Mitchell H. Katz, MD
Andrew R. Zolopa, MD
ESSENTIALS OF DIAGNOSIS
Risk factors: sexual contact with an infected person, parenteral exposure to infected blood by transfusion or needle sharing, perinatal exposure.
Prominent systemic complaints such as sweats, diarrhea, weight loss, and wasting.
Opportunistic infections due to diminished cellular immunity—often life-threatening.
Aggressive cancers, particularly Kaposi sarcoma and extranodal lymphoma.
Neurologic manifestations, including dementia, aseptic meningitis, and neuropathy.
The Centers for Disease Control and Prevention (CDC) AIDS case definition (Table 31–1) includes opportunistic infections and malignancies that rarely occur in the absence of severe immunodeficiency (eg, Pneumocystis pneumonia, central nervous system lymphoma). It also classifies persons as having AIDS if they have positive HIV serology and certain infections and malignancies that can occur in immunocompetent hosts but that are more common among persons infected with HIV (pulmonary tuberculosis, invasive cervical cancer). Several nonspecific conditions, including dementia and wasting (documented weight loss)—in the presence of a positive HIV serology—are considered AIDS. The definition includes criteria for both definitive and presumptive diagnoses of certain infections and malignancies. Finally, persons with positive HIV serology who have ever had a CD4 lymphocyte count below 200 cells/mcL or a CD4 lymphocyte percentage below 14% are considered to have AIDS. Inclusion of persons with low CD4 counts as AIDS cases reflects the recognition that immunodeficiency is the defining characteristic of AIDS. The choice of a cutoff point at 200 cells/mcL is supported by several cohort studies showing that AIDS will develop within 3 years in over 80% of persons with counts below this level in the absence of effective antiretroviral therapy (ART). The prognosis of persons with HIV/AIDS has dramatically improved due to the introduction of highly active antiretroviral therapy (HAART) in the mid 1990s. One consequence is that fewer persons with HIV ever develop an infection or malignancy or have a low enough CD4 count to classify them as having AIDS, which means that the CDC definition has become a less useful measure of the impact of HIV/AIDS in the United States. Conversely, persons in whom AIDS had been diagnosed based on a serious opportunistic infection, malignancy, or immunodeficiency may now be markedly healthier, with high CD4 counts, due to the use of HAART. Therefore, the Social Security Administration as well as most social service agencies focus on functional assessment for determining eligibility for benefits rather than the simple presence or absence of an AIDS-defining illness.
Table 31–1. CDC AIDS case definition for surveillance of adults and adolescents.
The modes of transmission of HIV are similar to those of hepatitis B, in particular with respect to sexual, parenteral, and vertical transmission. Although certain sexual practices (eg, receptive anal intercourse) are significantly riskier than other sexual practices (eg, oral sex), it is difficult to quantify per-contact risks. The reason is that studies of sexual transmission of HIV show that most people at risk for HIV infection engage in a variety of sexual practices and have sex with multiple persons, only some of whom may actually be HIV infected. Thus, it is difficult to determine which practice with which person actually resulted in HIV transmission.
Nonetheless, the best available estimates indicate that the risk of HIV transmission with receptive anal intercourse is between 1:100 and 1:30, with insertive anal intercourse 1:1000, with receptive vaginal intercourse 1:1000, with insertive vaginal intercourse 1:10,000, and with receptive fellatio with ejaculation 1:1000. The per-contact risk of HIV transmission with other behaviors, including receptive fellatio without ejaculation, insertive fellatio, and cunnilingus, is not known.
All per-contact risk estimates assume that the source is HIV infected. If the HIV status of the source is unknown, the risk of transmission is the risk of transmission multiplied by the probability that the source is HIV infected. This would vary by risk practices, age, and geographic area. A number of cofactors are known to increase the risk of HIV transmission during a given encounter, including the presence of ulcerative or inflammatory sexually transmitted diseases, trauma, menses, and lack of male circumcision.
The risk of acquiring HIV infection from a needlestick with infected blood is approximately 1:300. Factors known to increase the risk of transmission include depth of penetration, hollow bore needles, visible blood on the needle, and advanced stage of disease in the source. The risk of HIV transmission from a mucosal splash with infected blood is unknown but is assumed to be significantly lower.
The risk of acquiring HIV infection from illicit drug use with sharing of needles from an HIV-infected source is estimated to be 1:150. Use of clean needles markedly decreases the chance of HIV transmission but does not eliminate it if other drug paraphernalia are shared (eg, cookers).
When blood transfusion from an HIV-infected donor occurs, the risk of transmission is 95%. Fortunately, since 1985, blood donor screening using the HIV enzyme-linked immunosorbent assay (ELISA) has been universally practiced in the United States. Also, persons who have recently engaged in unsafe behaviors (eg, sex with a person at risk for HIV, injection drug use) are not allowed to donate. This essentially eliminates donations from persons who are HIV infected but have not yet developed antibodies (ie, persons in the “window” period). HIV antigen and viral load testing have been added to the screening of blood to further lower the chance of HIV transmission. With these precautions, the chance of HIV transmission with receipt of blood transfusion in the United States is about 1:1,000,000. Between 13% and 40% of children born to HIV-infected mothers contract HIV infection when the mother has not received treatment or when the child has not received perinatal HIV prophylaxis. The risk is higher with vaginal than with cesarean delivery, higher among mothers with high viral loads, and higher among those who breast-feed their children. The combination of prenatal HIV testing and counseling, antiretroviral treatment for infected mothers during pregnancy and for the infant immediately after birth, scheduled cesarean delivery when the mother has a viral load of >1000 copies/mL, and avoidance of breastfeeding has reduced the rate of perinatal transmission of HIV to less than 2% in the United States and Europe (see below).
HIV has not been shown to be transmitted by respiratory droplet spread, by vectors such as mosquitoes, or by casual nonsexual contact.
There are an estimated 1,148,200 Americans aged 13 years or older living with HIV infection and about 50,000 new infections each year. There are an estimated 487,692 persons in the United States living with AIDS. Of those, 76% are men, of whom 63% were exposed through male-to-male sexual contact, 16% were exposed through injection drug use, 11% were exposed through heterosexual contact, and 8% were exposed through male-to-male sexual contact and injection drug use. Women account for 24% of living persons with HIV infection, of whom 68% were infected through heterosexual contact and 29% were exposed through injection drug use. Children under the age of 13 account for < 0.1% of living cases. African Americans have been disproportionately hard hit by the epidemic. The estimated rate of new AIDS cases in the United States per 100,000 is 41.6 among African Americans, 12.9 among persons of multiple races, 12.2 among Latinos, 9.3 among native Hawaiians and Pacific Islanders, 6.4 among native Americans and native Alaskans, 4.2 among whites, 3.3 among Asians. In general, the progression of HIV-related illness is similar in men and women. However, there are some important differences. Women are at risk for gynecologic complications of HIV, including recurrent candidal vaginitis, pelvic inflammatory disease, and cervical dysplasia. Violence directed against women, pregnancy, and frequent occurrence of drug use and poverty all complicate the treatment of HIV-infected women. Although “safer sex” campaigns dramatically decreased the rates of seroconversions among men who have sex with men (MSM) living in metropolitan areas in the United States by the mid 1980s, relapse to unsafe sexual practices among MSM in several large cities in the United States and in western Europe has been observed. The higher rates of unsafe sex appear to be related to decreased concern about acquiring HIV due to the availability of HAART. Decreased interest in following safer sex recommendations and increasing use of crystal methamphetamine among certain risk groups also appears to be playing a role in the increased unsafe sex rates.
Worldwide there are an estimated 33 million persons infected with HIV, with heterosexual spread being the most common mode of transmission for men and women. In Central and East Africa, in some urban areas, as many as one-third of sexually active adults are infected. The reason for the greater risk for transmission with heterosexual intercourse in Africa and Asia than in the United States may relate to cofactors such as general health status, the presence of genital ulcers, relative lack of male circumcision, the number of sexual partners, and different HIV serotypes.
Centers for Disease Control and Prevention: HIV Surveillance Report, 2011; vol 23. http://www.cdc.gov/hiv/topics/surveillance/resources/reports/. Published February 2013.
Panel on treatment of HIV-infected pregnant women and prevention of perinatal transmission. Recommendations for use of antiretroviral drugs in pregnant HIV-1-infected women for maternal health and interventions to reduce perinatal HIV-1 transmission in the United States. July 31, 2012 Guideline. http://aidsinfo.nih.gov/contentfiles/lvguidelines/PerinatalGL.pdf
Clinically, the syndromes caused by HIV infection are usually explicable by one of three known mechanisms: immunodeficiency, autoimmunity, and allergic and hypersensitivity reactions.
Immunodeficiency is a direct result of the effects of HIV upon immune cells as well as the indirect impact of a generalized state of inflammation and immune activation due to chronic viral infection. A spectrum of infections and neoplasms is seen, as in other congenital or acquired immunodeficiency states. Two remarkable features of HIV immunodeficiency are the low incidence of certain infections such as listeriosis and aspergillosis and the frequent occurrence of certain neoplasms such as lymphoma or Kaposi sarcoma. This latter complication has been seen primarily in MSM or in bisexual men, and its incidence steadily declined through the first 15 years of the epidemic. A herpesvirus (KSHV or HHV-8) is the cause of Kaposi sarcoma.
Autoimmunity can occur as a result of disordered cellular immune function or B lymphocyte dysfunction. Examples of both lymphocytic infiltration of organs (eg, lymphocytic interstitial pneumonitis) and autoantibody production (eg, immunologic thrombocytopenia) occur. These phenomena may be the only clinically apparent disease or may coexist with obvious immunodeficiency. Moreover, HIV-infected individuals appear to have higher rates of allergic reactions to unknown allergens as seen with eosinophilic pustular folliculitis (“itchy red bump syndrome”) as well as increased rates of hypersensitivity reactions to medications (for example, the fever and sunburn-like rash seen with trimethoprim-sulfamethoxazole reactions).
The complications of HIV-related infections and neoplasms affect virtually every organ. The general approach to the HIV-infected person with symptoms is to evaluate the organ systems involved, aiming to diagnose treatable conditions rapidly. As can be seen in Figure 31–1, the CD4 lymphocyte count result enables the clinician to focus on the diagnoses most likely to be seen at each stage of immunodeficiency. Certain infections may occur at any CD4 count, while others rarely occur unless the CD4 lymphocyte count has dropped below a certain level. For example, a patient with a CD4 count of 600 cells/mcL, cough, and fever may have a bacterial pneumonia but would be very unlikely to have Pneumocystis pneumonia.
Figure 31–1. Relationship of CD4 count to development of opportunistic infections. MAC, Mycobacterium avium complex; CMV, cytomegalovirus; CNS, central nervous system.
Many individuals with HIV infection remain asymptomatic for years even without ART, with a mean time of approximately 10 years between infection and development of AIDS. When symptoms occur, they may be remarkably protean and nonspecific. Since virtually all the findings may be seen with other diseases, a combination of complaints is more suggestive of HIV infection than any one symptom.
Physical examination may be entirely normal. Abnormal findings range from completely nonspecific to highly specific for HIV infection. Those that are specific for HIV infection include hairy leukoplakia of the tongue, disseminated Kaposi sarcoma, and cutaneous bacillary angiomatosis. Generalized lymphadenopathy is common early in infection.
The specific presentations and management of the various complications of HIV infection are discussed under the Complications section below.
Specific tests for HIV include antibody and antigen detection (Table 31–2). Conventional HIV antibody testing is done by ELISA. Positive specimens are then confirmed by a different method (eg, Western blot). The sensitivity of screening serologic tests is > 99.9%. The specificity of positive results by two different techniques approaches 100% even in low-risk populations. False-positive screening tests may occur as normal biologic variants or in association with recent influenza vaccination or other disease states, such as connective tissue disease. These are usually detected by negative confirmatory tests. Molecular biology techniques (PCR) show a small incidence of individuals (< 1%) who are infected with HIV for up to 36 months without generating an antibody response. However, antibodies that are detectable by screening serologic tests will develop in 95% of persons within 6 weeks after infection.
Table 31–2. Laboratory findings with HIV infection.
Rapid HIV antibody tests of blood or oral fluid provides results within 10–20 minutes and can be performed in clinician offices, including by personnel without laboratory training and without a Clinical Laboratory Improvement Amendment (CLIA) approved laboratory. Persons who test positive on a rapid test should be told that they may be HIV-infected or their test may be falsely reactive. Standard testing (ELISA with Western blot confirmation) should be performed to distinguish these two possibilities. Rapid testing is particularly helpful in settings where a result is needed immediately (eg, a woman in labor who has not recently been tested for HIV) or when the patient is unlikely to return for a result. Rapid HIV home tests that allow the testers to learn their status privately by simply swabbing along their gum lines are also available (www.oraquick.com).
Nonspecific laboratory findings with HIV infection may include anemia, leukopenia (particularly lymphopenia), and thrombocytopenia in any combination, elevation of the erythrocyte sedimentation rate, polyclonal hypergammaglobulinemia, and hypocholesterolemia. Cutaneous anergy is common.
The most widely used marker is the absolute CD4 lymphocyte count to provide prognostic information and guide therapy decisions (Table 31–2). As counts decrease, the risk of serious opportunistic infection over the subsequent 3–5 years increases (Figure 31–1). There are many limitations to using the CD4 count, including diurnal variation, depression with intercurrent illness, and intralaboratory and interlaboratory variability. Therefore, the trend is more important than a single determination. The frequency of performance of counts depends on the patient’s health status and whether or not they are receiving antiretroviral treatment. All patients regardless of CD4 count should be offered ART; CD4 counts should be monitored every 3–6 months in patients on stable ART. Initiation of Pneumocystis jirovecii prophylactic therapy is recommended when the CD4 count drops below 200 cells/mcL and initiation of Mycobacterium avium prophylaxis is recommended when the CD4 count drops below 75–100 cells/mcL. Some studies suggest that the percentage of CD4 lymphocytes is a more reliable indicator of prognosis than the absolute counts because the percentage does not depend on calculating a manual differential. While the CD4 count measures immune dysfunction, it does not provide a measure of how actively HIV is replicating in the body. HIV viral load tests (discussed below) assess the level of viral replication and provide useful prognostic information that is independent of the information provided by CD4 counts.
HIV infection may mimic a variety of other medical illnesses. Specific differential diagnosis depends on the mode of presentation. In patients presenting with constitutional symptoms such as weight loss and fevers, differential considerations include cancer, chronic infections such as tuberculosis and endocarditis, and endocrinologic diseases such as hyperthyroidism. When pulmonary processes dominate the presentation, acute and chronic lung infections must be considered as well as other causes of diffuse interstitial pulmonary infiltrates. When neurologic disease is the mode of presentation, conditions that cause mental status changes or neuropathy—eg, alcoholism, liver disease, kidney dysfunction, thyroid disease, and vitamin deficiency—should be considered. If a patient presents with headache and a cerebrospinal fluid pleocytosis, other causes of chronic meningitis enter the differential. When diarrhea is a prominent complaint, infectious enterocolitis, antibiotic-associated colitis, inflammatory bowel disease, and malabsorptive symptoms must be considered.
Fever, night sweats, and weight loss are common symptoms in HIV-infected patients and may occur without a complicating opportunistic infection. Patients with persistent fever and no localizing symptoms should nonetheless be carefully examined, and evaluated with a chest radiograph (Pneumocystis pneumonia can present without respiratory symptoms), bacterial blood cultures if the fever is > 38.5°C, serum cryptococcal antigen, and mycobacterial cultures of the blood. Sinus CT scans or sinus radiographs should be considered to evaluate occult sinusitis. If these studies are normal, patients should be observed closely. Antipyretics are useful to prevent dehydration.
Exacerbating the decrease in caloric intake, many AIDS patients have an increased metabolic rate. This increased rate has been shown to exist even among asymptomatic HIV-infected persons, but it accelerates with disease progression and secondary infection. AIDS patients with secondary infections also have decreased protein synthesis, which makes maintaining muscle mass difficult.
Two pharmacologic approaches for increasing appetite and weight gain are the progestational agent megestrol acetate (80 mg orally four times a day) and the antiemetic agent dronabinol (2.5–5 mg orally three times a day), but neither of these agents increases lean body mass. Side effects from megestrol acetate are rare, but thromboembolic phenomena, edema, nausea, vomiting, and rash have been reported. Euphoria, dizziness, paranoia, and somnolence and even nausea and vomiting have been reported in 3–10% of patients using dronabinol. Dronabinol contains only one of the active ingredients in marijuana, and many patients report better relief of nausea and improvement of appetite with medical cannabis (administered via smoking, vaporization, essential oils or cooked in food). Twenty states allow patients to obtain marijuana for medicinal purposes with a letter of recommendation from their doctor. However, the use and sale of marijuana is still illegal under federal law. The Supreme Court has ruled that physicians cannot be prosecuted for recommending marijuana to their patients (it would be an infringement of freedom of speech). Therefore, while a physician’s recommendation may not completely protect patients, letters decrease the chance that patients will be prosecuted for use of marijuana.
Two regimens that have resulted in increases in lean body mass are growth hormone and anabolic steroids. Growth hormone at a dose of 0.1 mg/kg/d (up to 6 mg) subcutaneously for 12 weeks has resulted in modest increases in lean body mass. Treatment with growth hormone can cost as much as $10,000 per month. Anabolic steroids also increase lean body mass among HIV-infected patients. They seem to work best for patients who are able to do weight training. The most commonly used regimens are testosterone enanthate or testosterone cypionate (100–200 mg intramuscularly every 2–4 weeks). Testosterone transdermal system (apply 5 mg system each evening) and testosterone gel (1%; apply a 5-g packet [50 mg testosterone] to clean, dry skin daily) are also available. The anabolic steroid oxandrolone (20 mg orally in two divided doses) has also been found to increase lean body mass.
Hypoxemia may be severe, with a Po2 < 60 mm Hg. The cornerstone of diagnosis is the chest radiograph. Diffuse or perihilar infiltrates are most characteristic, but only two-thirds of patients withPneumocystis pneumonia have this finding. Normal chest radiographs are seen in 5–10% of patients with Pneumocystis pneumonia, while the remainder have atypical infiltrates. Apical infiltrates are commonly seen among patients with Pneumocystis pneumonia who have been receiving aerosolized pentamidine prophylaxis. Large pleural effusions are uncommon with Pneumocystis pneumonia; their presence suggests bacterial pneumonia, other infections such as tuberculosis, or pleural Kaposi sarcoma.
Definitive diagnosis can be obtained in 50–80% of cases by Wright-Giemsa stain or direct fluorescence antibody (DFA) test of induced sputum. Sputum induction is performed by having patients inhale an aerosolized solution of 3% saline produced by an ultrasonic nebulizer. Patients should not eat for at least 8 hours and should not use toothpaste or mouthwash prior to the procedure since they can interfere with test interpretation. The next step for patients with negative sputum examinations in whom Pneumocystis pneumonia is still suspected should be bronchoalveolar lavage. This technique establishes the diagnosis in over 95% of cases.
In patients with symptoms suggestive of Pneumocystis pneumonia but with negative or atypical chest radiographs and negative sputum examinations, other diagnostic tests may provide additional information in deciding whether to proceed to bronchoalveolar lavage. Elevation of serum lactate dehydrogenase occurs in 95% of cases of Pneumocystis pneumonia, but the specificity of this finding is at best 75%. A serum beta-glucan test is more sensitive and specific test for Pneumocystis pneumonia compared with serum lactate dehydrogenase and may avoid more invasive tests when used in the appropriate clinical setting. Either a normal diffusing capacity of carbon monoxide (DLCO) or a high-resolution CT scan of the chest that demonstrates no interstitial lung disease makes the diagnosis ofPneumocystis pneumonia very unlikely. In addition, a CD4 count > 250 cells/mcL within 2 months prior to evaluation of respiratory symptoms makes a diagnosis of Pneumocystis pneumonia unlikely; only 1–5% of cases occur above this CD4 count level (Figure 31–1). This is true even if the patient previously had a CD4 count lower than 200 cells/mcL but has had an increase with ART. Pneumothoraces can be seen in HIV-infected patients with a history of Pneumocystis pneumonia, especially if they have received aerosolized pentamidine treatment.
Nonspecific interstitial pneumonitis may mimic Pneumocystis pneumonia. Lymphocytic interstitial pneumonitis seen in lung biopsies has a variable clinical course. Typically, these patients present with several months of mild cough and dyspnea; chest radiographs show interstitial infiltrates. Many patients with this entity undergo transbronchial biopsies in an attempt to diagnose Pneumocystis pneumonia. Instead, the tissue shows interstitial inflammation ranging from an intense lymphocytic infiltration (consistent with lymphoid interstitial pneumonitis) to a mild mononuclear inflammation.
Central nervous system disease in HIV-infected patients can be divided into intracerebral space-occupying lesions, encephalopathy, meningitis, and spinal cord processes. Many of these complications have declined markedly in prevalence in the era of effective ART. Cognitive declines, however, may be more common in HIV patients especially as they age (> 50 years), even those who are taking fully suppressive ART.
Single lesions are atypical of toxoplasmosis. When a single lesion has been detected by CT scanning, MRI scanning may reveal multiple lesions because of its greater sensitivity. If a patient has a single lesion on MRI and is neurologically stable, clinicians may pursue a 2-week empiric trial of toxoplasmosis therapy. A repeat scan should be performed at 2 weeks. If the lesion has not diminished in size, biopsy of the lesion should be performed. A positive Toxoplasma serologic test does not confirm the diagnosis because many HIV-infected patients have detectable titers without having active disease. Conversely, < 3% of patients with toxoplasmosis have negative titers. Therefore, negative Toxoplasma titers in an HIV-infected patient with a space-occupying lesion should be a cause for aggressively pursuing an alternative diagnosis.
Stereotactic brain biopsy should be strongly considered if lesions are solitary or do not respond to toxoplasmosis treatment, especially if they are easily accessible. Diagnosis of lymphoma is important because many patients benefit from treatment (radiation therapy). Although a positive polymerase chain reaction (PCR) assay of cerebrospinal fluid for Epstein–Barr virus DNA is consistent with a diagnosis of lymphoma, the sensitive and specificity of the test are not high enough to obviate the need for a brain biopsy.
Metabolic abnormalities may also cause changes in mental status: hypoglycemia, hyponatremia, hypoxia, and drug overdose are important considerations in this population. Other less common infectious causes of encephalopathy include progressive multifocal leukoencephalopathy (discussed below), CMV, syphilis, and herpes simplex encephalitis.
An inflammatory demyelinating polyneuropathy similar to Guillain-Barré syndrome occurs in HIV-infected patients, usually prior to frank immunodeficiency. The syndrome in many cases improves with plasmapheresis, supporting an autoimmune basis of the disease. CMV can cause an ascending polyradiculopathy characterized by lower extremity weakness and a neutrophilic pleocytosis on spinal fluid analysis with a negative bacterial culture. Transverse myelitis can be seen with herpes zoster or CMV.
Peripheral neuropathy is common among HIV-infected persons. Patients typically complain of numbness, tingling, and pain in the lower extremities. Symptoms are disproportionate to findings on gross sensory and motor evaluation. Beyond HIV infection itself, the most common cause is prior ART with stavudine or didanosine. Although not used commonly in Western countries, stavudine is still being used in resource-limited settings through national ART programs. Caution should be used when administering these agents to patients with a history of peripheral neuropathy. Unfortunately, medication-induced neuropathy is not always reversed when the offending agent is discontinued. Patients with advanced disease may also develop peripheral neuropathy even if they have never taken ART. Evaluation should rule out other causes of sensory neuropathy such as alcoholism, thyroid disease, vitamin B12 deficiency, and syphilis.
Arthritis, involving single or multiple joints, with or without effusion, has been commonly noted in HIV-infected patients. Involvement of large joints is most common. Although the cause of HIV-related arthritis is unknown, most patients will respond to nonsteroidal anti-inflammatory medications. Patients with a sizable effusion, especially if the joint is warm or erythematous, should have the joint aspirated, followed by culture of the fluid to rule out suppurative arthritis as well as fungal and mycobacterial disease.
Several rheumatologic syndromes, including reactive arthritis, psoriatic arthritis, sicca syndrome, and systemic lupus erythematosus, have been reported in HIV-infected patients (see Chapter 20). However, it is unclear if the prevalence is greater than in the general population. Cases of avascular necrosis of the femoral heads have been reported sporadically, generally in the setting of advanced disease with long-standing infection and in patients receiving long-term ART. The etiology is not clear but is probably multifactorial in nature.
Osteoporosis and osteopenia appear to be more common in HIV infected patients with chronic infection and perhaps associated with long-term use of ART. Vitamin D deficiency appears to be quite common among HIV-infected populations and monitoring vitamin D levels and replacement therapy for detected deficiency is recommended. Bone mineral density scans for patients over the age of 50 is also recommended.
Myopathies are infrequent in the era of effective ART but can be related to either HIV-infection or ART, particularly with use of zidovudine (azidothymidine [AZT]). Proximal muscle weakness is typical, and patients may have varying degrees of muscle tenderness. Given its long-term toxicities, zidovudine is no longer recommended when alternative treatments are available (see below).
Complaints of visual changes must be evaluated immediately in HIV-infected patients. CMV retinitis, characterized by perivascular hemorrhages and white fluffy exudates, is the most common retinal infection in AIDS patients and can be rapidly progressive. In contrast, cotton wool spots, which are also common in HIV-infected people, are benign, remit spontaneously, and appear as small indistinct white spots without exudation or hemorrhage. This distinction may be difficult at times for the nonspecialist, and patients with visual changes should be seen by an ophthalmologist. Other rare retinal processes include other herpesvirus infections or toxoplasmosis.
Hairy leukoplakia is caused by the Epstein-Barr virus. The lesion is not usually troubling to patients and sometimes regresses spontaneously. Hairy leukoplakia is commonly seen as a white lesion on the lateral aspect of the tongue. It may be flat or slightly raised, is usually corrugated, and has vertical parallel lines with fine or thick (“hairy”) projections. Oral candidiasis can be bothersome to patients, many of whom report an unpleasant taste or mouth dryness. The two most common forms of oral candidiasis seen are pseudomembranous (removable white plaques) and erythematous (red friable plaques).
Gingival disease is common in HIV-infected patients and is thought to be due to an overgrowth of microorganisms. It usually responds to professional dental cleaning and chlorhexidine rinses. A particularly aggressive gingivitis or periodontitis will develop in some HIV-infected patients; these patients should be given antibiotics that cover anaerobic oral flora (eg, metronidazole, 250 mg four times a day for 4 or 5 days) and referred to oral surgeons with experience with these entities.
Aphthous ulcers are painful and may interfere with eating. They can be treated with fluocinonide (0.05% ointment mixed 1:1 with plain Orabase and applied six times a day to the ulcer). For lesions that are difficult to reach, patients should use dexamethasone swishes (0.5 mg in 5 mL elixir three times a day). The pain of the ulcers can be relieved with use of an anesthetic spray (10% lidocaine). Other lesions seen in the mouths of HIV-infected patients include Kaposi sarcoma (usually on the hard palate) and warts.
Treatment of HIV-infected persons with hepatitis C with peginterferon and ribavirin has been shown to be efficacious, although less so than in HIV-uninfected persons. HIV-infected persons are also more likely to have difficulty tolerating treatment with peginterferon than uninfected persons. The new PIs for hepatitis C, telaprevir and bocevavir, are being studied in HIV-coinfected patients and look promising, although they are associated with high rates of toxicities and side effects. HIV-infected patients with hepatitis C genotype 1 who received telaprevir therapy for 12 weeks had a better response than those who received only peginterferon with ribavirin. Telaprevir is approved in combination with peginterferon and ribavirin for treatment of hepatitis C in HIV-uninfected persons. Patients with advanced fibrosis or cirrhosis due to chronic hepatitis C infection should be considered for treatment with telaprevir, peginterferon, and ribavirin. However, this treatment regimen is difficult for many patients to tolerate, and there are a number of drug-drug interactions between the hepatitis PIs and many of the HIV antiretrovirals; therefore, coinfected patients with less advanced liver disease may benefit from waiting until newer direct-acting agents for hepatitis C treatment become available. Liver transplants have been performed successfully in HIV-infected patients. This strategy is most likely to be successful in persons who have CD4 counts > 100 cells/mcL and nondetectable viral loads.
Because of the wide range of agents known to cause enterocolitis, a stool culture and multiple stool examinations for ova and parasites (including modified acid-fast staining for Cryptosporidium) should be performed. Those patients who have Cryptosporidium in one stool with improvement in symptoms in < 1 month should not be considered to have AIDS, as Cryptosporidium is a cause of self-limited diarrhea in HIV-negative persons. More commonly, HIV-infected patients with Cryptosporidium infection have persistent enterocolitis with profuse watery diarrhea.
Patients with a negative stool examination and persistent symptoms should be evaluated with colonoscopy and biopsy. Patients whose symptoms last longer than 1 month with no identified cause of diarrhea are considered to have a presumptive diagnosis of AIDS enteropathy. Patients may respond to institution of effective antiretroviral treatment. Upper endoscopy with small bowel biopsy is not recommended as a routine part of the evaluation.
A malabsorption syndrome occurs commonly in AIDS patients. It can be due to infection of the small bowel with M avium complex, Cryptosporidium, or microsporidia.
Hypogonadism is probably the most common endocrinologic abnormality in HIV-infected men. The adrenal gland is also a commonly afflicted endocrine gland in patients with AIDS. Abnormalities demonstrated on autopsy include infection (especially with CMV and M avium complex), infiltration with Kaposi sarcoma, and injury from hemorrhage and presumed autoimmunity. The prevalence of clinically significant adrenal insufficiency is low. Patients with suggestive symptoms should undergo a cosyntropin stimulation test.
Although frank deficiency of cortisol is rare, an isolated defect in mineralocorticoid metabolism may lead to salt-wasting and hyperkalemia. Such patients should be treated with fludrocortisone (0.1–0.2 mg orally daily).
AIDS patients appear to have abnormalities of thyroid function tests different from those of patients with other chronic diseases. AIDS patients have been shown to have high levels of triiodothyronine (T3), thyroxine (T4), and thyroid-binding globulin and low levels of reverse triiodothyronine (rT3). The causes and clinical significance of these abnormalities are unknown.
The skin manifestations that commonly develop in HIV-infected patients can be grouped into viral, bacterial, fungal, neoplastic, and nonspecific dermatitides.
Four cancers are currently included in the CDC classification of AIDS: Kaposi sarcoma, non-Hodgkin lymphoma, primary lymphoma of the brain, and invasive cervical carcinoma. Epidemiologic studies have shown that between 1973 and 1987 among single men in San Francisco, the risk of Kaposi sarcoma increased more than 5000-fold and the risk of non-Hodgkin lymphoma more than 10-fold. The increase in incidence of malignancies is probably a function of impaired cell-mediated immunity. In the current treatment era, cancers not classified as AIDS-related, such as lung cancer, are being increasingly diagnosed in aging HIV-infected individuals despite optimal ART treatment. Cohort studies suggest that HIV-infected adults are at increased risk for a variety of cancers compared to age-matched uninfected populations. Mortality secondary to malignancies represents an increasing cause of death in HIV-infected populations.
HPV also appears to play a causative role in cervical dysplasia and neoplasia. The incidence and clinical course of cervical disease in HIV-infected women are discussed below.
Vaginal candidiasis, cervical dysplasia and neoplasia, and pelvic inflammatory disease are more common in HIV-infected women than in uninfected women. These manifestations also tend to be more severe when they occur in association with HIV infection. Therefore, HIV-infected women need frequent gynecologic care. Vaginal candidiasis may be treated with topical agents (see Chapter 36). However, HIV-infected women with recurrent or severe vaginal candidiasis may need systemic therapy.
The incidence of cervical dysplasia in HIV-infected women is 40%. Because of this finding, HIV-infected women should have Papanicolaou smears every 6 months (as opposed to the guidelines for HIV-uninfected women, see Chapter 18). Some clinicians recommend routine colposcopy or cervicography because cervical intraepithelial neoplasia has occurred in women with negative Papanicolaou smears. Cone biopsy is indicated in cases of serious cervical dysplasia. For 1 year following treatment of an abnormal Papanicolaou smear, women should have repeat smears every 3 to 4 months.
Cervical neoplasia appears to be more aggressive among HIV-infected women. Most HIV-infected women with cervical cancer die of that disease rather than of AIDS. Because of its frequency and severity, cervical neoplasia was added to the CDC definition of AIDS in 1993.
While pelvic inflammatory disease appears to be more common in HIV-infected women, the bacteriology of this condition appears to be the same as among HIV-uninfected women. At present, HIV-infected women with pelvic inflammatory disease should be treated with the same regimens as uninfected women (see Chapter 18). However, inpatient therapy is generally recommended.
HIV-infected persons are at higher risk for coronary artery disease than age- and sex-matched controls. Part of this increase in coronary artery disease is due to changes in lipids caused by antiretroviral agents (see Treatment section on Antiretroviral Therapy below), especially stavudine and several of the PIs. However, some of the risk appears to be due to HIV infection, independent of its therapy. It is important that clinicians pay close attention to this issue because myocardial infarctions tend to present at a younger age in HIV-infected individuals than in HIV-uninfected individuals. HIV-infected patients with symptoms of coronary artery disease such as chest pain or dyspnea should be rapidly evaluated. Clinicians should aggressively treat conditions that result in increased risk of heart disease, especially smoking, hypertension, hyperlipidemia, obesity, diabetes mellitus, and sedentary lifestyle.
With initiation of HAART, some patients experience inflammatory reactions that appear to be associated with immune reconstitution as indicated by a rapid increase in CD4 count. These inflammatory reactions may present with generalized signs of fevers, sweats, and malaise with or without more localized manifestations that usually represent unusual presentations of opportunistic infections. For example, vitreitis has developed in patients with CMV retinitis after they have been treated with HAART.
M avium can present as focal even suppurative lymphadenitis or granulomatous masses in patients receiving HAART. Tuberculosis may paradoxically worsen with new or evolving pulmonary infiltrates and lymphadenopathy. PML and cryptococcal meningitis may also behave atypically. Clinicians should be alert to these syndromes, which are most often seen in patients who have initiated ART in the setting of advanced disease and who show rapid increases in CD4 counts with treatment. The diagnosis of immune reconstitution inflammatory syndrome (IRIS) is one of exclusion and can be made only after recurrence or new opportunistic infection has been ruled out as the cause of the clinical deterioration. Management of IRIS is conservative and supportive with use of corticosteroids only for severe reactions. Most authorities recommend that ART be continued unless the reaction is life-threatening.
Until vaccination is a reality, prevention of HIV infection will depend on HIV testing and counseling, including precautions regarding sexual practices and injection drug use, initiation of antiretroviral therapy (ART) as a prevention tool, preexposure and postexposure use of ART, perinatal management including ART therapy for the mother, screening of blood products, and infection control practices in the health care setting.
For patients whose test results are negative, clinicians should review safer sex and needle use practices, including counseling not to exchange bodily fluids unless they are in a long-term mutually monogamous relationship with someone who has tested HIV antibody-negative and has not engaged in unsafe sex, injection drug use, or other HIV risk behaviors for at least 6 months prior to or at any time since the negative test.
To prevent sexual transmission of HIV, only latex condoms should be used, along with a water-soluble lubricant. Although nonoxynol-9, a spermicide, kills HIV, it is contraindicated because in some patients it may cause genital ulcers that could facilitate HIV transmission. Patients should be counseled that condoms are not 100% effective. They should be made familiar with the use of condoms, including, specifically, the advice that condoms must be used every time, that space should be left at the tip of the condom as a receptacle for semen, that intercourse with a condom should not be attempted if the penis is only partially erect, that men should hold on to the base of the condom when withdrawing the penis to prevent slippage, and that condoms should not be reused. Although anal intercourse remains the sexual practice at highest risk for transmitting HIV, seroconversions have been documented with vaginal and oral intercourse as well. Therefore, condoms should be used when engaging in these activities. Women as well as men having sex with men should understand how to use condoms to be sure that their partners are using them correctly. Partners of HIV-infected women should use latex barriers such as dental dams (available at dental supply stores) to prevent direct oral contact with vaginal secretions. Several randomized trials in Africa demonstrated that male circumcision significantly reduced HIV incidence in men, but there are a number of barriers to performing widespread circumcisions among men in Africa.
Persons using injection drugs should be cautioned never to exchange needles or other drug paraphernalia. When sterile needles are not available, bleach does appear to inactivate HIV and should be used to clean needles.
The choice of antiretroviral agents and the duration of treatment are the same as those for exposures that occur through the occupational route; the preferred regimen is tenofovir 300 mg with emtricitabine 200 mg daily with raltegravir 400 mg twice a day. Some clinicians prescribe a two-drug regimen of tenofovir 300 mg and emtricitabine 200 mg (Truvada) because it is a simpler for patients to take (single pill once a day), and more affordable for individuals and for public entities that provide this service to uninsured persons. In contrast to those with occupational exposures, some individuals may present very late after exposure. Because the likelihood of success declines with length of time from HIV exposure, treatment should be provided as soon as possible, and it is not recommended that treatment be offered more than 72 hours after exposure. In addition, because the psychosocial issues involved with postexposure prophylaxis for sexual and drug use exposures are complex, it should be offered only in the context of prevention counseling. Counseling should focus on how to prevent future exposures. Clinicians needing more information on postexposure prophylaxis for occupational or nonoccupational exposures should contact the National Clinician’s Post-exposure Hotline (1-888-448-4911; http://www.nccc.ucsf.edu/about_nccc/pepline/).
Epidemiologic studies show that needle sticks occur commonly among health care professionals, especially among surgeons performing invasive procedures, inexperienced hospital house staff, and medical students. Efforts to reduce needle sticks should focus on avoiding recapping needles and use of safety needles whenever doing invasive procedures under controlled circumstances. The risk of HIV transmission from a needle stick with blood from an HIV-infected patient is about 1:300. The risk is higher with deep punctures, large inoculum, and source patients with high viral loads. The risk from mucous membrane contact is too low to quantitate.
Health care professionals who sustain needle sticks should be counseled and offered HIV testing as soon as possible. HIV testing is done to establish a negative baseline for worker’s compensation claims in case there is a subsequent conversion. Follow-up testing is usually performed at 6 weeks, 3 months, and 6 months.
A case-control study by the CDC indicates that administration of zidovudine following a needle stick decreases the rate of HIV seroconversion by 79%. Therefore, providers should be offered ART as soon as possible after exposure and continued for 4 weeks. The preferred regimen is tenofovir 300 mg with emtricitabine 200 mg (Truvada) daily with raltegravir 400 mg twice a day. Providers who have exposures to persons who are likely to have antiretroviral medication resistance (eg, persons receiving therapy who have detectable viral loads) should have their therapy individualized, using at least two medications to which the source is unlikely to be resistant. Because reports have noted hepatotoxicity due to nevirapine in this setting, this agent should be avoided. Unfortunately, there have been documented cases of seroconversion following potential parenteral exposure to HIV despite prompt use of zidovudine prophylaxis. Counseling of the provider should include “safer sex” guidelines.
In the era prior to the development of highly effective antiretroviral treatment, cohort studies of individuals with documented dates of seroconversion demonstrate that AIDS develops within 10 years in approximately 50% of untreated seropositive persons. With currently available treatment, progression of disease has been markedly decreased. In addition to antiretroviral treatment, prophylactic regimens can prevent opportunistic infections and improve survival. Prophylaxis and early intervention prevent several infectious diseases, including tuberculosis and syphilis, which are transmissible to others. Recommendations for screening tests, vaccinations, and prophylaxis are listed in Table 31–3.
Table 31–3. Health care maintenance of HIV-infected individuals.
HIV-infected individuals should be counseled with regard to the importance of practicing safer sex even with other HIV-infected persons because of the possibility of contracting a sexually transmitted disease, such as gonorrhea or syphilis. There is also the possibility of transmission of a particularly virulent or a drug-resistant strain between HIV infected persons. Substance abuse treatment should berecommended for persons who are using recreational drugs. They should be warned to avoid consuming raw meat or eggs to avoid infections with Toxoplasma, Campylobacter, and Salmonella. HIV-infected patients should wash their hands thoroughly after cleaning cat litter or should forgo this household chore to avoid possible exposure to toxoplasmosis. To reduce the likelihood of infection withBartonella species, patients should avoid activities that might result in cat scratches or bites. Although the data are not conclusive, many clinicians recommend that HIV-infected persons—especially those with low CD4 counts—drink bottled water instead of tap water to prevent cryptosporidia infection.
Because of the emotional impact of HIV infection and subsequent illness, many patients will benefit from supportive counseling.
Baeten JM et al; Partners PrEP Study Team. Antiretroviral prophylaxis for HIV prevention in heterosexual men and women. N Engl J Med. 2012 Aug 2;367(5):399–410. [PMID: 22784037]
Choopanya K et al. Antiretroviral prophylaxis for HIV infection in injecting drug users in Bangkok, Thailand (the Bangkok Tenofovir Study): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2013 Jun 15;381(9883):2083–90. [PMID: 23769234]
Cohen MS et al; HPTN 052 Study Team. Prevention of HIV-1 infection with early antiretroviral therapy. N Engl J Med. 2011 Aug 11;365(6):493–505. [PMID: 21767103]
Kuhar DT et al. Updated US Public Health Service guidelines for the management of occupational exposures to human immunodeficiency virus and recommendations for postexposure prophylaxis. Infect Control Hosp Epidemiol. 2013 Sep;34(9):875–92. [PMID: 23917901]
Saunders KO. The design and evaluation of HIV-1 vaccines. AIDS. 2012 Jun 19;26(10):1293–302. [PMID: 22706011]
Stevens LM et al. JAMA patient page. HIV infection: the basics. JAMA. 2012 Jul 25;308(4):419. [PMID: 22820800]
U.S. Preventive Services Task Force. Screening for HIV: U.S. Preventive Services Task Force Recommendation Statement. April 2013.http://www.uspreventiveservicestaskforce.org/uspstf13/hiv/hivfinalrs.htm
Treatment for HIV infection can be broadly divided into the following categories: (1) prophylaxis for opportunistic infections, malignancies, and other complications of HIV infection; (2) treatment of opportunistic infections, malignancies, and other complications of HIV infection; and (3) treatment of the HIV infection itself with combination ART.
Treatment regimens for HIV infection are constantly changing. Clinicians may obtain up-to-date information on new and experimental treatments by calling the AIDS Clinical Trials Information Service (ACTIS), 800-TRIALS-A (English and Spanish), and the National AIDS Hot Line, 800-342-AIDS (English), 800-344-SIDA (Spanish), and 800-AIDS-TTY (hearing-impaired).
In general, decisions about prophylaxis of opportunistic infections are based on the CD4 count, other evidence of severe immunosuppression (eg, oral candidiasis), and a history of having had the infection in the past. In the era prior to HAART, patients who started taking prophylactic regimens were maintained on them indefinitely. However, studies have shown that in patients with robust improvements in immune function—as measured by increases in CD4 counts above the levels that are used to initiate treatment—prophylactic regimens can safely be discontinued.
Because individuals with advanced HIV infection are susceptible to a number of opportunistic pathogens, the use of agents with activity against more than one pathogen is preferable. It has been shown, for example, that trimethoprim-sulfamethoxazole confers some protection against toxoplasmosis in individuals receiving this medication for Pneumocystis prophylaxis.
Table 31–4. Pneumocystis jirovecii prophylaxis in order of preference.
Treatment of common AIDS-related complications is detailed above and in Table 31–5. In the era prior to the use of HAART, patients required lifelong treatment for many infections, including CMV retinitis, toxoplasmosis, and cryptococcal meningitis. However, among patients who have a good response to HAART, maintenance therapy for some opportunistic infections can be terminated. For example, in consultation with an ophthalmologist, maintenance treatment for CMV infection can be discontinued when persons receiving HAART have durable suppression of viral load (ie, < 50 copies/mL) and a CD4 count > 100–150 cells/mcL. Similar results have been observed in patients with M avium complex bacteremia. Cessation of secondary prophylaxis for Pneumocystis pneumonia is described above.
Table 31–5. Treatment of AIDS-related opportunistic infections and malignancies.1
Treating patients with repeated episodes of the same opportunistic infection can pose difficult therapeutic challenges. For example, patients with second or third episodes of Pneumocystis pneumonia may have developed allergic reactions to standard treatments with a prior episode. Fortunately, there are several alternatives available for the treatment of Pneumocystis infection. Trimethoprim with dapsone and primaquine with clindamycin are two combinations that often are tolerated in patients with a prior allergic reaction to trimethoprim-sulfamethoxazole and intravenous pentamidine. Patients in whom second episodes of Pneumocystis pneumonia develop while taking prophylaxis tend to have milder courses.
Well-established alternative regimens also exist for most AIDS-related opportunistic infections: amphotericin B or fluconazole for cryptococcal meningitis; ganciclovir, cidofovir, or foscarnet for CMV infection; and sulfadiazine or clindamycin with pyrimethamine for toxoplasmosis.
Adjunctive Treatments—Although conceptually it would seem that corticosteroids should be avoided in HIV-infected patients, corticosteroid therapy has been shown to improve the course of patients with moderate to severe P jirovecii pneumonia (oxygen saturation < 90%, Po2 < 65 mm Hg) when administered within 72 hours after diagnosis. Either intravenous methylprednisolone (Solu-medrol) or oral prednisone (40–80 mg daily tapering over 21 day) can be used. The mechanism of action is presumed to be a decrease in alveolar inflammation.
Corticosteroids have also been used to treat IRIS that can sometimes complicate the early treatment course when ART is initiated in patients with advanced AIDS (see section Inflammatory reactions [immune reconstitution inflammatory syndromes] above).
Epoetin alfa (erythropoietin) is approved for use in HIV-infected patients with anemia, including those with anemia secondary to zidovudine use. It has been shown to decrease the need for blood transfusions. The medication is expensive, and therefore an erythropoietin level < 500 mU/mL should be demonstrated before starting therapy. The starting dose of epoetin alfa is 8000 units subcutaneously three times a week. The target hematocrit is 35–40%. The dose may be increased by 12,000 units every 4–6 weeks as needed to a maximum dose of 48,000 units per week. Hypertension is the most common side effect.
Human G-CSF (filgrastim) and granulocyte-macrophage colony-stimulating factor (GM-CSF [sargramostim]) have been shown to increase the neutrophil counts of HIV-infected patients. Because of the high cost of this therapy, the dosage should be closely monitored and minimized, aiming for a neutrophil count of 1000/mcL. When the medication is used for indications other than cytotoxic chemotherapy, one or two doses at 5 mcg/kg per week subcutaneously are usually sufficient.
The availability of agents that in combination suppress HIV replication (Table 31–6) has had a profound impact on the natural history of HIV infection. Indeed, with the advent of antiretroviral treatment, the life expectancy of HIV-infected persons approaches that of uninfected persons when treatment is initiated early in the course of the disease.
Table 31–6. Antiretroviral therapy.
The greater potency and the improved side effect profile have led to the recommendation to start treatment for all HIV-infected persons regardless of CD4 count. This recommendation has not been broadly embraced; however, there is widespread consensus that at a minimum treatment should be initiated for all symptomatic patients, and for asymptomatic persons who (1) have CD4 cell counts below 500 cells/mcL, (2) have rapidly dropping CD4 counts (> 100 cells/mcL/yr) or very high viral loads (> 100,000/mcL), (3) have active infection with hepatitis B or C (rapid HIV replication is thought to hasten progression of hepatitis B and C), (4) have risk factors for cardiac disease (ongoing HIV replication may increase the risk of cardiac disease), (5) have HIV-related kidney impairment, (6) are pregnant, (7) have risk factors for non–AIDS-related cancers (rapid HIV replication may increase such cancers), or (8) are at high risk for transmitting HIV to another person. For patients with difficulty adhering to therapy, deferring ART until the patient is willing to commit to therapy may be a better strategy than inconsistent treatment. Because 5–20% of patients in developed countries who are treatment-naïve have a virus that is resistant to some medications, resistance testing is recommended for all patients prior to initiating ART.
Once a decision to initiate therapy has been made, several important principles should guide therapy. First, because medication resistance to antiretroviral agents develops in HIV-infected patients, a primary goal of therapy should be complete suppression of viral replication as measured by the serum viral load. Therapy that achieves a plasma viral load of < 20 or < 48 copies/mL (depending on the test used) has been shown to provide a durable response to the therapy. To achieve this and maintain virologic control over time, combination therapy with at least three medications from at least two different classes is necessary, and partially suppressive combinations such as dual nucleoside therapy should be avoided. Similarly, if toxicity develops, it is preferable to either interrupt the entire regimen or change the offending medication rather than reduce individual doses.
Randomized trials compared early initiation of ART (within 2 weeks of starting treatment for an opportunistic infection or tuberculosis) with ART that was deferred until after treatment of the opportunistic infection was completed (6 weeks after its start); results demonstrated that early initiation reduced death or AIDS progression by 50%. The reduced progression rates were related to more rapid improvements in CD4 counts in patients with advanced immunodeficiency. Furthermore, IRIS and other adverse events were no more frequent in the early ART arm. Based on these results, most treatment guidelines recommend that ART be initiated as early as is clinically feasible for patients with an acute AIDS-related opportunistic infection. For hospitalized patients, this recommendation requires close coordination between inpatient and outpatient physicians to ensure that treatment is continued once patients are discharged.
Several randomized studies have also demonstrated improved clinical outcomes in HIV/tuberculosis coinfected patients who initiate ART early in the setting of active treatment for tuberculosis and whose CD4 counts are < 50 cells/mcL. The exception to early ART in the setting of active infections may be in patients with a CNS-associated infection, such as cryptococcal or tuberculosis meningitis. Several studies from low-income countries have shown high mortality rates with early ART initiation in this setting, although this high mortality rate may be more related to the severity of the underlying infection at the time of entry to these studies.
Because the number of ART medications is finite, it is important to avoid medication resistance, which occurs when patients take medications in the setting of ongoing viral replication. Therefore, the best method for avoiding resistance is for the patient to be compliant with an efficacious regimen. Adherence can be promoted through the use of simple regimens (single pill once-a-day combination regimens (Table 31–8), and for those patients with more complicated regimens, medication boxes with compartments [eg, Medisets]). Many patients benefit from adherence counseling and some need daily supervision of therapy. Given these options treatment should not be withheld solely on the basis of a patient’s circumstances (eg, active drug use or housing status) alone. Often, a trial intervention such as offering Pneumocystis pneumonia prophylaxis may be helpful in determining the likelihood of adherence to a more complex antiretroviral regimen.
Monitoring of ART has two goals. Laboratory evaluation for toxicity depends on the specific medications in the combination but generally should be done approximately every 3–4 months once a patient is on a stable regimen. Patients who are intolerant of their initial regimen (eg, patients who cannot tolerate the neurologic side effects of efavirenz) should be changed to an alternative medication or regimen. The second aspect of monitoring is to regularly measure objective markers of efficacy. The CD4 cell count and HIV viral load should be repeated 1–2 months after the initiation or change of antiretroviral regimen and every 4–6 months thereafter in clinically stable patients (those with higher CD4 counts can have testing every 6 months). In a patient who is adherent to an effective regimen, viral loads should be undetectable within 12–24 weeks. For patients in whom viral loads are not suppressed or who have viral rebound after suppression, the major question facing the clinician is whether the patient is nonadherent or has resistance to the regimen, or both. The issue is complicated because many patients report being more compliant than they really are, not because they wish to be untruthful but because they wish to tell the clinician what he or she wants to hear. Patients who are having trouble adhering to their treatment should receive counseling on how to better comply with their treatment. In patients who are adherent or who have missed enough doses to make resistance possible, resistance testing should be performed. Based on the results of resistance testing, and assessment of the patient’s ability to comply with complicated regimens or to tolerate predictable side effects, the clinician should prescribe a combination of three medications to which there is no or only minimal resistance. Some patients whose counts rise dramatically on ART and who are fully suppressed (ie, plasma viral load < 20 or 48 copies/mL depending on test used) may be successfully transitioned from a multiple pill regimen to a simpler one with fewer side effects; however, this “switch strategy” needs to take into consideration the possibility for underlying drug resistance that may have developed during prior ART regimens; increased risk of virologic break-through has been reported when switching to simpler regimens. Stopping therapy in patients with high CD4 counts will generally result in patients reverting to their pretreatment nadir CD4 count in a matter of months and is therefore not recommended.
Although the ideal combination of medications has not yet been defined for all possible clinical situations, possible regimens can be better understood after a review of the available agents. These medications can be grouped into five major categories: nucleoside and nucleotide reverse transcriptase inhibitors (NRTI); nonnucleoside reverse transcriptase inhibitors (NNRTI); PIs; entry inhibitors, which include a fusion inhibitor and CCR5 antagonists; and integrase inhibitors. Once ART has been initiated in a patient, it is not advisable to stop the therapy unless there is a compelling reason (eg, toxicity, poor adherence, etc). So-called “drug holidays” or “structured treatment interruptions” have been shown to increase risk of AIDS-related complications, increase CD4 declines, and increase morbidity from non–AIDS-related complications (eg, myocardial infarctions and liver failure) and are not recommended.
Table 31–7. Fixed dose antiretroviral combinations.
Of the available agents, zidovudine is the most likely to cause anemia. Zidovudine and didanosine are the most likely to cause neutropenia. Stavudine is the most likely to cause lipoatrophy (loss of fat in the face, extremities, and buttocks) followed by zidovudine. Zalcitabine and didanosine are the most likely to cause peripheral neuropathy. Lamivudine, emtricitabine, and tenofovir have activity against hepatitis B. Didanosine, lamivudine, emtricitabine, and tenofovir can be administered daily. Information specific to each medication is given below, and recommendations on how to combine them appear in the Constructing regimens section below.
Abacavir is also formulated with zidovudine and lamivudine in a single pill (Trizivir, one tablet orally twice daily; Table 31–7). Trizivir is not recommended as solo treatment for HIV because it is not as efficacious as combining two nucleoside/nucleotide analogs with a PI/ritonavir or an NNRTI; its use as a sole regimen should be reserved only for patients who cannot tolerate a more complicated regimen.
Didanosine has been associated with pancreatitis. The incidence of pancreatitis with didanosine is 5–10%—of fatal pancreatitis, < 0.4%. Patients with a history of pancreatitis, as well as those taking other medications associated with pancreatitis (including trimethoprim-sulfamethoxazole and intravenous pentamidine) are at higher risk for this complication. Other common side effects with didanosine include a dose-related, reversible, painful peripheral neuropathy, which occurs in about 15% of patients, and dry mouth. Fulminant hepatic failure and electrolyte abnormalities, including hypokalemia, hypocalcemia, and hypomagnesemia, have been reported in patients taking didanosine. Because of the side-effect profile, didanosine is rarely used today.
The NNRTIs can be used with PIs in patients who are difficult to suppress on simpler regimens or when it is difficult to identify at least two nucleoside/nucleotide agents to which the patient is not resistant. Because these agents may cause alterations in the clearance of PIs, dose modifications may be necessary when these two classes of medications are administered concomitantly. There is a high degree of cross-resistance between the “first-generation” NNRTIs, such that resistance to one medication in this class uniformly predicts resistance to other medications. However, etravirine appears to have consistent antiviral activity in patients with prior exposure and resistance to nevirapine, efavirenz, or delavirdine. In particular, the K103N mutation does not appear to have an impact on etravirine (or rilpivirine). There is no therapeutic reason for using more than one NNRTI at the same time.
All the PIs—to differing degrees—are metabolized by the cytochrome P450 system, and each can inhibit and induce various P450 isoenzymes. Therefore, medication interactions are common and difficult to predict. Clinicians should consult the product inserts before prescribing PIs with other medications. Medications such as rifampin that are known to induce the P450 system should be avoided.
The fact that the PIs are dependent on metabolism through the cytochrome P450 system has led to the use of ritonavir to boost the medication levels of saquinavir, lopinavir, indinavir, atazanavir, tipranavir, darunavir and amprenavir, allowing use of lower doses and simpler dosing schedules of these PIs. In fact, current guidelines recommend that all PI-containing regimens use ritonavir boosting if possible. The only PIs that can be safely used without ritonavir boosting are nelfinavir and atazanavir.
When choosing which PI to use, prior patient experience, resistance patterns, side effects, and ease of administration are the major considerations. The first three PIs to be developed—indinavir, saquinavir, and ritonavir (as single agents)—are now rarely used because of the superiority of the second generation of PIs. Amprenavir has been almost entirely replaced by its prodrug, fosamprenavir. Unfortunately, all PIs, with the exception of unboosted atazanavir have been linked to a constellation of metabolic abnormalities, including elevated cholesterol levels, elevated triglyceride levels, insulin resistance, diabetes mellitus, and changes in body fat composition (eg, buffalo hump, abdominal obesity). The lipid abnormalities and body habitus changes are referred to as lipodystrophy. Although lipodystrophy is commonly associated with PIs, it has been seen also in HIV-infected persons who have never been treated with these agents. In particular, the lipoatrophy effects seen in patients receiving ART appears to be more related to the nucleoside toxicity and in particular to the thymidine analogs (stavudine and zidovudine).
Of the different manifestations of lipodystrophy, the dyslipidemias that occur are of particular concern because of the likelihood that increased levels of cholesterol and triglycerides will result in increased prevalence of heart disease. All patients taking PIs or NRTIs should have fasting serum cholesterol, low-density lipoprotein (LDL) cholesterol, and triglyceride levels performed every 12 months. Clinicians should calculate the Framingham 10-year coronary heart disease risk (see Chapter 28) and consider initiating dietary or medication therapy (or both) to achieve target LDL levels depending on the individual’s risk factors. Patients who are unable to meet their LDL goal based solely on dietary interventions should be given pravastatin (20 mg daily orally) or atorvastatin (10 mg daily orally). Lovastatin and simvastatin should be avoided because of their interactions with PIs. Fish oil (3000 mg daily) combined with exercise and dietary counseling has been found to decrease triglycerides levels by 25%. Patients with persistently elevated fasting serum triglyceride levels of 500 mg/dL or more who do not respond to dietary intervention should be treated with gemfibrozil (600 mg twice daily prior to the morning and evening meals).
Raltegravir is approved by the FDA for treatment-naïve patients. The dose of raltegravir is 400 mg orally twice daily. Common side effects are diarrhea, nausea, and headache, but overall it is well tolerated and has the additional advantage over PI-based regimens and efavirenz-based regimens in that appears to have little impact on lipid profiles or glucose metabolism.
Current evidence supports the use of Truvada (tenofovir and emtricitabine) as the “nucleoside/nucleotide backbone” combined with either efavirenz (three-medication combination marketed as Atripla) or one of two boosted PIs (atazanavir or darunavir) or any of the three available integrase inhibitors (raltegravir, dolutegravir or a boosted-integrase inhibitor [elvitegravir, marketed as a fixed-dose combination named Stribild]) as the initial regimen of choice (Table 31–8). In addition, the latest DHHS guidelines also classify dolutegravir combined with the nucleoside fixed dose combination of abacavir/lamivudine as a preferred regimen. These regimens are preferred because of their combination of antiviral potency and tolerability as well as dosing convenience. Atripla and Stribild offer the additional advantage of being available as a once-a-day single tablet and a once-a-day single tablet containing dolutegravir/abacavir/lamivudine is expected. Studies in treatment-naïve patients have demonstrated that raltegravir in combination with tenofovir/emtricitabine is as effective as efavirenz/tenofovir/emtricitabine for daily treatment and has fewer side effects. It has little adverse impact on lipid and glucose metabolism although it is not available in a single tablet. In a 5-year follow-up to the double-blind trial, the raltegravir arm actually out-performed the efavirenz combination regimen due largely to better long-term tolerability. Furthermore, the CD4 response appeared better in patients treated with the raltegravir combination. A single-pill regimen Complera (tenofovir, emtricitabine, and rilpivirine) is not considered a preferred option given its lower virologic efficacy in patients with high viral loads (ie, > 100,000/mL) but remains a very good choice with excellent tolerability in patients with lower viral loads. Because 8–10% of newly infected persons in some urban areas of the United States have NNRTI resistance (primarily K103N), resistance testing should be performed before initiating efavirenz in this population. Patients with NNRTI resistance would not be expected to respond fully to an efavirenz-based regimen. The boosted PI regimens require more pills, have many medication–medication interactions and may have additional undesirable metabolic impacts. In patients with increased risk of metabolic abnormalities or comorbidities, the unboosted integrase-based regimens should be considered preferred choices although lacking the convenience of once-a-day, single-pill regimens at present. Regimens that include only nucleoside and nucleotide analogs without nonnucleoside agents or PIs are clinically inferior and should only be used for patients that cannot adhere to a more complicated regimen.
Table 31–8. Preferred initial antiretroviral regimens.
The most important determinant of treatment efficacy is adherence to the regimen. Therefore, it is vitally important that the regimen chosen be one to which the patient can easily adhere (Figure 31–2). In general, patients are more compliant with medication regimens (Table 31–8) that offer a complete regimen in one pill that needs to be taken only once or twice a day, do not require special timing with regard to meals, can be taken at the same time as other medications, do not require refrigeration or special preparation, and do not have bothersome side effects.
Figure 31–2. Approach to initial and subsequent antiretroviral therapy.
In constructing regimens, toxicities should be nonoverlapping and agents that are either virologically antagonistic or incompatible in terms of drug–drug interactions should be avoided. For example, the combination of stavudine plus didanosine should be avoided, since there is increased risk of toxicities, in particular in pregnant women because of the increased risk of lactic acidosis, which can be fatal. Moreover, the nucleoside pair of zidovudine and stavudine should be avoided because of increased toxicity and the potential for antagonism that results from intracellular competition for phosphorylation. The combination of didanosine with tenofovir should be avoided because of observed declines in CD4 counts. Etravirine should not be used with boosted tipranavir because of drug-drug interactions. Finally, highly complex therapeutic regimens should be reserved for individuals who are capable of adhering to the rigorous demands of taking multiple medications and having this therapy closely monitored.
In designing second-line regimens for patients with resistance to initial therapy, the goal is to identify three medications from at least two different classes to which the virus is not resistant. This can be quite complicated because of the problem of cross-resistance between medications within a class. For example, the resistance patterns of lopinavir/ritonavir and indinavir are overlapping, and patients with virus resistant to these agents are unlikely to respond to nelfinavir or saquinavir even though they have never received treatment with these agents. Similarly, the resistance patterns of nevirapine and efavirenz are overlapping–as are the resistance patterns between raltegravir and elvitegravir. With several new classes of medications and new generations of existing medication classes now available, the ability to provide fully suppressive regimens even to patients with extensive treatment experience and medication resistance has become more realistic. The goal of therapy, therefore, should be to fully suppress viral loads to < 50 copies/mL even for highly treatment-experienced patients.
In addition to taking a careful history of what antiretroviral agents a patient has taken and for how long, genotypic and phenotypic resistance testing can provide useful information in designing second-line regimens.
Whatever regimen is chosen, patients should be coached in ways to improve adherence. For certain populations (eg, unstably housed individuals), specially tailored programs that include medication dispensing are needed.
Rarely, it is impossible to construct a tolerable regimen that fully suppresses HIV. In such cases, clinicians and patients should consider their goals. Patients maintained on effective antiretroviral agents often benefit from these regimens (eg, higher CD4 counts, fewer opportunistic infections) even if their virus is detectable. In some cases, patients may request a medication holiday during which they are taken off all medications. Patients often immediately feel better because of the absence of medication side effects. Unfortunately, structured treatment interruptions generally result in viral rebound and rapid CD4 decline followed by AIDS-related and non–AIDS-related morbidities and increased risk of death.
Current expert guidelines recommend resistance testing as part of standard baseline testing in all patients. Resistance testing is also recommended for patients who are receiving ART and have suboptimal viral suppression (ie, viral loads > 200 copies/mL). Both genotypic and phenotypic tests are commercially available and in randomized controlled studies their use has been shown to result in improved short-term virologic outcomes compared to making treatment choices without resistance testing. Furthermore, multiple retrospective studies have conclusively demonstrated that resistance tests provide prognostic information about virologic response to newly initiated therapy that cannot be gleaned from standard clinical information (ie, treatment history, examination, CD4 count, and viral load tests).
Because of the complexity of resistance tests, many clinicians require expert interpretation of results. In the case of genotypic assays, results may show that the mutations that are selected for during ART are medication-specific or contribute to broad cross-resistance to multiple medications within a therapeutic class. An example of a medication-specific mutation for the reverse transcriptase inhibitors would be the M184V mutation that is selected for by lamivudine or emtricitabine therapy—this mutation causes resistance only to those two medications. Conversely, the thymidine analog mutations (“TAMs”) of M41L, D67N, K70R, L210W, T215Y/F, and T219Q/K/E are selected for by either zidovudine or stavudine therapy, but cause resistance to all the medications in the class and often extend to the nucleotide inhibitor tenofovir when three or more of these TAMs are present. Further complicating the interpretation of genotypic tests is the fact that some mutations that cause resistance to one medication can actually make the virus that contains this mutation more sensitive to another medication. The M184V mutation, for example, is associated with increased sensitivity to zidovudine, stavudine, and tenofovir. The most common mutations associated with medication resistance and cross-resistance patterns for NRTIs, NNRTIs, PIs, and integrase inhibitors can be found at http://hivdb.stanford.edu. Phenotypic tests also require interpretation in that the distinction between a resistant virus and sensitive one is not fully defined for all available medications.
Both methods of resistance testing are limited by the fact that they may measure resistance in only some of the viral strains present in an individual. Resistance results may also be misleading if a patient is not taking antiretroviral medications at the time of testing. Thus, resistance results must be viewed cumulatively—ie, if resistance is reported to an agent on one test, it should be presumed to be present thereafter even if subsequent tests do not give the same result.
Despite the prevalence of resistance in patients who have not responded to multiple prior treatment regimens and given the availability of new class medications and new generation medications, virtually all patients—no matter how much resistance is present—can be treated with a combination of ART that should be fully suppressive.
Course & Prognosis
With improvements in therapy, patients are living longer after the diagnosis of AIDS. A population-based study conducted in Denmark found that HIV-infected persons at age 25 years without hepatitis C had a life expectancy similar to that of an uninfected 25-year-old. Unfortunately, not all HIV-infected persons have access to treatment. Studies consistently show less access to treatment for blacks, the homeless, and injection drug users. In addition to access to treatment, sustaining lower mortality will require developing new treatments for patients in whom resistance to existing agents develops. For patients whose disease progresses even though they are receiving appropriate treatment, meticulous palliative care must be provided (see Chapter 5), with attention to pain control, spiritual needs, and family (biologic and chosen) dynamics.
When to Refer
When to Admit
Patients with opportunistic infections who are acutely ill (eg, who are febrile, who have had rapid change of mental status, or who are in respiratory distress) or who require intravenous medications.
Abdool Karim SS et al. Integration of antiretroviral therapy with tuberculosis treatment. N Engl J Med. 2011 Oct 20;365(16):1492–501. [PMID: 22010915]
Cohen CJ et al; THRIVE Study Group. Rilpivirine versus efavirenz with two background nucleoside or nucleotide reverse transcriptase inhibitors in treatment-naïve adults infected with HIV-1 (Thrive): a phase 3, randomized, non-inferiority trial. Lancet. 2011;378(9787):229–37. [PMID: 21763935]
Eron JJ et al; BENCHMRK Study Teams. Efficacy and safety of raltegravir for treatment of HIV for 5 years in the BENCHMRK studies: final results of two randomised, placebo-controlled trials. Lancet Infect Dis. 2013 Jul;13(7):587–96. [PMID: 23664333]
Havlir DV et al; AIDS Clinical Trials Group Study A5221. Timing of antiretroviral therapy for HIV-1 infection and tuberculosis. N Engl J Med. 2011 Oct 20;365(16):1482–91. [PMID: 22010914]
Molina JM et al; ECHO Study Group. Rilpivirine versus efavirenz with tenofovir and emtricitabine in treatment-naïve adults infected with HIV-1 (ECHO): a phase 3 randomized double-blind active-controlled trial. Lancet. 2011 July 16;378 (9787):238–46. [PMID: 21763936]
Raffi F et al; extended SPRING-2 Study Group. Once-daily dolutegravir versus twice-daily raltegravir in antiretroviral-naive adults with HIV-1 infection (SPRING-2 study): 96 week results from a randomised, double-blind, non-inferiority trial. Lancet Infect Dis. 2013 Nov;13(11):927–35. [PMID: 24074642]
Rockstroh JK et al. A randomized, double-blind comparison of coformulated elvitegravir/cobicistat/emtricitabine/tenofovir DF vs ritonavir-boosted atazanavir plus coformulated emtricitabine and tenofovir DF for initial treatment of HIV-1 infection: analysis of week 96 results. J Acquir Immune Defic Syndr. 2013 Apr 15;62(5):483–6. [PMID: 23337366]
Török ME et al. Timing of initiation of antiretroviral therapy in human immunodeficiency virus (HIV)-associated tuberculous meningitis. Clin Infect Dis. 2011 Jun;52(11):1374–83. [PMID: 21596680]
U.S. Department of Health and Human Services. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. http://aidsinfo.nih.gov/guidelines/html/1/adult-and-adolescent-arv-guidelines/11/what-to-start
US Food and Drug Administration. FDA Drug Safety Communication: interactions between certain HIV or hepatitis C drugs and cholesterol-lowering statin drugs can increase the risk of muscle injury.http://www.fda.gov/Drugs/DrugSafety/ucm293877.htm
Walmsley SL et al; SINGLE Investigators. Dolutegravir plus abacavir-lamivudine for the treatment of HIV-1 infection. N Engl J Med. 2013 Nov 7;369(19):1807–18. [PMID: 24195548]
Wittkop L et al. Effect of transmitted drug resistance on virological and immunological response to initial combination antiretroviral therapy for HIV (EuroCoord-CHAIN joint project): a European multicohort study. Lancet Infect Dis. 2011 May;11(5):363–71. [PMID: 21354861]
Zolopa A et al; GS-US-236-0102 Study Team. A randomized double-blind comparison of coformulated elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate versus efavirenz/emtricitabine/tenofovir disoproxil fumarate for initial treatment of HIV-1 infection: analysis of week 96 results. J Acquir Immune Defic Syndr. 2013 May 1;63(1):96–100. [PMID: 23392460]