Part 5: AIDS-related Complaints

CHIEF COMPLAINT

MAKING A DIAGNOSIS

As noted above, 3 factors determine the positive predictive value of the test: the pretest probability, the sensitivity, and the specificity. Mr. A is asymptomatic and denies high-risk behaviors. However, he may not truly be at a low risk of HIV, since he had a prior sexually transmitted infection and did not always use a condom with his 4 sex partners. His history of alcohol binges may also point to forgotten prior high-risk behaviors. The history of simultaneous sexual partners is also a risk factor. His pretest probability of HIV infection is therefore significantly higher than he believes.

CASE RESOLUTION

Mr. A is infected with HIV-1 and his CD4TL count is diagnostic of immunologic AIDS. At this point, primary prophylaxis with trimethoprim-sulfamethoxazole (TMP/SMX) is indicated to prevent PJP because the CD4TL count is < 200 cells/mcL. Prophylaxis for toxoplasmosis is not necessary since he is seronegative for T gondii. He does not need isoniazid since his IGRA is negative.

The patient should undergo blood testing for CBC with platelets, comprehensive metabolic panel, lipid panel, HBsAg, HBsAb, HBc total Ab, HCV Ab with reflex HCV viral load, G6PD level, and syphilis testing (using the reverse sequence syphilis algorithm). Urine nucleic acid test for Chlamydia and N gonorrhoeae is recommended. He should receive the influenza vaccine as well as two conjugate vaccines: TDAP and the conjugated 13-valent pneumococcal vaccine (Prenar-13), which are both highly immunogenic. Two months later he can receive the polysaccharide 23-valent pneumococcal vaccine (Pneumovax 23), but it is best to wait until the CD4 has increased > 200 cells/mcL to improve immunogenicity. Hepatitis B and hepatitis A combined vaccine series should also be offered after the CD4 has increased above 200 cells/mcL.

He is in a monogamous sexual relationship with an HIV seronegative, uninfected female partner. To decrease her risk of acquiring HIV, they should use barrier precautions (male or female condoms are 95% effective), and he should start ART to lower his HIV viral load to below the level of detection (treatment as prevention > 95% effective). If he is adherent to ART and his viral load is kept below 20 copies/mL, there is virtually no risk of transmission. However, the use of barrier precautions is a safety feature in case he developed a detectable viral load due to imperfect adherence to ART. Another approach if barrier precautions are not acceptable or adhered to is to provide preexposure prophylaxis with the combination of tenofovir disoproxyl fumarate and emtricitabine daily to his girlfriend. The tenofovir alafenamide and emtricitabine combination is not yet approved for preexposure prophylaxis but the DISCOVER trial is expected to provide this information by 2019. If effective, it would be associated with less nephrotoxicity and osteoporosis.

CHIEF COMPLAINT

CONSTRUCTING A DIFFERENTIAL DIAGNOSIS

Three pivotal considerations help frame the differential diagnosis in HIV-infected persons with neurologic complaints: (1) the acuity of the symptoms, (2) the degree of immunosuppression (CD4TL), and (3) whether the patient has focal neurologic signs and/or a focal abnormality on neuroimaging.

The first pivotal step in evaluating the HIV-positive patient with headache is to determine the acuity of the presentation. Most OIs have a subacute onset. In HIV-infected patients with an acute onset of headache and fever (< 3 days), virulent pathogens must be considered including bacterial meningitis and viral encephalitis, most commonly herpes simplex-1 (HSV-1) and West Nile virus encephalitis.

The second pivotal issue is to assess the degree of immunosuppression. HIV-positive patients with intact immunity and CD4TL > 200 cells/mcL are at markedly diminished risk of OIs. The differential diagnosis of such headaches is therefore similar to patients without HIV infection; however, HIV itself can cause aseptic meningitis or encephalopathy in acute HIV with high viral loads. As the immunosuppression worsens and the CD4TL falls < 200 cells/mcL, the differential diagnosis broadens to include OIs and PCL.

The third pivotal issue is to determine whether or not the patient has focal neurologic signs typically associated with a focal abnormality on neuroimaging (mass lesion or focal white matter disease). The most common diagnoses in HIV-infected patients with low CD4TL who have focal neurologic signs or mass lesions on neuroimaging are toxoplasmosis and PCL, as well as PML (plaques of demyelination). The most common diagnoses in HIV-infected patients with low CD4TL who have a nonfocal neurologic presentation and without focal findings on neuroimaging are cryptococcal meningitis, other fungal meningitis (coccidioidomycosis and histoplasmosis), TB meningitis, and syphilis. Both CNS imaging (CT and MRI) and lumbar puncture (LP) are frequently required to confirm the diagnosis. In clinical practice, a CT scan is usually performed prior to LP because it rapidly rules out a large mass lesion that may cause post LP herniation. Platelet count, prothrombin time, and partial thromboplastin time should be checked to ensure the patient is not at an increased risk for developing a spinal epidural hemorrhage from the LP. An MRI is often performed subsequently due to its substantially increased sensitivity for several diagnoses. A diagnostic algorithm for the evaluation of headache in HIV-positive patients is summarized in Figure 5-4.

RANKING THE DIFFERENTIAL DIAGNOSIS

The first pivotal consideration is that Mr. S has had a headache for 2 weeks (subacute). This suggests a relatively less virulent OI rather than a virulent bacterial meningitis or HSV-1 encephalitis. Second, his prior CD4TL indicates profound immunosuppression. Therefore, he is at risk for all the serious OIs listed above. The third pivotal issue is whether there is a mass lesion. Ultimately, this will be confirmed or excluded on neuroimaging, but his photophobia suggests some form of meningoencephalitis. Cryptococcal meningitis is the most common meningitis seen in AIDS and is the leading hypothesis. Less common causes of meningoencephalitis include neurosyphilis, TB meningitis, and other fungal meningitis (coccidioidomycosis in the southwestern United States, and histoplasmosis and blastomycosis in the Midwest). HIV aseptic meningitis may present with headache. Should neuroimaging confirm a focal abnormality, common causes include toxoplasmosis, PML, and PCL. Since Mr. S has not taken TMP-SMX prophylaxis, he is at increased risk for toxoplasmosis, the most common CNS mass lesion in AIDS patients. Finally, given his history of IDU, he is also at risk for a brain abscess secondary to Staphylococcus aureus. Table 5-2 lists the differential diagnoses.

The normal CT scan markedly diminishes the likelihood of the diseases associated with mass lesion and increases the likelihood of one of the remaining causes of meningitis (Cryptococcus, neurosyphilis, TB). Cryptococcus is the most common. However, a brain MRI is more sensitive for mass lesions and demyelinating lesions and should be performed.

MAKING A DIAGNOSIS

The CSF findings strongly suggest cryptococcal meningitis. Positive CRAG or fungal culture will confirm the diagnosis. However, patients with AIDS may have simultaneous infections and you review other diagnoses on the differential. There is no travel history to the southwestern United States that would increase the probability of coccidioidomycosis. Neurosyphilis is highly unlikely because of the negative CSF venereal disease research laboratory (VDRL) and serum TP-EIA. An MRI is more sensitive in the detection of CNS mass lesions than a contrast CT and is indicated to confidently exclude alternative diagnoses associated with masses or demyelination.

Of note, multiplex (multi-target) PCR testing is available for CNS infections. For example, the BioFire FilmArray meningitis/encephalitis panel detects 14 targets including one fungal target (C neoformans/gattii), 6 bacterial targets (S pneumoniae, N meningitidis, L monocytogenes, Haemophilus influenzae, Escherichia coli K1, and Streptococcus agalactiae) and 7 viral targets (CMV, enterovirus, parechovirus, HSV-1, HSV-2, HHV-6, and VZV). The sensitivity of this test to detect Cryptococcus is reported high (96%) in untreated cryptococcal meningitis. With treatment, the PCR becomes negative rapidly, whereas the CSF CRAG remains detectable for months. When using a new diagnostic test like a multiplex PCR test for meningoencephalitis, it is essential to consider reported sensitivity and specificity as preliminary because later data may identify unrecognized test limitations (resulting in more false-positive and/or false-negative test results).

CASE RESOLUTION

Mr. S’s CSF culture confirms cryptococcal meningitis. The subacute course and lack of meningeal findings are common features of this disease. CSF analysis did not suggest concomitant mycobacterial infection or neurosyphilis, and the MRI did not suggest toxoplasmosis, PML or PCL.

CHIEF COMPLAINT

CONSTRUCTING A DIFFERENTIAL DIAGNOSIS

The most common pneumonias in HIV-infected patients are bacterial pneumonia, PJP, and pulmonary TB. Taken together, they account for 91% of pulmonary infections in HIV-positive patients. Three pivotal features aid in the diagnosis of these common pneumonias in HIV-infected persons. First, the CD4TL count gauges the level of immunocompromise. Virulent infections, such as pulmonary TB or bacterial pneumonia, may occur in patients with any CD4TL count. On the other hand, less virulent infections, such as PJP, are seen almost exclusively in patients with CD4TL < 200 cells/mcL.

The second pivotal feature is that certain diseases present acutely (bacterial pneumonia), but other diseases present subacutely or chronically (pulmonary TB or PJP).

The final pivotal feature that aids in the diagnosis of these complaints is the pattern on chest radiograph. Lobar infiltrates suggest bacterial pneumonia, whereas diffuse or interstitial infiltrates are seen in PJP and TB. Patterns that suggest pulmonary TB include apical or cavitary infiltrates (if CD4TL > 200 cells/mcL), hilar lymphadenopathy, or nodular infiltrates. The chest radiographic pattern in pulmonary TB varies depending on the patient’s degree of immunosuppression. Table 5-4 summarizes the typical CD4TL count, acuity, and chest radiographic pattern and approach to pulmonary infection in HIV-positive patients.

Tumors may also cause pulmonary complaints. Not surprisingly, aggressive neoplasms, such as lung cancer, may occur at any CD4TL count, whereas pulmonary lymphoma usually develops in patients with CD4TL counts < 500 cells/mcL, and Kaposi sarcoma usually develops in patients with CD4TL < 200 cells/mcL.

As noted above, the most common pneumonias in HIV-infected patients are bacterial pneumonia, PJP and pulmonary TB. PJP is reviewed in Chapter 10-10: Pneumocystis Jirovecii Pneumonia (PJP) and will be mentioned here only briefly. There are a large number of less common causes of pneumonia in HIV-infected patients that will not be reviewed here including endemic or geographically limited fungi (blastomycosis, coccidioidomycosis, and histoplasmosis), opportunistic fungi (cryptococcosis and, in late AIDS, aspergillosis), uncommon bacterial pathogens (Nocardia, Rhodococcus equi, M kanasii) and CMV. The remainder of this section will focus on bacterial pneumonia, pulmonary TB, and M avium infection in HIV-infected patients.

RANKING THE DIFFERENTIAL DIAGNOSIS

There are 2 key features to Mr. L’s presentation. The first pivotal feature is that his CD4TL count is only moderately reduced. This makes a variety of OIs unlikely (PJP, MAI, CMV, and cryptococcosis). On the other hand, pulmonary TB, bacterial pneumonia, and blastomycosis are sufficiently virulent to present in patients with normal or mildly impaired immune systems. The second pivotal feature is the rapid development of the pulmonary process, which strongly favors bacterial pneumonia over pulmonary TB. The differential diagnosis is summarized in Table 5-5.

MAKING A DIAGNOSIS

A critical decision at this point in the evaluation of an HIV-infected patient with pulmonary complaints is whether the patient needs bronchoscopy with bronchoalveolar lavage to establish the causative pathogen. In HIV-positive patients with infiltrates, bronchoalveolar lavage is highly sensitive (86%) if performed within 24 hours of starting antibiotics. Transbronchial biopsy increases the sensitivity further but is rarely performed. Due to the large number of potential pathogens, empiric treatment for community-acquired bacterial pneumonia is often inappropriate except in the cases in which bacterial pneumonia is strongly suspected. Acute onset and focal infiltrates suggest bacterial pneumonia whereas subacute/chronic progression, diffuse infiltrates, and cavitary lesions suggest other etiologies. Bronchoscopy is often necessary in such cases unless sputum analysis is diagnostic (positive AFB or rarely positive silver stain). Mr. L’s acute illness, and focal findings on the chest radiograph strongly suggest bacterial pneumonia. You wonder if pulmonary TB would present similarly in an HIV positive patient with this CD4TL count.

CASE RESOLUTION

Table 5-9 summarizes the predictive value of clinical, radiologic, and combined findings for the diagnosis of PJP, pulmonary TB, and bacterial pneumonia in HIV-infected patients.

TEXTBOOK PRESENTATION

Typical onset is acute (< 1 week) with productive cough and fever. Patients may produce purulent sputum and complain of pleuritic chest pain. Presentation is similar to bacterial pneumonia in HIV-negative patients.

DISEASE HIGHLIGHTS

1. Bacterial infection is the most common cause of pneumonia associated with HIV and AIDS. HIV should therefore be considered in any patient with severe or recurrent community-­acquired pneumonia.

2. Recurrent bacterial pneumonia (> 2 episodes within 1 year) is an AIDS-defining condition.

3. May occur at any time during course of HIV infection

4. Risk of bacterial pneumonia increases as CD4TL count falls. IDU further increases the risk.

   1. CD4TL count

      1. Rate of bacterial pneumonia in HIV-negative patients: 0.9%/year

      2. Rate of bacterial pneumonia in HIV-positive patients

         1. CD4TL > 500 cells/mcL: 2.3%/year

         2. CD4TL 200–500 cells/mcL: 6.8%/year

         3. CD4TL < 200 cells/mcL: 10.8%/year

         4. Two-thirds of cases in HIV-infected patients developed in those with CD4TL < 200 cells/mcL.

   2. IDU

      1. Pneumonia incidence in HIV-infected patients who are IDUs is twice that in HIV-infected patients who are not IDUs.

      2. Increased rate of septic emboli from infective endocarditis contribute to the increased risk of pneumonia.

   3. ART significantly reduces the risk of bacterial pneumonia (45%).

5. Etiology

   1. S pneumoniae is the most common cause of bacterial pneumonia. Other common bacterial etiologies are H influenzae; Mycoplasma pneumoniae; Legionella; S aureus, including community-acquired methicillin-resistant S aureus; and Pseudomonas aeruginosa.

   2. S pneumoniae is associated with higher WBC than P aeruginosa (12,400/mcL vs 5000/mcL) and higher average CD4TL count (106 cells/mcL vs 19 cells/mcL).

   3. P aeruginosa is the reported causative pathogen in up to 38% of hospital-acquired pneumonias and 3–25% of community-acquired pneumonias; it is associated with 33% in-hospital mortality rate.

   4. Concomitant PJP is present in 13% of patients with bacterial pneumonia.

6. Complications and prognosis

   1. Bacterial pneumonia progresses more rapidly and is more often complicated in HIV-infected persons than in Non-HIV infected persons.

   2. 30% of bacterial pneumonias are associated with bacteremia; bacteremia is more common with S pneumoniae.

   3. Among hospitalized patients, overall mortality is 9.3–27%.

      1. 6–13 times higher mortality than general US population (and 1.2–2.4 times higher than population > 65 years)

      2. 5 predictors of mortality include septic shock, CD4TL count < 100 cells/mcL, significant pleural effusion (extending beyond costophrenic angle), cavities and multilobar infiltrates. Mortality is proportional to number of risk factors (Table 5-6).

      3. Mortality increases during influenza season. Influenza infection may result in either severe influenza virus pneumonia or bacterial pneumonia, most often due to S pneumoniae or S aureus.

7. Pyogenic bacterial bronchitis with productive cough, fever, and absence of infiltrates is more common in HIV-infected patients.

TEXTBOOK PRESENTATION

Patients typically have a subacute headache, malaise, and fever that develop over days to weeks. Mental status changes may be seen. Importantly, meningismus is often absent due to the host’s inability to mount an inflammatory reaction.

DISEASE HIGHLIGHTS

1. Most common cause of meningoencephalitis in AIDS

2. Encapsulated fungus acquired via inhalation

3. CNS infection due to dissemination of primary infection

4. Usually in patients with CD4TL < 100 cells/mcL

5. Subacute onset over 2–4 weeks

6. Basilar meningitis or meningoencephalitis: classic meningeal symptoms and signs (neck stiffness, photophobia) present in a minority of patients (25–30%)

7. 70% of patients have increased intracranial pressure: > 20 cm H₂O in lateral decubitus position.

   1. Elevated intracranial pressure associated with increased risk of death

   2. Patients with elevated intracranial pressure have worse symptoms (headaches, clouded sensorium).

8. Meningovascular presentation (cerebrovascular accident from arteritis) and cryptococcoma (mass lesion) may be seen.

9. Mortality 6–12%

EVIDENCE-BASED DIAGNOSIS

1. History

   1. Fever: 65–95%

   2. Headache: 73–100%

   3. Median duration of symptoms: 31 days (1–120 days)

2. Physical exam

   1. Stiff neck: 22–27%

   2. Photophobia: 18–22%

   3. Mental status changes: 22%

   4. Focal neurologic signs or seizures: 10%

   5. No CNS signs or symptoms: 14%

   Cryptococcal meningitis in AIDS patients is often indolent. Only a minority of patients exhibit meningismus or photophobia. Some patients have only low-grade fever and malaise. A supple neck does not rule out the diagnosis, and a high index of suspicion is required.

3. Laboratory findings

   1. Blood tests

      1. Blood cultures positive in 55% in AIDS, much higher than in other populations with cryptococcal meningitis

      2. Serum cryptococcal antigen (CRAG)

         1. 95–100% sensitive, 96% specific

         2. LR+, 24; LR–, 0.05

         3. Negative serum CRAG makes cryptococcal meningitis unlikely.

         4. A positive serum CRAG may precede clinical cryptococcal meningitis by weeks to months.

   2. LP

      1. Neuroimaging required before LP to rule out mass effect. Mass lesions are often due to concomitant toxoplasmosis or PCL, and only rarely due to cryptococcoma.

      2. A platelet count, prothrombin time, and partial thromboplastin time are performed before LP to rule out a bleeding diathesis, with its risk of spinal epidural hematoma.

      3. LP is required in patients with suspected cryptococcal meningoencephalitis regardless of serum CRAG results.

         1. In patients with positive serum CRAG, LP is necessary to confirm cryptococcal meningitis, measure opening pressure, manage high intracranial pressure, and exclude other diagnoses.

         2. In patients with negative serum CRAG, LP is necessary to evaluate other diagnoses.

      4. Routine CSF findings are often normal or minimally abnormal in patients with cryptococcal meningitis.

         1. Normal glucose, protein, and WBC: 19–30%

         2. Glucose < 50 mg/dL: 64%

         3. Protein > 40 mg/dL: 64%

         4. CSF WBCs > 5 cells/mcL: 35%

         5. Increased opening pressure: 50–75%

         Routine CSF findings in patients with cryptococcal meningitis may be normal. Specific studies (fungal culture, cryptococcal antigen) must be obtained.

      5. Special CSF studies

         1. CSF CRAG: 91–100% sensitive, 93–98% specific

         2. CSF fungal culture: 95–100% sensitive, 100% specific

         3. CSF Gram stain may be positive, and India ink detects encapsulated yeast in 60–80% of cases but is no longer performed routinely.

         4. Cryptococcus polymerase chain reaction (PCR) may be included as part of a CSF multi-target PCR panel used for the diagnosis of meningoencephalitis (see below).

TREATMENT

1. Mortality is increased in patients with abnormal mental status, an increased opening pressure on LP, and those with a markedly elevated CSF CRAG (> 1:1024). Low glycorrachia and normal CSF cell counts also predict poor outcomes.

2. Induction therapy relies on the combination of IV liposomal amphotericin B (3–4 mg/kg) and oral flucytosine (100 mg/kg) for at least 2 weeks, and at least until clinical improvement and sterilization of CSF cultures.

3. After successful induction therapy, high-dose fluconazole (400 mg/day) is substituted for an additional 8–10 weeks.

4. Maintenance therapy should then be continued with lower-dose fluconazole (200 mg/day) for a minimum of 1 year. Usually fluconazole is then stopped in patients with an excellent response to ART and CD4TL > 100 cells/mcL.

5. In patients with high intracranial pressure, serial LPs are performed to lower opening pressure to < 20 cm H₂O or by 50%; patients with hydrocephalus may require ventricular shunts.

6. Optimal timing of starting ART is controversial in cryptococcal meningitis. Clearly, ART-associated IRIS can result in worsening intracranial pressure and neurologic status. It is reasonable to delay initiation of ART for at least 4 weeks or even longer if intracranial pressure remains elevated.

1. Acute neurologic presentation

   1. Bacterial meningitis due to Neisseria meningitidis, S pneumoniae, or Listeria monocytogenes

   2. Aseptic meningitis due to HIV or syphilis (especially secondary syphilis)

   3. Meningoencephalitis due to HSV-1, West Nile virus, or acute HIV infection

   4. Guillain-Barré syndrome associated with HIV infection

2. Neurologic presentation with subacute meningitis

   1. Cryptococcal meningitis

   2. Coccidioidomycosis (southwestern United States)

   3. Histoplasmosis and blastomycosis (Midwest)

   4. TB meningitis

   5. Meningovascular syphilis

3. Nonfocal neurologic presentation with diffuse, chronic brain involvement

   1. HIV encephalopathy in advanced AIDS

   2. CMV encephalitis

   3. Neurosyphilis with general paresis and dementia

4. Mass lesions or focal demyelination

   1. Toxoplasmosis (rim-enhancing mass lesions)

   2. PCL (diffusely-enhancing mass lesions)

   3. PML (focal areas of demyelination without enhancement or mass effect)

   4. Uncommon mass lesions: tuberculoma, cryptococcoma, Nocardia brain abscess, bacterial or fungal brain abscess

1. CD4TL count > 500 cells/mcL

   1. Bacterial pneumonia

   2. Pulmonary TB

   3. Lung cancer

2. CD4TL count 200–499 cells/mcL: all of the above plus lymphoma

3. CD4TL count 100–199 cells/mcL: all of the above plus PJP

4. CD4TL count < 100 cells/mcL: all of the above plus the following:

   1. Fungal infections (blastomycosis, coccidioidomycosis, cryptococcosis, histoplasmosis, and aspergillosis)

   2. CMV: when found in bronchoalveolar lavage culture, it usually reflects asymptomatic reactivation rather than the etiology of pneumonia, although CMV is occasionally responsible for pneumonia in advanced AIDS.

   3. Nontuberculous mycobacteria, especially MAI and M kansasii

   4. Kaposi sarcoma

1. Initial evaluation

   1. Should include a chest radiograph, blood and sputum cultures, sputum Gram stain, and WBC

   2. Urinary pneumococcal and Legionella pneumophila serogroup 1 Ag testing is performed routinely and often helpful.

2. Airborne precautions should be followed in all HIV-infected patients with pneumonia.

   1. They should be placed in a negative-pressure isolation room.

   2. 3 sputum acid-fast stains should be done to rule out pulmonary TB.

3. Toxic appearance is uncommon but suggests bacterial pneumonia over PJP or pulmonary TB (sensitivity, 10.6%; specificity, 97.8%; LR+, 4.8)

4. Pneumococcal pneumonia

   1. Common symptoms include cough (93%), subjective fever (90%), pleural pain (52–91%), and chills (74%); 51% of patients have hemoptysis and 63% have temperature > 38°C.

   2. The median duration of symptoms is 4 days.

   3. Sputum Gram stain is 58% sensitive and more frequently positive if collected within 24 hours of antibiotics.

   4. Sputum culture is 56% sensitive: the real pathogen is more often isolated if sputum culture is performed before starting antibiotics. When sputum culture is delayed > 24 hours after starting antibiotic, respiratory colonizers are more often isolated; for example, a respiratory sample obtained from a person with severe pneumonia caused by S pneumoniae who has been intubated in the ICU for 48 hours may grow P aeruginosa that colonizes the ventilator tubing without causing pneumonia.

   5. Blood cultures are positive in 31–95%.

   6. Pneumococcal urinary Ag: ≈79% sensitive and 94% specific (LR+, 13; LR–, 0.2). The test may be also be positive due to colonization or upper respiratory infections with S pneumoniae.

   Antibacterial coverage should not be limited to S pneumoniae in HIV-infected patients with pneumonia and a positive pneumococcal urinary Ag.

5. Legionella pneumonia

   1. One study reported that certain findings were more common in patients with Legionella pneumonia than S pneumoniae, including extra-respiratory symptoms (57% vs 24%), hyponatremia (57% vs 13%), and elevated creatine phosphokinase (57% vs 17%).

   2. Respiratory failure is more common with Legionella than S pneumoniae (33% vs 2%).

6. M pneumoniae is usually diagnosed by IgM ELISA, 4-fold change in IgG, or the presence of cold agglutination.

7. Chest radiograph

   1. Standard imaging includes posteroanterior plus lateral chest radiograph.

   2. Typically demonstrates lobar or multifocal consolidation.

   3. Lobar consolidation is not always seen but strongly suggests bacterial pneumonia over PJP or pulmonary TB (sensitivity, 54%; specificity, 90%; LR+, 5.6; LR–, 0.51).

   4. Lobar infiltrates in patients with fever for < 1 week strongly suggests bacterial pneumonia (sensitivity, 48%; specificity, 94%; LR+, 8.0; LR–, 0.55).

   5. Chest radiographic patterns did not distinguish S pneumoniae from P aeruginosa or Legionella infection.

   6. One report found that 82% of HIV-infected persons with pulmonary complaints had abnormalities, including pleural effusions, cavities and abscess, on high-resolution CT scans that were not detected on chest radiograph.

   High-resolution CT scanning should be considered for HIV-infected patients who do not respond to therapy and for ill patients with respiratory symptoms or signs but an unexpectedly normal chest radiograph.

8. Bronchoscopy

   1. Indicated in patients who do not respond to therapy or when concomitant infection is likely.

   2. Sensitivity of bronchoalveolar lavage for bacterial pneumonia: 70% (if performed early)

TREATMENT

1. Prevention

   1. TMP-SMX PJP prophylaxis in patients with a CD4TL count < 200 cells/mcL also decreases the incidence of bacterial pneumonia by 67%.

   2. Pneumococcal vaccines

      1. Two pneumococcal vaccines are recommended in HIV-infected persons: the 13-valent conjugated pneumococcal vaccine (Prevnar-13) and the 23-valent polysaccharide pneumococcal vaccine (Pneumovax). Both decrease pneumococcal disease significantly, but the combination is superior.

      2. The 23-valent polysaccharide pneumococcal vaccine covers 86% of serotypes but is not as immunogenic as the 13-valent conjugated pneumococcal vaccine.

      3. CDC recommends pneumococcal vaccine use as early as possible in HIV infection.

         1. Vaccination should be delayed 4 weeks in individuals initiating ART to allow for immune reconstitution.

         2. Usually, the more immunogenic conjugated pneumococcal vaccine is administered first, and the less immunogenic polysaccharide vaccine is administered 2 months later, although it may be preferable to wait for the latter until CD4 > 200 cells/mcL.

      4. A polysaccharide pneumococcal vaccine booster is recommended every 5 years. A booster may also be useful in patients whose initial CD4TL is < 200 cells/mcL after significant immune reconstitution occurs (an increase of CD4TL > 100 cells/mcL).

   3. Therapy for typical bacterial pneumonia is usually initiated empirically.

   4. Inappropriate antimicrobial therapy is associated with markedly increased mortality in patients with shock (85.7% compared with 25% with appropriate therapy).

   5. Antibiotics must cover common pathogens (S pneumoniae, S aureus, H influenzae, M pneumoniae, and P aeruginosa). Local resistance patterns should be considered.

   6. A common strategy includes azithromycin and ceftriaxone.

   7. There should be a low threshold for including anti-methicillin-resistant S aureus coverage, particularly in patients with a history of IDU; patients undergoing hemodialysis; MSMs; and patients with severe, presumably bacterial, pneumonia during influenza season.

   8. Pseudomonas infection

      1. Should be considered when the CD4TL is low.

      2. Treat with an antipseudomonal beta-lactam antibiotic

         1. Piperacillin/tazobactam, cefepime, ceftazidime, meropenem

         2. Ceftazidime/avibactam or ceftolozane/tazobactam for multidrug-resistant P aeruginosa isolates

      3. An aminoglycoside (usually tobramycin) may be added initially pending susceptibility data, but there is no benefit of continuing tobramycin if Pseudomonas is susceptible to the antipseudomonal beta-lactam.

   9. Patients with uncomplicated pneumonia have a time course of clinical and radiologic response to therapy similar to non–HIV-infected persons.

TEXTBOOK PRESENTATION

Patients with severe HIV encephalopathy typically have advanced AIDS with a slowly progressive dementia eventually accompanied by motor symptoms.

DISEASE HIGHLIGHTS

1. Subcortical dementia characterized by cognitive, behavioral, and psychomotor slowing

2. Prevalence 15–20% in AIDS prior to introduction of ART

3. 40–50% decrease in incidence since the introduction of ART. However, prevalence is rising due to increasing survival.

4. Severe form of HIV encephalopathy effectively eliminated if treated with ART

5. Milder deficits still commonly detected by neuropsychological testing

6. Principal target of HIV virus is perivascular CNS macrophages. Astrocytes may also become infected.

7. Severe HIV encephalopathy develops late with CD4TL typically < 200 cells/mcL.

8. Two-fold increased risk in patients aged ≥ 50 years.

9. Neurotoxicity of HIV may be synergistic with that of cocaine or methamphetamine.

EVIDENCE-BASED DIAGNOSIS

1. History and physical exam

   1. Memory complaints: 70%

   2. Cognitive slowing: 25–30%

   3. Gait difficulty: 45%

   4. Behavioral changes: 10–20%

   5. Seizures: 5–10%

   6. Focal findings uncommon

2. Laboratory findings

   1. MRI: T2 images with hyperintensities in the deep white matter and basal ganglia without contrast enhancement and/or atrophy; the distribution of lesions is symmetrical in contrast to PML lesions.

   2. CSF

      1. Useful to rule out other infections

      2. Mild CSF leukocytosis and protein elevations may be seen.

      3. CSF HIV RNA levels are not useful because they do not correlate with the severity of HIV encephalopathy.

      4. Cannot diagnose HIV encephalopathy with certainty

   3. Neuropsychological testing useful in evaluating the severity and response to ART

   HIV encephalopathy is a diagnosis of exclusion. Diagnostic evaluations serve to exclude other OIs, malignancy, or substance abuse.

TREATMENT

1. Most patients treated with ART show only partial reversal of neurologic deficits. Early therapy is therefore important.

2. Elevated levels of CSF beta-microglobulin (suggesting ongoing inflammation) predicted better neurologic recovery with ART.

TEXTBOOK PRESENTATION

Patients are typically HIV-positive MSM who present with a rash composed of nodular, nontender, pink to violaceous papules and nodules.

DISEASE HIGHLIGHTS

1. Caused by human herpes virus 8 (HHV 8) associated with HIV

2. Most affected patients are MSMs. Individual lesions are pink, red, or purple, and nontender in most cases.

3. Lesions on the extremities, trunk and face (Figure 5-11)

4. With decreasing CD4TL, the number of lesions increases.

5. Skin involvement is almost always present in Kaposi sarcoma.

6. Extracutaneous involvement includes oral cavity, gastrointestinal tract, lymph nodes and lungs (Figure 5-12).

7. Gastrointestinal involvement is common (40%) but usually asymptomatic. Bleeding and bowel perforation are uncommon complications.

8. Pleuro-pulmonary involvement common in advanced Kaposi sarcoma

   1. Presentations of pulmonary Kaposi sarcoma include lung nodules, infiltrates, dyspnea, large pleural effusions, and respiratory failure.

   2. Patient survival is shortened.

9. The incidence of Kaposi sarcoma has decreased dramatically, only in part due to the introduction of effective ART. A change in sexual behavior has also contributed to this decline.

EVIDENCE-BASED DIAGNOSIS

1. Skin biopsy shows the typical angioproliferation with slit-like vascular spaces and spindle cells.

2. Immunohistochemistry detects HHV 8 in infected endothelial cells.

3. Gastrointestinal Kaposi sarcoma: endoscopy is clinically suggestive, but the submucosal location of lesions makes tissue diagnosis difficult.

4. Pulmonary Kaposi sarcoma: high-resolution chest CT suggestive; bronchoscopy may show the lesions

TREATMENT

Effective ART is highly effective in early Kaposi sarcoma, but chemotherapy is required in pulmonary involvement.

TEXTBOOK PRESENTATION

MAI typically presents with constitutional symptoms, including fever, drenching sweats, and weight loss.

DISEASE HIGHLIGHTS

1. MAI (also known as Mycobacterium avium complex (MAC)) refers to M avium and M intracellulare. M avium is by far the most common nontuberculous mycobacteria in AIDS patients.

2. M avium is acquired through inhalation or ingestion.

3. No human-to-human transmission

4. Infection is common in immunocompetent persons, and pulmonary MAI disease may be progressive and require treatment.

5. Disseminated MAC

   1. Usually occurs in patients with profound immunosuppression.

      1. CD4TL < 50 cells/mcL in almost all disseminated MAC cases

      2. Mean CD4TL: 7 cells/mcL

   2. Disseminated MAC involves the liver, spleen, gastrointestinal tract, lungs, and bone marrow.

      1. Cultures of blood, bone marrow, and urine may be positive.

      2. Predominantly pulmonary or gastrointestinal disease is uncommon.

      3. Constitutional symptoms predominate.

   3. MAI detection in sputum and stool often indicate colonization rather than disease.

   4. Pulmonary disease occurs in < 5% of patients with disseminated disease. Nodules, infiltrates, lymphadenopathy, and cavities may be seen.

6. Marked decreased incidence of disseminated MAC since the introduction of ART.

EVIDENCE-BASED DIAGNOSIS

1. Signs and symptoms

   1. Fever: 18–87%

   2. Night sweats: 78%

   3. Cough: 78%

   4. Diarrhea: 32–47%

   5. Weight loss: 32–100%

   6. Hepatosplenomegaly: 24%

2. Laboratory findings

   1. Anemia: 85%

   2. Increased alkaline phosphatase: 45–53%

3. Culture

   1. Blood culture for AFB: 50–95% sensitive

   2. Bone marrow culture: 82% sensitive

4. Sputum

   1. Smears may be positive for AFB.

   2. Rapid PCR testing can distinguish MAI from TB in patients with positive AFB smears.

5. Chest radiograph

   1. Usually normal

   2. May demonstrate patchy consolidation, nodules, or cavities

TREATMENT

1. Therapy of disseminated MAC includes clarithromycin and ethambutol, plus rifabutin, especially in sicker patients. Drug interactions are complex and infectious disease consultation is recommended.

2. Susceptibility testing to macrolides should be performed at baseline and whenever patients do not respond to the treatment regimen.

3. Therapy may be discontinued after 1 year in patients responding to ART with CD4TL > 100 cells/mcL for more than 6 months.

4. Pulmonary infiltrates, hepatosplenomegaly, lymphadenopathy, or systemic symptoms may develop anew or worsen during institution of ART (IRIS).

TEXTBOOK PRESENTATION

Patients with neurosyphilis may be asymptomatic or have a number of clinical presentations, including aseptic meningitis, stroke-like symptoms, visual impairment, hearing loss, dementia, and various focal deficits.

DISEASE HIGHLIGHTS

1. Caused by the spirochete T pallidum

2. High-risk groups: MSMs, IDUs, and patrons of sex workers

3. Association of HIV and syphilis infection

   1. Studies document a high HIV coinfection rate in patients with syphilis: CDC reports that in 2016 among primary and secondary syphilis cases with known HIV-status, 47.0% of cases among MSM were HIV-positive, compared with 10.7% of cases among men who have sex with women, and 4.1% of cases among women.

      HIV infection in patients with syphilis is common, especially in MSMs.

   2. Neurosyphilis in HIV-infected less frequent (1%)

4. Syphilis commonly infects the CNS early in the course of disease in both HIV-infected and non–HIV-infected persons (25–33%).

5. The CNS infection is more often progressive in HIV-infected persons, increasing the need for detection in this group.

6. Infections develop in characteristic stages.

   1. Primary syphilis: syphilitic chancre

      1. Characterized by chancre: a 0.5- to 2-cm painless, indurated, well-circumscribed ulceration at the site of primary inoculation approximately 2–3 weeks after contact (Figure 5-7)

      2. Atypical presentations are common. Multiple chancres may be seen more often in HIV-infected patients.

      3. Lesion resolves with or without therapy.

   2. Secondary syphilis

      1. Symptoms usually start with a rash that is usually not itchy and may appear as the chancre is healing or up to several weeks later.

      2. The secondary syphilis rash is macular or maculopapular, and often involves the palms and/or soles, but may have an atypical aspect or be completely unnoticed (faint rash or darker skin) (Figure 5-8).

         Secondary syphilis should always be considered in the differential diagnosis of rash in sexually active patients.

      3. Other skin findings may be present:

         1. Mucosal patches are superficial erosions in the mouth and genital areas.

         2. Condyloma lata are large, moist, pink to gray/white raised lesions seen in perianal area, vulva, or scrotum.

      4. Other symptoms include fever, myalgias, sore throat, lymphadenopathy, headaches, and hair loss.

   3. Latent syphilis: 60–70% of untreated patients have no disease progression.

      1. Early latent syphilis: < 1 year duration

      2. Late latent syphilis: > 1 year duration

      3. Latent syphilis of unknown duration: no prior negative serology to determine duration

   4. Tertiary stage

      1. Develops in one-third of untreated patients

      2. Gummas (syphilitic granulomas with caseating necrosis) affect involved organs and usually develop over 4–10 years but may develop earlier in HIV-infected patients.

      3. Protean manifestations of tertiary syphilis include heart (aortic root and coronary artery involvement), eyes, skin, and CNS involvement

   5. Neurosyphilis

      1. May be asymptomatic (positive CSF findings) or symptomatic

      2. Neurosyphilis can develop early after syphilis infection in HIV-infected patients.

         1. Typical early symptoms include cranial nerve palsies, meningitis, or meningovascular symptoms (strokes secondary to arteritis). One report found visual symptoms in 51%; headache in 32%; and gait difficulty, hearing loss, meningismus, or altered mental status in < 5%.

         2. Early neurosyphilis develops in 1.7% of HIV-infected MSMs who acquire syphilis.

      3. Typical late symptoms of neurosyphilis include tabes dorsalis or syphilitic myelopathy with demyelination of the posterior columns and dorsal roots (sensory symptoms of formication and shooting pains, impaired proprioception with ataxic gait and positive Romberg signs) and general paresis of the insane or parenchymal brain syphilis (personality changes, progressive dementia associated with motor and psychotic features, seizures, and generalized or focal weakness with the Argyll-Robertson pupil which accommodates but does not react to light).

      4. Persons with secondary syphilis or neurosyphilis may have ophthalmic symptoms (anterior uveitis, panuveitis, optic atrophy) or neurosensory hearing loss.

EVIDENCE-BASED DIAGNOSIS

1. Serologic diagnosis of syphilis

   1. Types of syphilis tests

      1. Nontreponemal tests serum rapid plasma reagin (RPR) and CSF VDRL

         1. Detect antibodies to cardiolipin

         2. Not specific for treponemal infection (false-positive in 1–2% of the US population)

         3. Decrease in titer and may become negative after appropriate treatment of syphilis

         4. May be falsely negative in long-standing latent infection

      2. Treponemal tests: fluorescent treponemal antibody absorbed (FTA-ABS), T pallidum enzyme immunoassay (TP-EIA), T pallidum particle agglutination (TP-PA), and T pallidum microhemagglutination (MHA-TP)

         1. Detect specific treponemal antibodies

         2. May remain positive for life even after appropriate treatment

         3. Cannot distinguish between treated and untreated infections

   2. Classic algorithm for diagnosis of syphilis

      1. Nontreponemal test (RPR) is performed first

      2. If RPR is positive, a confirmatory treponemal test is performed (FTA-ABS)

      3. If RPR is positive, the lab determines the quantitative RPR titer (1, 2, 4, 8, 16…), useful to follow treatment responses.

      4. If both RPR and FTA-ABS are positive, syphilis is confirmed. Prior syphilis history and current symptoms are taken into account to decide whether and how to treat the patient.

      5. If RPR is positive and FTA-ABS is negative, the results are presumed to be a false positive.

   3. Reverse algorithm for diagnosis of syphilis (Figure 5-9)

      1. Larger labs use the reverse sequence syphilis algorithm because it is much less time-consuming for a large number of screenings.

      2. An initial treponemal test easily automated (TP-EIA) is performed first.

      3. If TP-EIA is negative, syphilis is ruled out.

      4. If TP-EIA is positive, a nontreponemal test (RPR) is performed. If RPR is positive, the lab determines the quantitative RPR titer.

      5. If RPR is negative, a second treponemal test (T pallidum particle agglutination) is performed.

      6. If only the initial TP-EIA is positive, it is most likely a false-positive.

      7. If two tests are positive (TP-EIA plus either RPR or T pallidum particle agglutination), the patient has evidence of either current or past syphilis. The screening does not differentiate prior treated and cured syphilis from current syphilis. Whether and how to treat depend on syphilis history and current clinical presentation.

2. Primary syphilis (chancre)

   1. Most patients with identified chancre and recognized risk factors for syphilis are diagnosed clinically and treated empirically.

   2. Dark-field exam of chancre, direct fluorescent antibody, and PCR may help confirm that an ulceration is indeed primary syphilis, but these tests are not readily available at the point of care.

   3. The diagnosis of chancre is confirmed by serology (treponemal or nontreponemal test) about 75% of the time, but repeat testing 2 weeks later improves the sensitivity.

3. Secondary syphilis: Serology is highly sensitive for secondary syphilis, and patients usually have a high RPR titer.

4. Tertiary syphilis

   1. Nonspecific treponemal tests of serum (RPR) positive in only two-thirds of patients

   2. Treponemal tests highly sensitive (FTA-ABS 100% sensitive)

5. Neurosyphilis

   1. Approximately half of men with neurosyphilis have no other history or evidence of syphilis.

      Consider neurosyphilis in HIV-infected patients with new visual symptoms or headache.

   2. CD4TL count: 25–882 cells/mcL; mean CD4TL count: 217–312 cells/mcL

   3. Estimating test accuracy difficult due to the lack of a gold standard

   4. Commonly used criteria include either positive CSF VDRL or positive serum serology for syphilis and CSF pleocytosis.

      1. CSF VDRL is highly specific, but sensitivity is only ≈ 50%.

      2. CSF pleocytosis is more sensitive but much less specific as other infections increase CSF WBCs (including HIV and OIs).

      3. Reverse transcriptase PCR testing of CSF for T pallidum has limited sensitivity.

      4. CSF FTA-ABS is highly sensitive but much less specific due to blood contamination during LP, even if no red blood cells are identified. A negative CSF FTA-ABS makes neurosyphilis unlikely.

   5. Perform LP to look for neurosyphilis in any HIV patient with syphilis and either:

      1. Neurologic symptoms of any type, including meningitis, stroke-like syndrome, visual loss, hearing loss, dementia, or CNS focal deficit

      2. Persistent signs of infection despite treatment: failure of RPR to fall fourfold with treatment

   6. Consider patients at higher risk for neurosyphilis if:

      1. Serum RPR titer ≥ 1:32

         1. Increases the likelihood of neurosyphilis in HIV-infected persons with syphilis

         2. 76–96% sensitive, 59% specific

         3. Most experts do not perform LP in every patient with RPR ≥ 1:32, but monitor such patients closely

      2. CD4TL count ≤ 350 cells/mcL

         1. Increases the likelihood of neurosyphilis in HIV-infected persons with syphilis

         2. 69% sensitive, 53% specific

      3. HIV-infected patients with late latent syphilis (> 1 year) or of unknown duration

TREATMENT

1. Primary and secondary syphilis

   1. Single-dose benzathine penicillin IM

   2. Penicillin allergy: doxycycline twice daily for 2 weeks

   3. Follow RPR every 3 months for 1 year to document 4-fold fall in titer.

2. Latent syphilis

   1. If duration < 1 year, treat like primary and secondary syphilis

   2. If duration > 1 year or unknown, administer IM benzathine penicillin weekly for 3 weeks.

   3. Follow RPR every 6 months for 2 years to document 4-fold fall in titer.

3. Neurosyphilis

   1. High-dose IV penicillin for 10–14 days

   2. Penicillin allergy: high-dose ceftriaxone daily for 14 days, or oral doxycycline 200 mg twice daily for 28 days, or desensitization to penicillin followed by IV penicillin for 10–14 days. The latter strategy is the most effective and an infectious disease consultant should be involved in these complex cases.

A summary of the clinical and radiological features, CD4TL count, and tests of choice of the common CNS disorders in AIDS patients is presented in Table 5-3.

TEXTBOOK PRESENTATION

Typically, PCL develops in patients with advanced AIDS. While patients may present with focal signs such as weakness, many patients present with altered mental status or seizures.

DISEASE HIGHLIGHTS

1. Biologically distinct from PCL in other immunocompromised states

2. Diffuse, high-grade, B cell, non-Hodgkin lymphoma arising and confined to the CNS (not due to CNS involvement by systemic lymphoma)

3. CD4TL usually < 50 cells/mcL

4. Consistently associated with EBV (early EBV RNA transcripts detected in 100% of biopsies)

5. Pathogenesis likely involves activation of latent EBV genes due to immunodeficiency. The relative immunologic sanctuary of the CNS from immune surveillance may facilitate growth of these tumors at this location.

6. Rapidly progressive with a short interval from symptoms to diagnosis (1.8 months)

7. Median survival without treatment is about 1 month.

8. Supratentorial location 3 times more common than infratentorial.

9. Most common cause of death in patients with PCL is other OI.

10. Marked reduction in PCL incidence (about 90%) from 1995 to 2000 because of the introduction of ART

EVIDENCE-BASED DIAGNOSIS

1. History and physical exam

   1. B symptoms (weight loss > 10% body weight, unexplained temperatures > 38.0°C, drenching sweats): present in 80%

   2. Focal neurologic deficits: 51%

   3. Mental status changes: 53%

   4. Seizures: 27%

2. Laboratory findings

   1. CSF EBV PCR:

      1. 87% sensitive, 98% specific

      2. LR+, 43; LR–, 0.13

   2. Positive CSF cytology only 15–23% sensitive. Special studies are required to distinguish monoclonal proliferations from reactive T cell populations.

3. Radiologic studies

   1. CT scanning

      1. 90% sensitive

      2. Usually reveals contrast enhancement (90%), characteristically diffuse rather than ring enhancement

      3. 48% single lesion, 52% multiple lesions

      4. Usually associated with mass effect (as in toxoplasmosis but not seen in PML)

   2. MRI more sensitive than CT scanning (see Figure 5-5)

   3. SPECT thallium imaging

      1. PCL usually demonstrates early uptake and retention (compared with decreased uptake in necrotic centers of toxoplasmosis).

         1. 86–100% sensitive, 77–100% specific (higher specificity if retention index measured).

         2. Increased uptake is noted in 15% of patients with TE not receiving ART but up to 50% of patients with TE receiving ART, making this test less useful when on ART.

4. Biopsy

   1. Positive CSF EBV PCR makes biopsy unnecessary if imaging is typical.

   2. Biopsy is useful when CSF EBV PCR is negative.

   3. Lympholytic effect of corticosteroids may render biopsy nondiagnostic.

   Corticosteroids should generally not be administered before brain biopsy in patients with suspected PCL unless the patient is at an increased risk for herniation.

TREATMENT

1. AIDS-related PCL is a complication of end-stage AIDS, and prognosis is grave without therapy, with a median survival of 3 months.

2. Options for treatment include whole-brain radiation therapy and high-dose methotrexate-based chemotherapy.

   1. Whole-brain radiation therapy is no longer considered first-line therapy, since it is associated with irreversible cognitive dysfunction and does not improve survival.

   2. Adding ART to high-dose methotrexate-based chemotherapy improves the prognosis.

TEXTBOOK PRESENTATION

PML typically presents with progressive neurologic deficits, in particular weakness or gait disorders, over weeks to months. PML may also present with visual problems, headache, alterations in mental status, or dementia with focal signs.

DISEASE HIGHLIGHTS

1. Etiologic agent is JC virus, a polyomavirus (not to be confused with Creutzfeldt-Jakob disease, a prion-related illness).

2. Primary JC virus infection is common in childhood and usually asymptomatic, with seroprevalence of 39–69% among adults.

3. PML is much more common in AIDS than in non–HIV-infected immunosuppressed persons: before ART, PML developed in 3–7% of persons with AIDS. Profound immunosuppression allows latent JC virus in reticuloendothelial system and kidney to gain access to CNS and replicate.

4. Subsequent infection and lysis of the myelin-producing oligodendrocytes results in PML. Astrocytes may be infected.

5. Multifocal or unifocal white matter lesions seen, forming large plaques distributed asymmetrically.

6. Mean CD4TL count 84–104 cells/mcL: 25% of patients have CD4TL count > 200 cells/mcL

7. ART is the mainstay of treatment: 63% of patients started on ART because of PML survive > 2 years. A majority of them have either improvement or stabilization of neurologic function.

EVIDENCE-BASED DIAGNOSIS

1. History and physical exam

   1. Limb weakness: 50–70%

   2. Gait disorder: 26–64%

   3. Speech disorder: 31–51%

   4. Visual impairment (hemianopsia): 21–50%

   5. Seizures: 5–23%

   6. Headaches: 23%

   7. Cognitive abnormalities/mental status changes: 25–65%

   8. Cranial nerve palsies: 31%

2. Laboratory findings

   1. Serum antibodies to JC virus are not useful due to high prevalence of infection.

   2. CSF

      1. Routine studies may be normal or nonspecifically elevated.

      2. CSF PCR for JC virus DNA:

         1. 70–90% sensitive, 98% specific

         2. LR+ (average), 40; LR–, 0.20

         3. Some tests are more sensitive (detect low level of JC virus) and repeat analysis increases sensitivity to 90%.

         4. Sensitivity is diminished in patients receiving ART.

   3. CNS imaging

      1. Typically shows extensive multifocal patchy white matter demyelination with sparing of the cortical gray matter

      2. MRI more sensitive than CT scanning (CT 63% sensitive) (See Figure 5-5)

      3. Lesions hypodense on CT scanning, low intensity on T1-weighted MRI, hyperintense on T2-weighted MRI

      4. On imaging, lesions are restricted to the subcortical white matter, respecting the gray-white junction of the cerebrum.

      5. There is overlap in the MRI features of TE, PCL, and PML. However, certain features suggest PML:

         1. Lack of enhancement (except peri-plaque enhancement after starting ART, consistent with IRIS)

         2. Lack of mass effect

         3. Less well-circumscribed lesions

      6. MRI typically shows scalloping at gray-white matter interface (see Figure 5-5).

      7. CT scanning typically demonstrates white matter hypodense lesions.

      8. Brain biopsy: 100% specific but sensitivities only 64% to 96% due to sampling error

   MRI is markedly superior to CT for diagnosis of PML.

TREATMENT

1. ART is associated with improvement or cure in some patients.

   1. Survival pre-ART averaged 4–6 months. Survival has improved to 60% since the introduction of ART.

   2. 80% of survivors have significant residual neurologic deficits

   3. Some patients receiving ART develop IRIS with worsening of symptoms and enhancement around the PML plaques on MRI; this is managed with corticosteroids.

2. Initiation of ART occasionally results in PML in previously asymptomatic patients due to increased inflammation associated with IRIS (unmasking IRIS).

TEXTBOOK PRESENTATION

Pulmonary TB typically presents subacutely with cough and fever that have gone on for over a week (and often much longer) and systemic symptoms of night sweats and weight loss are common¹. In patients with CD4TL > 200 cells/mcL, the chest radiographic pattern is similar to the one seen in non–HIV-infected patients—that is, with apical, cavitary, or nodular infiltrates. In patients with CD4TL < 200 cells/mcL, the pattern on chest radiograph is often atypical: lower lobe infiltrates, miliary infiltrates, and lymphadenopathy are more common. Extrapulmonary TB is also more common in AIDS.

DISEASE HIGHLIGHTS

1. There are currently more worldwide cases of TB than at any time in human history: per CDC data, in 2017, there were an estimated 10.0 million people with new TB and 1.3 million TB-related deaths worldwide. Latent TB infection affects a quarter of the world population.

2. HIV-infected persons are at highest risk for TB (170 times higher incidence).

   1. Risk increases further in patients from endemic areas and among IDUs.

   2. 9000 TB cases were reported in 2017 in the United States, a 1.6% decrease from 2016.

3. TB in turn increases both HIV replication and the risk of death.

4. Worldwide, TB accounts for 30% of HIV-related deaths.

5. Epidemic in sub-Saharan Africa and parts of Asia

6. 50% of cases secondary to recent infection (progressive primary TB)

7. TB may be the first manifestation of HIV infection and is an AIDS-defining illness.

   All patients with TB should be tested for HIV.

8. Clinical characteristics

   1. Early HIV infection: pulmonary TB is fairly typical.

   2. Advanced HIV infection

      1. Extrapulmonary TB more frequent

         1. More common in the AIDS population (30%) than in patients without AIDS (15%)

         2. Most common sites of extrapulmonary TB include blood, lymph nodes, bone marrow, genitourinary tract, CNS, and liver. 19% of patients had cervical or supraclavicular lymph node involvement.

         3. Other syndromes seen in these patients include weight loss, fever of unknown origin, and TB meningitis.

      2. Chest radiographic pattern more frequently atypical (see below).

   Extrapulmonary TB is common in HIV-­infected patients and extrapulmonary sites of infections may provide a target for diagnostic procedures.

EVIDENCE-BASED DIAGNOSIS

1. Prolonged fever (> 7 days) is more common in HIV-infected persons with pulmonary TB than in PJP or bacterial pneumonia (sensitivity, 56%; specificity, 78%; LR+, 2.5; LR–, 0.57).

2. Weight loss is also more common with pulmonary TB than with PJP or bacterial pneumonia (sensitivity, 67%; specificity, 68%; LR+, 2.1; LR–, 0.49).

3. Standard tests in patients with suspected pulmonary TB should include chest radiograph (with posteroanterior and lateral views), 3 sputum AFB stains and cultures, PPD or IGRA, and blood and urine cultures.

4. Chest radiography

   1. Certain radiographic findings, including cavitary lesions, hilar lymphadenopathy, and nodular lesions, are infrequent but suggestive of pulmonary TB (Table 5-7).

      The chest radiograph in HIV-infected patients with pulmonary TB may be typical or atypical. Pulmonary TB should be considered in patients with apical or cavitary disease, nodular infiltrates, or lymphadenopathy.

   2. However, the radiographic manifestations of pulmonary TB vary with degree of immunosuppression (Table 5-8).

      1. Early HIV infection (CD4TL > 200 cells/mcL): chest radiograph usually shows the typical reactivation pattern: upper lobe disease or apical segment of lower lobe with or without cavitation.

      2. Advanced HIV infection (CD4TL count < 200 cells/mcL):

         1. Middle and lower lobe consolidation, lymph node enlargement, pleural effusions, and miliary patterns more often seen.

         2. Pleural involvement more common

            1. Often accompanied by fever (85%), cough (77%), and chest pain (36%). Weight loss is common (74%).

            2. Unilateral exudative effusion

            3. Concomitant lower lobe parenchymal infiltrate present in 44–73%

      Pleural effusions without an infiltrate can be a manifestation of TB in HIV-infected patients.

   3. Cavitary lesions with night sweats or prolonged fever (> 7 days) not sensitive for pulmonary TB but highly predictive (sensitivity, 8–11%; LR+, ∞).

   4. Hilar lymphadenopathy with weight loss or with prolonged cough (> 7 days) was not sensitive for pulmonary TB but highly suggestive (sensitivity, 8%; LR+, 8–∞).

   5. Chest radiograph is normal in 10–21% of patients with pulmonary TB and advanced disease.

   Pulmonary TB can be present despite a normal chest radiograph and should be considered in HIV-positive patients with CD4TL < 200 cells/mcL and pulmonary symptoms. Such patients require isolation in a negative-pressure room.

5. PPD and IGRA: sensitivity depends on the degree of immunosuppression.

   1. CD4TL > 300 cells/mcL: 90% sensitive

   2. CD4TL < 100 cells/mcL:

      1. PPD (≥ 5 mm) 0% sensitive.

      2. IGRA test interpretation is complex in patients CD4TL < 100 cells/mcL. Most such patients have indeterminate IGRA results, which are not diagnostic. However, a negative result makes the diagnosis of TB less likely.

6. Sputum analysis

   1. AFB smear results

      1. Poor sensitivity (29–60%) is often due to the patient’s inability to produce adequate sputum. Sensitivity is 67% in patients able to produce adequate sputum.

      2. Specificity falls at lower CD4TL counts due to increasing incidence of MAI but remains remarkably high in this group (92%).

   2. AFB culture: Sensitivity ranges from 43% to 100%. Sensitivity approaches 100% in patients able to produce adequate sputum.

7. Mycobacterium tuberculosis PCR testing of sputum

   1. Helps distinguish pulmonary TB from MAI, M kansasii, or colonizing/contaminating nontuberculous mycobacteria (often Mycobacterium gordonae)

   2. Primarily used when AFB stains positive

   3. Particularly useful if suspicion of pulmonary TB is low

      1. Positive rapid tests help confirm pulmonary TB, negative tests make pulmonary TB less likely

      2. 95% sensitive and specific in this situation

   4. Also useful when clinical suspicion is high and smear negative

      1. Rapid tests reported 53% sensitive, 93% specific.

      2. Positive tests suggest pulmonary TB

      3. Cultures still required to test drug susceptibility

   5. A diagnostic algorithm is shown in Figure 5-10.

8. Blood culture for mycobacteria

   1. Blood cultures are positive in 26–42% of HIV-positive patients with TB.

   2. Sensitivity increases to 49% in patients with CD4TL < 100 cells/mcL.

9. Bronchoscopy

   1. Smear sensitivity: 50–57%; specificity: 99% in endemic area

   2. Culture sensitivity: nearly 100%

   3. Some studies report similar sensitivities to induced sputum.

   4. Bronchoscopy associated with increased transmission of M tuberculosis to medical personnel. Risk is minimal if bronchoscopy is performed in a negative-pressure room.

   5. Induced sputum is preferred.

   6. If bronchoscopy is performed for suspected miliary TB, transbronchial biopsy is recommended.

10. Pleural evaluation

    1. Pleural fluid smear positive in 15%

    2. Culture of pleural fluid positive in 33–90%

    3. Sputum smear or culture in patients with pleural TB is positive in 33–50%. Sputum may be positive in patients without parenchymal infiltrate.

       Obtain sputum for AFB stain and culture in HIV-infected patients with pleural effusions, even in those without infiltrates

    4. Effusion is unilateral and exudative with lymphocyte predominance.

    5. Pleural biopsy

       1. Positive smear: 44–69%

       2. Positive pathology (granuloma): 88%

TREATMENT

1. Chemoprophylaxis

   1. Indicated for HIV-infected patients who have either a positive PPD (induration ≥ 5 mm) or a positive IGRA; also indicated for HIV-infected patients who have had a recent and significant exposure to persons with infectious pulmonary TB regardless of PPD/IGRA results

   2. A chest radiograph should be performed and the patient evaluated to rule out active TB (pulmonary or extrapulmonary). In addition, even in patients with a normal chest radiograph but CD4TL < 200 cells/mcL, sputum AFB stain and culture should be obtained.

   3. Isoniazid prophylaxis for 9 months decreases the rate of progression from latent to active TB from 7.4% to 2.6% in HIV-infected patients.

   4. Patients should be evaluated monthly to monitor adherence and side effects of therapy.

   5. Isoniazid liver toxicity

      1. Elevation of transaminases in 10–20% of patients, but symptomatic hepatitis much less common

      2. Isoniazid should be stopped if transaminase elevation exceeds 5× the upper limit of normal, even if the patient is asymptomatic.

      3. Patients with alcohol abuse, chronic liver disease, or coinfection with hepatitis B or C virus should have monthly liver biochemical tests to rule out isoniazid-induced hepatitis. All HIV-infected patients are at higher risk for hepatotoxicity (NASH, drug adverse effects) and should receive monthly liver biochemical tests.

   6. Rifampin prophylaxis for 4 months is an alternative when isoniazid cannot be used or to shorten the duration of prophylaxis; however, drug interactions have to be carefully reviewed. Adverse effects include hepatitis, blood dyscrasias, rash, and hypersensitivity.

   7. Recently rifapentine plus isoniazid weekly for 12 weeks has become an acceptable alternative for HIV-infected patients with latent TB infection.

2. Active TB

   1. Active TB is usually treated with rifabutin, isoniazid, pyrazinamide, and ethambutol (RIPE). If the isolate is susceptible to rifampin and isoniazid, ethambutol is stopped. After 2 months of therapy, pyrazinamide is stopped. Rifabutin and isoniazid are continued to complete 6 months of therapy.

   2. Treating TB in HIV is complicated by clinically important drug interactions; consultation is recommended. Rifampin is rarely used in HIV-infected patients in the United States because rifabutin interactions are easier to manage. Unfortunately, rifabutin is expensive and not used extensively in low-income countries.

   3. Directly-observed therapy is recommended for all patients with active TB, including HIV-positive patients.

      1. Decreases relapse rate from 20% to 5%

      2. Decreases development of multidrug-resistant TB from 6% to 1%

   4. Monthly follow-up sputum cultures are obtained: if the 2-month culture remains positive, treatment is extended from 6 to 9 months.

   5. Multidrug resistance is a major health problem.

      1. Definitions

         1. Drug-resistant TB is resistant to any of the first-line drugs (rifampin, isoniazid, pyrazinamide, or ethambutol).

         2. Multidrug-resistant TB is defined as resistance to both rifampin and isoniazid.

         3. Extensively drug-resistant TB is defined as resistance to rifampin, isoniazid, fluoroquinolones (ciprofloxacin, moxifloxacin, levofloxacin) and one of the injectable second-line antituberculous drugs (capreomycin and aminoglycosides).

         4. Drug-resistant TB is more common in HIV patients, but multidrug-resistant TB is uncommon in the United States.

      2. Drug-resistant TB arises in nonadherent patients.

      3. Suspect drug-resistant TB in patients with prior TB treatment, contact with known multidrug-resistant TB, or immigrants from countries where multidrug-resistant or extensively drug-resistant TB is prevalent.

      4. Case fatality rate is high in patients with multidrug resistant or extensively drug-resistant TB and HIV.

      5. Multidrug-resistant TB typically requires 5 to 6 drugs, including 3 drugs to which TB is susceptible. Expertise in treating multidrug-resistant TB is required. Therapy is recommended for at least 2 years. Surgical resection of localized disease is required in some patients.

3. IRIS and pulmonary TB

   1. Infiltrates worsen in 36% of patients upon institution of ART due to immunologically mediated reactions (ie, IRIS).

   2. Increasing fever, infiltrates, and adenopathy may be seen.

   3. A second OI, poor adherence, drug resistance, or low potency of TB regimen needs to be excluded.

   4. IRIS is usually self-limited with pulmonary TB, but more severe reactions benefit from corticosteroids.

4. BCG

   1. BCG is a live-attenuated Mycobacterium bovis strain with limited efficacy: it may prevent TB meningitis and miliary TB, but does not prevent the more common presentations of primary or reactivation TB.

   2. BCG is contraindicated in HIV-positive patients due to increased incidence of active infection or dissemination of the BCG strain.

TEXTBOOK PRESENTATION

Toxoplasmic encephalitis (TE) in AIDS patients typically presents subacutely over 1–2 weeks. Focal neurologic manifestations are common. Confusion and mental status changes may dominate the clinical picture.

DISEASE HIGHLIGHTS

1. Seroprevalence of asymptomatic Toxoplasma infection (positive T gondii IgG) is around 11% in the US population versus 40–80% in some European, African, and Asian countries.

2. Primary infection is acquired after eating undercooked meat with tissue bradyzoites (tissue cysts) or ingesting oocysts shed in cat feces and matured in the environment for > 24 hours. In the United States, eating raw oysters, clams, and mussels has recently been identified as a risk factor.

3. TE usually causes focal abscess with headache, confusion, motor weakness, and fever. Focal neurologic findings may be present. Seizures and altered mental status may develop in untreated patients. CT scan and MRI of the brain often show multiple ring-enhancing mass lesions with significant surrounding edema, located in the gray matter of the cortex and basal ganglia. TE is the most common etiology of CNS mass lesion in AIDS patients.

4. TE is secondary to reactivation of latent toxoplasmosis in brain tissue cysts: > 95% of patients have positive IgG titers, but IgM is not usually identified. False-negative IgG may be seen even with reactivation.

5. CD4TL < 100 cells/mcL in 80% of patients; CD4TL < 50 cells/mcL increases the risk further

6. Before ART, the 12-month probability of developing TE was 33% in AIDS patients with CD4TL counts < 100 cells/mcL and positive toxoplasmosis serology if not receiving prophylaxis for TE. ART has decreased the incidence of TE.

7. TE may be the initial manifestation or a subsequent manifestation of HIV infection.

8. 27% mortality despite treatment

9. Other concurrent CNS infections common

EVIDENCE-BASED DIAGNOSIS

1. History

   1. Headache (often frontal and bilateral): 49–73%

   2. Seizures: 15–31%

   3. Hallucinations: 8%

   4. Fever: 4–68%

2. Physical exam

   1. Focal findings (weakness, abnormal gait, or other): 73–88%

   2. Mental status changes: 50–67%

   3. Mental status changes dominating clinical picture: 40%

   4. Cognitive impairment (with normal arousal): 66%

   5. Stiff neck: 0%

   Meningismus is distinctly uncommon in TE and suggests an alternate or additional disease process.

3. Laboratory findings

   1. Serology

      1. Toxoplasma IgG: ≈ 97% sensitive but does not confirm active TE

         TE unlikely in patients with negative Toxoplasma IgG

      2. Toxoplasma IgM: insensitive (15%) because disease is usually secondary to reactivation.

      3. Probability of TE in seropositive patients with mass effect markedly reduced in patients receiving TMP-SMX prophylaxis (from 87% to 59%)

   2. CSF analysis

      1. Standard CSF analysis may be normal or nonspecifically elevated.

      2. Percentage of patients with abnormal findings

         1. WBC > 5 cells/mcL: 50%

         2. Protein > 40 mg/dL: 81%

         3. Low glucose: 14%

      3. CSF PCR insensitive for CNS toxoplasmosis but highly specific

         1. 54% sensitive, 99% specific

         2. LR+, 54; LR–, 0.46

   3. Neuroimaging

      1. MRI is test of choice.

         1. Superior to contrast CT, affecting course in 40% of patients

         2. One or more ring-enhancing lesions with mass effect and edema (Figure 5-5)

         3. Lesions may be located in gray matter of basal ganglia, thalamus, and cortex.

         4. Single lesion in 14% of patients, multiple lesions in 86%

         5. Single lesion on MRI makes TE less likely and increases likelihood of PCL.

      2. CT scan with contrast abnormal in 87–96%

         1. Single ring-enhancing lesion: 35%

         2. ≥ 2 ring-enhancing lesions: 62%

         3. Hypodense lesions: 13%

         4. Moderate to severe cerebral edema: 48%

         5. 75% of lesions located in cerebral hemispheres

         6. MRI is recommended in patients with normal contrast CT scan or a single enhancing lesion.

      3. Positron emission tomography or single-photon emission computed tomography (SPECT) is helpful in distinguishing between TE and PCL, but no imaging technique is completely specific. SPECT thallium 201 reveals decreased isotope activity in patients with TE versus increased uptake in patients with PCL.

   4. Brain biopsy

      1. When positive, brain biopsy is the only method that confirms cerebral toxoplasmosis with certainty.

         1. False-negative results can occur due to sampling error.

         2. May diagnose concomitant infection

      2. Sensitivity of standard hematoxylin & eosin staining only 50–66%. Immunoperoxidase staining improves sensitivity.

      3. Brain biopsy is associated with 0.5–3.1% mortality and high morbidity.

      4. Brain biopsy is not done routinely due to complications and imperfect sensitivity.

TREATMENT

1. Empiric treatment for TE instituted in patients with all of the following criteria: multiple mass lesions, CD4TL < 100 cells/mcL, positive serum Toxoplasma IgG, and patient not already taking toxoplasmosis prophylaxis (Figure 5-6). Biopsy is reserved for atypical cases (ie, negative serology or nonresponders within 7–10 days).

2. Pyrimethamine plus sulfadiazine (pyrimethamine plus high-dose clindamycin if allergy or intolerance to sulfonamides)

3. Folinic acid also administered to patients taking pyrimethamine to decrease toxicity

4. TMP-SMX is a less effective alternative therapy.

5. Clinical improvement within first 2 weeks of drug therapy in > 90% of responders

6. Radiologic improvement in most patients within 3 weeks of treatment

7. After induction therapy for 6 weeks, suppressive therapy with lower doses is used. Suppressive therapy can be discontinued in asymptomatic patients in whom ART has restored CD4TL to > 200 cells/mcL for ≥ 6 months.

8. Corticosteroids are only indicated for patients with cerebral edema and midline shift, or clinical deterioration within first 48 hours of therapy. Corticosteroids complicate interpretation of response to therapy since they reduce edema and the size of PCL lesions.

9. ART should be started quickly, usually within 2–4 weeks after diagnosis of any OI in AIDS, except in CNS cryptococcosis. IRIS associated with TE is not as common (about 5%) and can be managed well with corticosteroids.

10. Prevention

    1. HIV-positive patients with CD4TL < 200 cells/mcL and positive serum Toxoplasma IgG should receive daily TMP-SMX as primary prophylaxis.

    2. If patients are allergic to sulfa, they may instead receive atovaquone (also effective in preventing Pneumocystis pneumonia) or dapsone plus pyrimethamine.

    3. The risk of TE is low unless the CD4TC count is < 100 cells/mcL.

TEXTBOOK PRESENTATION

Chronic HIV infection may present in a myriad of ways. Many patients are entirely asymptomatic in spite of long-standing HIV infection and advanced immune deficiency as demonstrated by an absolute CD4 T lymphocyte (CD4TL) count below 200 cells/mcL (immunologic AIDS). Some patients may have symptoms that are often seen with HIV but are nonspecific, such as chronic diarrhea, seborrheic dermatitis, multiple molluscum contagiosum, poorly responsive psoriasis, and prurigo nodularis. Other patients have conditions that are strongly associated with HIV infection but are also encountered in non–HIV-infected persons, such as tuberculosis (TB), idiopathic thrombocytopenic purpura, nephropathy, nonischemic cardiomyopathy, herpes zoster (shingles), and non-Hodgkin lymphoma. Unfortunately, patients may be found to have HIV only when they are admitted to the hospital with a life-threatening AIDS-defining condition, such as Pneumocystis jirovecii pneumonia (PJP), Cryptococcus neoformans meningitis, central nervous system (CNS) toxoplasmosis, or primary CNS lymphoma (PCL).

DISEASE HIGHLIGHTS

1. Epidemiology of HIV in the United States

   1. Prevalence: At the end of 2016, the Centers for Disease Control and Prevention (CDC) estimated that 1,130,000 persons were living with HIV infection in the United States of whom 973,846 persons had been diagnosed (an 11% increase over 2011).

   2. Incidence: In 2016, there were 39,782 new HIV diagnoses, a 5% decrease from 2011.

   3. The prevalence of HIV continues to increase in spite of the decreasing incidence because HIV-infected people live longer than in the past.

   4. The sex ratio of new HIV infections is about 4 males to 1 female.

   5. Men who have sex with men (MSMs) are disproportionately infected: male-to-male sexual contact accounts for 67% of new infections, heterosexual contact 24%, and injection drug use (IDU) 6%. About 3% of new infections are associated with both male-to-male sexual contact and IDU.

   6. Racial and ethnic disparities are significant: blacks account for 44% of new infections; whites, 26%; Hispanics, 25%; and Asians, 2%.

   7. Regional differences are also significant: the rates of new HIV diagnoses per 100,000 population are 16.8 in the South, 11.2 in the Northeast, 10.2 in the West, and 7.5 in the Midwest.

   8. Transmission

      1. Common modes of transmission include male-to-male sexual transmission, heterosexual transmission, and drug paraphernalia sharing among IDUs. Mother-to-child transmission during pregnancy, perinatally, or through breastfeeding has become uncommon in the United States (but remains common in Africa).

      2. The higher the viral load, the greater the risk of transmission.

         1. The viral load is high in both acute HIV infection and advanced AIDS.

         2. Coinfections, such as TB or syphilis, increase the viral load.

         3. Effective antiretroviral therapy (ART) results in a very low viral load, decreasing the risk of transmission by at least 95%.

      3. Sexual practices and sexually transmitted infections

         1. The highest risk of sexual transmission is among men with unprotected receptive anal intercourse and individuals with multiple sexual partners.

         2. The presence of genital inflammation or breakdown of genital mucosa increases the risk of transmission. Receptive anal intercourse is frequently associated with trauma as well as an increased risk of sexually transmitted infections.

         3. Sexually transmitted infections, whether they cause genital ulceration or not, significantly increase the risk of either transmitting or acquiring HIV.

         4. The risk is greater for persons with simultaneous rather than consecutive partners.

         5. During heterosexual intercourse, man-to-woman transmission is significantly more likely than woman-to-man transmission.

         6. Circumcised males are 65% less likely to acquire HIV through heterosexual intercourse, but circumcision does not reduce male-to-male sexual transmission.

         7. The consistent use of barrier methods (either male or female condoms) is about 95% effective in preventing HIV sexual transmission, but adherence is poor in most high-risk situations.

      4. Transmission through blood transfusion has been nearly eliminated by blood product screening. The risk associated with blood transfusion in the United States is estimated at < 1 in 1,800,000 units.

      5. Mother-to-child-transmission is common without ART prophylaxis. Effective therapy markedly reduces this risk (see below).

2. HIV and its target, the CD4TL

   1. The main target cell of HIV is the CD4TL. The HIV surface protein GP 120 binds first to the main HIV receptor, the CD4 receptor. Second, the surface protein binds to an HIV chemokine co-receptor, either CCR5 or CXCR4. HIV also infects secondary target cells that carry these receptors, such as macrophages, dendritic cells, and stem cells.

   2. HIV replicates mostly in activated CD4TL: 99% of HIV detected in the blood comes from recently infected, activated CD4TL.

   3. In acute HIV infection, there is a very rapid decrease in the number of CD4TL in the gut-associated lymphoid tissues but only a moderate and partially reversible decrease in the blood CD4TL.

   4. In chronic HIV infection, the absolute CD4TL count decreases slowly in the blood. About 2 billion CD4TL are destroyed and replaced every day. Both HIV-infected and noninfected CD4TL (innocent bystanders) are destroyed.

   5. In most infected individuals, the high rate of CD4TL death results in a progressive fall in the blood CD4TL.

   6. When the absolute CD4TL count falls below 200 cells/mcL, immunologic AIDS is diagnosed.

      1. The patient is susceptible to virulent pathogens, opportunistic infections (OIs), and AIDS-defining malignancies. The lower the CD4TL count, the greater the risk of any OI and the greater the spectrum of OIs seen.

      2. Some patients acquire an OI (such as TB) or AIDS-defining malignancy (such as lymphoma) at a CD4TL higher than 200 cells/mcL; in these cases clinical AIDS is diagnosed.

   7. About 5% of patients have stable CD4TL over many years (“long-term nonprogressors”). Rarely, the viral load is also undetectable (“elite controllers”).

   8. Accelerated evolution of HIV and quasi-species

      1. HIV evolves rapidly due to both a high rate of mutations introduced by an error-prone reverse transcriptase and a very high replication rate (10 billion new HIV virions per day). This allows for the rapid development of genetic variants (quasi-species), which may escape immune responses and become resistant to a number of antiretroviral agents.

      2. Effective ART requires complete suppression of viral replication to prevent new cell infections and the production of mutations associated with drug resistance.

3. Staging

   1. Stages of HIV infection include viral transmission, primary infection, seroconversion, clinically latent period, early symptomatic HIV infection, and AIDS.

      1. Primary HIV infection

         1. Most patients with primary HIV infection are symptomatic: many have nonspecific symptoms like fever, diarrhea, arthralgia, headache, or flu-like symptoms. Some present with a striking mononucleosis syndrome that includes fever, sore throat, rash, oral aphthous ulcers, and lymphadenopathy. Occasionally, they have neurologic complications, such as aseptic meningitis, acute encephalopathy, or Guillain-Barré syndrome.

            Acute HIV infection should be considered in patients with mononucleosis syndromes when tests are negative for Epstein-Barr virus (negative EBV viral capsid IgM) and cytomegalovirus (negative CMV IgM). Diagnosis of acute HIV requires a high index of suspicion.

         2. In primary HIV infection, the HIV viral load is almost always > 10,000/mcL and usually > 100,000/mcL. Therefore, a low-positive viral load in this context should be repeated to rule out a false-positive test.

      2. Seroconversion

         1. Seroconversion rapidly causes a fall in HIV viral load (due to both humoral and cellular immune responses).

         2. After about 6 months, the viral load is set at a level that remains relatively stable in any specific patient (the viral load “set point”) but varies from patient to patient.

         3. In the absence of ART, the set point predicts the rate of disease progression (higher viral loads are associated with more rapid declines in CD4TL counts).

      3. Clinically latent period

         1. Following primary infection, viral replication continues primarily within activated CD4TL, with progressive destruction of the CD4TL pool.

         2. Persistent generalized lymphadenopathy is often seen.

         3. Progression to an AIDS-defining illness is more common in patients with higher viral loads and lower CD4TL counts.

         4. Progressive depletion of CD4TL renders patients increasingly susceptible to OIs and malignancies: AIDS is predominantly a T-cell immunodeficiency. However, multiple other immune responses are abnormal: for example, HIV-infected patients often have polyclonal hypergammaglobulinemia and fail to mount antibody responses to either Streptococcus pneumoniae infection or the administration of the 23-valent pneumococcal polysaccharide vaccine.

      4. Early symptomatic HIV infection: At relatively high CD4TL counts (200–350 cells/mcL) HIV infection is associated with an increased risk of infections by virulent pathogens, especially pneumococcal pneumonia and TB.

      5. AIDS

         1. Advanced HIV disease is accompanied by severe CD4TL depletion (below 200 cells/mcL) and infection with less virulent, opportunistic pathogens.

         2. Specific opportunistic pathogens are mostly encountered when the CD4TL count falls below a critical level.

            1. CD4TL count < 200 cells/mcL: PJP, oral candidiasis

            2. CD4TL count < 100 cells/mcL: Toxoplasma gondii brain abscesses, Candida esophagitis, C neoformans meningitis, disseminated histoplasmosis, and meningeal coccidioidomycosis

            3. CD4TL count < 50 cells/mcL: Cytomegalovirus (CMV) retinitis and Mycobacterium avium/intracellulare (MAI); the latter is also called disseminated M avium complex (MAC)

         3. AIDS diagnostic criteria

            1. CD4TL count < 200 cells/mcL (immunologic AIDS)

            2. AIDS indicator conditions (clinical AIDS):

               1. AIDS-defining malignancies: PCL, non-Hodgkin lymphoma, Kaposi sarcoma, and invasive cervical cancer

               2. OIs: PJP, TB, disseminated MAC, recurrent bacterial pneumonia, esophageal candidiasis, cryptococcosis, progressive multifocal leukoencephalopathy (PML), toxoplasmosis, and cryptosporidiosis

               3. Other AIDS indicator conditions: HIV-associated dementia and AIDS wasting syndrome (“slim disease”)

            3. Advanced HIV infection is defined as CD4TL count < 50 cells/mcL.

EVIDENCE-BASED DIAGNOSIS

Similar to any other diagnosis, the positive predictive value is determined by 3 features: the pretest probability of disease, the sensitivity of the test, and the specificity of the test. Each feature must be carefully evaluated to interpret HIV results properly.

1. Estimating pretest probability of HIV infection

   1. Risk factors include MSM, IDU, and multiple sexual partners.

   2. The prevalence of HIV varies from 0.3% in the general US population to > 50% in very high-risk groups.

2. Diagnosis of HIV: the 3-step HIV screening sequence

   1. The diagnosis of HIV infection utilizes antibodies to HIV and tests for HIV RNA and HIV p24 antigen.

      1. HIV RNA and p24 antigen are present prior to HIV antibodies and allow for the diagnosis of early HIV infection prior to the presence of HIV antibodies (Figure 5-1).

      2. The CDC has recently recommended a 3-step HIV screening sequence to improve the sensitivity of early HIV diagnosis without increasing the rate of false-positive diagnosis (Figure 5-2).

         1. The first step is the fourth-generation HIV-1/2 antigen/antibody combination immunoassay: it detects both HIV 1/2 antibody (Ab) and HIV-1 p 24 antigen (Ag). Adding the p24 Ag to this test allows for recognition of early HIV infection before Ab is detectable.

         2. When the first step is positive, the second step of the sequence is the HIV-1/HIV-2 Ab differentiation immunoassay. This confirmatory test detects and differentiates Ab to HIV-1 and to HIV-2. The result is reported as HIV-1 Ab detected, HIV-2 Ab detected, non-differentiated HIV Ab detected, or no Ab detected.

         3. When the result of the second step does not confirm HIV (HIV-1 Ab is negative or indeterminate and HIV-2 Ab is negative), a third step is required, which is an HIV-1 nucleic acid test, usually the HIV-1 quantitative RNA viral load. A positive HIV-1 RNA viral load confirms HIV-1 infection. A negative HIV-1 RNA viral load rules out HIV infection.

         4. In summary, HIV-1 infection is only confirmed when 2 steps of the HIV screening sequence are positive.

   2. Specificity and sensitivity of the 3-step HIV sequence

      1. When both the first and either the second or the third tests are positive, the sensitivity > 99% and the specificity of the 2-step test is about 99.6%.

      2. Very recent HIV infection prior to the appearance of p24 Ag will be negative on the HIV screening sequence. Because p24 Ag appears around 14 days after infection, only few primary cases of HIV are missed. Still, these patients may have poor outcomes and cause further HIV infections.

PREVENTION AND TREATMENT

1. Prevention

   1. As noted above, male and female condoms are about 95% effective in preventing HIV sexual transmission, but adherence is poor in many high-risk situations.

   2. Blood product screening has virtually eliminated transfusion-associated HIV transmission in the United States.

   3. Effective ART results in a very low viral load, decreasing the risk of transmission by about 95%. The “treatment as prevention” strategy aims to identify HIV infection early and start effective therapy, reducing the spread of HIV.

   4. Preexposure prophylaxis (PreP)

      1. A highly effective strategy of treating a seronegative person with a daily combination tablet that includes 2 antiretroviral drugs, tenofovir disoproxyl fumarate and emtricitabine to prevent HIV infection.

      2. Should be offered to HIV sero-discordant couples and individuals at high risk for HIV infection.

      3. To improve implementation, preexposure prophylaxis should be initiated and monitored by all primary care providers and not restricted to infectious disease and HIV specialists.

      4. The cost of the preexposure prophylaxis combination is well covered by healthcare plans.

   5. Needle-exchange programs are effective in preventing the spread of HIV in IDUs.

   6. Mother-to-child-transmission

      1. Most cases occur at term (intrapartum) and with breastfeeding, but there is a significant risk during pregnancy.

      2. HIV-infected pregnant women are treated as soon as possible with ART so the viral load is undetectable during pregnancy and at the time of delivery.

      3. Postpartum, mothers are told not to breastfeed and the neonates receive postexposure ART prophylaxis.

      4. Women who do not reach a low viral load at term (viral load < 1000 copies/mL) are offered an elective cesarean section to decrease the risk of mother-to-child-transmission.

      5. Intravenous zidovudine is given during labor if there is no documentation of an undetectable viral load.

      6. This strategy has reduced mother-to-child-transmission by more than 90% in the United States.

2. Universal screening

   1. More than 1 million people live with HIV in the United States, and 14% of them are unaware of their infection, which contributes to further spread of HIV.

   2. In the absence of screening, many patients present with advanced immunodeficiency and OIs.

      1. Such patients are often very ill and severely immuno­compromised, and are at high risk for poor outcome.

      2. Even if they do well on ART, most only partially recover their immune function.

   3. Selective high-risk screening is inefficient

      1. Although most HIV-infected patients have increased risk factors, clinicians do not consistently ask about risk factors and may not even consistently screen patients who present with another sexually transmitted or blood borne infection (“missed opportunities” for HIV testing).

      2. Patients may not report risk factors accurately especially if they fear the clinician may be judgmental.

      3. Not all HIV-infected patients have identifiable risk factors, especially if HIV prevalence is higher in the general population.

      4. Therefore, selective HIV screening of high-risk individuals is very inefficient.

   4. Universal HIV screening recommended

      1. CDC recommends routine HIV screening for patients aged 13–64 years evaluated in all healthcare settings unless the prevalence of undiagnosed HIV infection had been documented to be below 0.1%.

      2. The United States Preventive Services Task Force recommends universal voluntary HIV screening of adolescents and adults (2012).

      3. Universal HIV screening has therefore become the recognized standard of care in the United States.

3. Treatment

   1. The first encounter: the role of the primary care clinician

      1. The first encounter is essential in establishing a good clinician/patient relationship.

      2. Patients who have just found out they have HIV tend to be distraught and confused even if they are not totally surprised by the diagnosis.

      3. Often patients do not believe that the diagnosis is correct (HIV denial).

      4. Patients may believe wrongly that their life is over because they perceive that they will die soon from HIV, will be unable to live a productive and fulfilling life, will face severe drug adverse effects, or might infect their household contacts. Such misconceptions also enhance the stigma associated with HIV.

      5. The primary care clinician should take the required time necessary to reassure the patient that HIV can be managed well on a simple ART regimen with acceptable side effects in most people, and clarify the diagnosis, transmission, and natural history.

      6. Providing ample time to answer questions and deal with anxiety, depression, addiction, housing issues, healthcare insurance coverage, and partner notification is important.

      7. Referral to an infectious disease specialist (or internist with specialized HIV practice) is required, but the primary care clinician should strongly consider continuing to provide primary care to his or her HIV-infected patients.

   2. The role of the HIV specialist

      1. The HIV specialist works with nurses, social workers, case managers, HIV support groups, AIDS legal support groups, addiction specialists, and psychiatrists to ensure effective HIV care and maximize adherence to ART.

      2. HIV-infected patients who adhere to ART are highly likely to achieve an undetectable HIV viral load and do well over many years.

      3. HIV-infected patients who do not take their ART as prescribed progress to AIDS and their virus may acquire resistance mutations to multiple agents.

   3. Laboratory testing

      1. Assessment of current immunocompetence: absolute CD4TL count and CD4/CD3 percentage

      2. Test the HIV isolate: baseline HIV viral load and HIV genotype to look for transmitted resistance-associated mutations before any ART is introduced

      3. Test for common coinfections

         1. Patients should be screened for syphilis, hepatitis B, hepatitis C, T gondii (IgG), C trachomatis and Neisseria gonorrhoeae infection (in women and MSM) and human papillomavirus–related carcinomas (cervical cancer in women and anal cancer in MSM).

         2. Latent TB infection

            1. The purified protein derivative (PPD) is the intradermal injection of tuberculin. In HIV and other immunocompromised patients, PPD is considered positive if there is > 5 mm of induration at 48–72 hours. The test has significant limitations:

               1. First, patients have to return for the reading 48–72 hours later.

               2. Second, the test is not specific: false positive PPD frequently occurs due to prior exposure to nontuberculous mycobacteria or prior administration of Bacille Calmette-Guerin (BCG).

               3. Third, PPD can be falsely negative when a patient infected with HIV is unable to mount a delayed-type hypersensitivity response, usually due to a low CD4 count.

            2. An interferon gamma release assay (IGRA) is frequently preferred to PPD in HIV patients.

               1. First, IGRA is much more specific for latent TB infection and is not affected by prior BCG vaccination, although it can be positive with prior exposure to Mycobacterium kansasii or Mycobacterium marinum.

               2. Second, when the patient is unable to mount an immune response to the M tuberculosis Ag included, IGRA will be indeterminate rather than negative. An indeterminate IGRA test is inconclusive and does not increase the probability of TB or latent TB infection.

         A positive PPD or IGRA never proves active TB, and a negative PPD or IGRA never rules out active TB.

      4. Baseline labs: CBC, comprehensive metabolic panel, lipid panel; glucose-6-phosphate dehydrogenase (G6PD) level, in case dapsone or primaquine required for PJP

   4. Immunizations

      1. The response to vaccines often is suboptimal unless the CD4TL count is > 200 cells/mcL. The response to conjugated vaccines is better so the tetanus/diphtheria/acellular pertussis (TDAP) vaccine and the 13-valent conjugated pneumococcal vaccine (Prevnar 13) are likely to be effective even at lower CD4 count.

      2. Since ART often leads to significant immune reconstitution, delaying or repeating immunizations may be useful.

      3. The recommendations for vaccinations in HIV-infected persons is summarized in Table 5-1.

   5. ART

      1. ART has revolutionized HIV care. AIDS-defining illnesses, mortality, and hospitalizations have decreased 60–80% since the introduction of ART.

      2. Effective ART requires complete suppression of viral replication to prevent the emergence of mutations associated with drug resistance.

      3. The cornerstone of therapy is the simultaneous and uninterrupted use of generally 3 antiretroviral drugs to which the virus is susceptible. A fourth drug may be added to boost the level of one of the active drugs. Often, it is possible to select a combination tablet that includes all required drugs, allowing a 1 pill once a day regimen.

      4. Complete suppression is realistic in most patients, prevents the worsening of immune deficiency and results in at least partial immune reconstitution.

      5. Lifetime ART is necessary to prevent viral rebound due to non-replicating, latent HIV in the reservoirs (including macrophages, resting CD4TL, memory cells and stem cells).

      6. Even in patients with a so-called “undetectable viral load,” there is a “residual HIV viremia” (1–5 copies/mL), which can only be assessed with advanced research techniques. When ART is interrupted, the residual viremia re-infects activated CD4TL, leading to a relapse. HIV is not curable with ART alone.

         Lifelong ART is required for all HIV infected persons

      7. Indications for ART

         1. ART is indicated all HIV-infected patients, including those with acute HIV infection and chronic symptomatic or asymptomatic infection

         2. With OIs that involve the brain, ART is delayed to prevent immune-reconstitution-inflammatory syndrome (IRIS) and cerebral edema associated complications.

         3. Treating an infected patient prevents transmission (epidemiologic benefit)

            1. Treating HIV-infected pregnant women prevents mother-to-child-transmission.

            2. Treating infected persons decreases transmission to sex partners.

      8. Antiretroviral agents

         1. Antiretroviral drugs belong to 5 classes

            1. Nucleoside reverse transcriptase inhibitors block reverse transcription of viral RNA into DNA by incorporation in the elongating chain (chain terminators).

            2. Nonnucleoside reverse transcriptase inhibitors (NNRTIs) block reverse transcription of viral RNA into DNA by binding to the “NNRTI pocket” in the p66 subunit of reverse transcriptase.

            3. Integrase inhibitors prevent the integration of HIV DNA into the cellular DNA.

            4. Protease inhibitors inhibit the HIV protease, resulting in lack of cleavage of a viral polyprotein precursor.

            5. Entry inhibitors

               1. Ibalizumab, a recently approved anti-CD4 receptor monoclonal Ab binds to the D2 domain of the CD4 receptor, leading to conformational changes to the CD4 receptor and HIV surface protein complex, which prevents further steps required for viral entry.

               2. Maraviroc prevents HIV cell entry by blocking the CCR5 chemokine receptor, a co-receptor for HIV surface protein. CCR5 receptor inhibitors are effective only if HIV is exclusively CCR5-tropic, and does not use CXCR4 at all. The use of the CXCR4 co-receptor increases in advanced HIV. The co-receptor tropism assay detects whether HIV is CCR5-tropic, CXCR4-tropic, or dual-tropic.

               3. Enfuvirtide, an oligopeptide, blocks the fusion of the HIV envelope with the cell membrane (fusion inhibitor) by binding to the transmembrane glycoprotein gp41.

      9. Adherence

         1. Patient adherence is key. The regimen should be easy to take and well tolerated. Most patients are able to take a single tablet once a day that combines 3 antiretroviral drugs with limited adverse effects.

         2. Adherence of 90–95% is required to maintain viral control and prevent resistance.

         3. High adherence has been shown to decrease morbidity and mortality.

         4. Moderately poor adherence (50–90%) still has still significant clinical benefits but promotes viral resistance, leading to eventual failure of therapy.

         5. Very poor adherence (below 50%) does not prevent progression to AIDS (nor select for resistance).

         6. Predictors of poor adherence include substance abuse, mental illness, lack of access to medical care or medications, lack of patient education, and poor trust between patient and clinician.

      10. Testing for viral resistance

          1. Performed at baseline to detect transmitted resistance and whenever the patient fails to achieve or maintain an undetectable viral load on ART

          2. Both genotype and phenotype are available, but the genotype is preferred because it provides faster results, costs less, and is as clinically useful as the phenotype.

          3. Decisions are complex and require expert guidance. Databases of resistance-associated mutations help decision-making. Stanford University HIV-DB is a very useful tool that is free and readily available on the Internet.

      11. Monitoring:

          1. Guidelines recommend monitoring viral load every 3 months and CD4TL count at intervals.

          2. Goal of therapy: undetectable viral load (< 20/mcL) by 4–6 months

          3. Failure to achieve viral suppression usually is secondary to patient nonadherence, HIV drug resistance, or both. Occasionally other factors are involved: malabsorption, drug interactions, selection of a suboptimal regimen with lower potency, and greater volume of distribution in late pregnancy.

   6. Primary and secondary OI prophylaxis

      1. Primary prophylaxis prevents the initial OI.

      2. Secondary prophylaxis prevents subsequent symptomatic episodes after the initial OI (may not eradicate the infection but can prevent illness).

      3. Primary OI prophylaxis

         1. The CD4TL cell count is the best predictor of susceptibility to OIs.

         2. ART raises CD4TL count in most but not all patients, and markedly decreases the risk of OIs.

         3. Susceptibility is determined by the current CD4TL count rather than the nadir CD4TL count.

            1. CD4TL < 200/mcL: PJP prophylaxis recommended

            2. CD4TL < 100/mcL: Toxoplasmosis prophylaxis recommended if Toxoplasma IgG is positive

            3. Isoniazid therapy for latent TB infection is recommended if PPD causes at least 5 mm of induration or the IGRA is positive.

      4. Primary or secondary OI prophylaxis may be stopped in patients in whom ART restores the CD4TL count above the level recommended for primary prophylaxis.

   7. Major socioeconomic barriers to diagnosis and treatment

      1. Lack of timely access to high-quality healthcare

      2. Only partial drug cost coverage

      3. Poor support for treatment of drug addiction and psychiatric conditions

      4. Entrenched homelessness

      5. Poor care of some patients in jail

      6. HIV-associated stigma remains an issue although significant progress has been achieved.

   8. The HIV Care Continuum and HIV Elimination

      1. One important goal of treatment as prevention is the prevention of new HIV infections. Patients on ART who achieve and maintain undetectable viral loads do not transmit HIV.

      2. A second goal of treatment is to achieve the UNAIDS 90-90-90% targets: by 2020, 90% of the HIV-positive population diagnosed, 90% of diagnosed individuals on ART, and 90% of patients on ART virologically suppressed. Currently in the United States, of all persons infected with HIV, 86% are diagnosed, 63% are in care, 49% are retained in care, and 51% have a suppressed viral load (Figure 5-3).

      3. HIV elimination would require that the reproductive rate of HIV infection be kept below one new infection per 100 infected patients per year, which leads to a decrease of prevalence over time.