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Antiretroviral Agents General Statement

Abacavir Sulfate, Amprenavir, Atazanavir Sulfate, Delavirdine Mesylate, Didanosine, Efavirenz, Emtricitabine, Enfuvirtide, Indinavir Sulfate, Lamivudine, Lopinavir and Ritonavir, Nelfinavir Mesylate, Nevirapine, Ritonavir, Saquinavir, Stavudine, Tenofovir Disoproxil Fumarate, Zalcitabine, Zidovudine

Laboratory Monitoring

Plasma HIV-1 RNA Levels and CD4+ T-cell Counts

Decisions regarding when to initiate or modify antiretroviral therapy should be guided by monitoring plasma HIV-1 RNA levels (viral load), CD4+ T-cell counts, and the clinical condition of the patient. Although various other surrogate markers and laboratory parameters were used in the past to assess the risk of progression of HIV infection and evaluate efficacy of antiretroviral agents (e.g., peripheral blood mononuclear cell [PBMC] HIV-1 titers, plasma concentrations or levels of HIV p core antigen [p gag protein], b2-microglobulin, neopterin), considerable experience has shown that the most important surrogate markers are plasma HIV-1 RNA levels and CD4+ T-cell counts. CD4+ T-cell counts can provide an assessment of the extent of HIV-induced immune system damage but do not always accurately predict clinical outcome when used alone; plasma HIV-1 RNA levels appear to reflect the overall replication of the virus in vivo and are a more sensitive measure of viral load and disease progression than other surrogate markers, especially in asymptomatic adults. Plasma HIV-1 RNA levels may predict subsequent changes in CD4+ T-cell counts.

Plasma HIV-1 RNA levels and CD4+ T-cell counts are, in general, independent predictors of clinical outcome. However, when evaluated together, changes in plasma HIV-1 RNA levels and CD4+ T-cell counts are strongly correlated with clinical progression of HIV infection and provide more prognostic information than that provided by either parameter alone.

Results of clinical studies have demonstrated that there is a statistically significant association between decreases in plasma viremia and improved clinical outcome based on standard end points of new AIDS-defining diagnoses and survival, and this relationship is observed over a range of patient baseline characteristics including pretreatment plasma HIV-1 RNA level, CD4+ T-cell counts, and prior drug exposure.

Therefore, viral load testing is an essential parameter in decisions to initiate or modify antiretroviral therapy. There also is some evidence that plasma HIV-1 RNA levels present after seroconversion (viral set-point) can predict clinical outcome and that HIV-infected adults who have high plasma HIV-1 RNA levels (e.g., exceeding 10,000 copies/mL) at seroconversion are at substantially greater risk of progression to acquired immunodeficiency syndrome (AIDS) over the next 5 years than individuals with lower set-point viral loads.

Three different methods are available to measure plasma HIV-1 RNA levels: reverse transcriptase polymerase chain reaction assay (RT-PCR; Amplicor HIV-1 Monitor®, Roche Diagnostics Systems), branched chain DNA assay (bDNA; Versant® HIV-1), and nucleic acid sequence-based amplification assay (NASBA; NucliSens® HIV-1 QT, Organon Technika). Plasma HIV-1 RNA levels usually are expressed as numbers of copies of HIV-1 RNA per mL of plasma (copies/mL) and/or as the logarithm (to the base 10) of the number of copies of HIV-1 RNA per mL. The RT-PCR and NASBA assays measure plasma HIV-1 RNA levels using target amplification and the bDNA assay uses signal amplification.

Currently available RT-PCR and NASBA assays have a lower limit of detection of plasma HIV-1 RNA levels of 50 copies/mL; the bDNA assay has a lower limit of detection of 75 copies/mL. While all 3 methods accurately quantitate plasma HIV-1 RNA levels and results of these assays are strongly correlated, the absolute values of HIV-1 RNA measured in the same plasma sample using 2 different assay methods can differ by twofold or more.

Therefore, plasma HIV-1 RNA levels reported using one assay method should not be directly compared with results from studies that employ another assay method. The CDC and other experts recommend that, until a common standard is available to normalize values obtained with different assay methods, it is advisable that one particular assay method (i.e., RT-PCR, NASBA, or bDNA) be used consistently in an individual patient.

Recommendations Regarding Plasma HIV-1 RNA Levels and CD4+ T-cell Counts

Antiretroviral Agents

Baseline CD4+ T-cell counts and plasma HIV-1 RNA levels should be measured in all newly diagnosed HIV-infected patients to provide information on the virologic and immunologic status of the patient and the risk of disease progression so that a decision can be made regarding whether to initiate antiretroviral therapy. In addition, plasma HIV-1 RNA levels should be measured in patients with a syndrome consistent with acute HIV infection since results can be used to establish the diagnosis when HIV antibody tests are negative or indeterminate; however, a diagnosis of HIV infection made by plasma HIV-1 RNA testing should be confirmed by standard methods (e.g., Western blot serology) 2-4 months after the initial test. Ideally, 2 serum specimens for viral load testing should be obtained within 1-2 weeks of each other to ensure accurate measurements and determine whether viral load is relatively stable or rapidly changing. In patients who present with advanced HIV disease, however, antiretroviral therapy should be initiated after the first set of tests and should not be delayed to wait for verification with a second set of tests.

If a decision is made not to initiate antiretroviral therapy, plasma HIV-1 RNA levels generally should be measured about every 3-4 months and CD4+ T-cell counts repeated about every 3-6 months unless there are symptomatic changes indicating a need for more frequent evaluation.

If a decision is made to initiate antiretroviral therapy, plasma HIV-1 RNA levels should be measured again immediately prior to initiation of therapy (to verify baseline levels), at 2-8 weeks after the initial regimen is started (to evaluate the initial effectiveness of the regimen), and about every 3-4 months thereafter (to evaluate the continuing effectiveness of the regimen). Some experts suggest that measurement of plasma HIV-1 RNA levels at 4 weeks after initiation of antiretroviral therapy in patients with acute infection is not helpful in evaluating the effect of therapy in such patients since viral load may be decreasing from peak viremia levels even in the absence of therapy.

In patients receiving antiretroviral therapy, plasma HIV-1 RNA levels should be repeated every 3-4 months and whenever a clinical event or significant decline in CD4+ T-cell count occurs. Before making any changes in the antiretroviral regimen based on plasma HIV-1 RNA levels or CD4+ T-cell counts, results should be verified with at least one repeat determination, preferably done by the same laboratory.

Plasma HIV-1 RNA levels should not be measured during or within 4 weeks after acute illness (e.g., bacterial pneumonia, tuberculosis, herpes simplex virus infection, Pneumocystis carinii pneumonia), successful treatment of any intercurrent infection, resolution of symptomatic illness, or immunization since such events can cause increases in plasma HIV-1 RNA levels for 2-4 weeks.

Interpretation of Plasma HIV-1 RNA Levels and CD4+ T-cell Counts

Initiation of a potent multiple-drug antiretroviral regimen in treatment-naive adults should result in a large (about 1 log) decrease in plasma HIV-1 RNA levels by 2-8 weeks. If the regimen is effective, viral load should continue to decrease over the next several weeks and plasma HIV-1 RNA levels should decrease to below the limits of detection (currently defined as less than 50 copies/mL by RT-PCR or NASBA assay or less than 75 copies/mL by bDNA assay) within 16-20 weeks in most individuals. The rate of decline in viral load is affected by baseline CD4+ T-cell counts, baseline HIV-1 RNA level, potency of the regimen, adherence to the regimen, prior exposure to antiretroviral agents, and presence of opportunistic infections.

When evaluating response to an antiretroviral regimen, a threefold (0. log) decrease or increase in plasma HIV-1 RNA levels generally is accepted as the minimally significant change in plasma viremia. In addition, a decrease of greater than 30% from baseline in absolute CD4+ T-cell count or a decrease of greater than 3% from baseline in CD4+ percentages generally is accepted as indicating a clinically significant decrease in CD4+ T-cell count. Discordance between the plasma HIV-1 RNA response and CD4+ T-cell response may occur, which can complicate decisions regarding antiretroviral therapy; however, viral load and trends in viral load generally are considered to be the more informative test for guiding decisions regarding such therapy.

With optimal initial antiretroviral therapy, plasma HIV-1 RNA levels after 24 weeks of therapy should be undetectable. Data from some clinical trials strongly suggest that a decrease in plasma HIV-1 RNA levels to less than 50 copies/mL by RT-PCR or NASBA assay or less than 75 copies/mL by bDNA assay is associated with more complete and durable viral suppression than a decrease in levels to 50-500 copies/mL. If plasma HIV-1 RNA levels are still detectable after 16-24 weeks of therapy (confirmed by a second measurement made within days or weeks), consideration should be given to modifying the antiretroviral regimen.The possibility that lack of response to the regimen may be related to failure of the patient to adhere to the regimen or the presence of malabsorption should be considered and clinicians also should be aware that plasma HIV-1 RNA levels may be elevated transiently for up to approximately 4 weeks after immunizations and intercurrent infections.

In Vitro Resistance Testing

In vitro genotypic assays to detect specific HIV-1 genetic variants (mutations) and in vitro phenotypic assays to measure HIV-1 drug resistance are commercially available. Genotypic assays detect drug resistance mutations that are present in the viral genes (i.e., reverse transcriptase, protease) and phenotypic assays measure the virus’s ability to replicate in the presence of different concentrations of antiretroviral drugs. Some experts suggest that testing for HIV resistance to antiretrovirals can be a rational adjunct to guide antiretroviral therapy and, when combined with a detailed drug history and efforts aimed at ensuring compliance, such testing may help maximize the benefits of antiretroviral therapy and improve short-term virologic response. Although the role of in vitro resistance testing prior to initiating antiretroviral therapy in most HIV-infected patients has not been fully determined, drug resistance assays may be useful for selecting initial antiretroviral regimens for patients with primary (acute) HIV infection and for modifying antiretroviral regimens in patients who have evidence of virologic failure or suboptimal response to potent antiretroviral regimens. There is some evidence that use of genotypic or phenotypic assays can improve outcome when selecting alternative or salvage regimens for patients with disease progression on prior antiretroviral regimens.

Although genotypic or phenotypic evidence of in vitro resistance to an antiretroviral agent suggests that the drug may not be effective in suppressing viral replication in vivo, such testing should not be used as the sole indicator that modifications need to be made to an antiretroviral regimen since factors other than viral resistance (e.g., poor compliance, pharmacokinetic interactions, drug potency) also affect virologic response to therapy and/or may contribute to disease progression, and some antiretroviral regimens can provide sustained viral suppression in vivo despite the presence of HIV-1 strains resistant to one of the components of the regimen. In addition, the absence of genotypic or phenotypic evidence of resistance does not necessarily predict a good response to a drug since minor variants may not be detected by current assays or resistance may be evolving at the time the assay is performed.

Recommendations Regarding In Vitro Resistance Testing

The Panel on Clinical Practices for Treatment of HIV Infection and a panel convened by the International AIDS Society—USA have made the following recommendations regarding use of in vitro resistance assays. These experts recommend use of in vitro resistance assays for patients with virologic failure during potent multiple-drug antiretroviral therapy and for patients with suboptimal suppression of plasma HIV-1 RNA levels after initiation of potent antiretroviral therapy since such testing could be used to determine the role of resistance in drug failure and maximize the number of active drugs included in a new regimen if indicated. These experts also suggest use of drug-resistance assays in patients with acute HIV infection since such testing could determine if the infection is caused by drug resistant virus and a change in the initial regimen could be made accordingly. The Panel on Clinical Practices for the Treatment of HIV Infection does not generally recommend use of drug resistance assays prior to initiation of antiretroviral therapy in patients with chronic HIV infection because of the uncertain prevalence of resistant virus and the fact that current assays may not detect minor drug resistance species. Use of resistance testing should be strongly considered for treatment-naive patients who may be infected with a resistant strain, particularly those with more recent infection, or when the initial response is suboptimal in the face of excellent drug adherence. Recommendations for use of in vitro resistance testing in pregnant women are the same as those for nonpregnant patients and may be useful for guiding decisions regarding the most appropriate regimen to treat the woman’s HIV infection.

Antiretroviral Agents

Because currently available in vitro resistance assays are not reliable in patients with low viral load, such testing is not recommended in patients with plasma HIV-1 RNA levels less than 1000 copies/mL.

There are no data to date to support the use of one type of in vitro resistance assay over another (i.e., genotypic or phenotypic) in different clinical situations. Therefore, one type of assay is recommended per sample; however, in the setting of a complex prior treatment history, both genotypic and phenotypic assays may provide important and complementary information. Resistance testing should be performed when the selective pressure of the failing regimen is still present because resistance may not be detected following withdrawal of the drugs.

Therapeutic Drug Monitoring

While therapeutic drug monitoring of antiretroviral agents is not used routinely in the management of HIV infection, information on plasma concentrations of antiretroviral agents may be useful in certain clinical situations. There are data and expert opinion to support the usefulness of monitoring plasma concentrations of antiretroviral agents when clinically important drug-drug or drug-food interactions may result in reduced efficacy or increased dose-related toxicities; in patients with pathologic states that may impair GI absorption or hepatic or renal impairment that may result in altered drug absorption, distribution, metabolism, or elimination of the drugs; in pregnant women; in treatment-experienced patients who may have viral isolates with reduced susceptibility; and in treatment-naive patients who experience virologic failure.

Therapeutic drug concentration monitoring also is useful when an alternative dosing regimen that has not been evaluated in clinical studies is used and when concentration-dependent drug-associated toxicities are expected. However, information on the association between antiretroviral plasma concentrations and virologic response is limited and studies have not demonstrated that therapeutic drug monitoring improves clinical outcome. Therefore, therapeutic drug monitoring for antiretroviral agents currently is not recommended for routine use in the management of HIV-infected adults. Therapeutic drug monitoring generally should be undertaken, when appropriate, in consultation with an expert (e.g., clinical pharmacologist, clinical pharmacist).

Adverse Effects

There have been some reported adverse effects that appear to be common to specific drug classes of commercially available antiretroviral agents (e.g., HIV protease inhibitors, NNRTIs, NRTIs). These adverse effects should be considered when selecting alternative agents. In some cases, adverse effects were initially reported to be strongly associated with one class of antiretroviral agents and then found to occur in patients receiving various antiretroviral regimens that may or may not have included these agents (e.g., adipogenic effects).

HIV Protease Inhibitors

Several different adverse effects reported in patients receiving HIV protease inhibitors (amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir) appear to be common to this drug class, including hyperglycemic and diabetogenic effects, adipogenic effects, hyperlipidemia and hypercholesteremia, and spontaneous bleeding episodes. Although a causal relationship has not been established in all cases, the possibility of these adverse effects should be considered whenever an HIV protease inhibitor is included in an antiretroviral regimen.

Hyperglycemic and Diabetogenic Effects

Hyperglycemia, new-onset diabetes mellitus, or exacerbation of preexisting diabetes mellitus has been reported during postmarketing surveillance in patients receiving HIV protease inhibitor therapy. Some patients required either initiation or dose adjustments of insulin or oral hypoglycemic agents; in some cases, diabetic ketoacidosis has occurred. In various retrospective studies, the incidence of hyperglycemia with or without diabetes has been reported to be 3-17%; the median time to onset of symptoms was approximately 60 days (range: 2-390 days) after initiation of HIV protease inhibitor therapy. The hyperglycemic or diabetic episodes generally resolve following discontinuance of HIV protease inhibitor therapy; however, hyperglycemia persisted in some patients, including a few without a known history of diabetes at baseline. HIV-infected patients with preexisting diabetes mellitus should be closely monitored during HIV protease inhibitor therapy, and the risk of new-onset diabetes mellitus should be considered in those without a history of the disease.

Patients receiving an HIV protease inhibitor should be advised about the warning signs of hyperglycemia and diabetes (e.g., increase thirst and hunger, unexplained weight loss, increased urination, fatigue, dry or itchy skin) and advised of the need to maintain ideal body weight. Although some clinicians recommend that fasting blood glucose determinations be performed every 3-4 months during the first year of HIV protease inhibitor therapy in patients with no prior history of diabetes, routine use of glucose tolerance testing in such patients is not recommended. Because pregnancy is an independent risk factor for impaired glucose tolerance, closer monitoring of blood glucose concentrations should be done in pregnant women receiving HIV protease inhibitors. It is unclear whether HIV protease inhibitor therapy should be discontinued in cases of new-onset or worsening of diabetes mellitus; most experts suggest that continuation of such therapy can be considered in the absence of severe diabetes mellitus.

Adipogenic Effects

Redistribution or accumulation of body fat, including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, breast enlargement, and general cushingoid appearance, has been reported in patients receiving HIV protease inhibitor therapy. These adipogenic effects have been reported most frequently with HIV protease inhibitors; however, similar adipogenic effects also have been reported in some patients receiving NRTIs without an HIV protease inhibitor. Adipogenic effects generally have been clinically apparent within 1-14 months after starting HIV protease inhibitor therapy. The incidence of lipodystrophy in patients receiving HIV protease inhibitor therapy is unclear, but has been variously reported to range from about 5-80% of patients.

Although further study is needed, the etiology of lipodystrophy reported in HIV patients receiving antiretroviral agents may be multifactorial. Several different mechanisms have been suggested, including inhibition of several proteins involved in lipid and carbohydrate metabolism resulting in interference with adipocyte differentiation and apoptosis. Long-term consequences of adipogenic effects that occur during antiretroviral therapy are unknown, and data are insufficient to date to guide management of patients who develop these effects. Discontinuance of HIV protease inhibitors has resulted in partial or complete resolution of symptoms in some patients. Some clinicians state that it may not be necessary to discontinue HIV protease inhibitor therapy on the basis of adipogenic effects alone.

Hyperlipidemia

Hypertriglyceridemia and hypercholesteremia have been reported in patients receiving HIV protease inhibitors. Patients receiving antiretroviral regimens that include HIV protease inhibitors may have increases in fasting cholesterol, triglycerides, low-density lipoprotein (LDL)-cholesterol, and very-low-density lipoprotein (VLDL)-cholesterol levels with either no change or decreases in high-density lipoprotein (HDL)-cholesterol. Most commercially available HIV protease inhibitors have been associated with increases in serum cholesterol and/or triglyceride concentrations.

These effects may be reported less frequently with atazanavir than with other HIV protease inhibitors and have been most pronounced with ritonavir. Hypertriglyceridemia and hypercholesteremia have been reported with or without adipogenic effects and/or hyperglycemia, and the relationship between alterations in body fat and lipid levels is unclear. Although further study is needed, there is some concern that lipid abnormalities in patients receiving HIV protease inhibitor therapy possibly may increase the risk of coronary artery disease and pancreatitis.

Indications for monitoring and treatment of dyslipidemias in HIV-infected patients are the same as those for other individuals. Dietary therapy, regular exercise, blood pressure control, and smoking cessation are important elements of care. Hypercholesterolemia might respond to hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins).

However, pharmacokinetic interactions between certain HMG-CoA reductase inhibitors and HIV protease inhibitors can result in increased plasma concentrations of the HMG-CoA reductase inhibitor. HMG-CoA reductase inhibitors that are not metabolized by the cytochrome P-450 (CYP) isoenzymes are preferred (e.g., pravastatin). HMG-CoA reductase inhibitors that are partially metabolized by CYP isoenzymes (e.g., atorvastatin) also can be used with caution and at reduced dosages.While monotherapy with fibric acid derivatives is less effective than HMG-CoA reductase inhibitors, fibric acid derivatives can be used in conjunction with HMG-CoA reductase inhibitors. However, additional monitoring is required because this combination is associated with an increased risk of rhabdomyolysis and hepatotoxicity.

Isolated triglyceride elevations respond to dietary therapy, fibric acid derivatives, or HMG-CoA reductase inhibitors. If dyslipidemia is severe or does not respond to therapy, consideration should be given to modification of the antiretroviral regimen. Replacing an HIV protease inhibitor with an NNRTI (nevirapine is better than efavirenz) or using an abacavir-containing triple NRTI regimen results in improved lipid concentrations.

Spontaneous Bleeding Episodes

Although a causal relationship has not been established, spontaneous bleeding episodes have been reported in patients with hemophilia A or hemophilia B receiving HIV protease inhibitor therapy. Bleeding episodes have occurred a median of 22 days after initiation of HIV protease inhibitor therapy and most reported cases involved bleeding in joints and soft tissues; however, serious intracranial and GI bleeding also have been reported.

Nonnucleoside Reverse Transcriptase Inhibitors

Dermatologic and Sensitivity Reactions

Rash is a common adverse effect with all currently available NNRTIs (delavirdine, efavirenz, nevirapine) and the major toxicity associated with this drug class is potentially life-threatening hypersensitivity reactions. Although most cases of rash are mild to moderate and occur during the first few weeks of therapy, severe and life-threatening skin reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis, and hypersensitivity reactions characterized by rash, constitutional findings, and organ dysfunction have been reported in patients receiving the drugs. Fatalities have been reported. A severe and possibly life-threatening syndrome of rash with eosinophilia and systemic symptoms (e.g., fever, hematologic abnormalities, multiple organ involvement) also has been described.

Among currently available NNRTIs, rash occurs most frequently and is most severe with nevirapine. NNRTIs should be immediately discontinued in any patient with signs or symptoms of hypersensitivity (e.g., fever, rash, fatigue, or GI symptoms such as nausea, vomiting, diarrhea, or abdominal pain). The incidence of cross hypersensitivity among the NNRTIs is not known.Although it has been reported that some patients with a history of rash associated with nevirapine therapy have been able to tolerate efavirenz, most experts do not recommend use of any NNRTI in a patient who has had a severe hypersensitivity reaction to one of the drugs. Initiating NNRTI therapy in a patient with a history of mild to moderate rash with another NNRTI should be done with caution and with close follow-up.

Nucleoside Reverse Transcriptase Inhibitors

HIV Fusion Inhibitors

Experience with enfuvirtide is limited to date. Hypersensitivity reactions that may include rash, fever, nausea, vomiting, chills, rigors, hypotension, and elevated serum transaminase concentrations have been reported; these reactions may recur on rechallenge.

Neonates and Children Younger than 12 Months of Age

The majority of pediatric HIV infections are acquired perinatally, and early identification of HIV-exposed neonates is important in providing effective treatment of these infants. Universal HIV counseling and HIV testing (with consent) of all pregnant women is an important tool in identifying neonates at risk for HIV infection and is recommended as a standard of care for all pregnant women in the US; if maternal HIV serostatus was not determined during the prenatal or immediate postpartum period, diagnostic testing of the infant is recommended. All infants born to HIV-infected women should receive diagnostic testing to determine if they are HIV infected.Diagnostic testing should be performed within 48 hours of birth and then repeated at 1-2 and 3-6 months of age; repeat testing at 14 days of age in those with a negative result at birth may be advantageous for early detection of infection. Because of improvements in virologic methods used to diagnose HIV infection in infants, a definitive diagnosis can be made in most infected infants by 1 month of age and in virtually all infected infants by 6 months of age. Specific references should be consulted for further information on diagnosis of HIV infection in pediatric patients.

Beginning as soon as possible after delivery (preferably within 8-24 hours after birth) and continued through 6 weeks of life, neonates born to HIV-infected woman should receive the postpartum neonatal component of the zidovudine regimen used to prevent maternal-fetal transmission of HIV. (See Guidelines for Use of Antiretroviral Agents: Antiretrovirals for Prevention of Maternal-fetal Transmission of HIV.)

The postpartum neonatal component of the regimen should be administered to the neonate even if the mother failed to receive the antepartum or intrapartum component. For neonates born to women with a history of prior antiretroviral therapy, some clinicians might consider using a regimen of zidovudine and other antiretroviral agents in the neonate, especially if the mother had disease progression while receiving zidovudine, received extensive prior zidovudine monotherapy, or is infected with HIV-1 with documented high-level zidovudine resistance; however, safety and efficacy of this approach and the most appropriate dosage regimens for these neonates are not completely established. If subsequent diagnostic testing indicates that a neonate receiving zidovudine prophylaxis is HIV infected, the zidovudine regimen should be changed to a multiple-drug antiretroviral regimen recommended for the treatment of pediatric HIV infection.

If diagnostic testing for HIV is negative during the first 6 weeks of life, it has been suggested that tests be repeated after completion of the neonatal prophylaxis regimen. Although there is no evidence that use of zidovudine prophylaxis in the neonate adversely affects or delays neonatal HIV diagnosis, it is unclear whether use of multiple-drug antiretroviral regimens in the mother and/or neonate has any effect on the sensitivity of neonatal virologic diagnostic testing.

Antiretroviral therapy should be initiated in any HIV-infected infant who is symptomatic or has evidence of immunosuppression, regardless of age or plasma HIV-1 RNA level. Because HIV-infected infants younger than 12 months of age are at high risk for disease progression, the Working Group states that, ideally, antiretroviral therapy should be initiated in this age group immediately after the diagnosis, regardless of clinical or immunologic status or viral load.

However, definitive clinical studies documenting therapeutic benefit from this approach are not available and the choice of appropriate antiretroviral regimens in this age group is complicated by the fact that data are limited to date regarding dosage regimens of many antiretroviral agents for use in children younger than 6 months. In addition, issues related to adherence should be fully assessed and discussed with caregivers of asymptomatic HIV-infected infants before a decision to initiate antiretroviral therapy is made.

Children 12 Months of Age or Older

Antiretroviral therapy should be initiated in any HIV-infected adolescent or child who is symptomatic or has evidence of immunosuppression, regardless of age or plasma HIV-1 RNA levels. For asymptomatic children 12 months of age or older without evidence of immunosuppression, there are 2 general approaches to initiating therapy that can be considered. The first approach is therapeutically more aggressive and involves initiating antiretroviral therapy regardless of age or symptom status.

The alternative approach is to defer initiation of antiretroviral therapy in asymptomatic children 12 months of age or older who have normal immune status in situations in which the risk for clinical disease progression is low (e.g., low viral load) and when other factors (e.g., concern for the durability of response, safety, and adherence) favor postponing treatment. In such cases, virologic, immunologic, and clinical status of the child should be monitored regularly and therapy should be initiated if clinical symptoms develop, plasma HIV-1 RNA levels are high or increasing, or CD4+ T-cell counts or percentages rapidly decline and approach those indicating moderate immunosuppression. The level of plasma HIV-1 RNA considered indicative of increased risk for disease progression is not well defined for young children.

However, any child (regardless of age) who has plasma HIV-1 RNA levels exceeding 100,000 copies/mL is at high risk for mortality and should receive antiretroviral therapy. In older children (30 months of age or older), the risk of disease progression or death at 2 years of follow-up is very low when plasma HIV-1 RNA levels are 15,000 copies/mL or less, but the risk increases to 13% or higher when HIV-1 RNA levels are higher. The Working Group recommends that antiretroviral therapy be offered (regardless of clinical or immunologic status or absolute level of viral load) to any child with a plasma HIV-1 RNA level that increases substantially (more than a fivefold increase for children younger than 2 years of age or more than a threefold increase for those 2 years of age or older) on repeated testing, provided there are no possible alternative causes for transient increases in these levels (e.g., concurrent vaccination or infection).

Adolescents

Currently, most HIV-infected adolescents were infected sexually during the adolescent period and are in a relatively early stage of infection. Adolescents infected with HIV through sexual exposure or IV drug use during adolescence generally experience a clinical course that is similar to that of adults, and such adolescents are treated most appropriately using the guidelines recommended for adults. There are, however, a growing number of adolescents who were either infected perinatally or as young children through HIV-infected blood products and such adolescents may have a unique clinical course that differs from other adolescents or those infected later in life.

When antiretroviral therapy is initiated in an adolescent, consideration should be given to the possibility that physiologic changes that occur at the time of puberty may affect the pharmacokinetics of the various antiretroviral agents and theoretically could impact efficacy of the drugs. Experience to date using NRTIs in adolescents has not revealed evidence of such an effect with these agents; however, experience is limited to date using HIV protease inhibitors and NNRTIs in adolescents. Therefore, the Working Group on Antiretroviral Therapy and Medical Management of HIV-infected Children and other clinicians recommend that dosage of antiretroviral agents be based on Tanner staging of puberty rather than age. These clinicians suggest that adolescents in early puberty (Tanner I-II) are most appropriately treated using pediatric guidelines and dosages and that those in late puberty (Tanner V) are most appropriately treated using adult guidelines and dosages. Those in the middle of their growth spurts (Tanner III in females and Tanner IV in males) should be monitored closely for antiretroviral agent efficacy and toxicity when choosing between adult and pediatric guidelines.

Evaluation and Testing of the Source

The individual whose blood or body fluids are the source of an occupational exposure should be immediately evaluated for HIV infection and HIV antibody testing performed if indicated. Use of a rapid HIV test for evaluation of the source individual after occupational exposures should be considered since this test offers the advantage of faster results than standard HIV enzyme immunoassay (EIA) and, therefore, can minimize use of unnecessary PEP. Use of direct virus assays (e.g., HIV p antigen EIA or tests for HIV RNA) for routine HIV screening of source individuals is not recommended.

If the source individual is known to be HIV seropositive, information regarding their stage of infection, immunologic status, viral load, current and previous antiretroviral therapy, and genotypic or phenotypic viral resistance testing should be collected and may be considered when selecting an appropriate PEP regimen for the exposed health-care worker; however, initiation of PEP should not be delayed while acquiring this information.

If the source individual is HIV seronegative and has no clinical evidence of AIDS or symptoms of HIV infection, no further testing of the source is indicated. The likelihood of the source individual being in the window period of HIV infection in the absence of symptoms of acute retroviral syndrome is extremely small.

If the exposure source is unknown or cannot be tested, the risk for HIV transmission should be assessed from information about where and under what circumstances the exposure occurred and decisions regarding PEP should be made on an individual basis. Important considerations in these cases are the severity of the exposure and the prevalence of HIV infection in the population group (i.e., institution, community) from which the contaminated source material is derived. An exposure that occurs in a geographic area where IV drug abuse is prevalent or an AIDS unit in a health-care facility would be associated with a higher risk than one that occurs in a health-care facility for geriatric individuals with no known HIV-infected residents.

HIV testing of needles or other sharp instruments involved in an exposure (regardless of whether the source is known) is not recommended since the reliability and interpretation of such findings are unknown. The reliability and interpretation of findings in such circumstances are unknown, and testing might be hazardous to the individual handling the sharp instrument.

Evaluation and Testing of the Exposed Health-care Worker

Following an occupational exposure, the health-care worker should be evaluated within hours (rather than days) and should be tested to establish HIV serostatus at the time of exposure and also should be evaluated for susceptibility to other bloodborne pathogens (e.g., hepatitis B, hepatitis C). The exposed health-care worker should be questioned regarding other drugs they may currently be taking and any current or underlying medical conditions or circumstances (e.g., pregnancy, breast feeding, renal or hepatic disease) that may influence choice of agents for a PEP regimen. A pregnancy test should be offered to all nonpregnant women of childbearing age whose pregnancy status is unknown.

Antiretroviral Agents

If the source individual is found to be HIV seronegative, baseline HIV testing and further follow-up of the health-care worker normally is not necessary. However, serologic testing should be made available to all health-care workers who are concerned that they might have been occupationally infected with HIV; appropriate psychological counseling also may be indicated.

Initiation of Postexposure Prophylaxis

Depending on the degree of risk for HIV transmission associated with the occupational exposure, PEP with a basic 2-drug regimen or an expanded 3-drug regimen of antiretroviral agents may be warranted and should be recommended or offered to the exposed health-care worker in conjunction with appropriate counseling and informed consent. In situations with negligible risk of HIV transmission, use of PEP generally is not justified.

If PEP is appropriate for the exposure and the exposed health-care worker elects to receive such therapy, it should be initiated as soon as possible following exposure. To ensure timely access to PEP, an occupational exposure should be regarded as an urgent medical concern. When there are some concerns regarding the most appropriate drugs to administer, it probably is preferable to immediately initiate therapy with the basic regimen rather than delaying PEP. Although there is some evidence from animal studies suggesting that prophylaxis is substantially less effective when initiated more than 24-36 hours after exposure, the interval after which there is no benefit from PEP has not been defined in humans. Therefore, appropriate for the exposure, PEP should be started even when the interval since exposure exceeds 36 hours. In addition, initiating therapy after a longer interval (e.g., 1 week) may be considered for exposures that represent an increased risk for transmission of HIV. The optimal duration of PEP is unknown. Based on evidence that 4 weeks of zidovudine appeared protective in occupational and animal studies, the CDC recommends that PEP be continued for 4 weeks, if tolerated.

Follow-up and Counseling of the Health-care Worker

Health-care workers with occupational exposure to HIV should receive counseling, postexposure testing, and medical evaluation regardless of whether they receive PEP. Follow-up HIV testing should be performed for at least 6 months after the exposure (e.g., at 6 weeks, 12 weeks, 6 months) to determine whether transmission of HIV occurred. Extended follow-up (e.g., for 12 months) is recommended for health-care workers who become infected with HCV following exposure to a source coinfected with both HIV and HCV; however, it is unclear whether extended follow-up is necessary in other circumstances.

Although rare cases of delayed HIV seroconversion have been reported, this probably does not warrant increasing the health-care worker’s anxiety by routinely extending the duration of postexposure follow-up. However, this does not preclude a decision to extend follow-up in an individual situation based on the clinical judgment of the health-care provider. HIV testing should be performed in any health-care worker who has an illness that is compatible with an acute retroviral syndrome, regardless of the interval since exposure.

Exposed health-care workers should be advised to use measures to prevent secondary transmission of HIV during the follow-up period, especially during the first 6-12 weeks following the exposure. These individuals should be counseled to use sexual abstinence or condoms to prevent sexual transmission, to avoid pregnancy, and refrain from donating blood, plasma, organs, tissue, or semen. If the exposed health-care worker is breastfeeding, she should be counseled about the risk of HIV transmission through breast milk and discontinuance of breastfeeding should be considered.

There is no need to modify the responsibilities of an exposed health-care worker; however, if HIV seroconversion occurs, the individual should be evaluated according to published recommendations for HIV-infected health-care workers.

Exposed individuals should be advised to seek medical evaluation for any acute illness that occurs during the follow-up period, including any illness characterized by fever, rash, myalgia, fatigue, malaise, or lymphadenopathy, since this may indicate acute HIV infection or may indicate an adverse effect of the PEP regimen. They should be advised of the potential adverse effects of the postexposure regimen and that evaluation of certain symptoms should not be delayed (e.g., back or abdominal pain, pain on urination, blood in the urine, symptoms of hyperglycemia). Health-care workers receiving PEP should be advised of the importance of completing the recommended regimen.

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