HIV/AIDS BOARD REVIEWHarold Henderson, MD

DiagnosisNatural HistoryClinical ManifestationsDrug Therapy, Toxicity, InteractionsOpportunistic Infections-diagnosis, treatment, prophylaxis

Sample Test Question

A 57 y/o healthy adult female with hypertension and diabetes comes to your office for a routine followup appointment. She takes HCTZ and follows an ADA diet for her diabetes. She feels well and has no complaints. She received the influenza vaccine from MSDH 3 days ago. You order HIV serology for routine screening, and the result is a positive EIA but an indeterminate Western Blot. The best explanation for this result is: 1. chronic asymptomatic HIV infection2. acute HIV infection3. lab error4. false positive EIA related to the influenza vaccine

DIAGNOSIS

EIA-sensitivity/specificity 99%; antibodies usually detectable within 2-6 weeks of acute infection; virtually 100% reactivity by 6 monthsNeeds to be confirmed with Western Blot or IFA; indeterminate results may be due to acute infection period Causes of false negative EIA-acute infection (“window” period)Causes of false positive EIA-hematologic malignancies, autoimmune disorders (SLE), + RPR, influenza and Hep B vaccinationOther tests: oral (rapid) test; home test; p24 antigen (may be detectable early in acute infection but <50%); PCR-can be used but false positive and negative rates are too high as screening toolNeonatal diagnosis-maternal antibodies cross placenta and may be detectable for >one year, PCR is test of choice

Sample Test Question

A 23 y/o male is evaluated in the ER with fever-101°, nausea, malaise and a diffuse, erythematous maculopapular rash for about 3 days. He denies the use of IV drugs but has multiple sexual partners and says “I usually use condoms.” He lives in Jackson and works at a local Target, has always been healthy and takes no meds. PE is normal except for painless, bilateral, 1x2 cm cervical adenopathy. Labs are unremarkable except for a platelet count of 77,000. The best diagnostic test to order is: 1. HIV serology2. HIV p24 antigen3. PCR HIV quantitative (viral load)4. measles serology

ACUTE HIV INFECTION SYNDROME

Common signs/symptoms (>50%)-fever, adenopathy, pharyngitis, rash (erythematous maculopapular), myalgiasLess common-headache, nausea/vomiting, hepatosplenomegaly, weight loss, thrush, neurologic symptoms (aseptic meningitis, meningoencephalitis, Guillain-Barre syndrome), thrombocytopeniaEIA usually negative, PCR is test of choice

Sample Test Question

A 30 y/o HIV+ male is followed by you as his primary care provider. He is asymptomatic and feels well, has a full time job. Lab results (on two separate occasions) include CD4 counts-576 & 553, and viral loads-36,000 & 59,000. He is interested in starting HAART if you recommend it. Which of the following is the best treatment plan?1. Start tenofovir/emtricitabine/efavirenz (Atripla).2. Delay starting HAART, and follow with repeat CD4s and viral loads every

3-4 months.3. Start zidovudine/lamivudine (Combivir).4. Start trimethoprim/sulfamethoxazole as PCP prophylaxis, and follow

every 3-4 months.

Antiviral Therapy- When to Start HAART

Status Recommendation

Symptomatic HIV Start therapy for alldisease patients

Asymptomatic Start therapyCD4<500

Asymptomatic CD4 > 500 Start therapy

Anti-HIV Drug Regimens

Minimum number of active drugs is three per combinationUsually two NRTIs and one NNRTI (such as AZT/lamivudine/efavirenz) or two NRTs and one protease inhibitor (such as abacavir/lamivudine/lopinavir-ritonavir)PI boosting with ritonavir-commonly done to increase levels of the PI; ritonavir does not count as an antiviral drug in the combination; example: AZT, lamivudine, atazanavir/ritonavir is a 3-drug combination Resistance testing used to help choose initial regimen and to guide salvage regimens after drug failure

Current ARV MedicationsNRTI Abacavir (ABC) Didanosine (ddI) Emtricitabine (FTC) Lamivudine (3TC) Stavudine (d4T) Tenofovir (TDF) Zidovudine (AZT, ZDV)

NNRTI Delavirdine (DLV) Efavirenz (EFV) Etravirine (ETR) Nevirapine (NVP) Rilpivirine (RPV)

PI Atazanavir (ATV) Darunavir (DRV) Fosamprenavir (FPV) Indinavir (IDV) Lopinavir (LPV) Nelfinavir (NFV) Ritonavir (RTV) Saquinavir (SQV) Tipranavir (TPV)

Integrase Inhibitor (II) Dolutegravir (DTG) Elvitegravir* (EVG) Raltegravir (RAL)

Fusion Inhibitor Enfuvirtide (ENF, T-20)

CCR5 Antagonist Maraviroc (MVC)

May 2014 www.aidsetc.org9

* EVG currently available only in coformulation with cobicistat (COBI)/ TDF/FTC

Preferred HAART Regimens for Initial Therapy

Tenofovir/emtricitabine/efavirenz (Atripla)Tenofovir/emtricitabine/atazanavir/ritonavirTenofovir/emtricitabine/darunavir/ritonavirTenofivir/emtricitabine/raltegravirTenofovir/emtricitabine/elvitegravir/cobicistatTenofovir/emtricitabine/dolutegravirAbacavir/emtricitabine/dolutegravir

Sample Test QuestionA 24 y/o HIV positive female, 15 weeks pregnant, is referred to you for medical therapy by her obstetrician, who plans to manage her pregnancy but is not familiar with HIV care. She was recently diagnosed, is asymptomatic, has no other significant past medical history and takes no medications. Lab results include a CD4-535 and a viral load-26,000. An HIV drug susceptibility test shows no drug resistance. Regarding HIV care during her pregnancy, the following is the best plan:1. She is asymptomatic with a good CD4 count, HAART is not indicated.2. Start zidovudine (AZT) 300 mg BID.3. Start tenofovir/emtricitabine/efavirenz (Atripla)4. Start zidovudine/lamuvidine (Combivir) and lopinavir/ritonavir

(Kaletra)

HIV and Pregnancy

Perinatal transmission of HIV is absence of HAART is 20-30%HAART decreases transmission to <2-3%, all pregnant HIV-infected women should be on HAART after the first trimesterDo not use efavirenz-?teratogenic

Sample Test Question

A 25 y/o male with AIDS (he is asymptomatic but has a CD4 count-153, viral load-49,900) is started on zidovudine/lamivudine (Combivir) and efavirenz (Sustiva) as HAART, and TMP/SMZ (Bactrim) SS-one tablet daily as PCP prophylaxis. He returns for followup 8 weeks later. He has no complaints except for very pronounced fatigue for the past two weeks. Lab findings now include a Hct-21 (decreased from 34 six weeks ago), MCV-107, WBC-3.9, a platelet count of 149,000, viral load-undetectable, and a negative FOBT. The following is the best treatment plan:1. Zidovudine should be stopped, another NRTI should be started in its

place, and he should receive a blood transfusion.2. TMP/SMZ should be stopped, monthly aerosolized pentamidine

should be started, and he should receive a blood transfusion.3. The same medications are continued, and he should receive a blood

transfusion.4. Blood should be obtained for B12 and folate levels, and then he

should receive a blood transfusion.

Individual NRTI Toxicity-Hematologic

AZT-anemia and/or neutropeniaTypically early (2-6 weeks), but may occur later in course of therapyMay be severe More common in advanced disease with pre-existing bone marrow suppressionGenerally resolves with drug discontinuation, but resolution may be quite slow

NRTI-Hypersensitivity

Abacavir, up to 5% incidenceGenerally occurs within first 8 weeksCharacterized by fever, fatigue, nausea, maculopapular rash, with myalgias, cough and dyspnea less commonSymptoms occur over several days, and may increase with each dosePredicted by HLA B5701 haplotypeTreatment-discontinue the drugRechallenge may be life-threatening

NRTI-Nephrotoxicity

Tenofovir may cause proximal renal tubular dysfunctionOccasional decrease in creatinine clearanceToxicity is usually mild (average increase in creatinine 0.15) and does not require drug discontinuationSevere nephrotoxicity uncommon (<5%) but does happenAvoid use in patients with pre-existing renal dysfunction?Use in diabetics and hypertensives

Sample Test QuestionA 37 y/o HIV infected male is admitted from the ER with nausea, vomiting and abdominal pain for 3 days. HIV infection was diagnosed two years ago. He has no other illnesses, has never had an AIDS-defining illness, and on his most recent clinic followup visit one month ago his viral load was undetectable and his CD4 count was 415. He drinks a glass of wine “occasionally” and does not smoke. His medications are tenofovir 300mg qday, didanosine 400mg qday, atazanavir 300mg qday, and ritonavir 100mg qday. Physical exam findings include orthostatic hypotension and diffuse epigastric tenderness. Lab results include a lipase-1163, ALT-177, AST-129, and normal bilirubin. Which of the following statements is best regarding his condition?1. He has tenofovir-induced pancreatitis.2. He has alcohol-induced pancreatitis.3. He has HIV enteropathy.4. He has didanosine-induced pancreatitis.

NRTI-GI Toxicity

Pancreatitis-didanosine, uncommon (0.5-5%) but potentially serious; be aware of interaction between ddI and tenofovir (dose of ddI needs adjusting)Hepatotoxicity

1) Mitochondrial toxicity with hepatic steatosis-AZT, stavudine, didanosine

2) Abacavir hypersensitivity3) Hepatitis B flares-withdrawal or development of

resistance to tenofovir, lamivudine, or emtricitabine

Test QuestionA 30 y/o HIV positive male has been on tenofovir/emtricitabine/ indinavir/ritonavir for 14 months. He has never had any other medical problems. He has been asymptomatic, his viral load has gone from its baseline of 114,000 to undetectable and his CD4 count has increased from 258 to 433. He now c/o nausea, right flank pain and gross hematuria for two days, no fever. He had normal baseline renal function, but labs now show WBC-6.1, BUN-37 and creatinine-2.2. Urinalysis shows hematuria. The following is the best statement about his condition:1. He most likely has HIV-induced renal failure and should be referred

to a nephrologist.2. He has tenofovir-induced nephrotoxicity, and the drug should be

stopped.3. He has indinavir-induced nephrotoxicity due to nephrolithiasis, and

the drug should be stopped.4. He most likely has a urinary tract infection. His HAART meds should

be continued, and he should be started on empiric antibiotics pending results of a urine culture.

TOXICITY-INDIVIDUAL PROTEASE INHIBITORS

Indinavir (Crixivan)-nausea, diarrhea, nephrolithisis/nephrotoxicity in 10-20%Ritonavir (Norvir)-nausea, diarrhea, circumoral paresthesias 5-10%Nelfinavir (Viracept)-diarrheaKaletra, fosamprenavir (Lexiva), tipranavir (Aptivus)-GI intoleranceatazanavir (Retataz)-increased indirect bilirubin, nephrolithiasis (uncommon)

Sample Test Question

A 33 y/o HIV positive female has been in good health on HAART (stavudine/lamivudine/lopinavir/ritonavir) for three years. Her most recent CD4 is 345 with an undetectable viral load 8 weeks ago. However she now complains of has 3 weeks of worsening fatigue, anorexia, and nausea, and she has lost 12 lbs during that time. Physical exam is unremarkable. Initial lab results include an AST-111, ALT-128, total bilirubin-0.8, lipase-126, Na-138, K-3.8, Cl-102, CO2-16, BUN-24, creatinine-1.4 and a normal CBC. The best diagnostic test(s) at this time is:1. CT of the abdomen/pelvis2. CK and aldolase levels3. Arterial Blood Gases4. lactic acid level

Lactic Acidosis Syndrome

Symptomatic disease uncommon, 0.5-1/100 patient years of NRTI exposureMost strongly associated with d4T(stavudine) and d4T/ddI use; other risk factors are pregnancy, ddI (didanosine) with ribavirin or hydroxyureaNon-specific symptoms: fatigue, nausea, vomiting, diarrhea, abdominal discomfort or distention; hepatic steatosisHigher lactic acid levels (>10mM) have worse prognosisTherapy: stop “d” drug, supportive care, ?vitaminsNo value to monitor lactic acid in absence of symptoms

Sample Test Question

A 35 y/o male with AIDS (last CD4-97) is in your care. He also has peripheral neuropathy and hyperlipidemia. His medications are tenofovir/emtricitabine/efavirenz (Atripla), TMP/SMZ (Bactrim), simvastatin, and gabapentin. He now c/o myalgias, anorexia and fatigue for two weeks. Lab results include total cholesterol-235, LDL-161, AST-205, ALT 187, and CK-851. The best plan at this time is:1. Increase simvastatin dose for better treatment of his hyperlipidemia.2. Stop simvastatin because on interaction with efavirenz is causing drug

toxicity.3. Stop tenofovir because of tenofovir-related hepatotoxicity.4. Stop tenofovir because of tenofovir-related myopathy.

Drug Interactions and Anti-HIV Agents

Lipid-lowering agents (statins)PIs, efavirenz (statin)use pravastatin or rosuvastatin (minimal) or atorvastatin (moderate)

Anticonvulsantsphenytoin, carbamazepine, phenobarbital-monitor levelsmost PIs

Miscellaneousmethadone-some PIs, nevirapine, efavirenzsildenafil, vardenafil-most PIswarfarin-most PIs, efavirenz

Drug Interactions and Anti-HIV AgentsAntifungals• itraconazole-most PIs ( itra), nevirapine and efavirenz ( itra)• voriconazole-ritonavir, efavirenz ( vori)Antimycobacterials rifampin-all PIs, nevirapine, rifabutin-all PIs, nevirapine, efavirenz (but <rifampin) clarithromycin-most PIs, nevirapine, efavirenz

Oral contraceptives most PIs, nevirapine, efavirenz

PCP (Pneumocystis jiroveci)-Clinical featuresUsually a CD4 < 200, co-existent thrush commonSub-acute presentation (weeks)Common symptoms-fever, weight loss, progressive DOE, coughHypoxemiaCXR-bilateral, interstitial infiltrates most common; normal, pneumothorax less commonDiagnosis-induced sputum (poorly sensitive), BAL >95% sensitivity; LDH and galactomannan may also be useful

PCP-Treatment

Preferred-Trimethoprim/sulfamethoxazole 15-20 mg/kg/day in 3-4 divided doses IV or oral (Bactrim DS two tabs TID PO)Hypoxemia-use steroids if room air PO <70mm or A-a gradient >35mmResponse to therapy may be slow (5-7 days)Alternatives:trimethoprim/dapsonepentamidine IVclindamycin/primaquineatovoquone

Tuberculosis

Much more common in setting of HIV diseaseMay have typical pulmonary TB at higher CD4 counts, atypical presentation very common at CD4 <100-extrapulmonary/disseminated TB and CXR may show infiltrates or miliary pattern without cavitationDiagnosis with AFB smears/culture/biopsyHigh false-negative rate with PPDTreatment-4 anti-TB drugs to start; beware of rifampin and drug interactionsResponse to therapy similar to HIV negative persons

OPPORTUNISTIC INFECTION QUESTION

A 36 y/o HIV infected male, CD4-33, is brought to the ER with 5 days of fever and headache. He has not been in care for more than one year and is taking no meds. He is lethargic on exam and has white patches on his tongue and buccal mucosa. An MRI of the head shows focal, enhancing lesions with surrounding edema-2 in right parietal lobe and one in left basal ganglia. The best evaluation/treatment plan is:1. Obtain an LP to evaluate for cryptococcal meningitis.2. start pyrimethamine and sulfadiazine3. consult neurosurgery for brain biopsy4. start HAART as therapy for AIDS-related PML

CNS TOXOPLASMOSIS

Most common cause of brain abscessCD4 usually <100Common presentation-fever, headache, altered mental status, focal neurologic deficits, seizureDiagnosis: Toxo serology positive in 95%; CNS imaging usually shows multiple, bilateral, ring-enhancing lesions; single lesions may be confused with lymphomaTreatment: pyrimethamine/sulfadiazine leucovorin, dexamethasone for mass effect due to edema; alternatives include pyrimethamine/clindamycin and BactrimClinical and/or radiographic improvement in 1-2 weeks

CRYPTOCOCCAL MENINGITIS

Most common cause of meningitisExtra-meningeal disease less common, sometimes with papular skin lesionsCD4 usually <100Usual presentation-subacute with fever, headache, altered mental status, seizureDiagnosis-CSF crypto antigen, culture, India Ink smear; blood cultures; serum CAG positive in >95%Treatment-initial (7-14 days) period of amphotericin with flucytosine, followed by fluconazole 400 mg qday x 8 weeks, then to 200 mg qdayElevated intracranial pressure-common, important cause of morbidity and mortality; treat with serial LPs or VP shunt

CMV DISEASE

Retinitis most common, CD4 usually <50Common presentation-floaters, visual field defect, loss of visual acuityDiagnosis via funduscopic exam by ophthalmologistTreatment: valgancyclovir 900 mg BID P0 x 14-21 days (systemic therapy required) with or without intraocular gancyclovir implant; alternatives include gancyclovir, foscarnet, and cidofovir; avoid AZTCMV GI disease: usually esophagitis or colitis, biopsy for diagnosis, treat with valgancyclovirCMV neurologic disease:encephalitis: lethargy, confusion, fever; dx-CMV PCR of CSFradiculopathy: rapidly progressive leg paresis, bowel and bladder dysfunction

PML-Polymorphonuclear Leukoencephalopathy

Caused by JC viral infection of CNSCD4 usually <200Common presentation-progressive cognitive and motor dysfunction over weeks to months; no feverMRI of head shows hypodense lesions of white matter; CT not as sensitiveDiagnosis: compatible clinical syndrome and imaging study with positive JC viral PCR of CSF (sensitivity-80%); also brain biopsyTreatment-HAART; no effective direct treatment known

Candidiasis and HIV Infection

Oral candidiasis-very common, CD4 usually <300; can be treated with local or systemic antifungal therapy; avoid chronic, daily use of azolesEsophageal candidiasisthrush usually present, CD4 usually <100Symptoms: dysphagia, usually no fever; odynophagia suggests esophageal ulcerationTreatment: fluconazole 200 mg daily for 14-21 days, response usually within 7 daysAlternatives for fluconazole-refractory disease include itraconazole elixir PO, IV amphotericin B or IV caspofungin

DISSEMINATED MAC-MYCOBACTERIUM AVIUM COMPLEX

Usually CD4 <50Typical presentation-subacute fever, night sweats, weight loss, diarrhea, anemia and neutropeniaDiagnosis via culture from blood or visceral organ; positive MAC cultures of sputum or stool document colonization onlyTreatmentHAART clarithromycin plus ethambutol plus/minus rifabutin, prolonged therapy necessarywatch for clarithromycin or rifabutin drug interactions

DISSEMINATED HISTOPLASMOSIS

CD4 usually <200Common symptoms include fever (may be up to 105°), fatigue, weight loss, nausea and diarrheaMultiorgan disease with lung, CNS, GI tract, liver, or bone marrow involvementDiagnosis-cultures of blood or BM, visualization of organisms in peripheral blood or BM biopsy, urine Histo antigen (>90% sensitive)Treatment:severe disease: amphotericin B initially, followed by itraconazolemild to moderate disease: itraconazole 200 mg BID x 8-12 weeks, then to 100 mg BID as maintenance

HERPES SIMPLEX

Any CD4 countOrolabial and genital ulcerative lesions common; with advanced AIDS lesions may be more extensive, and may disseminateDisease tends to be more extensive and refractory to therapy in AIDSTreatment:acyclovir 400 mg TID for 7-10 days for typical lesions, famcyclovir or valacyclovir also effectiveSevere disease: may need IV therapy initially, more prolonged courseacyclovir-resistant disease-foscarnet IV or cidofovir IVvisceral organ involvement/encephalitis-high-dose acyclovir IVchronic suppressive therapy for frequent recurrences or advanced AIDS

HIV-RELATED MALIGNANCIES

Kaposi’s sarcoma-caused by HHV-8, CD4 usually <300, brown/violaceous skin macules/nodules, may cause visceral organ involvement, much less common in HAART eraCervical cancer-associated with HPV, regular screening PAP smears in women recommended to monitor for dysplasiaNon-Hodgkin’s Lymphoma-CD4 usually <100, associated with EBV, often high-grade, multiple presentations possible including primary effusion lymphoma, prognosis much better in HAART eraCNS Lymphoma-CD4 usually <50, associated with EBV, MRI-irregular enhancing lesions often single by may be multiple usually in periventricular or periependymal areas, thallium SPECT scan helpful

OIs-PRIMARY PROPHYLAXIS

PCPrisk: CD4 <200, prior PCP or thrush preferred: TMP-SMX qdayalternatives: dapsone 100 mg qday, weekly dapsone/pyrimethamine, aerosolized pentamidine monthly, atovaquone qdayimmune reconstitution: stop prophylaxis if CD4 >200 for >3 months

• TBrisk: positive PPD (>5mm) or recent close contactpreferred: INH x 9 months

OIs-PRIMARY PROPHYLAXIS

Toxoplasmosisrisk: CD4 <100 plus positive Toxo serologypreferred: TMP-SMX qdayalternatives: dapsone plus pyrimethamineimmune reconstitution: stop prophylaxis if CD4 >200 for >3

months•Disseminated MAC

risk: CD4 <50preferred: azithromycin 1200 mg qweek or Biaxin 500 mg BIDalternative: rifabutin 300 mg qdayimmune reconstitution: stop prophylaxis if CD4 >100 for >3

months