OverviewHuman immunodeficiency virus (HIV) is a retrovirus that depletes the helper T-lymphocytes (CD4 cells), resulting incontinued destruction of the immune system and subsequent gradual development of opportunistic infections andmalignancies.Acquired immune deficiency syndrome (AIDS) is HIV with a CD4 count lower than 200 cells/mm3or a history ofopportunistic infection (e.g., unexplained fever for more than 2 weeks, thrush, Pneumocystis jiroveci pneumonia,toxoplasmosis, cryptococcal meningitis, histoplasmosis, Mycobacterium avium).EpidemiologyAt the end of 2007, global estimates of children and adults with HIV/AIDS were as follows:People living with HIV/AIDS: 33 millionNew HIV infections in 2007: 2.7 millionDeaths attributable to HIV/AIDS in 2007: 2 millionCumulative number of deaths attributable to HIV/AIDS: 33 millionComplete current world epidemiology can be found at www.unaids.org.At the end of 2006, estimates of children and adults with HIV/AIDS in the United States were as follows:People living with HIV/AIDS: 850,000–950,000New HIV infections in 2006: 56,300Deaths attributable to HIV/AIDS in 2006: 19,454Cumulative number of deaths attributable to HIV/AIDS: 549,594People who do not know they are infected with HIV: 180,000–280,000Complete current U.S. epidemiology can be foundatwww.cdc.gov/hiv/topics/surveillance/resources/slides/epidemiology/index.htm.HIV has two common subtypes:HIV-1: most commonly found in the United StatesHIV-2: most commonly found in AfricaClinical PresentationPatient has an opportunistic infection.Patient is not ill but has tested positive for HIV.Patient has acute retroviral syndrome:o 50% to 90% of patients acutely infected with HIV experience some of the symptoms.o Symptoms generally appear 2–4 weeks after virus exposure.
o Duration of the clinical syndrome is about TPV-RTV)14 days (the range is a few days to > 10weeks).o The disease is not readily recognized in the primary care setting because its symptoms are similarto those of the flu, mononucleosis, and other common illnesses.Testing RecommendationsThe U.S. Centers for Disease Control and Prevention recommend the following HIV testing in health care settings:Routine, voluntary, opt-out HIV screening for all persons 13–64 years of age in health care settings. Testingis not based on risk factors.HIV screening of pregnant women as part of the routine panel of prenatal screening tests. Testing is notbased on risk factors.Repeat HIV screening of persons with known risk at least annually:o Injection drug users and their sex partnerso Persons who exchange sex for money or drugso Sex partners of HIV-infected personso Men who have sex with meno Heterosexual persons who themselves or whose sex partners have had more than one sex partnersince their most recent HIV testPathophysiologyHIV is a retrovirus that replicates in and destroys CD4 cells. The result is a chronically deteriorating immune systemleading to opportunistic infections and eventual death. Seroconversion typically occurs about 3 weeks after the acuteinfection (the range is from 2 weeks to 6 months). Antibodies generally appear within 3 months of infection (the rangeis from 2 weeks to 6 months).Transmission is through infected blood or hazardous body fluids, which can occur during the following activities:Unprotected sexual contact with an infected persono Multiple partners increase risk.o Ongoing or past medical history of sexually transmitted disease increases risk.Sharing needles or syringes with an infected personTransfusions of infected blood or blood clotting factors (the United States began screening the blood supplyin 1985)Vertical transmission (infected mother to infant)Breast-feedingOccupational exposure and household contact are rare.Diagnostic CriteriaEnzyme-Linked Immunosorbent Assay
Enzyme-linked immunosorbent assay (ELISA) is the initial screening test for detection of anti-HIV antibodies. False-positive results can occur in patients withCollagen vascular diseasesChronic hepatitisOther chronic diseasesWestern BlotAll positive ELISA tests must be confirmed by a Western blot. Specificity and sensitivity of the Western blot is > 99%.The Western blot tests for anti-HIV antibodies.Other TestsOther diagnostic tests are available. All should be confirmed by a Western blot.Rapid diagnostic tests can give results from a finger stick or swab of oral fluid in 5–20 minutes.Monitoring ToolsViral LoadViral load testing measures the amount of virus in blood. It can assess disease progression and evaluate efficacy ofantiretroviral therapy. Its lower limit of detection is less than 50 copies/mL for ultrasensitive assays (less than 400copies/mL for nonultrasensitive assays). A minimally significant change in viral load is considered to be a threefold or0.5log10 increase or decrease.Acute illness and immunizations can cause increases in viral load for 2–4 weeks. Testing should not be performedduring this time.Baseline viral loads are established by averaging two viral loads (that do not differ by > 0.5log10) taken 2–4 weeksapart.Monitoring of viral load in patients not on antiretroviral therapy should occur every 3–4 months. Monitoring of viralload in patients starting a new regimen should occur 2–8 weeks after treatment initiation and then every 3–4 months.CD4 Cell CountCD4 cell count indicates the extent of immune system damage and the risk of developing opportunistic infections.Normal CD4+cell counts are 800– 1,200 cell/mm3.CD4+cell counts should be measured every 3–4 months in patients on or off antiretroviral therapy. A 30% increase ordecrease in CD4+cells from baseline is considered significant.Treatment Principles and GoalsGoals of TherapyTherapy has the following goals:Maximal and durable suppression of viral loadRestoration or preservation of immunologic functionImprovement in quality of life
Reduction of HIV-related morbidity and mortalityFactors involved in achieving goals of therapy are as follows:Adherence to the antiretroviral regimenRational sequencing of drugsPreservation of future treatment optionsUse of resistance testing in selected clinical settingsSee Table 34-1 for indications for the initiation of antiretroviral therapy in the chronically HIV-1 infected patient.Table 34-1. Indications for the Initiation of Antiretroviral Therapy in the Chronically HIV-1 Infected PatientGuidelines for prevention and treatment and medications used for the treatment of HIV can be located as a livingdocument at www.aidsinfo.nih.gov, which is updated three or four times a year.Indications for Consideration of Changing Antiretroviral TherapyConsider changing antiretroviral therapy (ART) with failure to suppress plasma HIV RNA (ribonucleic acid) toundetectable levels (< 50 copies/mL) within 4–6 months of initiating a therapy.Consider changing ART if virus is detected in plasma repeatedly following initial suppression to undetectable levels.Consider genotyping or phenotyping to assist in identifying drugs for the next regimen ifAdherent to failing regimen for at least the previous 4–6 weeks or within 4 weeks after regimendiscontinuationViral load above 1,000 copies/mLConsider changing ART if CD4+T cell numbers persistently decline, as measured on at least two separate occasions.Consider changing ART if patient evidences clinical deterioration.Never change just one medication in a failing regimen (i.e., use at least two new drugs, and preferably an entirelynew regimen).Change one medication in a successful regimen if a patient is experiencing intolerable side effects or if themedication has overlapping toxicity with other medications.Use the treatment history and past and current resistance test results to identify active agents (preferably two ormore) to design a new regimen.Drug Therapy
See Table 34-2 for antiretroviral agents recommended by the U.S. Department of Health and Human Services forinitial treatment of established HIV infection.Table 34-2. Antiretroviral Regimens for Treatment of HIV Infection in Antiretroviral-Naive PatientsNucleoside Reverse Transcriptase InhibitorsNucleoside reverse transcriptase inhibitors (NRTIs) are described in Table 34-3. The mechanism of action of NRTIsis to interfere with HIV viral RNA-dependent DNA (deoxyribonucleic acid) polymerase, resulting in chain terminationand inhibition of viral replication.Table 34-3. Nucleoside Reverse Transcriptase InhibitorsDidanosine, stavudine, and lamivudine are dosed on the basis of weight. Most NRTIs are not affected by food (exceptdidanosine). NRTIs have a low pill burden as a class and few drug interactions. All are pro-drugs requiring two orthree phosphorylations for activation.Four combination products are available:Combivir (zidovudine 300 mg + lamivudine 150 mg) every 12 hoursTrizivir (zidovudine 300 mg + lamivudine 150 mg + abacavir 300 mg) every 12 hoursTruvada (tenofovir 300 mg + emtricitabine 200 mg) every 24 hoursEpzicom (lamivudine 300 mg + abacavir 600 mg) every 24 hoursNo special storage requirements are necessary for drugs in this class.Usually, two NRTIs are used in combination with one non-nucleoside reverse transcriptase inhibitor (NNRTI) or oneprotease inhibitor (PI).Monitor for signs and symptoms of the following class toxicities:Lactic acidosisSevere hepatomegaly with steatosisThe following precautions should be kept in mind regarding NRTIs:Most patients should be dose-adjusted for renal impairment (exception: abacavir).Lamivudine and emtricitabine are chemically similar and should not be used in the same regimen.Do not use zidovudine with stavudine because of antagonism (both require thymidine for activation).
Do not use didanosine with stavudine during pregnancy because of increased risk of lactic acidosis and liverdamage.Tenofovir increases didanosine levels and decreases atazanavir levels. Dosage adjustments are required.Patients should be tested for HLA-B*5701 to determine risk for hypersensitivity reaction to abacavir. Onlynegative patients should start abacavir.The "D" drugs (ddI [didanosine] and d4T [stavudine]) can cause pancreatitis and peripheral neuropathy;when used together, this effect can be additive.The "D" drugs are more closely associated with lactic acidosis.Non-Nucleoside Reverse Transcriptase InhibitorsNNRTIs are described in Table 34-4. Their mechanism of action is to competitively inhibit reverse transcriptase,thereby resulting in inhibition of HIV replication.Table 34-4. Non-nucleoside Reverse Transcriptase InhibitorsOne-step mutation (K103N) confers resistance to all NNRTIs but etravirine. All should be dose-adjusted for hepaticimpairment.Most are not affected by food (except efavirenz). Efavirenz is contraindicated in pregnancy.Usually, one NNRTI should be used in combination with two NRTIs.No special storage requirements are necessary for drugs in this class. Class toxicities include rash and hepatictoxicity.Drug interactions can occur (see Tables 34-5 and 34-6). All are cytochrome P450 (CYP450)-3A4 inducers orinhibitors.Table 34-5. Drugs That Should Not Be Used with NNRTIsTable 34-6. Drug Interactions with NNRTIs Requiring Dose Modifications or Cautious UseProtease InhibitorsProtease inhibitors are described in Table 34-7.
Table 34-7. Protease InhibitorsTheir mechanism of action is to inhibit protease, which then prevents the cleavage of HIV polyproteins andsubsequently induces the formation of immature noninfectious viral particles.All should be dose-adjusted for hepatic impairment. Most should be taken with food (except fosamprenavir, tipranavir,lopinavir-ritonavir tablets, and indinavir). Atazanavir and indinavir require normal acid levels in the stomach forabsorption.Ritonavir is the most potent inhibitor in the class and is primarily used for intensification of other PIs. Ritonavir andtipranavir should be refrigerated.Goals of intensification are as follows:Decrease pill burden.Decrease frequency of doses (i.e., decrease from q8h to q12h).Increase drug levels, resulting in decreased resistance.Class toxicities are as follows:Fat maldistributionHyperglycemiaHyperlipidemiaHypertriglyceridemiaPossible increased bleeding episodes in patients with hemophiliaBaseline PI monitoring is done 4–6 weeks after starting the PI. Monitoring should then take place every 3–6 monthsthereafter. The following tests are required:Glucose testLiver function tests (LFTs)Total cholesterol panel (particularly triglycerides)Signs and symptoms of gastrointestinal (GI) side effectsSigns and symptoms of fat redistributionUsually, one PI (boosted PIs preferred) is used in combination with two NRTIs.All are CYP450-3A4 inhibitors, and drug interactions are typical of CYP450-3A4 inhibitors. See Tables 34-8 and 34-9 for more information about drug interactions.
Table 34-8. Drugs That Should Not Be Used with PIsTable 34-9. Drug Interactions with PIs Requiring Dose Modifications or Cautious UseEntry InhibitorsEntry inhibitors include enfuvirtide (T20) and maraviroc. Enfuvirtide is a fusion inhibitor, whereas maraviroc is a CCR5(chemokine [C-C motif] receptor 5) antagonist. See Table 34-10 for information.Table 34-10.Integrase and Entry InhibitorsEnfuvirtide (T20) (Fuzeon)Enfuvirtides mechanism of action is to bind to glycoprotein 41 on the HIV surface, thus inhibiting HIV binding to theCD4 cell.The dose is 90 mg subcutaneous every 12 hours. Side effects include injection-site reactions, an increased rate ofbacterial pneumonia, and hypersensitivity.Enfuvirtide is generally reserved for deep salvage regimens. Preferably, it should be used with at least two otheractive drugs. Resistance develops quickly with less potent regimens and in cases of poor adherence.No known significant drug interactions have been seen to date. Enfuvirtide can be taken without regard to meals. Itshould be stored at room temperature; the reconstituted form should be stored in the refrigerator, where it will bestable for 24 hours.Maraviroc (Selzentry)Maravirocs mechanism of action is to bind to CCR5 receptors on the CD4 cell surface, which inhibits HIV binding andentry into the CD4 cell.Perform Trofile testing before using maraviroc to determine patients tropism. The patient must be CCR5 tropic only.Maraviroc is a CYP450-3A4 substrate. The dose depends on drug reactions:Use 150 mg po every 12 hours when giving maraviroc with strong CYP3A4 inhibitors (most PIs).Use 300 mg po every 12 hours when giving maraviroc with enfuvirtide, tipranavir-ritonavir, nevirapine, orweak CYP3A4 inhibitors.Use 600 mg po every 12 hours when giving with CYP3A4 inducers (efavirenz, rifampin, etc.).
Side effects include abdominal pain, cough, dizziness, musculoskeletal symptoms, pyrexia, rash, upper respiratorytract infections, hepatotoxicity, and orthostatic hypotension.Preferably, use maraviroc with at least two other active drugs. Take it without regard to meals.Integrase InhibitorsIntegrase inhibitors include raltegravir, which is marketed under the trade name Isentress (Table 34-10). Itsmechanism of action is to block activity of the integrase enzyme, thereby preventing HIV DNA from meshing with theCD4 cell DNA. Metabolism is through UDP-glucuronosyltransferase 1A1 (UGT1A1) mediated glucuronidationDrug interactions occur with rifampin and other drugs that effect UGT1A1. The dose is 400 mg po every 12 hours.Side effects include nausea, headache, diarrhea, pyrexia, and creatinine phosphokinase (CPK) elevation. Preferably,raltegravir should be used with at least two other active drugs. Take it without regard to meals.Potential Benefits of Early TherapyMaintenance of a higher CD4 count and prevention of potentially irreversible damage to the immune systemDecreased risk for HIV-associated complications that can sometimes occur at CD4 counts greater than 350cells/mm3, including tuberculosis, non-Hodgkins lymphoma, Kaposis sarcoma, peripheral neuropathy,human papillomavirus– associated malignancies, and HIV-associated cognitive impairmentDecreased risk of nonopportunistic conditions, including cardiovascular disease, renal disease, liverdisease, and malignancies and infections that are not associated with AIDSDecreased risk of HIV transmission to others, which will have positive public health implicationsPotential Risks of Early TherapyDevelopment of treatment-related side effects and toxicitiesDevelopment of drug resistance because of incomplete viral suppression, resulting in loss of futuretreatment optionsLess time for the patient to learn about HIV and its treatment and less time to prepare for the need foradherence to therapyIncreased total time on medication, with greater chance of treatment fatiguePremature use of therapy before the development of more effective, less toxic, or better-studiedcombinations of antiretroviral drugsTransmission of drug-resistant virus in patients who do not maintain full virologic suppressionCounselingAll patients should be counseled on the importance of adherence. Greater than 95% adherence is necessary todecrease the incidence of resistance. Patients should be given tools to facilitate adherence to complicated regimens(e.g., pillboxes, calendars, pagers, etc).Patients should be counseled on class side effects, especially any that are unique or potentially serious.Antiretroviral Therapy in the HIV-Infected Pregnant WomanHighly active antiretroviral therapy (HAART) should be offered if the patient is not already receiving treatment:
Avoid efavirenz.Avoid combining stavudine and didanosine.Consider starting treatment after the first trimester.Continue current combination regimens (preferably with zidovudine) if the patient is already receiving therapy. Doingso decreases the risk of transmission from 30% to 2.5%.Zidovudine alone can decrease risk of transmission when taken during pregnancy. The mother should also receive IVzidovudine during labor. The infant should receive 6 weeks of zidovudine (Table 34-11).Table 34-11. AIDS Clinical Trials Group 076 Guidelines: Dosing of Zidovudine for Prevention of VerticalTransmissionSingle-dose nevirapine given at onset of labor in women who have had no prior ART and given once to the infantbetween 48 and 72 hours of age has been shown to decrease the transmission rate. This treatment can also result inresistance to nevirapine, which negatively affects future treatment options for the mother.Guidelines for prevention of vertical transmission can be located as a living document at www.aidsinfo.nih.gov, whichis updated three or four times a year.Postexposure ProphylaxisGeneral GuidelinesUniversal precautions should be taken. The most common infectious exposure is needlesticks or cuts (1 in 300 risk).The risk with mucous membrane exposure is much lower (1 in 1,000 risk).Postexposure prophylaxis (PEP) can reduce HIV infection by about 80%. Start therapy within 1–2 hours of exposure.The length of therapy is 4 weeks.Guidelines for PEP can be located as a living document at www.aidsinfo.nih.gov, which is updated three or four timesa year. See also Tables 34-12 and 34-13.Table 34-12. Recommended HIV PEP Treatment OptionsTable 34-13. Regimens for PEPNonoccupational Pep
Patients with exposure to HIV from a known positive source, such as sexual exposure or injection drug use, shouldreceive nonoccupational PEP (nPEP) within 72 hours of the exposure. The length of therapy is 28 days. Figure 34-1 provides an algorithm for evaluation and treatment when nonoccupational exposure occurs. Table 34-14 describesnPEP antiretroviral regimens.Figure 34-1.Algorithm for Evaluation and Treatment of NonoccupationalExposureView LargeTable 34-14.nPEP Antiretroviral RegimensOpportunistic InfectionsOnly two opportunistic infections require primary prophylaxis:Pneumocystis jiroveci pneumonia (PCP): Treatment is required when CD4+cells fall below 200/mm3. Thetreatment of choice is trimethoprim-sulfamethoxazole (TMP-SMX) DS poqd (see Table 34-15 foralternatives).Mycobacterium avium complex bacteremia (MAC): Treatment is required when CD4+cells fall below50/mm3. Azithromycin 1,200 mg po every week is the treatment of choice.Table 34-15. Opportunistic InfectionsAll other primary prophylaxis occurs only if the patient is antigen-positive or at high risk of exposure to the causativefactor. All other opportunistic infections are treated when the patient is diagnosed. After treatment, patients receivesuppressive therapy.Some primary and secondary prophylaxis could possibly be discontinued with immune reconstitution (undetectableviral load and an increase in CD4 cells in response to ART; see Table 34-15).
Immune reconstitution inflammatory syndrome in response to existing or indolent opportunistic infections cansometimes occur when ART is started.Guidelines for prophylaxis and treatment of opportunistic infections can be located as a living documentatwww.aidsinfo.nih.gov.Prevention GuidelinesAbstain from sex with an infected person.Ask about the sexual history of current and future sex partners.Reduce the number of sex partners to minimize the risk of HIV infection.Always use a latex condom from start to finish during any type of sex (vaginal, anal, or oral).Use only water-based lubricants.Avoid alcohol, illicit drugs, and sharing of needles (or syringes, cookers, or other drug paraphernalia).Do not share personal items such as toothbrushes, razors, or any devices used during sex. Such items maybe contaminated by blood, semen, or vaginal secretions.Do not donate blood, plasma, sperm, body organs, or tissues if you are infected with HIV or have engagedin sex or needle-sharing behaviors that are risk factors for infection with HIV.Hematologic ComplicationsAnemia can occur in HIV-infected patients. Causes include the following:HIV infection of marrow progenitor cellsDrug-induced marrow suppression (zidovudine, ganciclovir, amphotericin, ribavirin, pyrimethamine,interferon, TMP-SMX)Treatment of anemia is described in Figure 34-2.Figure 34-2.Guidelines for the Treatment of Anemia in the HIV PatientView Large