence of a specific diagnosis. For example, terminal patients with intractable fatigue/concentration problems may benefit from stimulants.
Thus, although symptoms are best managed by identifying and successfully treating an underlying cause, often this is not possible, especially in patients with advanced HIV disease. This chapter presents an outline for management of selected common symptoms when an underlying cause is not known or cannot be treated, or when its treatment does not resolve the symptoms. The chapter is not meant to be a guide to diagnostic evaluation of underlying causes. Thus, the differential diagnoses and diagnostic suggestions are purposely simplified and not exhaustive.
Because symptom assessment requires global and integrated patient assessment, these interventions are best formulated and monitored by a primary care practitioner.
It is crucial to acknowledge the very wide and gray line between active, "aggressive," life-prolonging treatment and "palliative" care.(5) Some palliative treatments are technologically intensive and/or costly, eg, radiotherapy for debulking Kaposi syndrome (KS), and some disease palliation, eg, intravenous ganciclovir for cytomegalovirus retinitis, may be life prolonging. The compass that best guides the clinician is "what best serves the patient" in maintaining their comfort and dignity. With disease progression, some symptoms may be best left untreated, with nonintervention being the best care approach.
| Case Example|
Jason, a 37-year-old white gay man, is having his first follow-up visit 3 months after starting nevirapine (Viramune), lamivudine, and stavudine. When asked, "How are you doing?" he says, "Fine." When asked about his adherence, he reports "missing less than 1 dose a month." When asked about antiviral side effects, he reports having "diarrhea from the Viramune."
When informed that Viramune doesn't cause diarrhea, he says, "A bunch of my friends on Viramune have diarrhea." Upon further inquiry, it turns out his friends are taking Viracept (nelfinavir), not Viramune. Stool studies are done and the Giardia antigen test is positive.
In this case, the patient misattributed a medical comorbidity (giardiasis) to a treatment side effect, partly because of mixing up medication names. However, had he not been asked about side effects, this symptom would not have been addressed.
Fatigue in HIV disease is often multifactorial.(6-7) Insomnia, chronic pain, medication side effects, anemia, hypogonadism,(8) and depression (9-11) can all contribute to fatigue. Additionally, some patients without these conditions may have idiopathic HIV fatigue.
1 for common diagnoses associated with fatigue.
| Idiopathic HIV Fatigue|
Idiopathic HIV fatigue is characterized by day-to-day variability and is not present on awakening (as is the case with depression). A patient with idiopathic HIV fatigue will wake refreshed and alert, only to become exhausted from performing a minor task (eg, preparing a meal). Idiopathic HIV fatigue is a diagnosis of exclusion, and there are no objective studies to rule it in or out. In addition to affecting quality of life, idiopathic HIV fatigue is usually disabling: patients with extremely unpredictable energy reserves may be unable to handle job commutes, standard work hours, or work deadlines. In addition to considering measures addressed in Table
1, clinicians must carefully document functionally significant HIV fatigue as a symptom that may be in itself disabling. Research in both HIV patients and non-HIV patients has demonstrated that standard stimulants such as methylphenidate (Ritalin) and dextroamphetamine (Dexedrine) may be useful on both a daily and an as-needed basis.(12) Newer stimulant preparations, developed for the treatment of attention deficit hyperactivity disorder, may allow for smoother onset of action and once-daily dosing. Stimulants are contraindicated in patients with a history of stimulant abuse; they can be used in patients with stable cardiovascular disease and in the elderly.
Depression can cause fatigue through multiple somatic variables: insomnia (early awakening), anhedonia, lack of motivation, escalated anxiety, pain amplification, and slowed cognitive processing. Depression is highly correlated with past or current substance use, a family history of mood disorder, chronic pain, and a history of childhood abuse.
Depression may be difficult to diagnose in HIV patients, as there is a substantial overlap in the somatic symptoms of depression and HIV disease itself (eg, fatigue, insomnia, pain, decreased libido, impaired concentration). In addition, the mood or affective symptoms of depression (hopelessness, lowered self-esteem) can appear as a normative reaction ("adjustment disorder") to the stressor of living with HIV disease. Psychiatric experts concede that there is no reliable way to accurately distinguish somatic symptoms secondary to depression (such as fatigue) from somatic symptoms due to HIV. Instead, medically ill patients with multiple depressive symptoms should receive a trial of psychotherapy, antidepressants, or both.
Studies in patients with HIV disease have demonstrated that standard antidepressants are safe and effective in HIV patients and that depression is a known risk factor for HIV medication adherence problems.(3)
2 lists pros and cons of antidepressants in the setting of HIV disease.
Hypogonadism (low testosterone) can affect men and women with HIV disease. It is more prevalent in patients with low nadir CD4 counts and persists after immune reconstitution and virologic control. Formal studies of the hypothalamic-pituitary axis have not determined the cause of this endocrine disorder. As with depression, there is a substantial overlap between the symptoms of hypogonadism and HIV disease (anemia, low libido, weight loss, concentration impairment, depressed mood).
One approach to the screening of hypogonadism is to obtain a baseline of free/total testosterone concentration in every HIV patient: if the patient later develops a symptom of hypogonadism, the testosterone concentration can be remeasured. Another approach is to screen for hypogonadism only if a symptom occurs, recognizing the broad range of symptoms (weight loss, depressed mood, cognitive impairment, fatigue) that suggest an evaluation for hypogonadism.
Another obstacle in the diagnosis of hypogonadism is the need to interpret testosterone concentrations in context. For example, most labs list the normal range of total testosterone in men to be between 350 and 1,100. However, this average includes a misleadingly wide range of "normal values" for testosterone levels in men. A level of 400 is typical for an 80-year-old man but low for a 30-year-old man. In addition, like most chronic inflammatory states, HIV disease causes elevations in testosterone binding proteins, in turn resulting in lower concentrations of free (unbound, biologically active) testosterone. Thus, for the most accurate assessment, free testosterone levels should be paired with total testosterone levels.
To date, the only complications of replacement doses of testosterone in HIV patients have been reversible: polycythemia, inflammatory acne, and in rare cases, irritability. In all patients, testosterone can cause modest reductions of high-density lipoprotein, can exacerbate benign prostatic hypertrophy, and potentially can accelerate pre-existing prostate cancer. (Male patients over 40 years of age who receive testosterone should have baseline prostate-specific antigen measurement and rectal examination, with repeat studies every 6-12 months.)
Women require much lower doses of testosterone replacement. The only commercially available preparation in these smaller doses is Estratest, a coformulation of estrogen and methyltestosterone developed for perimenopausal women. However, compounding pharmacies (eg, Women's International Pharmacy, tel: +1 623 214 7700) can prepare topical testosterone preparations in doses appropriate for women. Parenthetically, women with normal testosterone levels who have wasting can be treated with full dose (10 mg 2 times per day) oxandrolone, as it is a pure anabolic with no androgenic (ie, virulizing) side effects.
Formal sleep studies have shown that HIV disease is associated with sleep disorders, even in the absence of other factors such as depression, pain, and medication side effects.(13) Typically patients have impairment in both sleep duration (quantity) and sleep architecture (quality). Standard insomnia assessment and treatment protocols are relevant in HIV fatigue with the addition of several HIV-specific questions:
Have you been diagnosed as bipolar or as having a chronic anxiety or depression disorder?
Are you waking up due to specific symptoms? (eg, neuropathy pain, diarrhea, need to urinate)
Has your sleep partner noticed new snoring or erratic breathing? (Neck fat hypertrophy may cause new-onset sleep apnea.)
Does your sleep problem correlate with taking efavirenz (Sustiva)?
If standard sleep hygiene interventions are ineffective, medication is appropriate on an as-needed and, sometimes, nightly basis. Low-dose tricyclics (10-50 mg) are optimal for patients with chronic neuropathy pain and insomnia; benzodiazepines such as temazepam (Restoril), zolpidem (Ambien), and zaleplon (Sonata) are useful in anxious patients whose insomnia does not respond to psychotherapy or selective serotonin reputake inhibitors (SSRIs). In patients with severe, refractory insomnia or in those with organic brain disease, low to medium doses of atypical antipsychotics, eg, quetiapine (Seroquel), olanzapine (Zyprexa), and risperidone (Risperdal), often work well, and with a much better side-effect profile than older antipsychotics such as haloperidol (Haldol) and chlorpromazine (Thorazine).(13)
Analysis of data from newer studies of efavirenz has not clarified whether it causes chronic sleep disturbances, or whether sleep problems beginning months after initiation can be accurately attributed to efavirenz.(14) Many patients will have frank insomnia or nonrestful sleep for the first 2 weeks of therapy. This can be palliated with lorazepam (Ativan) at bedtime or with low-dose atypical antipsychotics (the latter being a better choice in patients with substance abuse problems). For patients with persistent sleep symptoms, a short "switch study" from efavirenz to another antiviral can help determine whether efavirenz was the cause of insomnia.
| Chronic Pain|
Like fatigue, chronic pain in HIV patients is typically underdiagnosed and undertreated.(15) This is due in part to clinicians expecting chronic pain to manifest in a manner similar to acute pain. Patients with chronic pain do not have symptoms commonly associated with pain (eg, their pulse and blood pressure are normal; they are not agitated; and they do not have an acute injury to demonstrate they are in pain). Furthermore, the specific etiology of chronic pain may be difficult to pin down, even for pain specialists. In one study performed by pain specialists at a leading academic center, 10% of HIV patients determined to have chronic pain had no specific etiology after thorough clinical evaluation.(16,17,18)
Current models of chronic pain suggest that chronic pain is generated by disregulation of afferent and efferent pain fibers in both the central (brain, spinal cord) and peripheral nerve systems. Chronic pain is best assessed by patient interview, ideally complemented by a nonverbal assessment tool such as a visual analogue scale (VAS). The VAS can be useful for documenting baseline symptoms as well as responses to therapy.
All HIV clinicians should be familiar with chronic pain assessment and treatment or have access to specialty colleagues for pain treatment. Prototypical pain algorithms like the World Health Organization pain guidelines can be readily applied to HIV patients, with a few caveats:
- Many analgesics, anticonvulsants, and psychiatric drugs may have drug interactions with non-nucleoside reverse transcriptase inhibitors and protease inhibitors. Clinically, only ritonavir (Norvir) and delavirdine (Rescriptor) are likely to cause meaningful interactions with these drugs. Extensive clinical experience, especially with ritonavir, has shown that CVP3A4-metabolized drugs such as methadone often need no dose adjustment. Additionally:
Patients with hepatic impairment due to hepatitis B or C should limit Tylenol intake to 1-2 grams/day. Tylenol #3 (acetaminophen/codeine) may be changed to pure codeine; Percocet (acetaminophen/oxycodone) may be changed to pure oxycodone.
Inflammatory pain responds best to nonsteroidal anti-inflammatory drugs (NSAIDs) and aspirin-based medications; neuropathic pain responds most predictably to tricyclics and anticonvulsants.
Chronic narcotics are appropriate and effective treatments for chronic pain that does not respond to other analgesics, anticonvulsants, or physical modalities.
The most common causes of chronic pain in HIV patients are postherpetic neuralgia, avascular necrosis (AVN), and distal symmetrical polyneuropathy. Each is discussed separately below.
| Postherpetic Neuralgia|
Postherpetic neuralgia refers to dermatomal pain that persists after an episode of herpes zoster (shingles). Early treatment of herpes zoster may reduce the risk of postherpetic neuralgia.
Postherpetic neuralgia can be palliated with oral medications (tricyclics, anticonvulsants), topical treatments (capsaicin, lidocaine), or physical measures (eg, acupuncture). Tricyclics are best for initial treatment if the pain results in disturbed sleep. Otherwise treatment selection is empiric. Corticosteroids have not been found to prevent postherpetic neuralgia.(19)
| Avascular Necrosis|
Avascular necrosis (AVN) can affect the shoulder, jaw, and hip but is most common in the hip. The pain is localized to the ipsolateral groin/inguinal area (not the lateral hip, the site of soft-tissue hip problems). It is usually reproducible with internal rotation of the hip, sometimes with external rotation or extreme hip flexion. While ordinary X-rays can detect late-stage AVN, magnetic resonance imaging (MRI) is more sensitive in early disease and can give the orthopedist important information for surgical planning.
Surgery for AVN in HIV patients usually results in excellent palliation of pain. Some patients prefer to have surgery early; other patients who have adequate pain control with analgesics may safely defer surgery until their pain control is unacceptable. AVN is often bilateral; its cause in individuals with HIV is unknown. (AVN cases occurred well before the era of antiretroviral therapy; most clinicians believe they are HIV-triggered phenomena, not complications of antiretroviral therapy.)
| Peripheral Neuropathy|
Peripheral neuropathy in HIV patients is usually shorthand for "distal, symmetrical peripheral neuropathy." This is a classic symmetrical "stocking glove" neuropathy, which begins in the feet and travels proximally over time. In HIV patients, it can be caused by:
HIV medications--the dideoxynucleoside analogues (d-drugs), d4T (stavudine/Zerit), ddI (didanosine/Videx), ddC (zalcitabine/Hivid)
HIV disease itself
Comorbid conditions (eg, diabetes, alcoholism, and chronic hepatitis)
Electromyogram (EMG) cannot distinguish these etiologies. Generally, a clinical trial of holding d-drugs for 6-8 weeks is necessary to see if the drug is causative, though neuropathy symptoms that correlate with initiation of a d-drug are likely to be d-drug induced.(20)
HIV patients, irrespective of d-drug exposure, are also at increased risk of compressive neuropathies (eg, carpel tunnel syndrome, peroneal nerve palsy). These compressive syndromes should be managed in standard fashion (eg, nighttime wrist splints for carpel tunnel symptoms).
HIV patients with "peculiar" lower extremity symptoms (cramps, thigh paresthesias) may have HIV-associated myelopathy (spinal cord disease). On exam, upper motor neuron findings (increased tone, hyperflexia) will be seen, often concomitantly with distal peripheral nerve findings (decreased sensation, hyporeflexia). Myelopathy pain can be due to muscle spasm or neuropathic pain. Muscle spasm can be treated with muscle relaxants such as baclofen and diazepam. A newer agent, tizanidine (Zanaflex), is less sedating but more costly than the older agents.
Peripheral neuropathy can cause balance problems (due to impaired proprioception), decreased sensation (numbness), and abnormal painful sensations (dysaethesias). Balance problems may be addressed with occupational therapy and occasionally with supportive devices. Numbness is irreversible; regular foot inspection is important for diagnosing silent infections. Dysaethesias can be sharp and electric ("lancinating") or constant and hot. Dysaethesias are treated with the same medications used to treat neuropathic pain (tricyclic antidepressants--TCAs, anticonvulsants, and analgesics) and with physical measures. Studies in HIV-positive and HIV-negative patients have not shown any treatments to be predictably effective for dysaesthesias.(21) Instead, treatment is largely empiric.
In HIV patients, gabapentin (Neurontin) and lamotrigine (Lamictal) (22) currently are preferred agents, gabapentin because it has no drug interactions with HIV antiretroviral medications, lamotrigine because it appears to be especially effective.(20) Most anticonvulsants must be titrated slowly to avoid side effects, and patients should be at target doses for 4 weeks before efficacy can be assessed. While acupuncture performed in research protocol contexts has not been shown to be beneficial, years of anecdotal experience suggest it may be extremely useful in some patients.
Foot pain is often due to both mechanical factors (metatarsal fat pad thinning, plantar fascitiis) and peripheral neuropathy. Clues to a mechanical component include localized pain on weight-bearing, pain on palpation, and pain localized to the sole, especially under the metatarsal bones. Podiatric assessment is crucial since proper footware, including orthotics, complements analgesic therapy. In refractory cases, an EMG may help distinguish mechanical from peripheral nerve etiologies.
Some pain specialists speculate that antidepressants that elevate more than one class of neurotransmitters, ie, those that are dually active, may be more effective at palliating neuropathic pain than, for example, SSRIs.(23) Examples of dual-acting antidepressants include venlafaxine, mirtazapine, and TCAs.
All analgesics, including narcotics, are potentially useful in treating chronic neuropathic pain.(24) Because narcotics can cause itching, constipation, and sedation, they should be used only if better-tolerated analgesics and other adjunctive treatments (eg, anticonvulsants and TCAs) are ineffective. Many patients will do best with multimodal treatments, eg, round-the-clock narcotics with bedtime TCAs.
Nausea associated with HIV disease is often multifactorial. Frequently, a specific cause or causes of the nausea cannot be identified. Nonetheless, identifying and managing nausea is critical, as untreated nausea can interfere with antiretroviral medication adherence, result in nutritional problems, and decrease quality of life.
Principal elements of nausea assessment in HIV patients include the following:
Gastrointestinal (GI) etiologies of nausea include esophageal, gastric, and intestinal disorders as well as pancreatic and liver disease. In patients at risk for opportunistic illnesses (CD4 lymphocyte count <200 cells/µL), initial evaluation should focus on ruling out opportunistic infections (OIs) in the digestive tract. Patients with higher CD4 lymphocyte counts are at risk for HIV-associated lymphoma. All HIV patients are at risk for non-HIV-associated disorders, eg, NSAID-induced gastritis and esophageal reflux. Esophageal reflux may present as morning nausea. Anecdotally, this is especially common in patients with advanced HIV disease, possibly reflecting HIV-associated autonomic nerve dysfunction. Patients with reflux may respond to metochlopramide, proton-pump inhibitors, and lifestyle modification.
Central nervous system (CNS) etiologies of nausea include HIV-associated CNS OIs and malignancies; however, nausea per se is rarely a clue to otherwise occult CNS disease. Patients at risk for CNS OIs and CNS lymphoma (CD4 lymphocyte count <200 cells/µL) should have neuroimaging (MRI, computerized tomography) if they have refractory unexplained nausea.
Medications can cause nausea by irritating effects on the GI tract or by nonspecific CNS effects. Among antivirals, PIs most frequently cause nausea. Nausea associated with some PIs can be mitigated by reducing pill burden through boosting with low-dose ritonavir. Some formulations of a medication may be better tolerated than others (eg, fosamprenavir vs amprenavir, hard-gel saquinavir vs soft-gel saquinavir). High-dose zidovudine (ie, 200 mg every 4 hours) commonly causes nausea, while current dosages (300 mg 2 times per day) rarely cause nausea after the first 2 to 4 weeks of treatment.
Some patients find that taking food with their antivirals reduces nausea. While some antivirals are best absorbed on an empty stomach, some drug regimens can be modified to allow for concomitant food. For example, didanosine may be taken with food if combined with tenofovir. (Due to a tenofovir/didanosine interaction, the didanosine dose should be reduced from 400 mg daily to 250 mg daily.) Indinavir, when boosted with ritonavir, achieves levels to allow coadministration with food.
Narcotics commonly cause nausea. Of oral narcotics, oxycodone (the narcotic in Percocet and Percodan) tends to cause less nausea than codeine, but requires more frequent dosing. For patients requiring chronic opiate therapy, fentanyl patches allow for reliable narcotic delivery in patients with nausea, and tend to cause less nausea than oral narcotics.
Nausea commonly causes anorexia. Dronabinol (Marinol) has been studied in both HIV and oncology patients, and is particularly useful for patients with both anorexia and nausea. Some patients respond best to round-the-clock (2.5-10 mg 3 times per day) dosing. Other patients do best with bedtime dosing, as some patients become "stoned"/sedated on daytime dronabinol. Inhaled cannabis ("medical marijuana") is associated with quicker, shorter peaks than dronabinol, and is better tolerated by some patients.
The appetite-promoting side effects of some medications may be useful in patients with nausea who do not respond to standard treatments. These include mirtazapine (Remeron), an antidepressant, and olanzapine (Zyprexa), a broad-spectrum neuroleptic/atypical antipsychotic. These two medications also help promote sleep and thus are useful in patients with appetite problems, nausea, and insomnia.
In all HIV patients, infectious causes of diarrhea always should be ruled out; in patients with very advanced disease, HIV enteropathy, or diarrhea associated with HIV itself, should be considered. However, many patients with stabilized HIV disease have chronic episodic diarrhea. In these patients, diarrhea frequently is related to medications (antiretrovirals) or is idiopathic.(25)
Of the antivirals, PIs most commonly cause diarrhea, as well as bloating and nausea.(26) PI-associated diarrhea may respond to altering the protease (switching drugs, boosting, changing formulations), to palliative medications (eg, pancreatic enzymes and antimotility agents), and to dietary modifications (eg, restriction of dairy products, sugar, wheat). While many of these palliative approaches have not been formally studied, clinical experience shows that they are safe. Most patients will need to try several strategies before finding helpful treatments. Some of the palliative strategies do not "make sense." For example, most patients with nelfinavir-associated diarrhea who respond to pancreatic enzymes do NOT have clinically apparent pancreatic dysfunction; some patients who respond to wheat elimination have no evidence of gluten enteropathy or wheat allergy.
Of note, for many patients it is the urgency of their diarrhea, not the volume or frequency of bowel movements, that is most distressing. For patients with limited access to a toilet, job commutes, or inflexible work situations, fecal incontinence can be both a practical problem and a psychological challenge. While formal assessment tools, such as AIDS Clinical Trial Group (ACTG) adverse events methodology, do not factor-in urgency, clinicians should consider urgency in order to best assess the functional impact of their patients' diarrhea.
For patients with sleep disturbance related to diarrhea, narcotics taken at bedtime may decrease diarrhea as well as promote sleep. These narcotics include standard ones such as acetaminophen (Tylenol with codeine), as well as tincture preparations such as tincture of opium. Patients with chronic diarrhea benefit from antidiarrheals taken from 1 to 4 times per day, complemented with fiber and calcium. Antispasmodic medications decrease motility, whereas fiber improves stool consistency. (Metoclopramide does NOT cause diarrhea as it acts only in the duodenum.) Patients with mixed constipation alternating with diarrhea may be treated with daily fiber and as-needed antispasmodics.
While fever in HIV patients may signal an underlying OI or malignancy (lymphoma, visceral KS), it is often due to medications, even in the absence of rash. HIV patients are prone to drug fevers because they have immune dysregulation and they tend to be on multiple medications.
Clues to drug fever include temporal association with drug initiation, fever/pulse discordance (moderate to high fever without tachycardia), and response to withdrawal of the medication. While some medications (eg, penicillins, sulfonamides, phenytoin) are well known to cause drug fever, other commonly used medications are often the unsuspected culprit. These include drugs with sulfa side-arms, such as thiazides, furosemide, and celecoxib (Celebrex).
Two antivirals can cause hypersensitivity reactions: abacavir and nevirapine. Typically, patients present with fever and rash; however, any patient who has been on abacavir or nevirapine for <6 months and has unexplained fever should be monitored closely for emerging hypersensitivity. Hypersensitivity reactions to abacavir and neverapine have not been reported in patients on these medications for >6 months.
Delirium--acute alteration in level of alertness--is a common complication of underlying organic brain disease. Untreated HIV patients with low CD4 lymphocyte counts (<200 cells/µL) can present with HIV dementia as their first symptom of HIV disease. More commonly, patients receiving antiretrovirals and having stabilized CD4 lymphocyte counts may develop more subtle but chronic signs of cognitive impairment. Comorbid conditions such as current or remote alcoholism/substance use, alcohol withdrawal, hepatitis C, malnutrition, and head injuries are additional risk factors for organic brain disease.
While any individual can develop delirium, adults with "bad brains" have a much lower threshold for delirium, be it from substance use, prescribed medications, metabolic disorders, or systemic infections. The following are helpful guides in assessing cognitive symptoms in these patients:
Dementia tends to proceed slowly; any acute change in a demented person's cognitive function should be investigated as a delirium (not ascribed to simple worsening of the dementia).
While HIV-associated CNS infections and tumors can cause delirium in HIV patients with low CD4 lymphocyte counts (<200 cells/µL), they are rare in patients with counts >200 cells/µL, and in patients with counts <200 cells/µL whose HIV viral load is chronically controlled. In this latter group of patients, as in most HIV-negative patients, common causes of delirium include street drugs and prescribed medications.
Delirium per se is dangerous. While the cause of the delirium is being evaluated, patients should be monitored regularly (ideally, in a critical care unit) and be aggressively medicated and reevaluated. Small studies of hospitalized HIV patients have demonstrated that standard doses of typical antipsychotics (eg, haloperidol) are more effective and safe than benzodiazepines. Because newer atypical antipsychotics cause less extrapyramidal and sedation side effects than the typical antipsychotics, they should be used if long-term treatment (eg, for sleep) proves necessary. The underlying cause of the delirium must be sought even if the delirium responds to palliative treatment.
Environmental stabilization is a key component of delirium treatment. Patients should have regular sleep times in a quiet environment, have caregiver continuity, and be calmed and reoriented by staff.
Medications commonly cause delirium. These include over-the-counter medications such as antihistamines (eg, Benadryl), antiemetics, TCAs, narcotics, and benzodiazepines. Indeed, the same medications that can relieve the psychomotor agitation of delirium (benzodiazepines, typical and atypical antipsychotics) can, when used inappropriately, cause delirium.
Medications used specifically in HIV treatment that can cause deliriumlike side effects include zidovudine, efavirenz, prednisone, foscarnet, amphotericin, high-dose sulfamethoxazole/trimethoprim, and interferon.
Sleep disruption and chronic pain are common cofactors in the precipitation of delirium.
|| ||Zaccarelli M, Soldani F, Liuzzi G. CNS side effects as a main risk factor for efavirenz failure and transitory HIV-RNA elevation. Presented at: 9th Conference on Retroviruses and Opportunistic Infections; February 24-28, 2002; Seattle, Wash.|