Fever, night sweats, and weight loss are common symptoms in HIV-infected patients and may occur without a complicating opportunistic infection. Patients with persistent fever and no localizing symptoms should nonetheless be carefully examined, and evaluated with a chest radiograph (Pneumocystis pneumonia can present without respiratory symptoms), bacterial blood cultures if the fever is greater than 38.5°C, serum cryptococcal antigen, and mycobacterial cultures of the blood. Sinus CT scans should be considered to evaluate occult sinusitis. If these studies are normal, patients should be observed closely. Antipyretics are useful to prevent dehydration.
Centers for Disease Control and Prevention. 2018 quick reference guide: Recommended laboratory HIV testing algorithm for serum or plasma specimens. https://stacks.cdc.gov/view/cdc/50872
et al. HIV and aging: reconsidering the approach to management of comorbidities. Infect Dis Clin North Am. 2019;33:769.
et al. NIH Workshop on HIV-associated comorbidities, coinfections, and complications: summary and recommendation for future research. J Acquir Immune Defic Syndr. 2021;86:11.
1. Weight loss and wasting syndrome
Weight loss is a particularly distressing complication of long-standing HIV infection. Patients typically have disproportionate loss of muscle mass, with maintenance or less substantial loss of fat stores. The mechanism of HIV-related weight loss is not completely understood but appears to be multifactorial.
AIDS patients frequently suffer from anorexia, nausea, and vomiting, all of which contribute to weight loss by decreasing caloric intake. In some cases, these symptoms are secondary to a specific infection, such as viral hepatitis. In other cases, however, evaluation of the symptoms yields no specific pathogen, and it is assumed to be due to a primary effect of HIV. Malabsorption also plays a role in decreased caloric intake. Patients may suffer diarrhea from infections with bacterial, viral, or parasitic agents.
Exacerbating the decrease in caloric intake, many AIDS patients have an increased metabolic rate. This increased rate has been shown to exist even among asymptomatic HIV-infected persons, but it accelerates with disease progression and secondary infection. AIDS patients with secondary infections also have decreased protein synthesis, which makes maintaining muscle mass difficult.
Several strategies have been developed to slow AIDS wasting. In the long term, nothing is as effective as antiretroviral treatment, since it treats the underlying HIV infection. In the short term, effective fever control decreases the metabolic rate and may slow the pace of weight loss, as does treating any underlying opportunistic infection. Food supplementation with high-calorie drinks may enable patients with not much appetite to maintain their intake. Selected patients with otherwise good functional status and weight loss due to unrelenting nausea, vomiting, or diarrhea may benefit from total parenteral nutrition (TPN). It should be noted, however, that TPN is more likely to increase fat stores than to reverse the muscle wasting process.
Two pharmacologic approaches for increasing appetite and weight gain are the progestational agent megestrol acetate liquid suspension (400–800 mg orally daily in divided doses) and the antiemetic agent dronabinol (2.5–5 mg orally three times a day), but neither of these agents increases lean body mass. Side effects from megestrol acetate are rare, but thromboembolic phenomena, edema, nausea, vomiting, and rash have been reported. In 3–10% of patients using dronabinol, euphoria, dizziness, paranoia, and somnolence and even nausea and vomiting have been reported. Dronabinol contains only one of the active ingredients in marijuana, and many patients report better relief of nausea and improvement of appetite with medical cannabis (administered via smoking, vaporization, essential oils, or cooked in food). In the United States, 34 states and the District of Columbia have legalized medical marijuana, and 13 states have legalized recreational (nonmedical) use. However, the use and sale of marijuana are still illegal under federal law.
Two regimens that have resulted in increases in lean body mass are growth hormone and anabolic steroids. Growth hormone at a dose of 0.1 mg/kg/day (up to 6 mg) subcutaneously for 12 weeks has resulted in modest increases in lean body mass. Treatment with growth hormone can cost as much as $10,000 per month. Anabolic steroids also increase lean body mass among HIV-infected patients. They seem to work best for patients who are able to do weight training. The most commonly used regimens are testosterone enanthate or testosterone cypionate (100–200 mg intramuscularly every 2–4 weeks). Testosterone transdermal system (apply 5 mg system each evening) and testosterone gel (1%; apply a 5-g packet [50 mg testosterone] to clean, dry skin daily) are also available. The anabolic steroid oxandrolone (20 mg orally in two divided doses) has also been found to increase lean body mass.
et al. Dronabinol
oral solution in the management of anorexia and weight loss in AIDS and cancer. Ther Clin Risk Manag. 2018;14:643.
Nausea leading to weight loss is sometimes due to esophageal candidiasis. Patients with oral candidiasis and nausea should be empirically treated with an oral antifungal agent. Patients with weight loss due to nausea of unclear origin may benefit from use of antiemetics prior to meals (prochlorperazine, 10 mg three times daily; metoclopramide, 10 mg three times daily; or ondansetron, 8 mg three times daily). Dronabinol (5 mg three times daily) or medical cannabis can also be used to treat nausea. Depression and adrenal insufficiency are two potentially treatable causes of weight loss.
VP. Common gastrointestinal complications associated with human immunodeficiency virus/AIDS: an overview. Crit Care Nurs Clin North Am. 2018;30:101.
et al. Cannabinoids: a guide for use in the world of gastrointestinal disease. J Clin Gastroenterol. 2020;54:769.
1. Pneumocystis pneumonia
(See also Chapter 36.) P jirovecii pneumonia is the most common opportunistic infection associated with AIDS. Pneumocystis pneumonia may be difficult to diagnose because the symptoms—fever, cough, and shortness of breath—are nonspecific. Furthermore, the severity of symptoms ranges from fever and no respiratory symptoms through mild cough or dyspnea to frank respiratory distress.
Hypoxemia may be severe, with a PO2 less than 60 mm Hg. The cornerstone of diagnosis is the chest radiograph (Figure 31–2). Diffuse or perihilar infiltrates are most characteristic, but only two-thirds of patients with Pneumocystis pneumonia have this finding. Normal chest radiographs are seen in 5–10% of patients with Pneumocystis pneumonia, while the remainder have atypical infiltrates. Apical infiltrates are commonly seen among patients with Pneumocystis pneumonia who have been receiving aerosolized pentamidine prophylaxis. Large pleural effusions are uncommon with Pneumocystis pneumonia; their presence suggests bacterial pneumonia, other infections such as tuberculosis, or pleural Kaposi sarcoma.
Pneumocystis pneumonia in a Haitian woman suspected of having underlying HIV/AIDS. Typical chest radiograph showing bilateral diffuse interstitial infiltrates extending out from the hilar areas. (Reproduced, with permission, from Grippi MA, Elias JA, Fishman JA et al (editors). Fishman’s Pulmonary Diseases and Disorders, 5th ed. McGraw-Hill, 2015.)
Definitive diagnosis can be obtained in 50–80% of cases by Wright-Giemsa stain or direct fluorescence antibody (DFA) test of induced sputum. Sputum induction is performed by having patients inhale an aerosolized solution of 3% saline produced by an ultrasonic nebulizer. Patients should not eat for at least 8 hours and should not use toothpaste or mouthwash prior to the procedure since they can interfere with test interpretation. The next step for patients with negative sputum examinations in whom Pneumocystis pneumonia is still suspected should be bronchoalveolar lavage. This technique establishes the diagnosis in over 95% of cases.
In patients with symptoms suggestive of Pneumocystis pneumonia but with negative or atypical chest radiographs and negative sputum examinations, other diagnostic tests may provide additional information in deciding whether to proceed to bronchoalveolar lavage. Elevation of serum lactate dehydrogenase occurs in 95% of cases of Pneumocystis pneumonia, but the specificity of this finding is at best 75%. A serum beta-glucan test is a more sensitive and specific test for Pneumocystis pneumonia compared with serum lactate dehydrogenase and may avoid more invasive tests when used in the appropriate clinical setting. Either a normal diffusing capacity of carbon monoxide (DLCO) or a high-resolution CT scan of the chest that demonstrates no interstitial lung disease makes the diagnosis of Pneumocystis pneumonia very unlikely. In addition, a CD4 count greater than 250 cells/mcL within 2 months prior to evaluation of respiratory symptoms makes a diagnosis of Pneumocystis pneumonia unlikely; only 1–5% of cases occur above this CD4 count level (Figure 31–1). This is true even if the patient previously had a CD4 count lower than 200 cells/mcL but has had an increase with antiretroviral treatment. Pneumothoraces can be seen in HIV-infected patients with a history of Pneumocystis pneumonia.
Trimethoprim-sulfamethoxazole is the preferred treatment of Pneumocystis pneumonia (Table 31–3). In addition to specific anti-Pneumocystis treatment, corticosteroid therapy has been shown to improve the course of patients with moderate to severe P jirovecii pneumonia (PaO2 less than 70 mm Hg on room air or alveolar-arterial O2 gradient greater or equal to 35 mm Hg) when administered within 72 hours of the start of anti-Pneumocystis treatment. It should be started as early as possible after initiation of treatment, using prednisone 40 mg orally twice daily for days 1–5, 40 mg daily for days 6–10, and 20 mg daily for days 11–21 (for patients who cannot take oral medication, intravenous methylprednisolone can be substituted at 75% of the oral dose). The mechanism of action is presumed to be a decrease in alveolar inflammation.
Table 31–3.Treatment of AIDS-related opportunistic infections and malignancies.1 ||Download (.pdf) Table 31–3. Treatment of AIDS-related opportunistic infections and malignancies.1
|Infection or Malignancy ||Treatment ||Complications2 |
|Pneumocystis jirovecii infection3 ||Preferred regimen: Trimethoprim-sulfamethoxazole, 15 mg/kg/day (based on trimethoprim component) intravenously or one double-strength tablet orally three times a day for 21 days. Add prednisone when PaO2 < 70 mm Hg on room air or alveolar-arterial O2 gradient > 35 mm Hg: 40 mg orally twice a day on days 1–5, 40 mg orally daily on days 6–10, 20 mg orally daily on days 11–21 ||Nausea, neutropenia, anemia, hepatitis, rash, Stevens-Johnson syndrome |
| ||Pentamidine, 3–4 mg/kg/day intravenously for 21 days plus prednisone when indicated as above ||Hypotension, hypoglycemia, anemia, neutropenia, pancreatitis, hepatitis |
| ||Primaquine, 30 mg/day orally, and clindamycin, 600 mg every 8 hours orally, for 21 days plus prednisone when indicated as above || |
Primaquine: hemolytic anemia in G6PD-deficient patients,3 methemoglobinemia, neutropenia, colitis
Clindamycin: rash, nausea, abdominal pain, colitis
| ||Not recommended for severe disease: Trimethoprim, 15 mg/kg/day orally in three divided doses, with dapsone, 100 mg/day orally, for 21 days,3 plus prednisone when indicated as above ||Nausea, rash, hemolytic anemia in G6PD3-deficient patients; methemoglobinemia (weekly levels should be < 10% of total hemoglobin) |
| ||Not recommended for severe disease: Atovaquone, 750 mg orally twice daily with food for 21 days, plus prednisone when indicated as above ||Rash, elevated aminotransferases, anemia, neutropenia |
|Mycobacterium avium complex infection ||Clarithromycin, 500 mg orally twice daily with ethambutol, 15 mg/kg/day orally (maximum, 1 g). May also add: || |
Clarithromycin: hepatitis, nausea, diarrhea
Ethambutol: hepatitis, optic neuritis
| ||Rifabutin, 300 mg orally daily ||Rash, hepatitis, uveitis |
|Toxoplasmosis ||Preferred regimen: Pyrimethamine, 200 mg orally as loading dose, followed by 50 mg daily (weight ≤ 60 kg) or 75 mg daily (weight > 60 kg), combined with sulfadiazine, 1000 mg orally four times daily (weight ≤ 60 kg) or 1500 mg orally four times daily (weight > 60 kg) and leucovorin 10–25 mg orally daily for at least 6 weeks. Longer courses are necessary for extensive disease or incomplete clinical or radiographic resolution. Maintenance therapy with pyrimethamine 25–50 mg orally plus sulfadiazine 2000–4000 mg in two to four divided doses plus leucovorin 10–25 mg orally daily. Long-term treatment should be maintained until immune reconstitution with antiretroviral treatment occurs. || |
Pyrimethamine: leukopenia, anorexia, vomiting
Sulfadiazine: nausea, vomiting, Stevens-Johnson syndrome
| ||For patients who are intolerant of sulfa who cannot be desensitized: Substitute clindamycin 600 mg intravenously or orally every 6 hours for the sulfadiazine in the above regimen || |
Pyrimethamine: leukopenia, anorexia, vomiting
Clindamycin: rash, nausea, abdominal pain, colitis
| ||If pyrimethamine not available: Trimethoprim-sulfamethoxazole, 10 mg/kg/day (based on trimethoprim component) ||Nausea, neutropenia, anemia, hepatitis, rash, Stevens-Johnson syndrome |
|Non-Hodgkin lymphoma ||Combination chemotherapy (eg, EPOCH with rituximab and G-CSF). Central nervous system disease: Radiation treatment with dexamethasone for edema ||Nausea, vomiting, anemia, neutropenia, thrombocytopenia, cardiac toxicity (with doxorubicin) |
|Cryptococcal meningitis ||Preferred regimen: Induction: Liposomal amphotericin B, 3–4 mg/kg/day intravenously, with flucytosine, 25 mg/kg/dose orally four times daily for minimum of 2 weeks (adjust flucytosine dose for kidney function), then fluconazole, 400 mg orally daily for a minimum of 8 weeks (consolidation), then 200 mg orally daily to complete a minimum of 1 year of therapy (maintenance) || |
Liposomal amphotericin: fever, chills, hypokalemia, kidney disease
Flucytosine: bone marrow suppression, kidney disease, hepatitis
| ||Induction: Amphotericin B, 0.7–1.0 mg/kg/day intravenously, with flucytosine, 25 mg/kg/dose orally four times daily for a minimum of 2 weeks (adjust flucytosine dose for kidney function), then fluconazole, 400 mg orally daily for a minimum of 8 weeks (consolidation), then 200 mg orally daily to complete a minimum of 1 year of therapy (maintenance) || |
Amphotericin: fever, chills, hypokalemia, kidney disease
Flucytosine: bone marrow suppression, kidney disease, hepatitis
|Cryptococcal meningitis (cont.) ||Fluconazole, used alone, is inferior to amphotericin B as induction therapy; it is recommended only for patients who cannot tolerate or do not respond to the preferred regimen above. If used for primary induction therapy, give fluconazole, 1200 mg orally daily, with flucytosine, 25 mg/kg/dose orally four times daily for a minimum of 2 weeks (adjust flucytosine dose for kidney function), then 400 mg orally daily for a minimum of 8 weeks (consolidation), then 200 mg orally daily to complete a minimum of 1 year of therapy. ||Hepatitis |
|Cytomegalovirus retinitis (immediate sight-threatening) ||Preferred regimen: First-line therapy is oral valganciclovir, 900 mg orally twice a day with food for 21 days followed by 900 mg daily (maintenance). For sight-threatening infections involving the macula or optic nerve, add intravitreal ganciclovir (2 mg/injection) or foscarnet (2.4 mg/injection) for 1–4 doses/day for 7–10 days ||For valganciclovir: Neutropenia, anemia, thrombocytopenia (avoid in patients with hemoglobin < 8 g/dL, neutrophil count below 500 cells/mcL [0.5 × 109/L] or platelet count below 25,000/mcL [25 × 109/L]. Potentially embryotoxic. |
| ||Ganciclovir, 10 mg/kg/day intravenously in two divided doses for 14–21 days, followed by 5 mg/kg daily (maintenance) || |
Neutropenia, anemia, thrombocytopenia
Adjust ganciclovir dose for kidney function.
| ||Foscarnet, 90 mg/kg intravenously every 12 hours for 14 days, followed by 90–120 mg/kg once daily || |
Nausea, hypokalemia, hypocalcemia, hyperphosphatemia, azotemia
Adjust foscarnet dose for kidney function.
| ||Cidofovir, 5 mg/kg/week intravenously for 2 weeks, then 5 mg/kg every other week with probenecid, 2 g orally 3 hours before dose, 1 g orally 2 hours after dose, and 1 g orally 8 hours after dose || |
Nephrotoxicity (to reduce likelihood, pre- and post-saline hydration, along with probenecid), ocular hypotony, anterior uveitis, neutropenia
Avoid in patients with sulfa allergy because of cross hypersensitivity with probenecid
|Esophageal candidiasis or recurrent vaginal candidiasis ||Fluconazole, 100–200 mg orally daily for 14–21 days for esophageal disease and > 7 days for recurrent vaginal disease ||Hepatitis, development of azole resistance. Fluconazole should not be given to women who are or may be pregnant because of risk of spontaneous abortion. |
|Herpes simplex infection ||Acyclovir, 400 mg orally three times daily for 5–10 days; or acyclovir, 5 mg/kg intravenously every 8 hours for severe cases ||Resistant herpes simplex with long-term therapy |
| ||Famciclovir, 500 mg orally twice daily for 5–10 days ||Nausea |
| ||Valacyclovir, 1 g orally twice daily for 5–10 days ||Nausea |
| ||Foscarnet, 40 mg/kg intravenously every 8 hours, for acyclovir-resistant cases || |
Nausea, hypokalemia, hypocalcemia, hyperphosphatemia, azotemia
Adjust foscarnet dose for kidney function
|Herpes zoster ||Preferred regimen: Valacyclovir, 1000 mg orally three times daily for 7–10 days ||Nausea |
| ||Preferred regimen: Famciclovir, 500 mg orally three times daily for 7–10 days ||Nausea |
| ||Acyclovir, 800 mg orally five times daily for 7–10 days. Intravenous therapy at 10 mg/kg every 8 hours for extensive cutaneous or visceral disease until clinical improvement, then switch to oral therapy to complete a 10- to 14-day course. For ocular involvement, consult an ophthalmologist immediately. ||Nausea |
|Kaposi sarcoma || || |
| Mild to moderate ||Initiation or optimization of antiretroviral treatment ||Side effects of antiretroviral treatment |
| Advanced disease ||Combination chemotherapy (eg, daunorubicin, bleomycin, vinblastine) ||Bone marrow suppression, cardiac toxicity (with daunorubicin), fever |
| ||Pomalidomide, 5 mg/day orally on days 1–21 of every 28-day cycle; alternative to chemotherapy ||Fatigue, asthenia, dyspnea, anemia, neutropenia; contraindicated in pregnancy |
JA. Pneumocystis jirovecii
. Semin Respir Crit Care Med. 2020;41:141.
et al. Lung ultrasound in the management of pneumocystis pneumonia: a case series. Int J STD AIDS. 2019;30:188.
et al. Pneumocystis pneumonia in HIV-1-infected patients. Respir Investig. 2019;57:213.
S. Recent advances in the diagnosis and management of Pneumocystis
pneumonia. Tuberc Respir Dis (Seoul). 2020;83:132.
2. Other infectious pulmonary diseases
Other infectious causes of pulmonary disease in AIDS patients include bacterial, mycobacterial, and viral etiologies.
Community-acquired pneumonia is the most common cause of pulmonary disease in HIV-infected persons. An increased incidence of pneumococcal pneumonia with septicemia and Haemophilus influenzae pneumonia has been reported. Pseudomonas aeruginosa is an important respiratory pathogen in advanced disease and, more rarely, pneumonia from Rhodococcus equi infection can occur.
The incidence of infection with Mycobacterium tuberculosis has markedly increased in metropolitan areas because of HIV infection as well as homelessness. Tuberculosis occurs in an estimated 4% of persons in the United States who have AIDS. Patients with active tuberculosis and CD4 counts above 350 cells/mcL are likely to present with upper lobe and hilar infiltrates and paratracheal adenopathy, findings similar to persons uninfected with HIV (Figure 31–3). With advanced immunodeficiency, lower lobe, middle lobe, interstitial, and miliary infiltrates are more common, along with mediastinal adenopathy and extrapulmonary involvement. Although a purified protein derivative (PPD) test or an interferon gamma release assay (IGRA, including the QuantiFERON and T-SPOT tests) should be performed on all HIV-infected persons in whom a diagnosis of tuberculosis is being considered, the lower the CD4 cell count, the greater the likelihood of falsely negative PPD or IGRA test results or of indeterminate IGRA test results. Because "anergy" skin test panels do not accurately classify those patients who are infected with tuberculosis but unreactive to the PPD, they are not recommended.
A 36-year-old man with pulmonary tuberculosis. There is an opacification of a portion of the left upper lung in association with a cavity, findings consistent with pulmonary tuberculosis. Also, there is an infiltrate in the right lung. The extent of his disease raises the specter that he has underlying HIV/AIDS. (Used, with permission, from Richard P. Usatine, MD, in Usatine RP, Smith MA, Mayeaux EJ Jr, Chumley H. The Color Atlas and Synopsis of Family Medicine, 3rd ed. McGraw-Hill, 2019.)
Treatment of HIV-infected persons with active tuberculosis is similar to treatment of HIV-uninfected tubercular individuals. However, rifampin should not be given to patients receiving a boosted protease inhibitor (PI) regimen. In these cases, rifabutin may be substituted, but it may require dosing modifications depending on the antiretroviral regimen. Multidrug-resistant tuberculosis has been a major problem in several metropolitan areas of the developed world, and reports from South Africa of “extremely resistant” tuberculosis in AIDS patients are a growing global concern. Noncompliance with prescribed antituberculous medications is a major risk factor. Several of the reported outbreaks appear to implicate nosocomial spread. The emergence of medication resistance makes it essential that antibiotic sensitivities be performed on all positive cultures. Medication therapy should be individualized. Patients with multidrug-resistant M tuberculosis infection should receive at least three medications to which their organism is sensitive.
Atypical mycobacteria can cause pulmonary disease in AIDS patients with or without preexisting lung disease and responds variably to treatment. Distinguishing between M tuberculosis and atypical mycobacteria requires culture of sputum specimens. If culture of the sputum produces acid-fast bacilli, definitive identification may take several weeks using traditional techniques. DNA probes allow for presumptive identification usually within days of a positive culture. While awaiting definitive diagnosis, clinicians should err on the side of treating patients as if they have M tuberculosis infection unless the risk of atypical mycobacteria is very high (eg, a person without risk for tuberculosis exposure with a CD4 count under 50 cells/mcL—see Figure 31–1), clinicians may wait for definitive diagnosis, and the person is smear-negative for acid-fast bacilli, clinically stable, and not living in a communal setting.
et al; STATIS ANRS 12290 Trial Team. Systematic or test-guided treatment for tuberculosis in HIV-infected adults. N Engl J Med. 2020;382:2397.
et al. Virtual CROI 2020: Tuberculosis and coinfections in HIV infection. Top Antivir Med. 2020;28:455.
et al. Prevalence of non-tuberculous mycobacteria in HIV-infected patients admitted to hospital with pneumonia. Int J Tuberc Lung Dis. 2019;23:491.
C. VIRAL (SARS-CoV-2 AND OTHER)
COVID-19, the illness caused by the novel 2019 coronavirus SARS-CoV-2, causes a very wide spectrum of illness, ranging from no symptoms, to a mild upper respiratory tract illness with fever and cough, to a clinical triad of fever, cough, and dyspnea, to pneumonia, to acute respiratory distress syndrome (ARDS), and even to fulminant multisystem organ failure and death. Chest radiographs and CT scans may be normal early in the disease course, then may show nonspecific diffuse ground glass opacities, multilobar infiltrates, and consolidations, some progressing to full-blown ARDS (see Chapter 32).
The limited data currently available do not indicate that the disease course of COVID-19 in persons with HIV differs from that in persons without HIV. Those patients with HIV who have other comorbidities (eg, cardiovascular disease, lung disease, long-term smoking) have an increased risk of a more severe course of COVID-19 illness.
Persons with HIV should not alter their antiretroviral regimens or add medications for the purpose of possibly preventing or treating SARS-CoV-2 infection. Patients who have a suppressed HIV viral load and are in stable health should postpone routine medical and laboratory visits if possible, and clinicians should use telephone or virtual visits to replace face-to-face encounters for nonurgent care and adherence counseling. CDC guidelines advise patients with HIV to maintain on-hand at least a 30-day—and ideally a 90-day—supply of antiretroviral drugs and other medications, and to change to pharmacy or mail order delivery of medications when possible. Persons with HIV may need additional assistance with food, housing, transportation, and childcare.
For persons with HIV in self-isolation or quarantine due to SARS-CoV-2 exposure, clinicians should devise a plan to evaluate patients if they develop COVID-19–related persistent fever, cough, or dyspnea, including possible transfer to a health care facility for care. When a person with HIV is hospitalized for presumed COVID-19, antiretroviral therapy should be continued. If the patient’s medications are not on the hospital’s formulary, the clinician may need to write an order that medications from the patients’ home supplies can be administered. Antiretroviral drug substitutions should be avoided.
Although information and data are rapidly evolving, it seems that persons with HIV on a suppressive antiretroviral regimen who contract COVID-19 have a prognosis similar to, and can be managed clinically the same as, persons who do not have HIV. However, additional caution is warranted for HIV-infected persons who develop COVID-19, especially those with poorly controlled HIV or advanced AIDS.
Isolation of cytomegalovirus (CMV) from bronchoalveolar lavage fluid occurs commonly in AIDS patients but does not establish a definitive diagnosis. Diagnosis of CMV pneumonia requires biopsy; response to treatment is poor. Histoplasmosis, coccidioidomycosis, and cryptococcal disease as well as more common respiratory viral infections should also be considered in the differential diagnosis of unexplained pulmonary infiltrates.
et al. Patterns of HIV and SARS-CoV-2 co-infection in Wuhan, China. J Int AIDS Soc. 2020;23:e25568.
et al; COVID-19 ID Team. Description of COVID-19 in HIV-infected individuals: a single-centre, prospective cohort. Lancet HIV. 2020;7:e554.
3. Noninfectious pulmonary diseases
Noninfectious causes of lung disease include Kaposi sarcoma, non-Hodgkin lymphoma, interstitial pneumonitis, and increasingly, in the current antiretroviral treatment era, lung cancer. In patients with known Kaposi sarcoma, pulmonary involvement complicates the course in approximately one-third of cases. However, pulmonary involvement is rarely the presenting manifestation of Kaposi sarcoma. Non-Hodgkin lymphoma may involve the lung as the sole site of disease, but more commonly involves other organs as well, especially the brain, liver, and gastrointestinal tract. Both of these processes may show nodular or diffuse parenchymal involvement, pleural effusions, and mediastinal adenopathy on chest radiographs.
Nonspecific interstitial pneumonitis may mimic Pneumocystis pneumonia. Lymphocytic interstitial pneumonitis seen in lung biopsies has a variable clinical course. Typically, these patients present with several months of mild cough and dyspnea; chest radiographs show interstitial infiltrates. Many patients with this entity undergo transbronchial biopsies in an attempt to diagnose Pneumocystis pneumonia. Instead, the tissue shows interstitial inflammation ranging from an intense lymphocytic infiltration (consistent with lymphoid interstitial pneumonitis) to a mild mononuclear inflammation.
Corticosteroids may be helpful in some cases refractory to antiretroviral treatment.
et al. Increasing burden of noninfectious lung disease in persons living with HIV: a 7-year study using the French nationwide hospital administrative database. Eur Respir J. 2018;52:1800359.
Chronic sinusitis can be a frustrating problem for HIV-infected patients. Symptoms include sinus congestion and discharge, headache, and fever. Some patients may have radiographic evidence of sinus disease on sinus CT scan in the absence of significant symptoms.
HIV-infected patients with purulent drainage should be treated for possible H influenzae with amoxicillin-potassium clavulanate (500 mg orally three times a day) (see Chapter 8). A 7-day course of pseudoephedrine 60 mg twice daily may be helpful in decreasing congestion. Prolonged treatment (3–6 weeks) with an antibiotic and guaifenesin (600 mg orally twice daily) is sometimes necessary. For patients not responding to amoxicillin-potassium clavulanate, levofloxacin may be tried (400 mg orally daily). In patients with advanced immunodeficiency, Pseudomonas infections should be suspected, especially if there is not a response to first-line antibiotics. Some patients may require referral to an otolaryngologist for sinus drainage and culture for possible fungal infection (Aspergillus, Histoplasma capsulatum).
et al. Otorhinolaryngological profile and surgical intervention in patients with HIV/AIDS. Sci Rep. 2018;8:12045.
et al. Histoplasma capsulatum
causing sinusitis: a case report in French Guiana and review of the literature. BMC Infect Dis. 2018;18:595.
C. Central Nervous System Disease
Central nervous system disease in HIV-infected patients can be divided into intracerebral space-occupying lesions, encephalopathy, meningitis, and spinal cord processes. Many of these complications have declined markedly in prevalence in the era of effective antiretroviral treatment. Cognitive declines, however, may be more common in HIV patients, especially as they age (older than 50 years), even those who are taking fully suppressive antiretroviral treatment.
et al. Central nervous system infections in the immunocompromised adult presenting to the emergency department. Emerg Med Clin North Am. 2021;39:101.
Toxoplasmosis is the most common CNS space-occupying lesion in HIV-infected patients. Headache, focal neurologic deficits, seizures, or altered mental status may be presenting symptoms. The diagnosis is usually made presumptively based on the characteristic appearance of cerebral imaging studies in an individual known to be seropositive for Toxoplasma. Typically, toxoplasmosis appears as multiple contrast-enhancing lesions on CT scan. Lesions tend to be peripheral, with a predilection for the basal ganglia.
Single lesions are atypical of toxoplasmosis. When a single lesion has been detected by CT scanning, MRI scanning may reveal multiple lesions because of its greater sensitivity. If a patient has a single lesion on MRI and is neurologically stable, clinicians may pursue a 2-week empiric trial of toxoplasmosis therapy. A repeat scan should be performed at 2 weeks. If the lesion has not diminished in size, biopsy of the lesion should be performed. A positive Toxoplasma serologic test does not confirm the diagnosis because many HIV-infected patients have detectable titers without having active disease. Conversely, less than 3% of patients with toxoplasmosis have negative titers. Therefore, negative Toxoplasma titers in an HIV-infected patient with a space-occupying lesion should be a cause for aggressively pursuing an alternative diagnosis. The preferred treatment of toxoplasmosis is with pyrimethamine and sulfadiazine (Table 31–3). If pyrimethamine is not available, patients can be treated with trimethoprim-sulfamethoxazole.
JE. HIV-related cerebral toxoplasmosis revisited: current concepts and controversies of an old disease. J Int Assoc Provid AIDS Care. 2019;18:2325958219867315.
2. Central nervous system lymphoma
Primary non-Hodgkin lymphoma is the second most common CNS space-occupying lesion in HIV-infected patients. Symptoms are similar to those with toxoplasmosis. While imaging techniques cannot distinguish these two diseases with certainty, lymphoma more often is solitary. Other less common lesions should be suspected if there is preceding bacteremia, positive tuberculin test, fungemia, or injection drug use. These include bacterial abscesses, cryptococcomas, tuberculomas, and Nocardia lesions.
Stereotactic brain biopsy should be strongly considered if lesions are solitary or do not respond to toxoplasmosis treatment, especially if they are easily accessible. Diagnosis of lymphoma is important because many patients benefit from treatment (radiation therapy). Although a positive polymerase chain reaction (PCR) assay of cerebrospinal fluid for Epstein–Barr virus DNA is consistent with a diagnosis of lymphoma, the sensitivity and specificity of the test are not high enough to obviate the need for a brain biopsy.
et al. Primary CNS lymphoma in HIV infection. Handb Clin Neurol. 2018;152:177.
et al. Imaging in differentiating cerebral toxoplasmosis and primary CNS lymphoma with special focus on FDG PET/CT. AJR Am J Roentgenol. 2021;216:157.
3. HIV-associated dementia and neurocognitive disorders
Patients with HIV-associated dementia typically have difficulty with cognitive tasks (eg, memory, attention), exhibit diminished motor function, and have emotional or behavioral problems. Patients may first notice a deterioration in their handwriting. The manifestations of dementia may wax and wane, with persons exhibiting periods of lucidity and confusion over the course of a day. The diagnosis of HIV-associated dementia is one of exclusion based on a brain imaging study and on spinal fluid analysis that excludes other pathogens. Neuropsychiatric testing is helpful in distinguishing patients with dementia from those with depression. Many patients improve with effective antiretroviral treatment. However, slowly progressive neurocognitive deficits may still develop in patients taking antiretroviral treatment as they age.
Metabolic abnormalities may also cause changes in mental status: hypoglycemia, hyponatremia, hypoxia, and drug overdose are important considerations in this population. Other less common infectious causes of encephalopathy include progressive multifocal leukoencephalopathy (discussed below), CMV, syphilis, and herpes simplex encephalitis.
et al. Pharmacologic approaches to HIV-associated neurocognitive disorders. Curr Opin Pharmacol. 2020;54:102.
et al. Montreal Cognitive Assessment (MoCA) for HIV-associated neurocognitive disorders. Neuropsychol Rev. 2019;29:313.
4. Cryptococcal meningitis
Cryptococcal meningitis typically presents with fever and headache. Less than 20% of patients have meningismus. Diagnosis is based on a positive latex agglutination test of serum that detects cryptococcal antigen (or “CRAG”) or positive culture of spinal fluid for Cryptococcus. Seventy to 90% of patients with cryptococcal meningitis have a positive serum CRAG. Thus, a negative serum CRAG test makes a diagnosis of cryptococcal meningitis unlikely and can be useful in the initial evaluation of a patient with headache, fever, and normal mental status. Treatment has three phases: induction, consolidation, and maintenance. Induction treatment is given for a minimum of 2 weeks plus evidence of clinical improvement and a negative CSF culture on repeat lumbar puncture. Treatment can be stopped after 1 year of maintenance therapy if the patient is asymptomatic, has a CD4 cell count of greater than 100/mcL for at least 3 months, and has suppressed viral load on effective antiretroviral treatment. The preferred treatment is liposomal amphotericin with flucytosine (Table 31–3).
et al. Recent advances in managing HIV-associated cryptococcal meningitis. F1000Res. 2019;8:743.
DS. Emerging concepts in HIV-associated cryptococcal meningitis. Curr Opin Infect Dis. 2019;32:16.
et al. Diagnosis and management of central nervous system cryptococcal infections in HIV-infected adults. J Fungi (Basel). 2019;5:E65.
et al. Treatment for HIV-associated cryptococcal meningitis. Cochrane Database Syst Rev. 2018;7:CD005647.
et al. Management of human immunodeficiency virus-associated cryptococcal meningitis: current status and future directions. Mycoses. 2019;62:874.
5. Meningococcal meningitis
HIV-infected persons are at increased risk for meningococcal disease. Treatment is the same as in uninfected persons. Therefore, the Advisory Committee on Immunization Practices recommends the meningococcal conjugate vaccine (serogroups A, C, W, and Y) for all HIV-infected persons aged 2 months or older.
et al. Meningococcal disease surveillance in men who have sex with men—United States, 2015–2016. MMWR Morb Mortal Wkly Rep. 2018;67:1060.
6. HIV meningitis and HIV myelopathy
HIV meningitis, characterized by lymphocytic pleocytosis of the spinal fluid with negative culture, is common early in HIV infection. Spinal cord function may also be impaired in HIV-infected individuals. HIV myelopathy presents with leg weakness and incontinence. Spastic paraparesis and sensory ataxia are seen on neurologic examination. Myelopathy is usually a late manifestation of HIV disease, and most patients will have concomitant HIV encephalopathy. Pathologic evaluation of the spinal cord reveals vacuolation of white matter. Because HIV myelopathy is a diagnosis of exclusion, symptoms suggestive of myelopathy should be evaluated by lumbar puncture to rule out CMV polyradiculopathy (described below) and an MRI or CT scan to exclude epidural lymphoma.
et al. HIV-vacuolar myelopathy: an unusual early presentation in HIV. Int J STD AIDS. 2021;32:205.
et al. HIV and spinal cord disease. Handb Clin Neurol. 2018;152:213.
7. Progressive multifocal leukoencephalopathy (PML)
PML is a viral infection of the white matter of the brain seen in patients with very advanced HIV infection. It typically results in focal neurologic deficits such as aphasia, hemiparesis, and cortical blindness. Imaging studies are strongly suggestive of the diagnosis if they show nonenhancing white matter lesions without mass effect. Extensive lesions may be difficult to differentiate from the changes caused by HIV. Several patients have stabilized or improved after the institution of effective antiretroviral treatment, and due to wide use of antiretroviral treatment, PML is now rarely seen.
et al. AIDS-related progressive multifocal leukoencephalopathy. Rev Soc Bras Med Trop. 2020;54:e02522020.
et al. Progressive multifocal leukoencephalopathy and the spectrum of JC virus-related disease. Nat Rev Neurol. 2021;17:37.
D. Peripheral Nervous System
Peripheral nervous system syndromes include inflammatory polyneuropathies, sensory neuropathies, and mononeuropathies.
An inflammatory demyelinating polyneuropathy similar to Guillain-Barré syndrome occurs in HIV-infected patients, usually prior to frank immunodeficiency. The syndrome in many cases improves with plasmapheresis, supporting an autoimmune basis of the disease. CMV can cause an ascending polyradiculopathy characterized by lower extremity weakness and a neutrophilic pleocytosis on spinal fluid analysis with a negative bacterial culture. Transverse myelitis can be seen with herpes zoster or CMV.
Peripheral neuropathy is common among HIV-infected persons. Patients typically complain of numbness, tingling, and pain in the lower extremities. Symptoms are disproportionate to findings on gross sensory and motor evaluation. Beyond HIV infection itself, the most common cause is prior antiretroviral treatment with stavudine or didanosine. Although not used commonly in Western countries, stavudine is still being used in resource-limited settings through national antiretroviral treatment programs. Caution should be used when administering these agents to patients with a history of peripheral neuropathy. Unfortunately, medication-induced neuropathy is not always reversed when the offending agent is discontinued. Patients with advanced disease may also develop peripheral neuropathy even if they have never taken antiretroviral treatment. Evaluation should rule out other causes of sensory neuropathy such as alcoholism, thyroid disease, vitamin B12 deficiency, and syphilis.
Treatment of peripheral neuropathy is aimed at symptomatic relief. Patients should be initially treated with gabapentin (start at 300 mg at bedtime and increase to 300–900 mg orally three times a day) or other co-analgesics for neuropathic pain (see Chapter 5). Opioid analgesics should be avoided because the condition tends to be chronic and patients are likely to become dependent on these agents without significant improvement in their well-being.
et al. Human immunodeficiency virus-related peripheral neuropathy: a systematic review and meta-analysis. Eur J Neurol. 2021;28:1420.
E. Rheumatologic and Bone Manifestations
Arthritis, involving single or multiple joints, with or without effusion, has been commonly noted in HIV-infected patients. Involvement of large joints is most common. Although the cause of HIV-related arthritis is unknown, most patients will respond to nonsteroidal anti-inflammatory medications. Patients with a sizable effusion, especially if the joint is warm or erythematous, should have the joint aspirated, followed by culture of the fluid to rule out suppurative arthritis as well as fungal and mycobacterial disease.
Several rheumatologic syndromes, including reactive arthritis, psoriatic arthritis, sicca syndrome, and systemic lupus erythematosus, have been reported in HIV-infected patients (see Chapter 20). However, it is unclear if the prevalence is greater than in the general population. Cases of avascular necrosis of the femoral heads have been reported sporadically, generally in the setting of advanced disease with long-standing infection and in patients receiving long-term antiretroviral treatment. The etiology is not clear but is probably multifactorial in nature.
Osteoporosis and osteopenia appear to be more common in HIV-infected patients with chronic infection and perhaps associated with long-term use of antiretroviral treatment. Vitamin D deficiency appears to be quite common among HIV-infected populations and monitoring vitamin D levels and instituting replacement therapy for detected deficiency are recommended. Bone mineral density scans for HIV-infected postmenopausal women and men over the age of 50 are also recommended.
et al. Prevalence of and risk factors for low bone mineral density assessed by quantitative computed tomography in people living with HIV and uninfected controls. J Acquir Immune Defic Syndr. 2020;83:165.
et al. Human immunodeficiency virus infection (HIV)-associated rheumatic manifestations in the pre- and post-HAART eras. Clin Rheumatol. 2020;39:2515.
Myopathies are infrequent in the era of effective antiretroviral treatment but can be related to either HIV infection or antiretroviral treatment, particularly with use of zidovudine (azidothymidine [AZT]). Proximal muscle weakness is typical, and patients may have varying degrees of muscle tenderness. Given its long-term toxicities, zidovudine is no longer recommended when alternative treatments are available.
et al. Neuromuscular complications of HIV infection. Handb Clin Neurol. 2018;152:201.
et al. Neuromuscular diseases associated with human immunodeficiency virus infection. J Neurol Sci. 2018;387:27.
In HIV-infected patients, complaints of visual changes must be evaluated immediately by an ophthalmologist familiar with the manifestations of HIV disease. CMV retinitis, characterized by perivascular hemorrhages and white fluffy exudates, is the most common retinal infection in AIDS patients and can be rapidly progressive (Figure 31–4). In contrast, cotton wool spots, which are also common in HIV-infected patients, are benign, remit spontaneously, and appear as small indistinct white spots without exudation or hemorrhage. Other rare retinal processes include other herpesvirus infections or toxoplasmosis. Choice of treatment for CMV retinitis (Table 31–3) depends on severity and location of lesions, and the patient’s overall condition and circumstances.
CMV retinitis. Retina has classic “pizza pie” or “cheese and ketchup” appearance, with hemorrhages and dirty white, granular appearing retinal necrosis adjacent to major vessels (see diagrammatic map). (Photo used, with permission, from Richard E. Wyszynski, MD. Diagram used, with permission, from Knoop KJ, Stack LB, Storrow AB, Thurman RJ. The Atlas of Emergency Medicine, 5th ed. McGraw Hill, 2021.)
et al. Active cytomegalovirus retinitis after the start of antiretroviral therapy. Br J Ophthalmol. 2019;103:157.
et al. Clinical features of cytomegalovirus retinitis in HIV infected patients. Front Cell Infect Microbiol. 2020;10:136.
et al. HIV-induced retinitis. Ocul Immunol Inflamm. 2020;28:1259.
Oral candidiasis can be bothersome to patients, many of whom report an unpleasant taste or mouth dryness. The two most common forms of oral candidiasis seen are pseudomembranous (removable white plaques) (eFigure 31-1A) and erythematous (red friable plaques) (eFigure 31-1B and eFigure 31-1C). Angular cheilitis—fissures at the sides of the mouth—is usually due to Candida as well (eFigure 31-1B)
Pseudomembranous form of oral candidiasis is the most common; the white plaques over the hard palate raise the suspicion of underlying HIV/AIDS. They can be scraped off with a tongue blade, placed on a slide, and mixed with potassium hydroxide solution to make the diagnosis of Candida albicans (see eFigure 31–1C). (Used, with permission, from Richard P. Usatine, MD, in Usatine RP, Smith MA, Mayeaux EJ Jr, Chumley H. The Color Atlas of Family Medicine, 2nd ed. McGraw-Hill, 2013.)
This man with HIV-AIDS has the (less common) erythematous form of oral candidiasis. The patient also has perlèche or angular cheilitis (Candida infection at the corners of the mouth). (Used, with permission, from Richard P. Usatine, MD, in Usatine RP, Smith MA, Mayeaux EJ Jr, Chumley H. The Color Atlas of Family Medicine, 2nd ed. McGraw-Hill, 2013.)
Photomicrograph of Candida albicans on potassium hydroxide (KOH) preparation. When an oral candidiasis lesion is scraped, added to a slide with KOH under a cover slip, and examined under low power microscopy, the pseudohyphae and/or budding yeast forms of C albicans are seen. (Used, with permission, from Usatine RP, Smith MA, Mayeaux EJ, Chumley HS. The Color Atlas of Family Medicine, 2nd ed. McGraw-Hill, 2013.)
Hairy leukoplakia is caused by the Epstein-Barr virus. The lesion is not usually troubling to patients and sometimes regresses spontaneously. Hairy leukoplakia is commonly seen as a white lesion on the lateral aspect of the tongue. It may be flat or slightly raised, is usually corrugated, and has vertical parallel lines with fine or thick (“hairy”) projections (Figure 8–6).
The presence of oral candidiasis or hairy leukoplakia is significant for several reasons. First, these lesions are highly suggestive of HIV infection in patients who have no other obvious cause of immunodeficiency. Second, several studies have indicated that patients with candidiasis have a high rate of progression to AIDS even with statistical adjustment for CD4 count.
Gingival disease is common in HIV-infected patients and is thought to be due to an overgrowth of microorganisms. Aphthous ulcers are painful and may interfere with eating.
Other lesions seen in the mouths of HIV-infected patients include Kaposi sarcoma (usually on the hard palate) and warts.
Treatment of oral candidiasis is with topical agents such as clotrimazole 10-mg troches (one troche four or five times a day). Patients with candidiasis who do not respond to topical antifungals can be treated with fluconazole (50–100 mg orally once a day for 3–7 days). Angular cheilitis can be treated topically with ketoconazole cream (2%) twice a day.
Gingival disease usually responds to professional dental cleaning and chlorhexidine rinses. A particularly aggressive gingivitis or periodontitis will develop in some HIV-infected patients; these patients should be given antibiotics that cover anaerobic oral flora (eg, metronidazole, 250 mg four times a day for 4 or 5 days) and referred to oral surgeons with experience with these entities.
Aphthous ulcers (eFigure 31-2A; eFigure 31-2B; eFigure 31-2C) can be treated with fluocinonide (0.05% ointment mixed 1:1 with plain Orabase and applied six times a day to the ulcer). For lesions that are difficult to reach, patients should use dexamethasone swishes (0.5 mg in 5 mL elixir three times a day). The pain of the ulcers can be relieved with use of an anesthetic spray (10% lidocaine).
Recurrent oral aphthous stomatitis. A 58-year-old man presented with a 1-year history of recurrent painful sores in his mouth. He had lost 20 pounds over the year because it hurt so much to eat. The ulcers, which had a red base and were covered with a central white membrane, occurred in different locations—on his tongue, gums, inner lips, and buccal mucosa (shown here). HIV-AIDS is an underlying systemic disease that can be documented on work-up of such patients. (Used, with permission, from Richard P. Usatine, MD, in Usatine RP, Smith MA, Mayeaux EJ Jr, Chumley H. The Color Atlas of Family Medicine, 2nd ed. McGraw-Hill, 2013.)
Two aphthous ulcers on the tongue. (Used, with permission, from Richard P. Usatine, MD in Usatine RP, Smith MA, Mayeaux EJ, Chumley HS. The Color Atlas of Family Medicine, 2nd ed. McGraw-Hill, 2013.)
Minor aphthous ulcer occurring on the buccal mucosa. (Used, with permission, from Richard P. Usatine, MD in Usatine RP, Smith MA, Mayeaux EJ, Chumley HS. The Color Atlas of Family Medicine, 2nd ed. McGraw-Hill, 2013.)
MR. Non-Hodgkin’s lymphoma of the oral cavity and maxillofacial region: a pathologist viewpoint. Expert Rev Hematol. 2018;11:737.
et al. Oral manifestations of HIV: can they be an indicator of disease severity? (A systematic review). Oral Dis. 2020;26:133.
AR. The global changing pattern of the oral manifestations of HIV. Oral Dis. 2020;26:22.
I. Gastrointestinal Manifestations
1. Candidal and other esophagitis
(See also Chapter 15.) Esophageal candidiasis is a common AIDS complication. In a patient with characteristic symptoms, empiric antifungal treatment is begun with fluconazole (100–200 mg orally daily for 14–21 days). Improvement in symptoms should be apparent within 1–2 days of antifungal treatment. If there is no improvement, further evaluation to identify other causes of esophagitis (herpes simplex, CMV) is recommended.
et al. Risk factors, endoscopic features, and clinical outcomes of cytomegalovirus esophagitis based on a 10-year analysis at a single center. Clin Gastroenterol Hepatol. 2020;18:736.
et al. Diagnosis and treatment of esophageal candidiasis: current updates. Can J Gastroenterol Hepatol. 2019;2019:3585136.
Autopsy studies have demonstrated that the liver is a frequent site of infections and neoplasms in HIV-infected patients. However, many of these infections are not clinically symptomatic. Mild elevations of alkaline phosphatase and aminotransferases are often noted on routine chemistry panels. Mycobacterial disease, CMV, hepatitis B virus, hepatitis C virus, and lymphoma cause liver disease and can present with varying degrees of nausea, vomiting, right upper quadrant abdominal pain, and jaundice. Sulfonamides, imidazole medications, antituberculous medications, pentamidine, clarithromycin, and didanosine have also been associated with hepatitis. All nucleoside reverse transcriptase inhibitors cause lactic acidosis, which can be fatal. Lactic acidosis, however, occurs most commonly when didanosine is used with stavudine; this combination is no longer recommended in antiretroviral treatment regimens. HIV-infected patients with chronic hepatitis may have more rapid progression of liver disease because of the concomitant immunodeficiency or hepatotoxicity of antiretroviral treatment. Percutaneous liver biopsy may be helpful in diagnosing liver disease, but some common causes of liver disease (eg, M avium complex, lymphoma) can be determined by less invasive measures (eg, blood culture, biopsy of a more accessible site).
With patients living longer as a result of advances in antiretroviral treatment, advanced liver disease and hepatic failure due to chronic active hepatitis B and/or C are increasing causes of morbidity and mortality. HIV-infected individuals who are coinfected with hepatitis B should be treated with antiretroviral regimens that include medications with activity against both viruses (tenofovir disoproxil fumarate [TDF] or tenofovir alafenamide [TAF], lamivudine, or emtricitabine). Entecavir may be used if HIV viral load is suppressed; otherwise, its use can lead to lamivudine/emtricitabine-resistant HIV. It is important to be extremely cautious about discontinuing these medications in coinfected patients as sudden discontinuation could lead to a fatal flare of hepatitis B infection.
Hepatitis C is more virulent in persons with HIV and should be treated using the new HCV direct-acting antivirals (Table 16–6 found in Chapter 16-06: Chronic Viral Hepatitis). Prior to treatment, the patient’s HCV viral load and HCV genotype should be determined. Depending on the genotype and the proposed treatment regimen, HCV resistance testing is recommended. For example, HCV resistance testing is recommended for patients with genotype 1a (the most common hepatitis C genotype in the United States) who are being considered for treatment with elbasvir/grazoprevir because substitutions in certain amino acid positions confer resistance. Because the appropriate treatment regimen depends on genotype, resistance profile, whether the patient is treatment naïve or not, as well as whether or not the patient has cirrhosis (and, if so, whether it is compensated or decompensated), clinicians should check the guidelines of the AASLD/IDSA (see website in references below) to see the recommended regimens (see also Tables 16–6 and 16–7 Chapter 16-06: Chronic Viral Hepatitis). Costs of the different regimens vary by purchaser, and many clinicians choose the least expensive of the recommended regimens.
Although the recommended regimens are the same for HIV-infected patients, potential drug interactions with antiretroviral treatment may complicate treatment. Clinicians should check the guidelines of the AASLD/IDSA and US Department of Health and Human Services or the guidelines of the University of Liverpool to determine interactions between proposed hepatitis C regimen and HIV regimen.
Liver transplants have been performed successfully in HIV-infected patients. This strategy is most likely to be successful in persons who have CD4 counts greater than 100 cells/mcL and nondetectable viral loads.
et al. Real-world efficacy of direct acting antiviral therapies in patients with HIV/HCV. PLoS One. 2020;15:e0228847.
DL. Antiretroviral effects on HBV/HIV co-infection and the natural history of liver disease. Clin Liver Dis. 2019;23:473.
Cholecystitis presents with manifestations similar to those seen in immunocompetent hosts but is more likely to be acalculous. Sclerosing cholangitis and papillary stenosis have also been reported in HIV-infected patients. Typically, the syndrome presents with severe nausea, vomiting, and right upper quadrant pain. Liver enzymes generally show alkaline phosphatase elevations disproportionate to elevation of the aminotransferases. Although dilated ducts can be seen on ultrasound, the diagnosis is made by endoscopic retrograde cholangiopancreatography, which reveals intraluminal irregularities of the proximal intrahepatic ducts with “pruning” of the terminal ductal branches. Stenosis of the distal common bile duct at the papilla is commonly seen. CMV, Cryptosporidium, and microsporidia are thought to play inciting roles in this syndrome, but these conditions are rarely seen unless the patient is suffering with very advanced HIV-related immunodeficiency.
et al. Epidemiology, determinants, and management of AIDS cholangiopathy: a review. World J Gastroenterol. 2018;24:767.
et al. Multimethodological approach to gastrointestinal microsporidiosis in HIV-infected patients. Acta Parasitol. 2019;64:658.
Enterocolitis is a common problem in HIV-infected individuals. Organisms known to cause enterocolitis include bacteria (Campylobacter, Salmonella, Shigella), viruses (CMV, adenovirus, SARS-CoV-2), and protozoans (Cryptosporidium, Entamoeba histolytica, Giardia, Isospora, microsporidia). HIV itself may cause enterocolitis. Several of the organisms causing enterocolitis in HIV-infected individuals also cause diarrhea in immunocompetent persons. However, HIV-infected patients tend to have more severe and more chronic symptoms, including high fevers and severe abdominal pain that can mimic acute abdominal catastrophes. Bacteremia and concomitant biliary involvement are also more common with enterocolitis in HIV-infected patients. Relapses of enterocolitis following adequate therapy have been reported with both Salmonella and Shigella infections.
Because of the wide range of agents known to cause enterocolitis, a stool culture and multiple stool examinations for ova and parasites (including modified acid-fast staining for Cryptosporidium) should be performed. Those patients who have Cryptosporidium in one stool with improvement in symptoms in less than 1 month should not be considered to have AIDS, as Cryptosporidium is a cause of self-limited diarrhea in HIV-negative persons. More commonly, HIV-infected patients with Cryptosporidium infection have persistent enterocolitis with profuse watery diarrhea.
To date, no consistently effective treatments have been developed for Cryptosporidium infection except to improve immune function through the use of effective antiretroviral treatment. The diarrhea can be treated symptomatically with diphenoxylate with atropine (one or two tablets orally three or four times a day). Those who do not respond may be given paregoric with bismuth (5–10 mL orally three or four times a day). Octreotide in escalating doses (starting at 0.05 mg subcutaneously every 8 hours for 48 hours) has been found to ameliorate symptoms in approximately 40% of patients with cryptosporidia, although the benefit is often short-lived.
Patients with a negative stool examination and persistent symptoms should be evaluated with colonoscopy and biopsy. Patients whose symptoms last longer than 1 month with no identified cause of diarrhea are considered to have a presumptive diagnosis of AIDS enteropathy. Patients may respond to institution of effective antiretroviral treatment or octreotide. Upper endoscopy with small bowel biopsy is not recommended as a routine part of the evaluation.
et al. Widespread occurrence of Cryptosporidium
infections in patients with HIV/AIDS: epidemiology, clinical feature, diagnosis, and therapy. Acta Trop. 2018;187:257.
et al. Prevalence of Cryptosporidium
, microsporidia and Isospora
infection in HIV-infected people: a global systematic review and meta-analysis. Parasit Vectors. 2018;11:28.
Two other important gastrointestinal abnormalities in HIV-infected patients are gastropathy and malabsorption. It has been documented that some HIV-infected patients do not produce normal levels of stomach acid and therefore are unable to absorb medications that require an acid medium. This decreased acid production may explain, in part, the susceptibility of HIV-infected patients to Campylobacter, Salmonella, and Shigella, all of which are sensitive to acid concentration. There is no evidence that Helicobacter pylori is more common in HIV-infected persons.
A malabsorption syndrome occurs commonly in AIDS patients. It can be due to infection of the small bowel with M avium complex, Cryptosporidium, or microsporidia.
VP. Common gastrointestinal complications associated with human immunodeficiency virus/AIDS: an overview. Crit Care Nurs Clin North Am. 2018;30:101.
J. Endocrinologic Manifestations
Hypogonadism is probably the most common endocrinologic abnormality in HIV-infected men. The adrenal gland is also a commonly afflicted endocrine gland in patients with AIDS. Abnormalities demonstrated on autopsy include infection (especially with CMV and M avium complex), infiltration with Kaposi sarcoma, and injury from hemorrhage and presumed autoimmunity. The prevalence of clinically significant adrenal insufficiency is low. Patients with suggestive symptoms should undergo a cosyntropin stimulation test.
Although frank deficiency of cortisol is rare, an isolated defect in mineralocorticoid metabolism may lead to salt-wasting and hyperkalemia. Such patients should be treated with fludrocortisone (0.1–0.2 mg orally daily).
AIDS patients appear to have abnormalities of thyroid function tests different from those of patients with other chronic diseases. AIDS patients have been shown to have high levels of triiodothyronine (T3), thyroxine (T4), and thyroid-binding globulin and low levels of reverse triiodothyronine (rT3). The causes and clinical significance of these abnormalities are unknown.
et al. Use of testosterone
in men infected with human immunodeficiency virus in the Veterans Healthcare System. AIDS Care. 2018;30:1207.
et al. Endocrinological aspects of HIV infection. J Endocrinol Invest. 2018;41:881.
et al. The importance of SHBG and calculated free testosterone
for the diagnosis of symptomatic hypogonadism in HIV-infected men: a single-centre real-life experience. Infection. 2021;49:295.
et al. Human immunodeficiency virus infection and the endocrine system. Endocrinol Metab (Seoul). 2019;34:95.
The skin manifestations that commonly develop in HIV-infected patients can be grouped into viral, bacterial, fungal, neoplastic, and nonspecific dermatitides.
A. HERPES SIMPLEX INFECTIONS
These infections (Figure 31–5) occur more frequently, tend to be more severe, and are more likely to disseminate in AIDS patients than in immunocompetent persons. Because of the risk of progressive local disease, all herpes simplex attacks should be treated for 5–10 days with acyclovir (400 mg orally three times a day), famciclovir (500 mg orally twice daily), or valacyclovir (500 mg orally twice daily) (Table 31–3). To avoid the complications of attacks, many clinicians recommend suppressive therapy for HIV-infected patients with a history of recurrent herpes. Options for suppressive therapy include acyclovir (400 mg orally twice daily), famciclovir (250 mg orally twice daily), and valacyclovir (500 mg orally daily). Long-term suppressive herpes prophylaxis with acyclovir does not reduce HIV transmission between heterosexual men and women from developing countries.
Herpes simplex viral skin infection, frequently found in HIV-positive men. Shown are grouped vesicles typical of herpes simplex on the penis, with both intact vesicles of initial eruption and visible crusts of resolving lesions. (Reproduced, with permission, from Eric Kraus, MD, in: Usatine RP, Smith MA, Mayeaux EJ Jr, Chumley H. The Color Atlas and Synopsis of Family Medicine, 3rd ed. McGraw-Hill, 2019.)
et al. The anti-HIV drug tenofovir, a reverse transcriptase inhibitor, also targets the herpes simplex virus (HSV) DNA polymerase. J Infect Dis. 2018;217:790.
This is a common manifestation of HIV infection (eFigure 31–3). Patients with herpes zoster infections should be treated for 7–10 days with famciclovir (500 mg orally three times a day) or valacyclovir (500 mg three times a day). Acyclovir can also be used, but it requires very frequent dosing (800 mg orally four or five times per day for 7 days). Vesicular lesions should be cultured if there is any question about their origin, since herpes simplex responds to much lower doses of acyclovir. Disseminated zoster and cases with ocular involvement should be treated with intravenous (10 mg/kg every 8 hours for 7–10 days) rather than oral acyclovir. The recombinant zoster vaccine (Shingrix, two doses administered 2–6 months apart) can be given to HIV-infected patients. Because it is not a live virus like the previous zoster vaccine (Zostavax), it is not contraindicated in patients with immune deficiency but, based on other vaccines, HIV-infected patients are likely to develop more robust immune response to the vaccine when their CD4 count is greater than 200/mcL. The long-term benefit of Shingrix in preventing shingles in HIV-infected persons has yet to be established.
Herpes zoster. A painful vesicular eruption developed over the right forehead in this 44-year-old HIV-positive man. Herpes zoster was diagnosed clinically and confirmed by a positive direct fluorescent antibody test on fluid from one of the vesicles. (Used, with permission, from Usatine RP, Smith MA, Mayeaux EJ Jr, Chumley H. The Color Atlas of Family Medicine, 2nd ed. McGraw-Hill, 2013.)
et al. Recommendations of the Advisory Committee on Immunization Practices for use of herpes zoster vaccines. MMWR Morb Mortal Wkly Rep. 2018;67:103.
et al. Shingrix: the new adjuvanted recombinant herpes zoster vaccine. Ann Pharmacother. 2018;52:673.
This infection is caused by a pox virus and is seen in HIV-infected patients, as in other immunocompromised patients. The characteristic umbilicated fleshy papular lesions (eFigure 31–4) have a propensity for spreading widely over the patient’s face and neck (Figure 31–6) and should be treated with topical liquid nitrogen.
Molluscum contagiosum. Close-up of a molluscum contagiosum lesion showing a dome-shaped pearly papule with a characteristic umbilicated center. (Reproduced, with permission, from Usatine RP, Smith MA, Mayeaux EJ Jr, Chumley H. The Color Atlas and Synopsis of Family Medicine, 3rd ed. McGraw-Hill, 2019.)
Molluscum contagiosum. Extensive molluscum contagiosum lesions on the face of a young woman, suggestive she may be HIV-positive. (Used, with permission, from Richard P. Usatine, MD, in Usatine RP, Smith MA, Mayeaux EJ Jr, Chumley H. The Color Atlas and Synopsis of Family Medicine, 3rd ed. McGraw-Hill, 2019.)
et al. Non-HPV perianal and anorectal sexually transmitted viral infections. Clin Colon Rectal Surg. 2019;32:340.
2. Bacterial dermatitides
A. STAPHYLOCOCCAL INFECTION
Staphylococcus is the most common bacterial cause of skin disease in HIV-infected patients; it usually presents as folliculitis, superficial abscesses (furuncles), or bullous impetigo. These lesions should be treated aggressively since sepsis can occur. Folliculitis is initially treated with topical clindamycin or mupirocin, and patients may benefit from regular washing with an antibacterial soap such as chlorhexidine. Intranasal mupirocin has been used successfully for staphylococcal decolonization in other settings. In HIV-infected patients with recurrent staphylococcal infections, weekly intranasal mupirocin should be considered in addition to topical care and systemic antibiotics. Abscesses often require incision and drainage. Patients may need antistaphylococcal antibiotics as well. Due to high frequency of methicillin-resistant Staphylococcus aureus (MRSA) skin infections in HIV-infected populations, lesions should be cultured prior to initiating empiric antistaphylococcal therapy. Recommendations for empiric treatment are either (1) trimethoprim-sulfamethoxazole (one double-strength tablet orally twice daily) with or without clindamycin (500 mg orally three times daily); or (2) doxycycline (100 mg orally twice daily) with close follow-up.
et al. Staphylococcal skin and soft tissue infections. Infect Dis Clin North Am. 2021;35:81.
et al. The global and regional prevalence, burden, and risk factors for methicillin-resistant Staphylococcus aureus
colonization in HIV-infected people: a systematic review and meta-analysis. Am J Infect Control. 2019;47:323.
B. BACILLARY ANGIOMATOSIS
It is caused by two closely related organisms: Bartonella henselae and Bartonella quintana. The epidemiology of these infections suggests zoonotic transmission from fleas of infected domestic cats. The most common manifestation is raised, reddish, highly vascular skin lesions (eFigure 31–5) that can mimic lesions of Kaposi sarcoma. Fever is a common manifestation of this infection; involvement of bone, lymph nodes, and liver has also been reported. The infection responds to doxycycline, 100 mg orally twice daily, or erythromycin, 250 mg orally four times daily for at least 14 days. Patients who are seriously ill with visceral involvement may require months of therapy.
Bacillary angiomatosis. Bacillary angiomatosis is a systemic infection caused by Bartonella species. Its cutaneous lesions appear as scattered papules and nodules (like the one shown here) or as abscesses. In HIV-infected patients, bacillary angiomatosis most often occurs when the CD4 count is below 200/mcL. It can be treated with antibiotics. (Reproduced, with permission, from Usatine RP, Moy RL, Tobinick EL, Siegel DM. Skin Surgery: A Practical Guide. Mosby, 1998. Copyright © Elsevier.)
et al. Cat-scratch disease in an AIDS patient presenting with generalized lymphadenopathy: an unusual presentation with delayed diagnosis. Am J Case Rep. 2018;19:906.
et al. Endocarditis caused by Bartonella quintana,
a rare case in the United States. IDCases. 2019;17:e00533.
A. RASHES DUE TO DERMATOPHYTES ANDCANDIDA
Most fungal rashes afflicting AIDS patients are due to dermatophytes and Candida. While particularly common in the inguinal region, they may occur anywhere on the body. Fungal rashes generally respond well to topical clotrimazole (1% cream twice a day) or ketoconazole (2% cream twice a day).
This is more common in HIV-infected patients. Scrapings of seborrhea have revealed Malassezia furfur (Pityrosporum ovale), implying that the seborrhea is caused by this fungus. A consistent finding is that seborrhea responds well to topical clotrimazole (1% cream) as well as hydrocortisone (1% cream).
et al. Isolation of Malassezia
spp. in HIV-positive patients with and without seborrheic dermatitis. An Bras Dermatol. 2019;94:527.
et al. Seborrheic dermatitis—looking beyond Malassezia
. Exp Dermatol. 2019;28:991.
4. Neoplastic dermatitides
See Chapter 6 and the Kaposi sarcoma section below.
5. Nonspecific dermatitides
This condition presents in HIV-infected patients with severe pruritus. The patient may have no rash, or nonspecific excoriations from scratching. Treatment is with emollients (eg, absorption base cream) and antipruritic lotions (eg, camphor 9.5% and menthol 0.5%).
Psoriasis can be very severe in HIV-infected patients. Phototherapy and etretinate (0.25–9.75 mg/kg/day orally in divided doses) may be used for recalcitrant cases in consultation with a dermatologist.
L. HIV-Related Malignancies
Four cancers are currently included in the CDC classification of AIDS: Kaposi sarcoma, non-Hodgkin lymphoma, primary lymphoma of the brain, and invasive cervical carcinoma. Epidemiologic studies have shown that between 1973 and 1987, among single men in San Francisco, the risk of Kaposi sarcoma increased more than 5000-fold and the risk of non-Hodgkin lymphoma more than 10-fold. The increase in incidence of malignancies is probably a function of impaired cell-mediated immunity. In the current treatment era, cancers not classified as AIDS-related, such as lung cancer, are being increasingly diagnosed in aging HIV-infected individuals despite optimal antiretroviral treatment. Cohort studies suggest that HIV-infected adults are at increased risk for a variety of cancers compared to age-matched uninfected populations. Mortality secondary to malignancies represents an increasing cause of death in HIV-infected populations.
et al. Malignant melanoma in HIV: epidemiology, pathogenesis, and management. Dermatol Ther. 2020;33:e13180.
et al. Incidence of first and second primary cancers diagnosed among people with HIV, 1985–2013: a population-based, registry linkage study. Lancet HIV. 2018;5:e647.
et al. Projected cancer incidence rates and burden of incident cancer cases in HIV-infected adults in the United States through 2030. Ann Intern Med. 2018;168:866.
et al. Cancer prevention in patients with human immunodeficiency virus infection. World J Clin Oncol. 2018;9:71.
et al. AIDS-associated malignancies. Cancer Treat Res. 2019;177:1.
et al. Lung cancer surgery in HIV-infected patients: an analysis of postoperative complications and long-term survival. Thorac Cancer. 2020;11:2146.
Lesions may appear anywhere; careful examination of the eyelids, conjunctiva, pinnae, palate, and toe webs is mandatory to locate potentially occult lesions. In light-skinned individuals, Kaposi lesions usually appear as purplish, nonblanching lesions that can be papular or nodular (eFigure 31–6; eFigure 6–94). In dark-skinned individuals, the lesions may appear browner. In the mouth, lesions are most often palatal papules, though exophytic lesions of the tongue and gingivae may also be seen. Kaposi lesions may be confused with other vascular lesions such as angiomas and pyogenic granulomas. Kaposi sarcoma lesions can occur shortly after initiating antiretroviral treatment, especially in patients starting antiretroviral treatment who have advanced immunodeficiency. In this situation, Kaposi sarcoma is likely to be an immune reconstitution reaction (see Inflammatory Reactions below). Kaposi sarcoma can also cause visceral disease (eg, gastrointestinal, pulmonary).
Kaposi sarcoma. A 35-year-old man presented with several reddish-purple papular lesions on his elbow. When these were diagnosed on shave biopsy as Kaposi sarcoma (KS), he was tested and found to be positive for HIV. Systemic treatment with combination antiretroviral therapy and topical treatment with alitretinoin gel was started, and the KS lesions eventually resolved. (Used, with permission, from Heather Wickless, MD, in Usatine RP, Smith MA, Mayeaux EJ Jr, Chumley H. The Color Atlas of Family Medicine, 2nd ed. McGraw-Hill, 2013.)
Patients with mild to moderate forms of Kaposi sarcoma do not require specific treatment as the lesions usually resolve with effective antiretroviral treatment. However, it should be noted that the lesions may flare when antiretroviral treatment is first initiated—probably as a result of an immune reconstitution process. Advanced disease is treated with combination chemotherapy (Table 31–3).
et al. Recent advances in HIV-associated Kaposi sarcoma. F1000Res. 2019;8:970.
et al. Regression of human immunodeficiency virus-associated oral Kaposi sarcoma with combined antiretroviral therapy: a case report and literature review. Head Neck. 2019;41:E21.
et al. The world-wide incidence of Kaposi's sarcoma in the HIV/AIDS era. HIV Med. 2018;19:355.
et al. Antiretroviral therapy for HIV-associated cutaneous Kaposi’s sarcoma: clinical, HIV-related, and sociodemographic predictors of outcome. AIDS Res Hum Retroviruses. 2021;37:368.
Non-Hodgkin lymphomas in HIV-infected persons tends to be very aggressive. These malignancies are usually of B cell origin and characterized as diffuse large-cell tumors. Over 70% of the malignancies are extranodal.
The prognosis of patients with systemic non-Hodgkin lymphoma depends primarily on the degree of immunodeficiency at the time of diagnosis. Patients with high CD4 counts do markedly better than those diagnosed at a late stage of illness. Patients with primary central nervous system lymphoma are treated with radiation. Response to treatment is good, but prior to the availability of antiretroviral treatment, most patients died within a few months after diagnosis due to their underlying disease. Systemic disease is treated with combination chemotherapy (eg, EPOCH [etoposide, prednisolone, vincristine, cyclophosphamide, doxorubicin]) with rituximab. Granulocyte colony-stimulating factor (G-CSF; filgrastim) is used to maintain white blood counts.
et al. Primary CNS lymphoma in HIV infection. Handb Clin Neurol. 2018;152:177.
et al. Epidemiology of haematological malignancies in people living with HIV. Lancet HIV. 2020;7:e641.
et al. Human immunodeficiency virus-associated lymphoproliferative disorders. Surg Pathol Clin. 2019;12:771.
et al. Malignant lymphoma in the HIV-positive patient. Eur J Haematol. 2018;101:119.
et al. Early consolidation with high-dose therapy and autologous stem cell transplantation is a feasible and effective treatment option in HIV-associated non-Hodgkin lymphoma at high risk. Bone Marrow Transplant. 2018;53:228.
et al. Biology and management of primary effusion lymphoma. Blood. 2018;132:1879.
Although Hodgkin disease is not included as part of the CDC definition of AIDS, studies have found that HIV infection is associated with a fivefold increase in the incidence of Hodgkin disease. HIV-infected persons with Hodgkin disease are more likely to have mixed cellularity and lymphocyte depletion subtypes of Hodgkin disease and to seek medical attention at an advanced stage of disease.
et al. Cytodiagnostic sensitivity of fine needle aspiration biopsy for Hodgkin’s lymphoma is decreased in patients with human immunodeficiency virus infection. Acta Cytol. 2019;63:352.
et al. HIV and lymphoma: from epidemiology to clinical management. Mediterr J Hematol Infect Dis. 2019;11:e2019004.
4. Anal dysplasia and squamous cell carcinoma
These lesions have been strongly correlated with previous infection by human papillomavirus (HPV) and noted in both HIV-infected men and women. Although many of the infected MSM report a history of anal warts or have visible warts, a significant percentage have silent papillomavirus infection. Cytologic (using Papanicolaou smears) and papillomavirus DNA studies can easily be performed on specimens obtained by anal swab. Because of the risk of progression from dysplasia to cancer in immunocompromised patients, some experts advise annual anal cytologic examinations in all HIV-infected persons. An anal Papanicolaou smear is performed by rotating a moistened Dacron swab about 2 cm into the anal canal. The swab is immediately inserted into a cytology bottle. However, there is no evidence that screening for anal cancer with Papanicolaou smears decreases the incidence of invasive cancer.
HPV also appears to play a causative role in cervical dysplasia and carcinoma in HIV-infected women (discussed below).
et al. Risk of invasive anal cancer in HIV-infected patients with high-grade anal dysplasia: a population-based cohort study. Dis Colon Rectum. 2019;62:934.
et al. Importance of anal cytology and screening for anal dysplasia in individuals living with HIV with an emphasis on women. Cancer Cytopathol. 2019;127:407.
et al. Multidisciplinary approach to the management and treatment of anal dysplasia. Clin Colon Rectal Surg. 2018;31:361.
et al. Accuracy of anal cytology for diagnosis of precursor lesions of anal cancer: systematic review and meta-analysis. Dis Colon Rectum. 2019;62:112.
et al. Management of anal intraepithelial neoplasia and anal squamous cell carcinoma at a tertiary referral centre with a dedicated infectious diseases unit: an 18-year review. Int J Colorectal Dis. 2020;35:1855.
et al. HPV-associated anal cancer in the HIV/AIDS patient. Cancer Treat Res. 2019;177:183.
M. Gynecologic Manifestations
Vaginal candidiasis, cervical dysplasia and neoplasia, and pelvic inflammatory disease are more common in HIV-infected women than in uninfected women. These manifestations also tend to be more severe when they occur in association with HIV infection. Therefore, HIV-infected women need frequent gynecologic care. Vaginal candidiasis may be treated with topical agents or a single dose of oral fluconazole (150 mg) (see Chapter 36). Recurrent vaginal candidiasis should be treated with fluconazole (100–200 mg) for at least 7 days. However, fluconazole increases the risk of spontaneous abortion and should not be given to women who are or may be pregnant.
The incidence of cervical dysplasia in HIV-infected women is 40%. Because of this finding, recommended screening for HIV-infected women is more extensive than for uninfected women (see Chapter 18). For women younger than age 30 years, a Papanicolaou smear should be performed within a year of the onset of sexual activity, but no later than age 21 years. If normal, Papanicolaou smears should be performed yearly. After three negative examinations, screening should be done every 3 years. HPV DNA testing of the cervical specimen is not recommended for women younger than age 30 years.
For women age 30 and older, screening should continue beyond age 65 (unlike the general population). There are two accepted screening protocols: cytology alone and cytology with HPV DNA cotesting. A Papanicolaou smear is done when HIV is diagnosed and every 12 months thereafter, and after three negative smears, ongoing screening can be performed every 3 years. Alternatively, a Papanicolaou smear with cotesting for HPV DNA can be performed when HIV is diagnosed or starting when patients are age 30 years old. If Papanicolaou smear is normal and HPV test is negative, then the next screening can be in 3 years.
The management of abnormal Papanicolaou tests and positive HPV tests is the same in infected women as in uninfected women. Treatment should follow the consensus guidelines in the references below.
While pelvic inflammatory disease appears to be more common in HIV-infected women, the bacteriology of this condition appears to be the same as among HIV-uninfected women. HIV-infected women with pelvic inflammatory disease should be treated with the same regimens as uninfected women (see Chapter 18).
G. Clinical implications of the interaction between HPV and HIV infections. Best Pract Res Clin Obstet Gynaecol. 2018;47:95.
et al; ART and HPV Review Group. Association of antiretroviral therapy with high-risk human papillomavirus, cervical intraepithelial neoplasia, and invasive cervical cancer in women living with HIV: a systematic review and meta-analysis. Lancet HIV. 2018;5:e45.
et al. Gynecologic cancer in HIV-positive women: a systematic review and meta-analysis. Am J Obstet Gynecol. 2019;221:194.
et al. Primary HPV and molecular cervical cancer screening in US women living with HIV. Clin Infect Dis. 2021;72:1529.
N. Coronary Artery Disease
HIV-infected persons are at higher risk for coronary artery disease than age- and sex-matched controls. Part of this increase in coronary artery disease is due to changes in lipids caused by antiretroviral agents (see below), especially stavudine and several of the PIs. However, some of the risk appears to be due to HIV infection, independent of its therapy. It is important that clinicians pay close attention to this issue because myocardial infarctions tend to present at a younger age in HIV-infected individuals than in HIV-uninfected individuals. HIV-infected patients with symptoms of coronary artery disease such as chest pain or dyspnea should be rapidly evaluated. Clinicians should aggressively treat conditions that result in increased risk of heart disease, especially smoking, hypertension, hyperlipidemia, obesity, diabetes mellitus, and sedentary lifestyle.
et al. Cardiovascular events recurrence and coronary artery disease in HIV patients: the price we have to pay for the chronicization of the disease. Can J Cardiol. 2020;36:127.
JS. Management of long-term complications of HIV disease: focus on cardiovascular disease. Top Antivir Med. 2018;25:133.
et al. HIV infection and coronary heart disease: mechanisms and management. Nat Rev Cardiol. 2019;16:745.
et al. Coronary artery disease in patients with HIV infection: an update. Am J Cardiovasc Drugs. 2020. [Epub ahead of print]
O. Inflammatory Reactions (Immune Reconstitution Inflammatory Syndromes)
With initiation of antiretroviral treatment, some patients experience inflammatory reactions that appear to be associated with immune reconstitution as indicated by a rapid increase in CD4 count. These inflammatory reactions may present with generalized signs of fevers, sweats, and malaise with or without more localized manifestations that usually represent unusual presentations of opportunistic infections. For example, vitreitis has developed in patients with CMV retinitis after they have been treated with antiretroviral treatment.
M avium can present as focal even suppurative lymphadenitis or granulomatous masses in patients receiving antiretroviral treatment. Tuberculosis may paradoxically worsen with new or evolving pulmonary infiltrates and lymphadenopathy. PML and cryptococcal meningitis may also behave atypically. Clinicians should be alert to these syndromes, which are most often seen in patients who have initiated antiretroviral treatment in the setting of advanced disease and who show rapid increases in CD4 counts with treatment. The diagnosis of immune reconstitution inflammatory syndrome (IRIS) is one of exclusion and can be made only after recurrence or new opportunistic infection has been ruled out as the cause of the clinical deterioration. Management of IRIS is conservative and supportive with use of corticosteroids only for severe reactions. Most authorities recommend that antiretroviral treatment be continued unless the IRIS reaction is life-threatening.
et al. Increased metabolic activity on 18F-fluorodeoxyglucose positron emission tomography-computed tomography in human immunodeficiency virus–associated immune reconstitution inflammatory syndrome. Clin Infect Dis. 2019;68:229.
I. Immune reconstruction inflammatory syndrome in HIV infection: beyond what meets the eye. Top Antivir Med. 2020;27:106.
et al. Prospective international study of incidence and predictors of immune reconstitution inflammatory syndrome and death in people living with human immunodeficiency virus and severe lymphopenia. Clin Infect Dis. 2020;71:652.