Hospital Medicine

HIV

I. Problem/Condition.

"Acute HIV", or "acute retroviral syndrome", is the clinical presentation of early HIV seroconversion and represents the time between initial infection and detection of HIV antibodies. Often undiagnosed, its non-specific presentation can make it a difficult diagnosis, particularly if no HIV exposure is identified.

In general, about 2/3 of patients acutely infected with HIV will exhibit symptoms, which typically last anywhere from 3 days to several weeks. Symptoms, which overlap with many other acute viral illnesses, include:

  • fever (80-90%)

  • pharyngitis (+/- exudate)

  • lymphadenopathy (generalized)/splenomegaly

  • rash (erythemous, maculopapular, central > peripheral)

  • mucosal ulcers

  • fatigue/anorexia

  • myalgia/arthralgia

  • headache, retro-orbital pain

  • neuro symptoms (aseptic meningitis, radiculitis, CN palsies, myelitis)

II. Diagnostic Approach.

A. What is the differential diagnosis for this problem?

Acute HIV symptoms often overlap with other viral illnesses:

  • Mononucleosis

  • Influenza

  • Acute Hepatitis B

  • Acute CMV

  • Acute Toxoplasmosis

  • Enterovirus

  • Secondary Syphilis

B. Describe a diagnostic approach/method to the patient with this problem.

Because the symptoms of HIV infection can be non-specific and variable in presentation, clinical suspicion and routine screening are recommended for most patients seen in the Emergency Department or admitted to the hospital. In 2006, the Centers for Disease Control and Prevention (CDC) recommended routine screening for HIV infections among all patients between the ages of 13-64, pregnant women and individuals at increased risk for HIV infection.

1. Historical information important in the diagnosis of this problem.

Patients with high risk behaviors are at increased risk for HIV infection. Since 1981, 1.7 million Americans have been infected and over 580,000 have died through 2007. An estimated 21% of people living with HIV are undiagnosed, and every 9.5 minutes someone in the United States is infected with HIV. New infections disproportionately affect African-Americans, Latinos, young adults, and gay and bisexual men. Patients with a history of intravenous drug use are also at risk.

2. Physical Examination maneuvers that are likely to be useful in diagnosing the cause of this problem.

Physical exam findings include:

  • Fever

  • Pharyngeal exudate

  • Mucosal ulcers

  • Diffuse lymphadenopathy

  • Splenomegaly

  • Generalized erythematous rash (usually central more than peripheral)

  • Focal neurologic deficits.

Patients should also be evaluated for presence of AIDS defining illnesses or opportunist infections (OIs), including oropharyngeal candidiasis, Kaposi's sarcoma, etc.

3. Laboratory, radiographic and other tests that are likely to be useful in diagnosing the cause of this problem.

Laboratory tests

In early infection, the immune system may not have had enough time to produce antibodies to HIV. The HIV ELISA, which is the most common test used to detect HIV, looks for HIV antibodies and occasionally may not be positive for the first 6-8 weeks of infection. Counseling patients at the time of initial testing is recommended so that patients understand that a negative test does not ensure that a patient is not infected with HIV without repeat testing.

  • HIV Ab test - negative in acute HIV; should be checked 4-6 weeks after acute HIV diagnosis to confirm seroconversion.

  • HIV RNA viral load - usually greater than 100,000 in setting of acute HIV. False positives are seen in less than 5%, usually with viral loads only in the thousands.

  • Absolute CD4 count - to help guide anti-retroviral therapy (ART) treatment and determine risk for opportunistic infections.

  • HIV genotype - for confirmed positive acute HIV patients and all ART naive patients. Even if treatment is deferred initially, genotyping can help determine resistance patterns and guide future ART (mutations may be difficult to detect later).

Imaging

As clinically indicated.

III. Management while the Diagnostic Process is Proceeding.

A. Management of Clinical Problem HIV.

Immediate management

Supportive therapy as necessary initially. Patients with acute HIV could be started with anti-retroviral therapy, as treatment may help preserve immune function, decrease severity of acute illness, decrease viral load and risk of viral transmission to others. However, to date, little evidence exists for long-term benefits. On the other hand, adherence challenges in the setting of a new diagnosis, potential medication toxicities and possibility for drug resistance must be weighed against the benefits. Consultation with an infectious disease or HIV specialist may be helpful.

Laboratory tests

Initial laboratory tests as noted above. No specific daily, laboratory tests necessary unless otherwise clinically indicated by complicating conditions.

Long-term management

HIV care follow-up, CD4 monitoring, opportunistic infection prophylaxis as indicated. Screening for cervical cancer, hepatitis B vaccine, hepatitis C antibody, lipid profile, dental oral exam, syphilis, tuberculosis infection (active or latent), chlamydia/gonorrhea, appropriate vaccinations, substance use, and toxoplasma antibody.

Renal insufficiency

Renal disease in patients with HIV can be primary (HIV associated nephropathy = HIVAN), secondary to systemic illness (e.g., diabetes mellitus, hypertension) or as an adverse event from medications. ART should be given to patients with renal disease according to usual ART recommendations, with specific medication recommendations based on degree of renal failure.

The most notable mediation to be aware of is tenofovir which can cause renal insufficiency and Fanconi's syndrome. Most nucleoside reverse transcriptase inhibitors (NRTIs) need dose adjustment based on renal function, whereas protease inhibitors (PIs) and non-NRTIs do not (except with dialysis). Antiretroviral (ARV) medications that need to be dose-adjusted based on renal function include: didanosine, emtricitabine, lamivudine, stavudine, tenofovir, zidovudine and truvada (emtricitabine and tenofovir).

Fixed dose combination drugs, including Atripla, Complera, Combivir, Epzicom/Kivexa, and Trizivir, should be substituted by the dose-appropriate individual component drugs.

Liver insufficiency

In the setting of liver insufficiency, medications should be monitored closely for hepatotoxicity. ARV medications that can cause hepatotoxicity or should be used cautiously include nevirapine, high-dose ritonavir, and tripanavir. Other medications, including fluconazole, isoniazid, and acetaminophen, should be used very cautiously as well.

All HIV-infected individuals should be tested for HBV, HCV and HAV infection and immunity. Among HIV/HCV co-infected individuals, liver disease is now the leading cause of death, having surpassed AIDS-related illnesses. The decision to initiate treatment for Hep B or Hep C in the setting of HIV infection is complicated, and specialist consultation is recommended.

Systolic/diastolic heart failure

No change in standard management.

Peripheral vascular disease (PVD)/coronary artery disease (CAD)

Patients with HIV are at increased risk for CAD due to HIV infection (as shown in SMART trial) and from ARV medications (D:A:D trial). HIV increases the likelihood of dyslipidemia and insulin resistance, and ARV meds also contribute to dyslipidemia. However, the risk of HIV-related CAD (from no ARV treatment) likely outweighs the risk of ARV-related CAD. Otherwise there is no change in standard management.

Diabetes/endocrine

Along with traditional risk factors (obesity, family history) and comorbidities, certain ARV medications can lead to hyperglycemia and increase the risk of diabetes. In particular, some PIs and prolonged NRTI exposure have been implicated. Consider treatment regimens without a PI (NNRTI instead) or a PI with a favorable metabolic profile. Otherwise there is no change to standard management.

Other endocrine: ritonavir is a potent inhibitor of CYP 450 3A4, which happens to be the same target for fluticasone (inhaled or intranasal). When taken concomitantly, patients can develop significant steroid accumulation, adrenal suppression, and Cushing's syndrome. Consider a significant dose reduction of fluticasone, substituting a safer steroid (such as budesonide, beclomethasone, flunisolide, or triamcinolone), changing to oral montelukast, or substituting ritonavir. At a minimum, patient receiving ritonavir and any form of steroids should be monitored for both steroid accumulation and withdrawal.

Immunosuppression

Depending on CD4 levels or evidence of AIDS defining illnesses, HIV-infected individuals are at increased risk of opportunistic infections (OIs). Prophylaxis is given to prevent a first episode (primary prophylaxis) or recurrence of an OI (secondary prophylaxis). Prophylaxis is continued until CD4 counts improve and remain stable for a certain duration, usually anywhere from 3-12 months, depending on primary or secondary prophylaxis.

Table I reflects general guidelines for management; please consult a specialist as needed for specific management issues.

Table I.

General guidelines for management of opportunist infections.
Opportunistic infection CD4threshold Recommended regimen Alternative regimen Comments
Pneumocystis Pneumonia <200 TMP-SMX DS daily; TMP-SMX SS daily; TMP-SMXDS TIW Dapsone 100mg daily or50mg BID Dapsone - checkG6PD before starting
Toxoplasmosis <100 TMP-SMX DS daily TMP-SMX SS daily;TMP-SMX DS TIW;Dapsone 50mg daily +Pyrimethamine 50mg/folinic acid 25mg wkly;Atovaquone 1.5g daily No need to treat ifToxo IgG Abnegative.
Mycobacteriumavium complex <50 Azithromycin 1.2g weekly;Azithromycin 600mg BIW;Clarithromycin 500mg BID Rifabutin 300mg daily Caution: rifabutinand clarithromycinhave many druginteractions; evaluatebefore starting

In addition to the above opportunistic infections, HIV-infected individuals are at risk for fungal infections depending on their geographic region, their degree of environmental exposure, and positive serologies confirming exposure. The guidelines below can be considered for individuals who meet the above criteria. Again, specialist consultation may be warranted for specific management considerations. (SeeTable II)

Table II.

Guidelines for management of opportunistic mycoses
>Opportunisticinfection orpositive serology CD4threshold Recommended regimen Alternative regimen Comments
Histoplasmosis <150 Itraconazole 200mg daily Caution: Itraconazolehas many druginteractions; evaluatebefore starting
Coccidioides <250 Fluconazole 400mg daily;Itraconazole 200mg BID

With regards to organ transplants and immunosuppression in HIV-infected individuals, there is no change in standard management other than to account for any drug-drug interactions with immunosuppressive medications.

Primary lung disease

For patients with airway disease, as noted in the Endocrine section, ritonavir is a potent inhibitor of CYP450-3A4, which happens to be the same target for fluticasone (inhaled or intranasal). When taken concomitantly, patients can develop significant steroid accumulation, adrenal suppression, and Cushing's syndrome. Patients need to be assessed for bacterial and other infections, particularly OIs.

Tuberculosis (TB) is the leading cause of death in patients with HIV worldwide. Patients with HIV and latent TB infection are 20-30 times more likely to have TB reactivate compared to the general population and precautions should be taken to evaluate HIV-infected patients with pulmonary disease. Additionally, pneumococcal pneumonia risk is 150-fold higher than the general population and may cause repeated episodes of lung infection.

GI/Nutritional Issues

Patients with HIV should be carefully screened for any oral disease and gastrointestinal (GI) malignancies, especially anal carcinoma for those co-infected with HPV/HIV. Involuntary weight loss is associated with disease progression and is an independent predictor of death.

Hematologic/coagulation

Patients with HIV often have a macrocytosis without anemia. This can also be seen with ART, particularly zidovudine and stavudine.

While yet to be well established, it appears that HIV-infected individuals are at slightly increased risk of venous thromboembolism compared to the general population.

Dementia/psychiatric illness

Altered mental status:a patient with HIV presenting with altered mental status has a broad range of biologic causes which need to be ruled out, including psychological disorders, substance abuse, metabolic derangements, infections (systemic versus CNS), malignancy, medications (of note, some ARV medications, especially Efavirenz, can cause delirium), and toxicology.

The HIV-related neurocognitive disorders, which include minor cognitive motor disorder (MCMD) and HIV-associated dementia (HAD), are both considered AIDS-defining conditions, and are diagnoses of exclusion. HIV is a neurotropic virus and enters the brain with infection where it can lead to deficits in cognition, behavior and motor functioning. MCMD and HAD reflect the clinical effects of this process, respectively reflecting increasing severity.

ART is the treatment of choice for HIV-associated neurocognitive disorders, and can reverse effects of disease. Appropriate ART that maintains low viral loads is optimal. By suppressing HIV RNA in the serum, you can often decrease HIV in CNS; however, limited data suggest ARV medications with good CNS penetration can be more effective in treating HAD. These include abacavir, emtricitabine, zidovudine (NRTIs); nevirapine (NNRTI); indinavir/ritonavir and lopinavir/ritonavir (PIs) and maraviroc (CCR5 antag).

Depression/anxiety: check for interactions between ARV and anti-depressant medications. PIs (including ritonavir-boosted PIs) in particular need careful monitoring. Ritonavir affects cytochrome P450 and can often significantly increase serum levels of tricyclic antidepressants, leading to potential toxicity (routine TCA blood level monitoring recommended). Most antidepressants should be started at low dosages and titrated slowly.

Conversely, some PIs decrease paroxetine, sertraline, and bupropion levels; efavirenz also lowers sertraline and bupropion levels. St John's Wort decreases many ARV serum levels - it should be avoided.

PIs and NNRTIs increase blood concentration of many benzos: start low and titrate. Note that midazolam is contraindicated with PIs, efavirenz and delavirdine.

Transitions of care

A) Sign-out - patients should continue on ART unless there is a specific contraindication.

B) Anticipated length of stay - pending work-up to ensure no other infectious processes present (OIs, TB etc. as indicated). Hospital stay may depend on patient's access to follow-up care.

C) Readiness for discharge - when appropriate treatment plan has been instituted.

D) Arranging clinical follow-up:

  • When/with whom (general medicine physician - preferably with certification in HIV medicine; infectious disease; case management - patients without insurance may be eligible for the AIDS Drug Assistance Program (ADAP) for medications and other funds (Ryan White Federal Funds) for care. HIV support/counseling is helpful as many patients may also be dealing with adjustment disorder, other psychiatric illness, or drug/alcohol addiction issues.

  • Tests prior to discharge. See below.

  • Outpatient tests prior to clinic visit: complete blood count (CBC) with differential, basic metabolic panel (BMP), liver function tests (LFT), hepatitis A antibody, hepatitis C antibody, hepatitis B surface antibody (HBV sAb), hepatitis B surface antigen (HBV sAg), hepatitis B core antibody (HBV cAb), toxoplasma antibody immunoglobulin G (IgG), rapid plasma reagin (RPR), urinalysis, HIV viral load, HIV genotype, CD4 count, chlamydia/gonorrhea screen.

E) Placement considerations - none specifically. If non-home placement, then likely PPD required (place on hospital day 1).

F) Prognosis and patient counseling - patients diagnosed with HIV need intensive support and education about the diagnosis, course of disease progression, prognosis, risk/benefit of ART treatment. Counseling should include safe sex/safe injection techniques. In the acute HIV stage, patients are highly infectious and need to be counseled about high risk of infecting others.

Patient safety/quality measures

A) Core indicator standards and documentation - The Health Resources and Services Administration HIV/AIDS Bureau created sets of performance measures to help monitor quality of care. The Core Clinical Performance Measures for Adults and Adolescents below comprises three groups of measures which are organized by strength of clinical guidelines. Each measure is reported as a percentage of clients/patients who meet the recommended guideline.

Group 1

  • Pregnant women with HIV prescribed ART

  • CD4 measurements at least twice a year

  • Medical visits in HIV care setting at least twice a year

  • ART therapy prescribed for patients with AIDS

  • CD4 count less than 200 prescribed pneumocystis pneumonia prophylaxis

Group 2

  • Adherence assessment and counseling at least twice yearly

  • Cervical cancer screening yearly

  • Hepatitis B vaccination

  • Hepatitis C screening at least once

  • HIV risk counseling yearly

  • Lipid panel yearly

  • Oral examination by dentist at least once yearly

  • Syphilis screening yearly

  • Tuberculosis screening since HIV diagnosis

Group 3

  • Chlamydia/gonorrhea screening yearly for patients at risk for sexually transmitted infections

  • Hepatitis B screening

  • Alcohol counseling for HIV-infected patients with hepatitis B or C

  • Influenza vaccination yearly

  • CD4 count less than 50 prescribedMycobacterium avium complex (MAC) prophylaxis

  • Mental health screening

  • Pneumococcal vaccination

  • Substance use screening

  • Tobacco cessation counseling yearly

  • Toxoplasma screening at least once since HIV diagnosis

B) Prophylaxis/other measures to prevent readmission - no change in standard management.

  • Vaccines: avoid live vaccines unless benefit outweighs risk. In general, vaccines may not be effective - and for live vaccines, safe - unless CD4 count is greater than 200. If vaccines are given when the CD4 count is less than 200, consider follow-up vaccination when CD4 rises above 200 or evaluating for immunity before considering re-vaccination.

  • Pneumococcal: all patients around time of diagnosis; one-time repeat vaccination 5 years later.

  • Influenza: all patients; yearly (most effective when CD4 > 100; live vaccine contraindicated).

  • Hepatitis B: all patients unless documented immunity or active infection (surface antigen + or core antibody+ with HBV viremia). High dose (40mcg) vaccine likely improves immune response. Monitor response (HBV sAb).

  • Hepatitis A: consider for all; recommended for liver disease, IV drug use, MSM, international travel, hemophilia. Monitor response (HAV Ab).

  • MMR (live vaccine): for all non-immune with CD4 greater than 200; contraindicated with CD4 less than 200.

  • VZV (live vaccine): consider for non-immune with CD4 greater than 200; contraindicated with CD4 less than 200. Monitor for infection, treat with acyclovir as needed. VZ immune globulin for non-immune patients with recent (<96 hours) exposure.

  • Human papillomavirus (HPV): per usual guidelines (female or male age 9-26). Limited data with HIV population; no data for preventing anal dysplasia.

  • TDaP/Meningococcal: per usual guidelines.

  • Guidance: medication adherence and ART.

B. Common Pitfalls and Side-Effects of Management of this Clinical Problem

A common pitfall in the diagnosis of HIV is failure to re-check HIV ELISA when acute HIV seroconversion is suspected (i.e. just testing once). Other tests may be helpful in acute HIV infection before seroconversion such as nucleic acid amplification testing (like PCR viral load test or bDNA viral load test).

Another pitfall includes checking CD4 counts before the establishment of HIV as a diagnosis. CD4 counts are very helpful to establish disease severity and patient risk once HIV has been diagnosed, however checking CD4 counts on their own (based on suspicion for opportunistic infection etc.) is of little clinical benefit. In addition, in the setting of acute bacterial infection, CD4 counts may be falsely low and not a good indicator of immune status.

Immune reconstitution inflammation syndrome (IRIS) - starting ART will improve the immune system's response to pathogens, including partially or successfully treated OIs or previously undiagnosed OIs, and potentially release inflammatory mediators. A small percentage of patients will be diagnosed clinically with IRIS; an exacerbation of partially or fully treated OI, or unmasking of a sub-clinical OI. IRIS develops in response to many pathogens, notablyMycobacteria tuberculosis (TB),Mycobacterium avium complex (MAC), cytomegalovirus,Cryptococcus neoformans, Pneumocystis pneumonia (PCP), Toxoplasmosis, hepatitis B and Varicella zoster virus (VZV). IRIS is seen weeks to months after the initiation of ART, and usually in the context of a marked rise in CD4 count from low pre-treatment levels (CD4 <100).

Severity can vary significantly, but rarely is IRIS fatal. Mainstay of treatment is to continue ART if possible, treating opportunistic infections as indicated and starting anti-inflammatory medications (non-steroidal anti-inflammatory drugs, steroids) as needed. Consult with a specialist for questions about timing for initiation of ART in setting of active opportunistic infections. Ideally, ART should be started within 2 weeks of an AIDS defining illness. Of note, IRIS is not unique to HIV and can be seen with treatment of other infectious diseases.

What's the evidence?

El Sadr, WM, Lundgren, JD, Neaton, JD. "Strategies for Management of Antiretroviral Therapy (SMART) Study Group. CD4+ count-guided interruption of antiretroviral treatment". N Eng J Med.. vol. 355. 2006. pp. 2283-2296.

Friis-Moller, N, Reiss, P, Sabin, CA. "D:A:D Study Group. Class of antiretroviral drugs and the risk of myocardial infarction". N Eng J Med.. vol. 356. 2007. pp. 1723-1735.

Mahlab-Guri, K, Asher, I, Gradstein, S, Zung, A, Radian-Sade, S, Elbirt, D, Sthoeger, Z. "Inhaled fluticasone causes iatrogenic cushing's syndrome inpatients treated with ritonavir". J Asthma.. vol. 48. 2011. pp. 860-863.

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