Browse the corpus

H IVIAIDS TABLE *3. Recommended lnitial Laboratory Screening and Other Studies in Persons with HIV lnfection Test Comments HlV-specific tests for all persons with HtV HIV antigen/anti body testing lf written evidence of diagnosis not available or if viral load low or undetectable CD4 cell count and percentage Assess need for opportunistic infection prophylaxis Plasma HIV RNA polymerase chain Establish baseline and monitor viral suppression reaction (HlV viral load) HIV resistance testinq Baseline genotype for protease inhibitor, nonnucleoside RTl, nucleoside/nucleotide RTI mutations for persons who have never initiated therapy, are reengaging in care and not receiving therapy, or with inconsistent access to therapy. INSTI genotype is recommended only if suspicion for INSTI mutation transmission.

TABLE *3. Recommended lnitial Laboratory Screening and Other Studies in Persons with HIV lnfection Test Comments HlV-specific tests for all persons with HtV HIV antigen/anti body testing lf written evidence of diagnosis not available or if viral load low or undetectable CD4 cell count and percentage Assess need for opportunistic infection prophylaxis Plasma HIV RNA polymerase chain Establish baseline and monitor viral suppression reaction (HlV viral load) HIV resistance testinq Baseline genotype for protease inhibitor, nonnucleoside RTl, nucleoside/nucleotide RTI mutations for persons who have never initiated therapy, are reengaging in care and not receiving therapy, or with inconsistent access to therapy. INSTI genotype is recommended only if suspicion for INSTI mutation transmission. Other laboratory tests Complete blood count with Assess for anemia, neutropen ia, th rom bocytopen ia differential Alanine aminotransferase, as partate Assess for evidence of liver damage, hepatitis, or systemic infection (e.g., elevated alkaline a m i notransferase, tota I bil i ru bin, phosphatase level with some opportu n istic i nfections) alkaline phosphatase Totalprotein and albumin levels High total protein level common with untreated HIV infeaion because of increased immunoglobulin fraction secondary to B-cell hyperplasia; low albumin level may indicate nutritional deficiency or nephrotic syndrome Electrolytes, blood urea nitrogen, Assess kidney function; creatinine level for calculation of estimated glomerular filtration rate creatinine Lipid profile and blood glucose; Fasting not needed for initial lipid and glucose assessment; if abnormal, repeat fasting hemoglobin 41. Hemoglobin 41. measured before ART initiation but not used for diagnosis of diabetes in those taking ART Urinalysis Assess for evidence of proteinuria, hematuria

Other laboratory tests Complete blood count with Assess for anemia, neutropen ia, th rom bocytopen ia differential Alanine aminotransferase, as partate Assess for evidence of liver damage, hepatitis, or systemic infection (e.g., elevated alkaline a m i notransferase, tota I bil i ru bin, phosphatase level with some opportu n istic i nfections) alkaline phosphatase Totalprotein and albumin levels High total protein level common with untreated HIV infeaion because of increased immunoglobulin fraction secondary to B-cell hyperplasia; low albumin level may indicate nutritional deficiency or nephrotic syndrome Electrolytes, blood urea nitrogen, Assess kidney function; creatinine level for calculation of estimated glomerular filtration rate creatinine Lipid profile and blood glucose; Fasting not needed for initial lipid and glucose assessment; if abnormal, repeat fasting hemoglobin 41. Hemoglobin 41. measured before ART initiation but not used for diagnosis of diabetes in those taking ART Urinalysis Assess for evidence of proteinuria, hematuria Screening for coinfections Cervical Pap test 21-29 years of age: annual Pap test; if three consecutive Pap tests are normal, follow-up screening in 3 years. >30 years of age: three consecutive normal Pap tests without an HPVtest, follow-up Pap in 3 years; Pap with HPVtesting are both negative, follow-up Pap in 3 years after combined test

Screening for coinfections Cervical Pap test 21-29 years of age: annual Pap test; if three consecutive Pap tests are normal, follow-up screening in 3 years. >30 years of age: three consecutive normal Pap tests without an HPVtest, follow-up Pap in 3 years; Pap with HPVtesting are both negative, follow-up Pap in 3 years after combined test Anal Pap test" Anal Pap test for all persons with a history of receptive anal intercourse, genital wafts, or abnormal cervical Pap result if access to appropriate referral for follow-up, including high- resolution anoscopy, is available Gonorrhea, chlamydia At least annual screening using nucleic acid amplification testing with sites based on exposure history (e.g., urine, vaginal, rectal, oropharyngeal; three-site testing preferred for all patients) Trichomoniasis Annual screening in all persons who have vaginal sex Syphilis At least annual screening using local protocol (either rapid plasma reagin or treponemal- specific antibody tests) Late nt Myco b acte ri u m tu be rculosis TST or IGRA; IGRA preferred if history of BCG vaccination

Anal Pap test" Anal Pap test for all persons with a history of receptive anal intercourse, genital wafts, or abnormal cervical Pap result if access to appropriate referral for follow-up, including high- resolution anoscopy, is available Gonorrhea, chlamydia At least annual screening using nucleic acid amplification testing with sites based on exposure history (e.g., urine, vaginal, rectal, oropharyngeal; three-site testing preferred for all patients) Trichomoniasis Annual screening in all persons who have vaginal sex Syphilis At least annual screening using local protocol (either rapid plasma reagin or treponemal- specific antibody tests) Late nt Myco b acte ri u m tu be rculosis TST or IGRA; IGRA preferred if history of BCG vaccination Varicel la-zoster vi rus Anti-varicella lgG if no known history of chicken pox or shingles Hepatitis A, B, and C virus HBsAg, HBsAb, HBcAb, HCVAb; HAVtotal or lgG antibody. lf HBsAg+ or HBcAb+, order HBV DNA level; if HCVAb+, order HCV RNA level and HCV genotype. Screen for hepatocellular carcinoma for all adult patients with cirrhosis and noncirrhotic patients with chronic HBV for an extended period. Measles titer Adequate evidence of immunity includes being born in the United States before 1957, written documentation of adequate vaccination, or serologic evidence of immunity. Persons born in the 1 960s may have been vaccinated with a vaccine other than MMR and may have waning immunity. Patients may opt to receive a booster MMR vaccine rather than check serology.

Varicel la-zoster vi rus Anti-varicella lgG if no known history of chicken pox or shingles Hepatitis A, B, and C virus HBsAg, HBsAb, HBcAb, HCVAb; HAVtotal or lgG antibody. lf HBsAg+ or HBcAb+, order HBV DNA level; if HCVAb+, order HCV RNA level and HCV genotype. Screen for hepatocellular carcinoma for all adult patients with cirrhosis and noncirrhotic patients with chronic HBV for an extended period. Measles titer Adequate evidence of immunity includes being born in the United States before 1957, written documentation of adequate vaccination, or serologic evidence of immunity. Persons born in the 1 960s may have been vaccinated with a vaccine other than MMR and may have waning immunity. Patients may opt to receive a booster MMR vaccine rather than check serology. strand transfer inhibitor; MMR = measles, mumps, rubella; RTI = reverse transcriptase inhibitor; TST = tuberculin skin test. "At this time, no national guidelines are available for this intervention. Adapted with permission from Thompson MA, Horberg MA, Agwu AL, et al. Primary Care Guidance for Persons With Human lmmunodeficiency Virus: 2020 update by the HIV Medicine Association of the lnfectious Diseases Society of America. Clin lnfect Dis. 2020 Nov 6:ciaa 1 391 . Epub ahead of print' IPM lD: 332253491doi: 1 0 1 O93/cidlciaa 1 391 91

H IV/AIDS TABLE 64. Prophylaxis against Opportunistic lnfections in HIV/AIDS Opportunistic lnfection lndication Preferred Drug P n e u m o cy sti s j i rov e ci i CD4 cell count <200/1tL" TM P-S MX, d ou ble-stren gth or si n g e-stren gth ta bl et I once dailyb Toxoplasmosis CD4 cell count <1 00/pL and positive TMP-SMX, double-strength tablet once dailyc serologic resultsa Mycob acte ri u m avi u m com plex CD4 cell count <50/pld Azithromycin, 1200 mg once weekly or 600 mg twice weekly; clarithromycin,500 mg twice daily Latent tuberculosis TST >5 mm or positive IGRA results 3 months of isoniazid plus rifapentine given once weekly 3 months of isoniazid plus rifampin given daily" IGRA = lnterferon y release assay; TMP SMX = trimethoprim-sulfamethoxazole; TST = tuberculin skin test. "Prophylaxis may be discontinued in patients with CD4 cell count >200/pLfor >3 months; emerging evidence suggests prophylaxis may be discontinued in patients with CD4 cell count of 1 00 200/gL and a suppressed viral load for >3 months. pneumocystis pneumonia "Prophylaxis no longer recommended in patients who start antiretroviraltherapy immediately. need to be modified. Daily pyridoxine is recommended in patients who will receive isoniazid because of the risk for peripheral neuropathy. See Mycobacterium tuberculosis the treatment of latent tuberculosis infection: recommendations from the NationalTuberculosis Controllers Association and CDC, 2020. MMWR Recomm Rep.2020;69 1-11. IPMID: 32053584] doi:1 0.1 5585/mmwr.116901 a1

need to be modified. Daily pyridoxine is recommended in patients who will receive isoniazid because of the risk for peripheral neuropathy. See Mycobacterium tuberculosis the treatment of latent tuberculosis infection: recommendations from the NationalTuberculosis Controllers Association and CDC, 2020. MMWR Recomm Rep.2020;69 1-11. IPMID: 32053584] doi:1 0.1 5585/mmwr.116901 a1 than 200/pL. The recombinant zoster vaccine should be given associated with manifestations of accelerated aging, and neu to individuals 50 years and older with CD4 cell count greater rocognitive impairment can be exacerbated by HIV. Age- than 200/prl. All persons with HIV infection should be associated comorbidities and declines in kidney and liver vaccinated for meningococcal disease with the quadrivalent function can also complicate management through drug inter- meningococcal vaccine, including boosters every 5 years. actions and increased toxicity. Prophylaxis for opportunistic infections depends on the HIV infection itself and some antiretrovirals affect lipids patient's CD4 cell count (Table 04). Before beginning prophy- and can worsen hyperlipidemia; this is especially true for laxis, active inf'ection should be ruled out clinically and with boosted protease inhibitor-based regimens, which can also any indicated testing to avoid undertreatment and selection worsen insulin resistance. Fasting glucose or hemoglobin A,. for resistance, especially for tuberculosis and disseminated and lipid levels should be checked at baseline and 3 months M y cob acte rium au ium complex. after initiating or changing antiretrovirals; hemoglobin A,. should not be used for the diagnosis of diabetes in those taking KTY POI l{TS ART. . All persons with HIV should receive the 13-valent pneu- Chronic kidney disease is increasingly common in HIV mococcal conjugate and 23-valent polysaccharide vac- infection, although, with effective AKI, it is less often attrib- cines, hepatitis B vaccine series (in those not already uted to HIV nephropathy. It is recommended that kidney func infected or immune), and meningococcal vaccine; tion be assessed at least every 6 months in patients with HIV. COVID-19, influenza, tetanus-diphtheria-perfussis, Tenofovir, a very commonly used nucleoside analogue, is asso- hepatitis A, and human papillomavirus vaccines are ciated with risk for tubular nephrotoxicity, which usually indicated as for the general population. manifests as proteinuria. Patients using a regimen containing o Measles-mumps-rubella, varicella, and recombinant tenofovir should undergo urinalysis or quantitative measure- zoster vaccines can be given as long as the CD4 cell count ment of urine protein twice per year. is greater than 200/prl. Bone mineral densig is reduced in HIV and tenofovir is also associated with possible worsening of bone density. Dual- ener$/ x-ray absorptiometry scanning is recommended in Complications of HIV Infection men older than 50 years, postmenopausal women, patients with a history of fragility fracture, those with chronic gluco- in the Antiretroviral Therapy Era corticoid use, and those at high risk for falls. The newer pro- Metabolic, Kidney, and Liver Disorders drug of tenofovir, TAFI, achieves high intracellular levels of As HIV has become a treatable illness and persons with HIV active drug with much lower dosing and lower systemic levels age, metabolic disorders and specific organ diseases have compared with the older formulation, TDF. Compared with become increasingly significant. HIV infection itself may be TDF, TAF has equal antiviral efficacy with reduced kidney and

than 200/pL. The recombinant zoster vaccine should be given associated with manifestations of accelerated aging, and neu to individuals 50 years and older with CD4 cell count greater rocognitive impairment can be exacerbated by HIV. Age- than 200/prl. All persons with HIV infection should be associated comorbidities and declines in kidney and liver vaccinated for meningococcal disease with the quadrivalent function can also complicate management through drug inter- meningococcal vaccine, including boosters every 5 years. actions and increased toxicity. Prophylaxis for opportunistic infections depends on the HIV infection itself and some antiretrovirals affect lipids patient's CD4 cell count (Table 04). Before beginning prophy- and can worsen hyperlipidemia; this is especially true for laxis, active inf'ection should be ruled out clinically and with boosted protease inhibitor-based regimens, which can also any indicated testing to avoid undertreatment and selection worsen insulin resistance. Fasting glucose or hemoglobin A,. for resistance, especially for tuberculosis and disseminated and lipid levels should be checked at baseline and 3 months M y cob acte rium au ium complex. after initiating or changing antiretrovirals; hemoglobin A,. should not be used for the diagnosis of diabetes in those taking KTY POI l{TS ART. . All persons with HIV should receive the 13-valent pneu- Chronic kidney disease is increasingly common in HIV mococcal conjugate and 23-valent polysaccharide vac- infection, although, with effective AKI, it is less often attrib- cines, hepatitis B vaccine series (in those not already uted to HIV nephropathy. It is recommended that kidney func infected or immune), and meningococcal vaccine; tion be assessed at least every 6 months in patients with HIV. COVID-19, influenza, tetanus-diphtheria-perfussis, Tenofovir, a very commonly used nucleoside analogue, is asso- hepatitis A, and human papillomavirus vaccines are ciated with risk for tubular nephrotoxicity, which usually indicated as for the general population. manifests as proteinuria. Patients using a regimen containing o Measles-mumps-rubella, varicella, and recombinant tenofovir should undergo urinalysis or quantitative measure- zoster vaccines can be given as long as the CD4 cell count ment of urine protein twice per year. is greater than 200/prl. Bone mineral densig is reduced in HIV and tenofovir is also associated with possible worsening of bone density. Dual- ener$/ x-ray absorptiometry scanning is recommended in Complications of HIV Infection men older than 50 years, postmenopausal women, patients with a history of fragility fracture, those with chronic gluco- in the Antiretroviral Therapy Era corticoid use, and those at high risk for falls. The newer pro- Metabolic, Kidney, and Liver Disorders drug of tenofovir, TAFI, achieves high intracellular levels of As HIV has become a treatable illness and persons with HIV active drug with much lower dosing and lower systemic levels age, metabolic disorders and specific organ diseases have compared with the older formulation, TDF. Compared with become increasingly significant. HIV infection itself may be TDF, TAF has equal antiviral efficacy with reduced kidney and 92

H IV/AIDS bone toxici[z and should be used preferentially over TDF in Neu rocog nitive Decl ine patients with or at risk for bone or kidney disease. Screening for neurologic compiications, especially cognitive Liver disease is also increased in HIV infection, often because impairment, is important at entry into HIV care. Assessment of coinfection with hepatitis B or C virus. All patients with HIV should be repeated in older adults, especially if concerns arise should be screened for hepatitis B and C viruses and immunized regarding adherence to care and ART. As persons living with if they are HBV negative. If coinfected with HIV and HBV, patients HIV age, neurocognitive impairment may be exacerbated by should receive treatment with a TDF or TAF plus emtricitabine or the effect of HIV infection on the brain. Classified as HIV lami'uudine-based regimen, which treats both viruses. Patients associated neurocognitive disorders (HAND), manifestations coinfectedwith hepatitis C virus should be given a course of cura- range from asymptomatic neurocognitive impairment to tive direct acting antiviral treatment, although attention must be severe HlV-associated dementia (HAD). anf initiation and paid to drug interactions between the antiviral regimens (see continuation is the main treatment for HAND, and it has a MKSAP 19 Gastroenterologz and Hepatolory). clear role in prevention and treatment of HAD. I(EY POIilTS I(EY POITT o Fasting glucose or hemoglobin A,. and lipid levels o Manifestations of HIV associated neurocognitive disor- should be checked at baseline and 3 months after initi- ders (HAND) range from asymptomatic neurocognitive ating or changing antiretroviral therapy; hemoglobin impairment to severe HIV associated dementia; if not Ar. should not be used for the diagnosis of diabetes in already being provided, ART should be instituted those taking antiretroviral therapy. immediately as part of prevention and treatment of . Tenofovir disoproxil fumarate (TDF) is associated with HAND. increased risks of tubular nephrotoxicity and worsening of bone mineral density; tenofovir alafenamide should Immune Reconstitution lnflammatory Syndrome be used preferentially over TDF in patients with or at Immune reconstitution inflammatory syndrome (IRIS) is a risk for bone or kidney disease. disorder associated with worsening of a pre-existing infec- tious process (paradoxical IRIS) or with revelation of a previ ously unrecognized pre-existing infection (unmasking IRIS). Card iovascu lar Disease It has also been reported with noninfectious complications, Rates of cardiovascular disease, including myocardial infarc- such as lymphoma. IRIS usually occurs within a few months tion and stroke, are higher in persons with HIV infection; this of initiating effective ART in patients with low pretreatment association remains after correction for increased risk factors CD4 cell counts (<tOOlpl-). Management includes continuing such as smoking. Some of the increase may result from hyper- ART while treating the opportunistic infection. In select lipidemia, but evidence indicates that the increase partially patients, NSAIDs or glucocorticoids may be useful in mitigat results from HIV infection being a chronic inflammatory state. ing inflammatory symptoms. It is clear that patients with untreated HIV infection have a I( EY PO I T{T higher risk of cardiovascular events compared with patients taking effective ART, regardless of any worsening of lipid levels o Immune reconstitution inflammatory syndrome is from the ART. Attention to traditional risk factors such caused by an inflammatory response to a pre-existing as smoking,lipid levels. and hypertension is crucial in patients infectious process; it usually occurs within a few with HIV as is use of statin therapy (with attention to drug months of initiating effective antiretroviral therapy and interactions between some statins and some antiretrovirals) presents with a wide variety of infections and noninfec based on current risk calculations. Guidelines from the tious complications. American College of Cardiologr/American Heart Association recommend patients with HIV infection and borderline risk Opportu nistic I nfections for atherosclerotic cardiovascular disease (57, to <7 .5o/o) should Mucocutaneous Condido inf'ections can occur in HlV-infected be engaged in risk discussion regarding initiating moderate- patients at relatively preserved CD4 cell counts. HlV-infected intensity statin therapy. An international multicenter trial is patients do not usually develop invasive Candida infection addressing whether patients with HIV should be treated with unless they have other risk factors. Oral candidiasis usually statins even with a lO-year risk less than7.5'/u. presents as thrush, with mucosal whitish plaques (Figure 37), and can be treated topically (e.g., with clotrimazole troches) or I(EY POI ilT with a short course of oral fluconazole. Swallowing symptoms o Rates of cardiovascular disease, including myocardial suggest esophageal disease, which requires systemic treat infarction and stroke, are higher in persons with HIV ment, such as fluconazole, for a longer course; a lack of treat infection; control of cardiovascular risk factors (smok ment response is an indication for endoscopy. ing, lipid levels, and hypertension) is essential, includ- Reactivation of latent tuberculosis is also significantly ing statin therapy based on clinical risk calculations. increased in HIV infection, even without a decreased CD4 cell

bone toxici[z and should be used preferentially over TDF in Neu rocog nitive Decl ine patients with or at risk for bone or kidney disease. Screening for neurologic compiications, especially cognitive Liver disease is also increased in HIV infection, often because impairment, is important at entry into HIV care. Assessment of coinfection with hepatitis B or C virus. All patients with HIV should be repeated in older adults, especially if concerns arise should be screened for hepatitis B and C viruses and immunized regarding adherence to care and ART. As persons living with if they are HBV negative. If coinfected with HIV and HBV, patients HIV age, neurocognitive impairment may be exacerbated by should receive treatment with a TDF or TAF plus emtricitabine or the effect of HIV infection on the brain. Classified as HIV lami'uudine-based regimen, which treats both viruses. Patients associated neurocognitive disorders (HAND), manifestations coinfectedwith hepatitis C virus should be given a course of cura- range from asymptomatic neurocognitive impairment to tive direct acting antiviral treatment, although attention must be severe HlV-associated dementia (HAD). anf initiation and paid to drug interactions between the antiviral regimens (see continuation is the main treatment for HAND, and it has a MKSAP 19 Gastroenterologz and Hepatolory). clear role in prevention and treatment of HAD. I(EY POIilTS I(EY POITT o Fasting glucose or hemoglobin A,. and lipid levels o Manifestations of HIV associated neurocognitive disor- should be checked at baseline and 3 months after initi- ders (HAND) range from asymptomatic neurocognitive ating or changing antiretroviral therapy; hemoglobin impairment to severe HIV associated dementia; if not Ar. should not be used for the diagnosis of diabetes in already being provided, ART should be instituted those taking antiretroviral therapy. immediately as part of prevention and treatment of . Tenofovir disoproxil fumarate (TDF) is associated with HAND. increased risks of tubular nephrotoxicity and worsening of bone mineral density; tenofovir alafenamide should Immune Reconstitution lnflammatory Syndrome be used preferentially over TDF in patients with or at Immune reconstitution inflammatory syndrome (IRIS) is a risk for bone or kidney disease. disorder associated with worsening of a pre-existing infec- tious process (paradoxical IRIS) or with revelation of a previ ously unrecognized pre-existing infection (unmasking IRIS). Card iovascu lar Disease It has also been reported with noninfectious complications, Rates of cardiovascular disease, including myocardial infarc- such as lymphoma. IRIS usually occurs within a few months tion and stroke, are higher in persons with HIV infection; this of initiating effective ART in patients with low pretreatment association remains after correction for increased risk factors CD4 cell counts (<tOOlpl-). Management includes continuing such as smoking. Some of the increase may result from hyper- ART while treating the opportunistic infection. In select lipidemia, but evidence indicates that the increase partially patients, NSAIDs or glucocorticoids may be useful in mitigat results from HIV infection being a chronic inflammatory state. ing inflammatory symptoms. It is clear that patients with untreated HIV infection have a I( EY PO I T{T higher risk of cardiovascular events compared with patients taking effective ART, regardless of any worsening of lipid levels o Immune reconstitution inflammatory syndrome is from the ART. Attention to traditional risk factors such caused by an inflammatory response to a pre-existing as smoking,lipid levels. and hypertension is crucial in patients infectious process; it usually occurs within a few with HIV as is use of statin therapy (with attention to drug months of initiating effective antiretroviral therapy and interactions between some statins and some antiretrovirals) presents with a wide variety of infections and noninfec based on current risk calculations. Guidelines from the tious complications. American College of Cardiologr/American Heart Association recommend patients with HIV infection and borderline risk Opportu nistic I nfections for atherosclerotic cardiovascular disease (57, to <7 .5o/o) should Mucocutaneous Condido inf'ections can occur in HlV-infected be engaged in risk discussion regarding initiating moderate- patients at relatively preserved CD4 cell counts. HlV-infected intensity statin therapy. An international multicenter trial is patients do not usually develop invasive Candida infection addressing whether patients with HIV should be treated with unless they have other risk factors. Oral candidiasis usually statins even with a lO-year risk less than7.5'/u. presents as thrush, with mucosal whitish plaques (Figure 37), and can be treated topically (e.g., with clotrimazole troches) or I(EY POI ilT with a short course of oral fluconazole. Swallowing symptoms o Rates of cardiovascular disease, including myocardial suggest esophageal disease, which requires systemic treat infarction and stroke, are higher in persons with HIV ment, such as fluconazole, for a longer course; a lack of treat infection; control of cardiovascular risk factors (smok ment response is an indication for endoscopy. ing, lipid levels, and hypertension) is essential, includ- Reactivation of latent tuberculosis is also significantly ing statin therapy based on clinical risk calculations. increased in HIV infection, even without a decreased CD4 cell 93

Htv/AtDs FTGURE 37. Secondaryacuteoralcandidiasispresentingaswhiteto-redpainful plaques in a patient with HIV/AIDS. count. Tuberculosis is also more likely to present in extrapul- monary sites or with an atypical chest radiograph. Tuberculosis treatment in HIV must consider interactions of rifamycins with many antiretrovirals. Inlcctions with other opportunistic organisms usually occur at CD4 cell counts less than 200/1tL. Pneumocystis jiroueciipneumonia usually presents as a subacute illness with fever, dyspnea, and dry cough in a patient with a CD4 cell FIGURE 3 8. Cerebral toxoplasmosis characterized by a ring-enhancing brain lesion associated with edema and mass effect in a patient with AIDS. Although this count less than 2OOlytLwho is not receiving prophylaxis. Chest patient has only a single apparent lesion, multiple lesions are more common. radiographs most often show bilateral interstitial infiltrates; cavitation or pleural effusion is unusual and suggests another diagnosis. A normal chest radiograph does not exclude the (CNS) lymphoma, which most often appears as a single lesion diagnosis, and chest CT is more sensitive, demonstrating on imaging, and progressive multifocal leukoencephalopathy, patchy "ground-glass" opacities. Normal lactate dehydroge- which is usually nonenhancing. Diagnosis of CNS toxoplasmo- nase levels and stable exercise oxygen saturation have a high sis is usually presumptive based on presentation, imaging, and negative predictive value, but elevated lactate dehydrogenase response to empiric treatment. levels and oxygen desaturation with exercise are nonspecific. Mycobacterium auium complex infection usually pre- Diagnosis depends on demonstration of causative organisms sents as disseminated disease in patients with CD4 cell counts and often requires bronchoscopy. The treatment of choice is less than 50/pL; symptoms and signs include fever, sweats, high-dose trimethoprim-sulfamethoxazole; patients with weight loss, hepatosplenomegaly, lymphadenopathy, and cyto- hypoxia at presentation should be given adjunctive glucocor- penias. Blood cultures for acid-fast bacilli will usually grow M. ticoids to prevent worsening that may accompany treatment auium complex, but it may also be found on lymph node or initiation. liver biopsy when necessary. Crgptococcus infection usually presents as subacute Qrtomegalovirus most commonly presents with CD4 cell meningitis with headache, mental status changes, and fever. counts less than 50/pL. Cytomegalovirus retinitis, presenting The diagnosis can be made most swiftly by antigen testing of with vision changes or floaters, is much more likely in AIDS cerebrospinal fluid and blood. Management includes anti- than in other immunocompromised conditions, such as after fungal therapy and attention to increased intracranial pres- transplantation. Gastrointestinal cytomegalovirus disease is sure, which is usually responsible for the morbidity and also common, most often as esophagitis or colitis. mortality associated with cryptococcal meningitis (see Fungal Patients with AIDS are also more likely to develop certain Infections). malignancies, especially those related to viruses. Non-Hodgkin Toxoplasma gondii infection in AIDS usually presents in lymphoma, especially primary CNS lymphoma related to patients with CD4 cell counts less than 100/pL. Because it is a Epstein-Barr virus, is significantly increased compared with reactivation disease, patients are usually serologr positive. age-matched controls. Kaposi sarcoma is caused by human Clinical presentation includes headache, fever, and focal neu- herpes virus type 8 and presents as dark red, brown, or viola- rologic deficits. Imaging by CT or MRI (which is more sensi- ceous lesions of the skin or mucous membranes (Figure 39); tive) reveals multiple ring-enhancing lesions (Figure 88). The human herpes virus type 8 can also cause primary effusion differential diagnosis includes primary central nervous system lymphoma and Castleman disease (giant lymph node

count. Tuberculosis is also more likely to present in extrapul- monary sites or with an atypical chest radiograph. Tuberculosis treatment in HIV must consider interactions of rifamycins with many antiretrovirals. Inlcctions with other opportunistic organisms usually occur at CD4 cell counts less than 200/1tL. Pneumocystis jiroueciipneumonia usually presents as a subacute illness with fever, dyspnea, and dry cough in a patient with a CD4 cell FIGURE 3 8. Cerebral toxoplasmosis characterized by a ring-enhancing brain lesion associated with edema and mass effect in a patient with AIDS. Although this count less than 2OOlytLwho is not receiving prophylaxis. Chest patient has only a single apparent lesion, multiple lesions are more common. radiographs most often show bilateral interstitial infiltrates; cavitation or pleural effusion is unusual and suggests another diagnosis. A normal chest radiograph does not exclude the (CNS) lymphoma, which most often appears as a single lesion diagnosis, and chest CT is more sensitive, demonstrating on imaging, and progressive multifocal leukoencephalopathy, patchy "ground-glass" opacities. Normal lactate dehydroge- which is usually nonenhancing. Diagnosis of CNS toxoplasmo- nase levels and stable exercise oxygen saturation have a high sis is usually presumptive based on presentation, imaging, and negative predictive value, but elevated lactate dehydrogenase response to empiric treatment. levels and oxygen desaturation with exercise are nonspecific. Mycobacterium auium complex infection usually pre- Diagnosis depends on demonstration of causative organisms sents as disseminated disease in patients with CD4 cell counts and often requires bronchoscopy. The treatment of choice is less than 50/pL; symptoms and signs include fever, sweats, high-dose trimethoprim-sulfamethoxazole; patients with weight loss, hepatosplenomegaly, lymphadenopathy, and cyto- hypoxia at presentation should be given adjunctive glucocor- penias. Blood cultures for acid-fast bacilli will usually grow M. ticoids to prevent worsening that may accompany treatment auium complex, but it may also be found on lymph node or initiation. liver biopsy when necessary. Crgptococcus infection usually presents as subacute Qrtomegalovirus most commonly presents with CD4 cell meningitis with headache, mental status changes, and fever. counts less than 50/pL. Cytomegalovirus retinitis, presenting The diagnosis can be made most swiftly by antigen testing of with vision changes or floaters, is much more likely in AIDS cerebrospinal fluid and blood. Management includes anti- than in other immunocompromised conditions, such as after fungal therapy and attention to increased intracranial pres- transplantation. Gastrointestinal cytomegalovirus disease is sure, which is usually responsible for the morbidity and also common, most often as esophagitis or colitis. mortality associated with cryptococcal meningitis (see Fungal Patients with AIDS are also more likely to develop certain Infections). malignancies, especially those related to viruses. Non-Hodgkin Toxoplasma gondii infection in AIDS usually presents in lymphoma, especially primary CNS lymphoma related to patients with CD4 cell counts less than 100/pL. Because it is a Epstein-Barr virus, is significantly increased compared with reactivation disease, patients are usually serologr positive. age-matched controls. Kaposi sarcoma is caused by human Clinical presentation includes headache, fever, and focal neu- herpes virus type 8 and presents as dark red, brown, or viola- rologic deficits. Imaging by CT or MRI (which is more sensi- ceous lesions of the skin or mucous membranes (Figure 39); tive) reveals multiple ring-enhancing lesions (Figure 88). The human herpes virus type 8 can also cause primary effusion differential diagnosis includes primary central nervous system lymphoma and Castleman disease (giant lymph node 94

HIV/AIDS preferably combining two nucleoside reverse transcriptase inhibitors with an integrase strand transfer inhibitor. Preferred regimens also feature a high barrier to resistance, good toler- ability and safety, and combination pills with once-daily dos- ing to facilitate adherence (Table 66). Patients with or at risk for reduced kidney function or osteopenia should not be given TDFI, To reduce the risk of h5rpersensitivity, patients who are prescribed abacavir must first undergo HLA-B.57:01 testing to show they are negative. Many antiretrovirals interact with other drugs, and potential drug interactions must always be assessed when beginning HIV therapy or beginning any drug for someone already taking ARL Such assessment is especially necessary when pharma- cokinetic boosters (ritonavir or cobicistat) are used specificatly to inhibit drug metabolism and raise levels of antiretrovirals. Viral load levels and CD4 cell counts are monitored to FIG U RE 3 9. Kaposi sarcoma, presenting as firm purple nodules on the face and ensure effectiveness and to determine immune recovery. With purple palatal nodules, is seen in a patient with AIDS. optimal therapy, HIV RNA in blood should become and stay undetectable. CD4 cell counts will increase, although cell counts hyperplasia) . Human papillomavirus -related malignancies are may take time to improve and may not show full recovery espe- significantly increased in HIV including cervical and anal cially in those who are older orwho have other factors affecting cancers, and regular guideline-based screening is important. lymphocytes. Patients taking ART who are stable with a CD4 cell count of 500/pL or more for more than 2 years can stop T-cell monitoring as long as viral load remains undetectable. o Pneumocystis jirouecii pneumonia usually presents as a subacute illness with fever, dyspnea, and dry cough; Resistance Testing although chest radiographs most often show bilateral Viral resistance testing should be performed at baseline to interstitial infiltrates, a normal chest radiograph does ensure selection of a fullyactive regimen and shouldbe repeated not exclude the diagnosis. if the viral load increases during ART The most common reason a Successful management of Cryptococcus infection in for breakthrough viremia is poor medication adherence. Plasma patients with HIV includes antifungal therapy and levels of HIV RNA must generally be greater than 500 copies/ml attention to increased intracranial pressure; which is to provide enough virus for resistance testing. Viral resistance usually responsible for the morbidity and mortality testing can be genotypic (looking for mutations associated with associated with cryptococcal meningitis. drug resistance) or phenotypic (assessing whether virus can HVC . MRI is more sensitive than CT in revealing the charac- replicate in the presence of the d*g). Genotypic testing is faster, teristic ring-enhancing lesions of Toxoplasma gondii cheaper, and more commonly used. Resistance testing results infection in patients with HIV. are used to guide selection of a new regimen in the event resist ant virus develops, but previous resistance testing results as well as previous regimens and responses must also be considered. Resistance testing may not be reliable if performed while the Management of HIV lnfection patient is not taking an antiretroviral regimen because resist When to lnitiate Treatment ance may not be detectable without the selective pressure of the All persons with HIV infection should begin ART as soon as antiretrovirals. Once selected for, previous mutations are gener- they are ready, regardless of CD4 cell count. Rapid initiation of ally archived in the viral population and may re-emerge even if ARI (on the day or within 2 weeks of initial diagnosis) has resistance testing does not demonstrate the mutation. A regi- been shown to improve viral suppression and should be con- men may also be switched because of adverse effects or to ease sidered if no medical (symptoms suggesting opportunistic adherence or avoid drug interactions. Laboratory monitoring infections in which immediate ART is contraindicated) or tests should be repeated 1 month after switching regimens to structural (staffing and linkage to care service availability) bar- assess effectiveness and toxicity. riers prevent doing so.

preferably combining two nucleoside reverse transcriptase inhibitors with an integrase strand transfer inhibitor. Preferred regimens also feature a high barrier to resistance, good toler- ability and safety, and combination pills with once-daily dos- ing to facilitate adherence (Table 66). Patients with or at risk for reduced kidney function or osteopenia should not be given TDFI, To reduce the risk of h5rpersensitivity, patients who are prescribed abacavir must first undergo HLA-B.57:01 testing to show they are negative. Many antiretrovirals interact with other drugs, and potential drug interactions must always be assessed when beginning HIV therapy or beginning any drug for someone already taking ARL Such assessment is especially necessary when pharma- cokinetic boosters (ritonavir or cobicistat) are used specificatly to inhibit drug metabolism and raise levels of antiretrovirals. Viral load levels and CD4 cell counts are monitored to FIG U RE 3 9. Kaposi sarcoma, presenting as firm purple nodules on the face and ensure effectiveness and to determine immune recovery. With purple palatal nodules, is seen in a patient with AIDS. optimal therapy, HIV RNA in blood should become and stay undetectable. CD4 cell counts will increase, although cell counts hyperplasia) . Human papillomavirus -related malignancies are may take time to improve and may not show full recovery espe- significantly increased in HIV including cervical and anal cially in those who are older orwho have other factors affecting cancers, and regular guideline-based screening is important. lymphocytes. Patients taking ART who are stable with a CD4 cell count of 500/pL or more for more than 2 years can stop T-cell monitoring as long as viral load remains undetectable. o Pneumocystis jirouecii pneumonia usually presents as a subacute illness with fever, dyspnea, and dry cough; Resistance Testing although chest radiographs most often show bilateral Viral resistance testing should be performed at baseline to interstitial infiltrates, a normal chest radiograph does ensure selection of a fullyactive regimen and shouldbe repeated not exclude the diagnosis. if the viral load increases during ART The most common reason a Successful management of Cryptococcus infection in for breakthrough viremia is poor medication adherence. Plasma patients with HIV includes antifungal therapy and levels of HIV RNA must generally be greater than 500 copies/ml attention to increased intracranial pressure; which is to provide enough virus for resistance testing. Viral resistance usually responsible for the morbidity and mortality testing can be genotypic (looking for mutations associated with associated with cryptococcal meningitis. drug resistance) or phenotypic (assessing whether virus can HVC . MRI is more sensitive than CT in revealing the charac- replicate in the presence of the d*g). Genotypic testing is faster, teristic ring-enhancing lesions of Toxoplasma gondii cheaper, and more commonly used. Resistance testing results infection in patients with HIV. are used to guide selection of a new regimen in the event resist ant virus develops, but previous resistance testing results as well as previous regimens and responses must also be considered. Resistance testing may not be reliable if performed while the Management of HIV lnfection patient is not taking an antiretroviral regimen because resist When to lnitiate Treatment ance may not be detectable without the selective pressure of the All persons with HIV infection should begin ART as soon as antiretrovirals. Once selected for, previous mutations are gener- they are ready, regardless of CD4 cell count. Rapid initiation of ally archived in the viral population and may re-emerge even if ARI (on the day or within 2 weeks of initial diagnosis) has resistance testing does not demonstrate the mutation. A regi- been shown to improve viral suppression and should be con- men may also be switched because of adverse effects or to ease sidered if no medical (symptoms suggesting opportunistic adherence or avoid drug interactions. Laboratory monitoring infections in which immediate ART is contraindicated) or tests should be repeated 1 month after switching regimens to structural (staffing and linkage to care service availability) bar- assess effectiveness and toxicity. riers prevent doing so. Antiretroviral Regimens o All persons with HIV infection should begin antiretrovi- Antiretroviral agents used in the United States are shown in ral therapy as soon as they are ready, regardless ofCD4 Table 65. Standards for effective antiretroviral regimens cell count' (continued) include use of three drugs from two different classes,

Antiretroviral Regimens o All persons with HIV infection should begin antiretrovi- Antiretroviral agents used in the United States are shown in ral therapy as soon as they are ready, regardless ofCD4 Table 65. Standards for effective antiretroviral regimens cell count' (continued) include use of three drugs from two different classes, 95

H tv/ArDs Class Agenta Adverse Effects Nucleoside RTls Abacavir Hypersensitivityb (excl ude HLA-B"57 : 0 1 before prescri bi ng) Emtricitabine Minimal toxicity; has activity against HBV and exacerbations have occurred with discontinuation of therapy Lamivudine Minimal toxicity; has HBV activity, but dosing differs for HIV and HBVtreatment TDF Nausea, kidney disease, Fanconi syndrome, decreased bone density; has activity against HBV and exacerbations have occurred with discontinuation of therapy TAF' Nausea; more weight gain than TDF; less kidney and bone toxicitythan TDF Zidovudine Nausea, headache, anemiab, leukopeniab, lactic acidosisb, lipodystrophy, myopathyb Nonnucleoside RTls Efavirenz Neuropsychiatric symptoms (dizziness, somnolence, sleep disturbance, vivid dreams, mood changes), rash, dyslipidemia Etravirine Nausea, rash Nevirapine Hypersensitivityb, rash, hepatitisb Rilpivirine Rash, headache, insomnia; requires food and gastric acid (no concomitant PPI use) for absorption Doravirine Nausea, headache Protease inhibitors Atazanavir Nausea, hyperbilirubinemia, nephrolithiasis, rash; requires food and gastric acid (no concomitant PPI use) for absorption Darunavir Nausea, diarrhea, rash Lopinavir Nausea, diarrhea, hyperlipidemia, insulin resistance

Emtricitabine Minimal toxicity; has activity against HBV and exacerbations have occurred with discontinuation of therapy Lamivudine Minimal toxicity; has HBV activity, but dosing differs for HIV and HBVtreatment TDF Nausea, kidney disease, Fanconi syndrome, decreased bone density; has activity against HBV and exacerbations have occurred with discontinuation of therapy TAF' Nausea; more weight gain than TDF; less kidney and bone toxicitythan TDF Zidovudine Nausea, headache, anemiab, leukopeniab, lactic acidosisb, lipodystrophy, myopathyb Nonnucleoside RTls Efavirenz Neuropsychiatric symptoms (dizziness, somnolence, sleep disturbance, vivid dreams, mood changes), rash, dyslipidemia Etravirine Nausea, rash Nevirapine Hypersensitivityb, rash, hepatitisb Rilpivirine Rash, headache, insomnia; requires food and gastric acid (no concomitant PPI use) for absorption Doravirine Nausea, headache Protease inhibitors Atazanavir Nausea, hyperbilirubinemia, nephrolithiasis, rash; requires food and gastric acid (no concomitant PPI use) for absorption Darunavir Nausea, diarrhea, rash Lopinavir Nausea, diarrhea, hyperlipidemia, insulin resistance CCR5 antagonist Maraviroc Hypersensitivity, hepatitisb lntegrase inhibitorsd Dolutegravir" Elevated creatinine level (decrease in tubular secretion, not GFR), insomnia, headache (generally well tolerated) Elvitegravir Nausea, diarrhea (generally well tolerated) Raltegravir Rash, myopathy (generally well tolerated)

CCR5 antagonist Maraviroc Hypersensitivity, hepatitisb lntegrase inhibitorsd Dolutegravir" Elevated creatinine level (decrease in tubular secretion, not GFR), insomnia, headache (generally well tolerated) Elvitegravir Nausea, diarrhea (generally well tolerated) Raltegravir Rash, myopathy (generally well tolerated) Bictegravi/ Elevated creatinine level (decrease in tubular secretion, not GFR), nausea, diarrhea, headache (generally well tolerated) Pharmacokinetic boosters Cobicistat Elevated creatinine level (decrease in tubular creatinine secretion, not GFR), not recommended if CrCl<70 mUmin Ritonavir Nausea, d iarrhea, hyperl i pidem ia, i nsu i n resistance, i podystrophy, d ru g I I interactionsb CrCl =creatinineclearance;$[ft=glomerularfiltrationrate; HBV=hepatitisBvirus;PPl =protonpumpinhibitor; RTls=reversetranscriptaseinhibitors; TAF=tenofovir alafenamide; TDF = tenofovir disoproxil fumarate. "Many agents are also available as components of combination medications. bBlack box warning. Note that all nucleoside analogues have a black box warning about possible lactic acidosis, although it is far more likely with stavudine, didanosine, and zidovudine than the other agents. 'TAF is not recommended in pregnant women because of insufficient safety data. dlntegrase inhibitors are associated with more weight gain than other antiretroviral classes. "Dolutegravir may be used as an alternative antiretroviral drug for women of childbearing age who are sexually active and not using contraception; it may be used as a recommended option forthose using effective contraception. rlnsufficient safety data exist regarding bictegravir around the time of conception or in pregnant women.

"Dolutegravir may be used as an alternative antiretroviral drug for women of childbearing age who are sexually active and not using contraception; it may be used as a recommended option forthose using effective contraception. rlnsufficient safety data exist regarding bictegravir around the time of conception or in pregnant women. o Standards for effective antiretroviral regimens include Management of Pregnant Patients use of three drugs from two different classes; preferred with HIV Infection regimens combine two nucleoside reverse transcriptase The management of pregnant women with HIV is similar to the inhibitors with an integrase strand transfer inhibitor. management of nonpregnant women. Initiating ART is recom- o Viral resistance testing should be performed at baseline mended as soon as possible in pregnant women with HIV who are not already being treated, and it is especially important that to ensure selection of a fully active regimen and should women already receiving HIV treatment who become pregnant be repeated if the viral load increases during antiretro- continue treatment without interruption. ARIT in pregnancy viral therapy. benefits the woman and significantly reduces the risk of 96

Viral lnfections TABLE 66. Recommended Regimens for lnitialTreatment of Most Persons with HIV lnfection" Viral Infections ART can be initiated before drug resistance testing and HLA- B*57:01 test results are available.ln this setting, one of the lnfluenza Viruses fol lowing antiretrovira I therapy regimens is reiommended : Overview B i cte g ravi r/te n ofovi r a I afe n a m i d e/e mtri cita b i n e Three Upes of influenza viruses primarily infect humans: A, Dolutegravir with tenofovirb plus emtricitabine or lamivudine B, and C. Influenza A viruses are divided into subtypes based on two surface proteins, hemagglutinin (H) and neuramini- Additional recommended regimens include: dase (N). Influenza A viruses can infect animals and humans Dol uteg ravir / abacavir /la m ivud i ne' and produce epidemics and pandemics. Influenza B viruses Dol uteg ravi r/la m ivud i ned only affect humans and cause yearly epidemics but not pan- Raltegravir plus (emtricitabine or lamivudine) plus tenofovirb demics. Influenza C causes mild illness and does not cause epidemics. "Revised based on the 2018 lnternational Antiviral Society-USA Panel guidelines and the 2019 Department of Health and Human Services guideline update. A Minor changes in the H and N surface envelope glyco- sample for genotypic testing should be sent before ART initiation. Before initiating treatment in a person of childbearing potential, a pregnancy test should be proteins (antigenic drift) of influenza AandB viruses cause performed. Before prescribing ART to a person of childbearing potential, please refer to the guideline for information (https://clinicalinfo.hiv.gov/en/guidelines). yearly epidemics, and major changes (antigenic shrft) in bTenofovir alafenamide (TAF) and tenofovir disoproxil fumarate (TDF) are two forms influenza A after genetic recombination from animals of tenofovir that are approved in the United States. TAF has fewer bone and kidney cause global pandemics. The last influenza pandemic toxicities than TDF, whereas TDF is associated with lower lipid levels. Safety, cost, and accessibility are among the factors to consider when choosing between these drugs. occurred in 2009 and was caused by H1N1. Emerging sub 'Only for patients who are HLA-B*57:01 negative and without hepatitis B virus types of importance include H7N9, which circulates among coinfection (Al). poultry in China and can cause severe illness in humans; dExcept in those with a pretreatment HIV RNA level >500,000 copies/mL, chronic HSN1, which infects humans through close contact with hepatitis B virus coinfection, or before results of HIV genotyping are available. infected poultry and can spread from person to persoa; and variants circulating in pigs that can sporadically infect perinatal transmission of HIV to her baby. Recent data show no humans. difference in birth defect rates with some antiretrovirals com- Other respiratory viruses that may be documented in pared with the general population, including neural tube adults are outlined in Table 67. defects with efavirenz. Initial treatment regimen selection in pregnant women is similar to that for nonpregnant women; Clinical Features and Evaluation however, some antivirals are not recommended (see Table 65). During the winter, influenza A causes a self-limiting illness I(EY POIilTS with fever, cough, rhinorrhea, myalgia, and headache in most o Pregnant women should promptly initiate or continue patients; influenza B causes a milder illness. Older adults (>6s years), young children, pregnant and postpartum women, receiving HIV treatment without interruption; efavirenz and tenofovir disoproxil fumarate can be safely used. immunocompromised patients, patients with chronic medical conditions (especially chronic lung disease), persons wilr. o In pregnant women with HIV, bictegravir and tenofovir obesity (BMI >40), persons with neuromuscular disease, and alafenamide are not recommended. residents of extended-care facilities are at higher risk for

TABLE 66. Recommended Regimens for lnitialTreatment of Most Persons with HIV lnfection" Viral Infections ART can be initiated before drug resistance testing and HLA- B*57:01 test results are available.ln this setting, one of the lnfluenza Viruses fol lowing antiretrovira I therapy regimens is reiommended : Overview B i cte g ravi r/te n ofovi r a I afe n a m i d e/e mtri cita b i n e Three Upes of influenza viruses primarily infect humans: A, Dolutegravir with tenofovirb plus emtricitabine or lamivudine B, and C. Influenza A viruses are divided into subtypes based on two surface proteins, hemagglutinin (H) and neuramini- Additional recommended regimens include: dase (N). Influenza A viruses can infect animals and humans Dol uteg ravir / abacavir /la m ivud i ne' and produce epidemics and pandemics. Influenza B viruses Dol uteg ravi r/la m ivud i ned only affect humans and cause yearly epidemics but not pan- Raltegravir plus (emtricitabine or lamivudine) plus tenofovirb demics. Influenza C causes mild illness and does not cause epidemics. "Revised based on the 2018 lnternational Antiviral Society-USA Panel guidelines and the 2019 Department of Health and Human Services guideline update. A Minor changes in the H and N surface envelope glyco- sample for genotypic testing should be sent before ART initiation. Before initiating treatment in a person of childbearing potential, a pregnancy test should be proteins (antigenic drift) of influenza AandB viruses cause performed. Before prescribing ART to a person of childbearing potential, please refer to the guideline for information (https://clinicalinfo.hiv.gov/en/guidelines). yearly epidemics, and major changes (antigenic shrft) in bTenofovir alafenamide (TAF) and tenofovir disoproxil fumarate (TDF) are two forms influenza A after genetic recombination from animals of tenofovir that are approved in the United States. TAF has fewer bone and kidney cause global pandemics. The last influenza pandemic toxicities than TDF, whereas TDF is associated with lower lipid levels. Safety, cost, and accessibility are among the factors to consider when choosing between these drugs. occurred in 2009 and was caused by H1N1. Emerging sub 'Only for patients who are HLA-B*57:01 negative and without hepatitis B virus types of importance include H7N9, which circulates among coinfection (Al). poultry in China and can cause severe illness in humans; dExcept in those with a pretreatment HIV RNA level >500,000 copies/mL, chronic HSN1, which infects humans through close contact with hepatitis B virus coinfection, or before results of HIV genotyping are available. infected poultry and can spread from person to persoa; and variants circulating in pigs that can sporadically infect perinatal transmission of HIV to her baby. Recent data show no humans. difference in birth defect rates with some antiretrovirals com- Other respiratory viruses that may be documented in pared with the general population, including neural tube adults are outlined in Table 67. defects with efavirenz. Initial treatment regimen selection in pregnant women is similar to that for nonpregnant women; Clinical Features and Evaluation however, some antivirals are not recommended (see Table 65). During the winter, influenza A causes a self-limiting illness I(EY POIilTS with fever, cough, rhinorrhea, myalgia, and headache in most o Pregnant women should promptly initiate or continue patients; influenza B causes a milder illness. Older adults (>6s years), young children, pregnant and postpartum women, receiving HIV treatment without interruption; efavirenz and tenofovir disoproxil fumarate can be safely used. immunocompromised patients, patients with chronic medical conditions (especially chronic lung disease), persons wilr. o In pregnant women with HIV, bictegravir and tenofovir obesity (BMI >40), persons with neuromuscular disease, and alafenamide are not recommended. residents of extended-care facilities are at higher risk for TABLE 67. Respiratory Viruses Causing lllness in Adults Virus Clinical Presentation Populations at Risk Treatment Parainfluenza virus Otitis media, pharyngitis, Older adults; Supportive conj u nctivitis, crou p, i mm unosu ppressed persons, Children with croup are treated tracheobronchitis, pneumonia, especially HSCT recipients; 50% with glucocorticoids respiratory failure and death moftality with pneumonia Respi ratory syncytia I vi rus Upper and lower respiratory Older adults; Aerosolized or oral ribavirin in tract infection, including asthma immunosuppressed persons, HSCT and lung transplant and COPD exacerbation, especially lung transplant and Palivizumab for prophylaxis in pneumonia, and respiratory HSCT recipients; those with children only failure and death underlying cardiac and lung comorbidities Human metapneumovirus Upper and lower respiratory Older adults; Supportive tract infection, incl uding immunosuppressed persons; bronchiolitis, pneumonia, those with underlying cardiac or asthma, and COPD exacerbation respiratory comorbid ities

TABLE 67. Respiratory Viruses Causing lllness in Adults Virus Clinical Presentation Populations at Risk Treatment Parainfluenza virus Otitis media, pharyngitis, Older adults; Supportive conj u nctivitis, crou p, i mm unosu ppressed persons, Children with croup are treated tracheobronchitis, pneumonia, especially HSCT recipients; 50% with glucocorticoids respiratory failure and death moftality with pneumonia Respi ratory syncytia I vi rus Upper and lower respiratory Older adults; Aerosolized or oral ribavirin in tract infection, including asthma immunosuppressed persons, HSCT and lung transplant and COPD exacerbation, especially lung transplant and Palivizumab for prophylaxis in pneumonia, and respiratory HSCT recipients; those with children only failure and death underlying cardiac and lung comorbidities Human metapneumovirus Upper and lower respiratory Older adults; Supportive tract infection, incl uding immunosuppressed persons; bronchiolitis, pneumonia, those with underlying cardiac or asthma, and COPD exacerbation respiratory comorbid ities HSCT = hematopoietic stem cell transplantation

TABLE 67. Respiratory Viruses Causing lllness in Adults Virus Clinical Presentation Populations at Risk Treatment Parainfluenza virus Otitis media, pharyngitis, Older adults; Supportive conj u nctivitis, crou p, i mm unosu ppressed persons, Children with croup are treated tracheobronchitis, pneumonia, especially HSCT recipients; 50% with glucocorticoids respiratory failure and death moftality with pneumonia Respi ratory syncytia I vi rus Upper and lower respiratory Older adults; Aerosolized or oral ribavirin in tract infection, including asthma immunosuppressed persons, HSCT and lung transplant and COPD exacerbation, especially lung transplant and Palivizumab for prophylaxis in pneumonia, and respiratory HSCT recipients; those with children only failure and death underlying cardiac and lung comorbidities Human metapneumovirus Upper and lower respiratory Older adults; Supportive tract infection, incl uding immunosuppressed persons; bronchiolitis, pneumonia, those with underlying cardiac or asthma, and COPD exacerbation respiratory comorbid ities HSCT = hematopoietic stem cell transplantation 97

Viral lnfections severe primary influenza, complications such as superim- should also be initiated as soon as possible for all other patients posed bacterial pneumonia caused by Streptococcus pneumo- at high risk for influenza-related complications. Treatment niae or Staphylococcus aLtrelts, and death (see Community can also be considered for otherwise healthy outpatients if Acquired Pneumonia). Less common but severe complications started within 48 hours, household contacts of severely immu- include asthma or chronic obstructive pulmonary disease nosuppressed patients, and health care workers who care for exacerbations, myocarditis, encephalitis, rhabdomyolysis, patients at high risk of developing complications from myositis, sepsis, and multiorgan failure. Parotitis caused by influenza. influenza was reported during the 2015 to 2016 influenza Neuraminidase inhibitors are active against influenza A and season. B and can be given orally (oseltamivir), intranasally (zanamivir), During the endemic season, patients can be diagnosed or intravenously (peramivir). Antiviral therapy should be given within 20 minutes using either rapid antigen tests or poly- for at least 5 days, but in severely ill or immunosuppressed merase chain reaction (PCR) testing of nasopharyngeal patients. a longer duration should be considered with repeat swabs. Both tests are highly specific, but PCR has a sensitiv follow-up testing to document clearance. Immunosuppressed ity of nearly 100%; the rapid antigen tests have a sensitivity patients are at risk for neuraminidase inhibitor resistance during between 59'2, and 93%. The Infectious Diseases Society of or after therapy. America (IDSA) has recently published updated guidelines Baloxavir is a polymerase acidic endonuclease inhibitor for seasonal influenza evaluation and management, recom that can be given as single dose therapy for uncomplicated mending PCR over rapid antigen tests. During seasonal influenza. It must be started within 48 hours of symptom influenza activity, testing for influenza should occur in onset and appears to be as effective as a 5-day course of patients at high risk who present with influenza-like illness, oseltamivir. Baloxavir is FDA approved for the treatment of pneumonia, or nonspecific respiratory illness if the testing patients at high risk of influenza complications. result will influence clinical management (decisions on anti- Widespread influenza vaccination is the most impor- viral treatment initiation, impact on other diagnostic test- tant preventive intervention; all persons aged 6 months or ing, antibiotic treatment decisions, and infection control older without contraindications and all health care per- practices). Other outpatient candidates for testing include sonnel should be vaccinated (see MKSAP 19 General those who present with acute onset of respiratory symptoms Internal Medicine 2). Oral oseltamivir and baloxavir and and either exacerbation of chronic medical conditions or inhaled zanamivir are FDA approved for chemoprophy with known complications of influenza, such as pneumonia, laxis (zanamivir is not approved in patients with chronic if the testing result will influence clinical management. lung diseases) to contain outbreaks in institutional settings During times of influenza activity, testing for influenza at (such as long-term care facilities) and hospitals in con- hospital admission is recommended for all patients with junction with droplet precautions and vaccination. acute respiratory infection and in patients with acute wors- Chemoprophylaxis should be initiated as soon as possible ening of chronic cardiopulmonary disease. In all cases. and no later than 48 hours after exposure and should be treatment decisions should not be delayed pending con- continued for 7 days after the most recent exposure. Good firmatory results. hand hygiene and face masks can prevent secondary infec- tions in households. KEY POIITTS . Older adults (>OS years), young children, pregnant and KEY POIT{TS postparhrm women, and patients with chronic medical o Widespread influenza vaccination is the most important conditions (especially chronic lung disease, immuno preventive intervention; all persons aged 6 months or compromise, and BMI >40) are at higher risk for severe older without contraindications and all health care per- primary influenza, superimposed bacterial pneumonia sonnel should be vaccinated. caused by Streptococcus pneumoniae or Staphylococcus r Antiviral therapy should be initiated as soon as possi- altreus, and death. ble for adults with documented or suspected influ- HVC . The Infectious Diseases Society of America recom- enza who are hospitalized and for outpatients with mends using polymerase chain reaction testing over severe or progressive illness regardless of illness dura- rapid antigen tests for the diagnosis of influenza if test- tion; treatment should be initiated as soon as possible ing is likely to change management. for all other patients at high risk of influenza-related complications.

severe primary influenza, complications such as superim- should also be initiated as soon as possible for all other patients posed bacterial pneumonia caused by Streptococcus pneumo- at high risk for influenza-related complications. Treatment niae or Staphylococcus aLtrelts, and death (see Community can also be considered for otherwise healthy outpatients if Acquired Pneumonia). Less common but severe complications started within 48 hours, household contacts of severely immu- include asthma or chronic obstructive pulmonary disease nosuppressed patients, and health care workers who care for exacerbations, myocarditis, encephalitis, rhabdomyolysis, patients at high risk of developing complications from myositis, sepsis, and multiorgan failure. Parotitis caused by influenza. influenza was reported during the 2015 to 2016 influenza Neuraminidase inhibitors are active against influenza A and season. B and can be given orally (oseltamivir), intranasally (zanamivir), During the endemic season, patients can be diagnosed or intravenously (peramivir). Antiviral therapy should be given within 20 minutes using either rapid antigen tests or poly- for at least 5 days, but in severely ill or immunosuppressed merase chain reaction (PCR) testing of nasopharyngeal patients. a longer duration should be considered with repeat swabs. Both tests are highly specific, but PCR has a sensitiv follow-up testing to document clearance. Immunosuppressed ity of nearly 100%; the rapid antigen tests have a sensitivity patients are at risk for neuraminidase inhibitor resistance during between 59'2, and 93%. The Infectious Diseases Society of or after therapy. America (IDSA) has recently published updated guidelines Baloxavir is a polymerase acidic endonuclease inhibitor for seasonal influenza evaluation and management, recom that can be given as single dose therapy for uncomplicated mending PCR over rapid antigen tests. During seasonal influenza. It must be started within 48 hours of symptom influenza activity, testing for influenza should occur in onset and appears to be as effective as a 5-day course of patients at high risk who present with influenza-like illness, oseltamivir. Baloxavir is FDA approved for the treatment of pneumonia, or nonspecific respiratory illness if the testing patients at high risk of influenza complications. result will influence clinical management (decisions on anti- Widespread influenza vaccination is the most impor- viral treatment initiation, impact on other diagnostic test- tant preventive intervention; all persons aged 6 months or ing, antibiotic treatment decisions, and infection control older without contraindications and all health care per- practices). Other outpatient candidates for testing include sonnel should be vaccinated (see MKSAP 19 General those who present with acute onset of respiratory symptoms Internal Medicine 2). Oral oseltamivir and baloxavir and and either exacerbation of chronic medical conditions or inhaled zanamivir are FDA approved for chemoprophy with known complications of influenza, such as pneumonia, laxis (zanamivir is not approved in patients with chronic if the testing result will influence clinical management. lung diseases) to contain outbreaks in institutional settings During times of influenza activity, testing for influenza at (such as long-term care facilities) and hospitals in con- hospital admission is recommended for all patients with junction with droplet precautions and vaccination. acute respiratory infection and in patients with acute wors- Chemoprophylaxis should be initiated as soon as possible ening of chronic cardiopulmonary disease. In all cases. and no later than 48 hours after exposure and should be treatment decisions should not be delayed pending con- continued for 7 days after the most recent exposure. Good firmatory results. hand hygiene and face masks can prevent secondary infec- tions in households. KEY POIITTS . Older adults (>OS years), young children, pregnant and KEY POIT{TS postparhrm women, and patients with chronic medical o Widespread influenza vaccination is the most important conditions (especially chronic lung disease, immuno preventive intervention; all persons aged 6 months or compromise, and BMI >40) are at higher risk for severe older without contraindications and all health care per- primary influenza, superimposed bacterial pneumonia sonnel should be vaccinated. caused by Streptococcus pneumoniae or Staphylococcus r Antiviral therapy should be initiated as soon as possi- altreus, and death. ble for adults with documented or suspected influ- HVC . The Infectious Diseases Society of America recom- enza who are hospitalized and for outpatients with mends using polymerase chain reaction testing over severe or progressive illness regardless of illness dura- rapid antigen tests for the diagnosis of influenza if test- tion; treatment should be initiated as soon as possible ing is likely to change management. for all other patients at high risk of influenza-related complications. Management The IDSA guidelines recommend initiating antiviral treatment Novel Coronaviruses as soon as possible for adults with documented or suspected Coronaviruses are enveloped RNA viruses. Seven known influenza who are hospitalized and for outpatients with severe types infect humans, with some infecting animals as well. or progressive illness regardless of illness duration. Treatment Four are frequent causes of minor respiratory and

Management The IDSA guidelines recommend initiating antiviral treatment Novel Coronaviruses as soon as possible for adults with documented or suspected Coronaviruses are enveloped RNA viruses. Seven known influenza who are hospitalized and for outpatients with severe types infect humans, with some infecting animals as well. or progressive illness regardless of illness duration. Treatment Four are frequent causes of minor respiratory and 98

Viral lnfections gastrointestinal diseases. Three novel coronaviruses, severe patients with suspected infection. All adults should receive acute respiratory syndrome-coronaviruses (SARS-CoV and the COVID-19 vaccine. For the most current information, SARS-CoV-2) and Middle East respiratory syndrome- please see COVID-19: An ACP Physicians Guide and Resources coronavirus (MERS-CoV), can infect animals and also cause (https : //assets. acponline. org/coronavirus /scormcontent /) . severe disease and epidemics in humans. In 2OO2, SARS- CoV emerged in China, causing an acute pneumonia epidemic with a mortality rate of approximately 10%. No . Severe acute respiratory syndrome-coronavirus 2 and SARS-CoV infections have been reported since 2004. MERS Middle East respiratory syndrome-coronavirus are CoV emerged in 2Ol2 in Saudi Arabia in humans and cam- novel coronaviruses that can cause severe disease and els, with most infections occurring in the Arabian Peninsula. epidemics in humans. MERS-CoV causes pneumonia, diarrhea, and kidney failure with a mortality rate of approximately 4O%. In December 2019, the third novel, deadly coronavirus, SARS-CoV-2, Human Herpesvirus Infeqtions emerged in the city of Wuhan, China and rapidly spread to Human herpesviruses (HHVs) are a group of eight DNA pandemic levels. Symptomatic disease is characterized by viruses (table 6S). In humans, infection with HHV results in fever, fatigue, dry cough, gastrointestinal symptoms, and lifelong viral latency with the possibility of reactivation and loss of taste and smell; severe respiratory disease leading to oncogenesis. HHV can be transmitted by physical or sexual death can occur, but most infections are mild or asympto- contact during active infection or through asymptomatic matic. Symptoms of SARS-CoV-2 may persist following mild shedding of the virus (in saliva, semen, or cervical secre- and severe infections. Because all types of coronaviruses tions); other routes include blood transfusion, organ trans- may spread from human to human, contact and respiratory plantation, or maternofetal transmission. Varicella-zoster precautions should be implemented for hospitalized virus (VZV) is the only HHV that can be transmitted by the

gastrointestinal diseases. Three novel coronaviruses, severe patients with suspected infection. All adults should receive acute respiratory syndrome-coronaviruses (SARS-CoV and the COVID-19 vaccine. For the most current information, SARS-CoV-2) and Middle East respiratory syndrome- please see COVID-19: An ACP Physicians Guide and Resources coronavirus (MERS-CoV), can infect animals and also cause (https : //assets. acponline. org/coronavirus /scormcontent /) . severe disease and epidemics in humans. In 2OO2, SARS- CoV emerged in China, causing an acute pneumonia epidemic with a mortality rate of approximately 10%. No . Severe acute respiratory syndrome-coronavirus 2 and SARS-CoV infections have been reported since 2004. MERS Middle East respiratory syndrome-coronavirus are CoV emerged in 2Ol2 in Saudi Arabia in humans and cam- novel coronaviruses that can cause severe disease and els, with most infections occurring in the Arabian Peninsula. epidemics in humans. MERS-CoV causes pneumonia, diarrhea, and kidney failure with a mortality rate of approximately 4O%. In December 2019, the third novel, deadly coronavirus, SARS-CoV-2, Human Herpesvirus Infeqtions emerged in the city of Wuhan, China and rapidly spread to Human herpesviruses (HHVs) are a group of eight DNA pandemic levels. Symptomatic disease is characterized by viruses (table 6S). In humans, infection with HHV results in fever, fatigue, dry cough, gastrointestinal symptoms, and lifelong viral latency with the possibility of reactivation and loss of taste and smell; severe respiratory disease leading to oncogenesis. HHV can be transmitted by physical or sexual death can occur, but most infections are mild or asympto- contact during active infection or through asymptomatic matic. Symptoms of SARS-CoV-2 may persist following mild shedding of the virus (in saliva, semen, or cervical secre- and severe infections. Because all types of coronaviruses tions); other routes include blood transfusion, organ trans- may spread from human to human, contact and respiratory plantation, or maternofetal transmission. Varicella-zoster precautions should be implemented for hospitalized virus (VZV) is the only HHV that can be transmitted by the TABLE 6S, Human Herpesviruses and Associated Manifestations Type Synonym Subfamily Manifestations Latency Site HHV-1 Herpes simplex virus 1 0, Primary infection: oral and/or genital Nerve ganglion herpes (predominantly orofacial: gingivostomatitis, pharyngitis, herpes labialis) Reactivation : Bel I palsy, vi ra I encepha itis; I

TABLE 6S, Human Herpesviruses and Associated Manifestations Type Synonym Subfamily Manifestations Latency Site HHV-1 Herpes simplex virus 1 0, Primary infection: oral and/or genital Nerve ganglion herpes (predominantly orofacial: gingivostomatitis, pharyngitis, herpes labialis) Reactivation : Bel I palsy, vi ra I encepha itis; I other sites, including skin and eye (recu rrent herpes labialis) HHV-2 Herpes simplex virus 2 C[ Primary infection: oral and/or genital Nerve ganglion herpes (predominantly genital); meningitis, sacral radiculopathy, and transverse myelitis HHV.3 Varicella-zoster virus cx, Varicella (chickenpox), herpes zoster Nerve ganglion (shingles)

HHV-2 Herpes simplex virus 2 C[ Primary infection: oral and/or genital Nerve ganglion herpes (predominantly genital); meningitis, sacral radiculopathy, and transverse myelitis HHV.3 Varicella-zoster virus cx, Varicella (chickenpox), herpes zoster Nerve ganglion (shingles) HHV-4 Epstein-Barr virus lnfectious mononucleosis, nasopharyngeal B cell carcinoma; in immunocompromised patients: Burkitt lymphoma, primary central neryous system lymphoma (in patients with Al DS), posttra nspla nt lym phoproliferative disease, hairy leukoplakia HHV-5 CMV p CMV mononucleosis; in immunocompro- Monocyte,lym phocyte mised patients: CMV retinitis, leukopenia endothelialcel l, and thrombocytopenia, pneu monitis, epithelialcell colitis, esophagitis, or hepatitis HHV-6 (64 and 68) Roseolovirus, herpes p Mononucleosis-like syndrome, roseola T cell lymphotropic virus (sixth disease, exanthema subitum) in children; may affect various organ systems in transplant patients

HHV-4 Epstein-Barr virus lnfectious mononucleosis, nasopharyngeal B cell carcinoma; in immunocompromised patients: Burkitt lymphoma, primary central neryous system lymphoma (in patients with Al DS), posttra nspla nt lym phoproliferative disease, hairy leukoplakia HHV-5 CMV p CMV mononucleosis; in immunocompro- Monocyte,lym phocyte mised patients: CMV retinitis, leukopenia endothelialcel l, and thrombocytopenia, pneu monitis, epithelialcell colitis, esophagitis, or hepatitis HHV-6 (64 and 68) Roseolovirus, herpes p Mononucleosis-like syndrome, roseola T cell lymphotropic virus (sixth disease, exanthema subitum) in children; may affect various organ systems in transplant patients HHV-7 Roseolovirus p Usually asymptomatic; may be associated T cell with pityriasis rosea; roseola (sixth disease, exanthema subitum) in children

HHV-7 Roseolovirus p Usually asymptomatic; may be associated T cell with pityriasis rosea; roseola (sixth disease, exanthema subitum) in children HHV-8 Kaposi sarcoma- I Kaposi sarcoma, PEL, multicentric B cell, endothelial cell associated virus Castleman disease CMV = cytomegalovirus; HHV = human herpesvirus; PEL = primary effusion lymphoma. 99