Posted by: Indonesian Children | June 14, 2009

HIV IN CHILDREN : MANAGEMENT AND TREATMENT

Treatment

Medical Care:

Antiretroviral treatment

Antiretroviral treatment (ART) is the mainstay in HIV treatment.

The inadequacy of merely reducing the viral load has been realized in recent years. Quick suppression of the viral load with highly active antiretroviral therapy (HAART) significantly slows viral replication and prevents resistant mutations.

Unlike HIV treatment in adults, most patients with vertically acquired HIV are treated regardless of their immune status. All children younger than 1 year should be treated aggressively. Therapy may be deferred in children older than 1 year, but any progression of disease should indicate the initiation of HAART.

Double- and triple-drug therapy should start with 2 nucleoside reverse transcriptase inhibitors (NRTIs) or 2 NRTIs plus a non-nucleoside reverse transcriptase inhibitor (NNRTI) or a protease inhibitor. Initial NRTI combinations may include zidovudine with didanosine or lamivudine. A 10- or 5-fold decrease in the viral load is expected in 2-3 months with triple-drug therapy or double-drug therapy, respectively, but not all infants have an undetectable viral load. Reduction in the mortality rate from perinatally acquired HIV-1 over the past 5 years is a result of improved antiretroviral therapy. Only triple combination therapy, however, appears to significantly reduce the relative hazard ratio of death, when compared with no treatment.

Drug interactions with antiretroviral agents

Antiretroviral drug regimens often contain 3 or more agents. In addition, other drugs are typically required for the management of the numerous infectious and systemic consequences of AIDS; therefore, the likelihood of drug interactions increases. The outcome of drug interactions may reduce or eliminate the efficacy or increase the toxicity of one or both drugs. A thorough understanding of the mechanisms of interactions is essential to minimize or prevent adverse effects and to avoid inadequate treatment.

Regarding the mechanisms of drug interactions, drug interactions are classified as either pharmacokinetic or pharmacodynamic. Pharmacokinetic interactions alter drug absorption, distribution, or elimination (ie, metabolism, excretion). Pharmacodynamic alterations are exhibited via additive, synergistic, or antagonistic drug effects. Several antiretrovirals may affect or be affected by absorption kinetics. Didanosine contains an aluminum and magnesium buffer that may affect the absorption of other drugs (eg, ciprofloxacin). Delavirdine is poorly absorbed when the GI pH increases.

Many antiretroviral drug pharmacokinetic interactions alter the cytochrome 450 (CYP450) metabolic enzyme system. Cytochromes are metabolic enzymes in the liver. CYP450 denotes the specific enzyme. The CYP450 system is further classified into families (described with numbers); 3 of these are important in humans: CYP1, CYP2, CYP3. Further delineation into subfamilies is denoted by a capital letter (eg, CYP3A). The nomenclature is completed with the description of individual proteins called isoenzymes, which are delineated with a second number (eg, CYP3A4).

Drugs may be substrates, inhibitors, and/or inducers of particular isoenzymes. Substrates are metabolized via the CYP450 system. They may also be classified as inhibitors (ie, those with reversible and competitive action that decreases metabolism) and/or inducers (ie, those with reversible and competitive action that increases metabolic rate). Inhibitors decrease the hepatic metabolism of isoenzyme substrates (ie, increase serum concentrations), and inducers increase this metabolism (ie, decrease serum levels).

All currently approved PIs and NNRTIs are metabolized by the CYP450 system, principally by the 3A4 isoenzyme. Some also induce or inhibit CYP3A4, respectively decreasing or increasing 3A4 substrate serum levels. Strong inhibitors (ie, ritonavir) have also been used in small doses to increase drug levels (eg, lopinavir and ritonavir combination), increasing efficacy with a low enough dose of ritonavir to limit the risk of adverse effects.

The effects of NRTIs, PIs, and NNRTIs can be found in the supplementary material about Antiretroviral agents.

Drug interactions among antiretroviral agents may be used to increase and sustain serum levels of one another, enhancing efficacy and decreasing adverse effects (eg, Kaletra combination product of lopinavir and ritonavir). Other interactions may lead to decreased levels, causing concern about sufficient efficacy.

The supplementary material, Drug Interactions with Antiretroviral Agents, highlights these drug interactions and includes recommendations supported with sufficient data.

Abbreviations of antiretrovirals are also listed in Drug Interactions with Antiretroviral Agents.

  • Common antiretroviral therapies include the following regimens: 
    • Zidovudine, lamivudine, and nelfinavir, ritonavir, or nevirapine 
    • Stavudine, didanosine, and nelfinavir, ritonavir, or nevirapine 
    • Stavudine, lamivudine, and nelfinavir, ritonavir, or nevirapine 
    • Zidovudine, lamivudine, nevirapine, and nelfinavir or efavirenz

     

  • Avoid using the following drugs together: 
    • Zidovudine and stavudine (Zidovudine inhibits phosphorylation of stavudine, decreasing its effectiveness.) 
    • Zalcitabine and didanosine, stavudine, or lamivudine (Lamivudine decreases phosphorylation of zalcitabine, whereas stavudine and didanosine have additive peripheral neuropathic effects.)

     

  • Indications to change ART therapy include the following: 
    • Developmental regression 
    • New neurologic symptoms 
    • Growth failure 
    • Clinical disease progression 
    • Declining immunologic function 
    • Increasing viral load 
    • No decrease in viral load compared with that at therapy initiation
  • Treatment for those at risk for vertical transmission
  • Within 6-12 hours of delivery of a neonate at risk, zidovudine therapy should be started after a baseline CBC count is obtained. Zidovudine therapy should be continued until the infant is aged 6 weeks, at which time it may be discontinued if all DNA HIV PCR results are negative. 
  • PCP prophylaxis should be started in all infants aged 6 weeks who were born to HIV-infected mothers and continued until HIV infection has been ruled out. 
  • DNA HIV PCR or viral cultures are used to detect infection during the first 24 months of an infant’s life. Compared with viral cultures, DNA HIV PCR has a similar accuracy and is less costly. DNA HIV PCR should be performed in neonates and infants at birth, 1-2 weeks, 4-6 weeks, and 4-6 months. Within the first 48 hours, 14 days, and 4 weeks of life, 38%, 93%, and 96% of infected children, respectively, have positive HIV DNA PCR results. Any positive HIV DNA PCR finding should be confirmed with follow-up HIV DNA PCR before infection is diagnosed. 
  • HIV infection can be ruled out if one of the following is true: 
    • DNA HIV PCR results are consistently negative in an infant older than 4 months in the absence of breastfeeding. 
    • Two DNA HIV PCR results obtained at least a month apart are negative in an infant older than 6 months.
  • Treatment for hematopoietic disturbances
  • Thrombocytopenia is common in HIV infection, and platelet production generally decreases regardless of the platelet count. Immune-mediated platelet destruction develops in approximately 20% of children with HIV infection. In children with advanced disease, severe thrombocytopenia may need to be managed. 
    • The platelet count may transiently increase with IV immunoglobulin (IVIG), interferon (IFN)-alfa, corticosteroids, or anti-Rh immunoglobulin. IVIG is the treatment of choice. Regimens include 1-2 g/kg of IVIG per day for 2-5 days. Three million units of IFN-alfa administered 3 times per week increases the platelet count in 50% of adults after 3 weeks. A 4-week course of prednisone at 1-2 mg/kg followed by a 2-4-week taper is an alternative, but the immunosuppressive adverse effects must be considered carefully. 
    • Anti-Rh immunoglobulin is useful in Rh-positive patients who have not undergone splenectomy, and it is relatively inexpensive. The 1- to 2-g decrease in the hemoglobin level must be considered, and this effect limits the use of this therapy in anemic patients. In most patients, 25 mcg/kg intravenously administered on 2 consecutive days with repeated doses of IV anti-Rh or intramuscular anti-D every 2-4 weeks increases the platelet count. Alternatively, 6-13 mcg/kg intramuscularly administered every week also produces a reasonable increase in the platelet count. 
    • More permanent therapy includes splenectomy or the use of zidovudine or danazol. High-dose zidovudine can reverse HIV-related idiopathic thrombocytopenia purpura (HIV-ITP) in most adults. Treatment of HIV infection, especially with zidovudine, appears to improve the platelet count and platelet production. In adults, 400-800 mg of danazol every day increases the platelet count in 1-2 months. Splenectomy is an effective long-term treatment. Although splenectomy is not associated with an increased mortality rate, the risk of fulminant infections with encapsulated bacteria is increased.

     

  • Iatrogenic anemia is not uncommon, and HIV infection commonly causes bone marrow suppression and reduces serum erythropoietin levels and bone marrow responses to erythropoietin. An infectious or neoplastic agent may cause new-onset anemia. A standard anemia workup should be performed along with a determination of the erythropoietin level, reticulocyte count, and indirect bilirubin level. 
    • A high reticulocyte count indicates a good bone marrow response. When accompanied by a high indirect bilirubin level, hemolytic anemia should be suspected. Sulfonamides, dapsone, or oxidant drugs in glucose-6-phosphate dehydrogenase (G-6-PD) deficiency can cause iatrogenic erythrocyte hemolysis. A low indirect bilirubin level indicates response to acute blood loss or recent replacement of a necessary cofactor. 
    • Disseminated intravascular coagulation and thrombotic thrombocytopenic purpura also can cause hemolytic anemia and are associated with fragmented red cells on the smear and thrombocytopenia. 
    • Although the prevalence of erythrocyte autoantibodies is high in HIV infected patients, especially those with hypergammaglobulinemia, the rate of hemolysis by this mechanism is low. 
    • Hemophagocytic syndrome occurs when macrophages in the bone marrow phagocytose erythrocytes. 
    • A low reticulocyte count indicates bone marrow suppression or ineffective erythropoiesis. Vitamin B-12 or folic acid deficiency produces a high indirect bilirubin level and MCV. Patients with HIV are especially at risk for these deficiencies because of poor nutrition and poor small-bowel function. As many as 33% of patients with HIV have a negative vitamin B-12 balance. 
    • Folic acid deficiency causes the production of large oval erythrocytes, hypersegmented polymorphonucleocytes, and pancytopenia. Vitamin B-12 deficiency causes subacute combined degeneration of the spinal cord, along with high cortical dysfunction. Before treatment with supplemental parenteral vitamin B-12 and enteral folic acid, serum folate and vitamin B-12 levels must be measured. 
    • A low or normal indirect bilirubin value suggests secondary myelosuppression. 
    • A high MCV indicates iatrogenic pharmaceutical suppression of erythropoiesis. A low MCV suggests iron deficiency anemia. A normal MCV suggests HIV anemia, anemia related to chronic disease, an infectious etiology, or neoplastic marrow invasion. 
    • Many pharmaceuticals and parvovirus B19 cause neutropenia in addition to anemia. 
    • Ancillary hematologic laboratory tests may help clarify the differential diagnosis, and an investigation of an infectious etiology may be warranted if the CD4 count is low. 
    • Multiple etiologies may be involved, resulting in laboratory values that may not correlate with a particular type of anemia. Clinical evaluation and correlation with laboratory values is necessary. Bone marrow biopsy may be necessary if laboratory and clinical findings are inconclusive. 
    • Serum erythropoietin levels less than 500 IU/L and anemia due to bone marrow suppression as a result of infection, inflammation, or pharmaceutical agents should be managed with erythropoietin. Other causes of anemia must be ruled out and managed before erythropoietin in used. Erythropoietin should be started at 100 U/kg subcutaneously (SC) 3 times per week and may be increased to 200 U/kg/dose. Once the hematocrit level has normalized, dosing should be decreased to once every week or every other week to maintain a stable hematocrit level. Adverse effects include pain at the injection site and fever. Supplemental iron always should be given with erythropoietin.
  • Neutropenia is relatively common in advanced disease and creates a significant risk for infection. In one fourth of patients with moderate neutropenia, bacterial infections develop, most often within 24 hours of neutropenia onset. The following myelosuppressive medications, especially zidovudine, trimethoprim-sulfamethoxazole, and ganciclovir, can induce neutropenia: 
    • Zidovudine 
    • Lamivudine 
    • Didanosine 
    • Stavudine 
    • Ganciclovir 
    • Foscarnet 
    • Flucytosine 
    • Amphotericin 
    • Sulfonamides 
    • Trimethoprim, trimethoprim-sulfamethoxazole (TMP-SMZ) 
    • Pyrimethamine 
    • Pentamidine

     

  • Infectious agents such as parvovirus B19 can cause myelosuppression, as can invasive neoplastic processes of the marrow. 
  • Granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF) treat neutropenia and promote granulocyte production and function. GM-CSF has more adverse effects than G-CSF and promotes viral replication; however, GM-CSF does not increase the viral load if it is used with antiretroviral therapy. G-CSF is started at 5 mcg/kg/d and is given until neutropenia resolves. Titration of G-CSF to once or twice per week is typical. Adverse effects of G-CSF are minimal and include bone pain and elevations in lactate dehydrogenase (LDH) and alkaline phosphatase levels. GM-CSF is started at 5 mcg/kg/d SC for 5 days and then titrated for effect. Adverse effects include flulike symptoms, myalgias, bone pain, fatigue, and fever.

Surgical Care:

  • Children who require chronic parenteral medications may need central venous access line placement. Placement of subcutaneous ports are common in children requiring chronic parenteral therapy, but the risks of placing such a line should be weighed against the possible need for recurrent replacement required because of repeated line infections.
  • Gastrostomy placement may be necessary in children who cannot take oral medications or who cannot ingest adequate nutrition by mouth. Gastrostomy tubes are well tolerated and are often more comfortable than nasogastric or nasojejunal tubes.
  • A biopsy should be taken of enlarged lymph nodes of undetermined cause, especially if they are singular, hard, nonmotile, or not accompanied by generalized lymphadenopathy.

Consultations:

  • The infectious-disease specialist is usually the primary care provider who coordinates care by the other specialty services.
  • In general, a team of specialists is best to manage the medical care of the child with HIV infection.
  • A human development specialist, nutritionist, psychologist, and case manager should be involved in the treatment of every child with HIV infection.
  • Cardiology, endocrinology, gastroenterology, nephrology, neurology, and pulmonology specialists should be consulted when necessary.

Diet:

  • Malnutrition with an accompanying failure to thrive is not uncommon in children infected with HIV.
  • The patient’s dietary habits should be reviewed on a regular basis, and a nutrition specialist should be involved in the patient’s treatment.
  • Poor appetite results in poor nutritional intake; in such cases, appetite stimulants can be useful.
  • High-energy, high-protein nutritional supplements are commonly needed, and caretakers must be instructed to avoid giving the child any food or water that has a high risk of being contaminated with any infectious agent. HIV and accompanying opportunistic infections can worsen gastrointestinal symptoms.
  • Nasogastric, nasojejunal, and gastrostomy tubes may be needed to support the patient’s nutritional and fluid status.
  • Parenteral hyperalimentation also may be necessary in cases in which the patient’s gastrointestinal tract cannot support significant feedings.

Medication

Antiretroviral agents inhibit reverse transcriptase; thus, they cause chain termination when incorporated into a growing viral strand. Used in combination for HIV postexposure prophylaxis (PEP). Agents included in this class of drugs are NRTIs (eg, zidovudine, abacavir, didanosine, lamivudine, stavudine, zalcitabine), protease inhibitors (eg, indinavir, nelfinavir, ritonavir, saquinavir), NNRTIs (eg, delavirdine, efavirenz, nevirapine), and fusion inhibitors (eg, enfuvirtide). Those that inhibit reverse transcriptase act by preventing the spread of the virus to uninfected cells, whereas protease inhibitors act during a late stage of viral replication, preventing the maturation of the viral particle to an infective form.

Enfuvirtide (Fuzeon) is the first agent in a new class of anti-HIV drugs known as fusion inhibitors. Enfuvirtide blocks HIV from entering the human immune cell by inhibiting gp41 protein, thereby disrupting structural rearrangement for the virus to fuse with healthy immune cells and preventing HIV replication. Clinical trials have shown immunologic improvements were twice as likely to achieve undetectable HIV-1 plasma levels (ie, <40 copies/mL) when enfuvirtide was added to antiretroviral optimized regimens.

The adult dose of enfuvirtide is 90 mg SC bid. The dose for pediatric patients older than 6 years is 2 mg/kg/dose SC bid, not to exceed 90 mg/dose. The most common adverse effect is local injection site reactions. Other common adverse effects may include diarrhea, nausea, fatigue, headaches, peripheral neuropathy, dizziness, myalgia, or pancreatitis. Enfuvirtide may cause a systemic allergic reaction (eg, shortness of breath, a fever, a rash, chills, vomiting, hypotension). Monitoring for bacterial pneumonia is recommended (although uncommon, those receiving enfuvirtide developed pneumonia more often than those not taking enfuvirtide).

Monotherapy with antiretroviral has failed to produce sustained clinical benefits, including improved survival. This failure is partly due to the development of drug-resistant variants of HIV. Resistance develops rapidly during monotherapy, and cross-resistance between related drugs is reported.

Combination therapy with antiretroviral drugs (a strategy analogous to the treatment of tuberculosis and other infectious diseases) has improved efficacy, minimized toxicity, and delayed drug resistance.

Double- and triple-drug therapy should start with 2 NRTIs or 2 NRTIs plus an NNRTI or a protease inhibitor. A 10- or 5-fold decrease in viral load is expected in 2-3 months with triple-drug therapy or double-drug therapy, respectively, but not all infants have an undetectable viral load. Only triple combination therapy, however, appears to significantly reduce the relative hazard ratio of death, when compared with no treatment.

Treatment guidelines from the Centers for Disease Control (CDC) change constantly. The most current guidelines may be viewed at the HIV/AIDS Treatment Information Service Web site.

Recommended basic and expanded HIV PEP regimens have recently been updated by the CDC; see the CDC Basic and Expanded HIV Postexposure Prophylaxis Regimens Web site. The following list is an overview of these recommendations.

 

  • Basic regimen – Zidovudine plus lamivudine 
  • Alternative basic regimen – Lamivudine plus stavudine or didanosine plus stavudine 
  • Expanded regimen – Basic regimen plus one of the following: 
    • Indinavir 
    • Nelfinavir 
    • Efavirenz 
    • Abacavir

     

  • Use the following only with expert consultation: 
    • Saquinavir 
    • Amprenavir 
    • Delavirdine 
    • Lopinavir and ritonavir combination product (Kaletra)

     

  • The use of nevirapine is generally not recommended.

See also the supplementary material about Antiretroviral Agents, Drug Interactions with Antiretroviral Agents, and Use of Antiretroviral Drugs in Pregnancy.

Drug Category: NRTIs — These are nucleoside analogues with antiviral activity. They are indicated for use in the treatment of HIV infection and delay the progression of the disease.

Drug Name Abacavir (ABC, Ziagen) — Patients and parents must be cautioned about the risk of a serious hypersensitivity reaction. A medication guide and warning card should be provided.
Adult Dose 300 mg PO bid
Pediatric Dose 1-3 months: 8 mg/kg/dose PO q12h (investigational)
3 months to 13 years: 8 mg/kg PO bid; not to exceed 300 mg/dose
Contraindications Documented hypersensitivity
Interactions Ethanol decreases elimination, slightly increasing levels
Pregnancy C – Safety for use during pregnancy has not been established.
Precautions Nausea, vomiting, headache, fever, rash, anorexia, and fatigue common; diarrhea, pancreatitis, increased liver enzyme levels, elevated blood glucose levels, elevated triglyceride levels, and lactic acidosis uncommon
Potentially fatal hypersensitivity reaction in 5% of adults and children; symptoms include fever, fatigue, malaise, nausea, vomiting, diarrhea, abdominal pain, respiratory symptoms (eg, cough, dyspnea, pharyngitis), lymphadenopathy, ulceration of mucous membranes, maculopapular or urticarial rash (can occur without rash), elevated liver function test results, elevated creatine phosphokinase level, elevated creatinine level, and lymphopenia; hypersensitivity reaction generally occurs in the first 6 wk of therapy; in suspected hypersensitivity, ABC should be stopped and not restarted; report hypersensitivity reactions to Abacavir Hypersensitivity Registry at 1-800-270-0425
Drug Name Didanosine (ddI, dideoxyinosine, Videx) — Purine nucleoside analogue with antiviral activity.
Adult Dose <60 kg: 125 mg PO bid
>60 kg: 200 mg PO bid
Pediatric Dose Neonates: 50 mg/m2 PO bid
Children: 90-150 mg/m2 PO bid
Higher dose for central nervous system disease
Contraindications Documented hypersensitivity
Interactions Suboptimal absorption with ketoconazole, itraconazole, dapsone, tetracycline, fluoroquinolone antibiotics, delavirdine; allow 2 h between use of these with ddI and more than 1 and 2 h with indinavir and ritonavir, respectively; methadone decreases ddI levels (adjust dose)
Pregnancy B – Usually safe but benefits must outweigh the risks.
Precautions Diarrhea, abdominal pain, nausea, vomiting, dose-related peripheral neuropathy, electrolyte abnormalities, and hyperuricemia common; pancreatitis, increased liver enzyme levels, and retinal depigmentation uncommon; do not administer with meals; refrigerated oral solution stable for 30 d; administer 2 tab/dose for adequate buffering
Drug Name Lamivudine (3TC, Epivir) — Dideoxynucleoside analogue with antiretroviral activity. In combination with oral zidovudine, has produced significant and sustained increases in CD4+ counts and decreases in viral load in HIV-infected patients.
Adult Dose <50 kg: 2 mg/kg PO bid
>50 kg: 150 mg PO bid
Pediatric Dose Neonates: 2 mg/kg PO bid
Children: 4 mg/kg PO bid; not to exceed 150 mg/dose
Contraindications Documented hypersensitivity
Interactions Bactrim increases blood levels; with ZDV, resistance to ZDV may be prevented and reversed; decrease dose in renal impairment; decreases phosphorylation of zalcitabine, decreasing effect
Pregnancy C – Safety for use during pregnancy has not been established.
Precautions Headache, fatigue, nausea, diarrhea, rash, and abdominal pain common; pancreatitis, peripheral neuropathy, decreased neutrophil count, and increased liver enzyme levels uncommon
Drug Name Stavudine (d4T, Zerit) — Indicated as a first-line component of a combination antiretroviral therapy regimen in patients infected with HIV-1.
Adult Dose <60 kg: 30 mg PO bid
>60 kg: 40 mg PO bid
Pediatric Dose Neonates: AIDS Clinical Trial Group protocol 332 in progress
Children <30 kg: 1 mg/kg PO bid
Contraindications Documented hypersensitivity
Interactions Zidovudine inhibits intracellular phosphorylation, decreasing its efficacy (do not administer together); levels increase with drugs that decrease renal function or in renal impairment; additive peripheral neuropathy with lamivudine and zalcitabine
Pregnancy C – Safety for use during pregnancy has not been established.
Precautions Headache, GI disturbances, and rashes common; peripheral neuropathy, pancreatitis, and increased liver enzyme levels uncommon; refrigerated oral solution is stable for 30 d if refrigerated
Drug Name Zalcitabine (ddC, HIVID) — Dideoxynucleoside analogue with antiviral activity.
Adult Dose 0.75 mg PO tid
Pediatric Dose 0.005-0.01 mg/kg PO tid
Contraindications Documented hypersensitivity
Interactions Do not use with ddI, d4T, or pentamidine IV due to increased risk of peripheral neuropathy and pancreatitis, respectively; level may be increased in renal impairment and concurrent cimetidine, amphotericin, foscarnet, and aminoglycosides; antacids decrease absorption; lamivudine decreases phosphorylation, decreasing effect
Pregnancy C – Safety for use during pregnancy has not been established.
Precautions Headache, GI disturbances, malaise common; peripheral neuropathy, pancreatitis, hepatic toxicity, oral ulcers, esophageal ulcers, hematologic toxicity, skin rashes uncommon; administer to patient with an empty stomach
Drug Name Zidovudine (ZDV, AZT, Retrovir) — Thymidine analog that inhibits viral replication.
Adult Dose 200 mg PO tid or 300 mg PO bid
Pediatric Dose Premature neonates: 1.5 mg/kg IV bid until aged 2 wk, then 2 mg/kg IV tid
Neonates: 1.5 mg/kg IV qid or 2 mg/kg PO qid
Children: 160 mg/m2 PO tid or 180 mg/m2 PO bid when given with other ART; 120 mg/m2/ IV qid or 20 mg/m2/h IV; IV infusions over 1 h
Contraindications Documented hypersensitivity
Interactions Increased toxicity may be observed with ganciclovir, IFN-alpha, Bactrim, acyclovir, and drugs associated with bone marrow suppression; probenecid, atovaquone, methadone, valproic acid, and fluconazole may increase toxicity; cimetidine may decrease renal clearance; rifampin, rifabutin, and clarithromycin interfere with absorption; ribavirin decreases intracellular phosphorylation; may increase or decrease phenytoin concentrations; do not administer with d4T (decreases phosphorylation, decreasing effect)
Pregnancy C – Safety for use during pregnancy has not been established.
Precautions Granulocytopenia, anemia, and headache common; determine baseline CBC before therapy; measure granulocyte and hematocrit levels monthly during initiation; erythropoietin, filgrastim, or reduced dose of 120 mg/m2 may be necessary if granulocytopenia or anemia develop; myopathy, myositis, and liver toxicity uncommon; decrease dose in severe renal impairment and hepatic dysfunction

 

Drug Category: NNRTIs — NNRTIs inhibit both DNA- and RNA-directed polymerase functions of HIV-1 reverse transcriptase. The different site of action of non-nucleoside and nucleoside inhibitors suggests potential synergistic effects with these agents and potential activity of these agents against nucleoside-resistant HIV strains.

Drug Name Delavirdine (DLV, Rescriptor) — Potent non-nucleoside HIV-1 reverse transcriptase inhibitor used primarily in combination regimens.
Adult Dose 400 mg PO tid
Pediatric Dose Not established
Contraindications Documented hypersensitivity; do not use with rifampin or rifabutin
Interactions Metabolized by hepatic CYP3A, may effect drugs metabolized by this pathway; absorption decreased with antacids or histamine2-receptor antagonists; ketoconazole or fluoxetine increases trough levels; clarithromycin increases levels of both; increases dapsone and quinidine levels; level decreases while increasing saquinavir and indinavir levels
Pregnancy C – Safety for use during pregnancy has not been established.
Precautions Headache, fatigue, GI upset, and severe rash common; should not be taken within 1 h of ddI or antacids
Drug Name Efavirenz (DMP-266, EFV Sustiva) — Used only in combination regimens.
Adult Dose 600 mg PO qhs
Pediatric Dose ❤ years: Not established
10 to <15 kg: 200 mg/d PO
15 to <20 kg: 250 mg/d PO
20 to <25 kg: 300 mg/d PO
25 to <32.5 kg: 350 mg/d PO
32.5 to <40 kg: 400 mg/d PO
>40 kg: Administer as in adults
Contraindications Documented hypersensitivity; do not use with the antihistamines astemizole or terfenadine, sedative-hypnotics midazolam or triazolam, cisapride, ergot alkaloid derivatives, or clarithromycin
Interactions Mixed inducer-inhibitor of CYP-450 3A4 enzymes; can affect drugs using this pathway; highly bound by plasma protein; may interact with other highly protein-bound drugs; carefully monitor with coadministration of warfarin or ethinyl estradiol; rifampin, rifabutin, phenobarbital, and phenytoin decrease levels; decreases levels of saquinavir and indinavir and increases levels of nelfinavir
Pregnancy D – Unsafe in pregnancy
Precautions Neural tube defects in neonates reported with first trimester exposure; rash, CNS symptoms (eg, psychiatric abnormalities, sleep disturbance), increased LFT results common; capsule contents can be added to liquids or foods; peppery taste may be disguised with grape jelly
Drug Name Nevirapine (NVP, Viramune) — Indicated for use in combination with other antiretroviral agents for the treatment of HIV-1 infection.
Adult Dose 100 mg PO bid for 2 wk; then 200 mg PO bid
Pediatric Dose Neonates: 5 mg/kg/d PO for 14 d; then 120 mg/m2 PO bid for 14 d; then 200 mg/m2 PO bid
Children: 120 mg/m2/d PO for 14 d; then 200 mg/m2 PO bid
Contraindications Documented hypersensitivity
Interactions Induces hepatic CYP3A, causing autoinduction and potential drug interactions; carefully monitor with rifampin, rifabutin, oral contraceptives, sedative-hypnotics, oral anticoagulants, digoxin, phenytoin, and theophylline; decreases levels of indinavir, saquinavir, and ritonavir
Pregnancy C – Safety for use during pregnancy has not been established.
Precautions Possibly severe and life-threatening rash (usually within the first 6 wk of therapy; if in the initial 14 d, do not increase dose until rash resolves), sedation, headache, diarrhea, and nausea common; increased liver enzyme levels and hepatitis uncommon

Drug Category: Protease inhibitors — Protease inhibitors inhibit HIV protease, which is required for HIV replication and the formation of mature, infectious viral particles.

Drug Name Indinavir (Crixivan, IDV) — Prevents formation of protein precursors necessary for HIV infection of uninfected cells and viral replication.
Adult Dose 800 mg PO tid
Pediatric Dose 500 mg/m2 PO tid
Contraindications Documented hypersensitivity
Interactions Potent inhibitor of CYP450 3A4; increases astemizole, cisapride, midazolam, isoniazid, stavudine, trimethoprim, terfenadine, triazolam, and oral contraceptive levels; fluconazole and rifampin decrease levels; quinidine and ketoconazole increase levels; decreases lamivudine levels
Pregnancy C – Safety for use during pregnancy has not been established.
Precautions Nausea, abdominal pain, headache, metallic taste, dizziness, and asymptomatic hyperbilirubinemia common; nephrolithiasis, worsening of chronic liver disease, spontaneous bleeding episodes in hemophiliacs, hyperglycemia, ketoacidosis, diabetes, and hemolytic anemia uncommon; decrease dose in hepatic insufficiency
Drug Name Nelfinavir (Viracept, NPV) — Inhibits HIV-1 protease, resulting in the production of an immature and noninfectious virus.
Adult Dose 750 mg PO tid with meals
Pediatric Dose Neonates: 40 mg/kg PO q12h (Pediatrics AIDS Group Trial protocol 353)
Children: 20-30 mg PO tid
Contraindications Documented hypersensitivity
Interactions Increases astemizole, cisapride, midazolam, isoniazid, stavudine, trimethoprim, terfenadine, triazolam, and oral contraceptive levels; fluconazole and rifampin decrease levels; quinidine and ketoconazole increase levels; nelfinavir decreases lamivudine levels
Pregnancy B – Usually safe but benefits must outweigh the risks.
Precautions Diarrhea common; asthenia, abdominal pain, rash, exacerbation of chronic liver disease, spontaneous bleeding episodes in hemophiliacs, hyperglycemia, ketoacidosis, and diabetes uncommon; administer with meal or snack but not within 2 h of ddI; taste improved with chocolate milk, pudding, ice cream, or formula; do not mix with acidic food or juice
Drug Name Ritonavir (Norvir, RTV) — HIV protease inhibitor used as a part of double or triple therapy with nucleosides and other protease inhibitors.
Adult Dose 300 mg PO bid initially; increase to 600 mg PO bid over 5 d
Pediatric Dose Neonates: Not established; pharmacokinetic studies underway
250 mg/m2 PO bid initially; gradually increase over 5 d to 400 mg/m2 PO bid over 5 d
Contraindications Documented hypersensitivity; do not administer with cisapride, benzodiazepines, narcotics, anesthetics, antiarrhythmics, or amiodarone
Interactions Coadministration with propoxyphene, quinidine, amiodarone, bupropion, cisapride, clozapine, encainide, astemizole, bepridil, flecainide, meperidine, rifabutin, piroxicam, propafenone, and terfenadine may cause arrhythmias, hematologic abnormalities, and seizures coadministration with alprazolam, clorazepate, diazepam, estazolam, flurazepam, midazolam, triazolam and zolpidem may significantly increase toxicity
Pregnancy C – Safety for use during pregnancy has not been established.
Precautions Nausea, vomiting, diarrhea, headache, abdominal pain, and anorexia common; circumoral paresthesias, increased LFT results, spontaneous bleeding episodes in hemophiliacs, pancreatitis, increased triglyceride and cholesterol levels, hyperglycemia, ketoacidosis, diabetes, and hepatitis uncommon; do not give within 2 h of ddI; taste improved with chocolate milk, pudding, or ice cream; dull taste buds with Popsicles, spoonfuls of frozen juice concentrate, or peanut butter, or give strong-flavored foods after administration
Drug Name Saquinavir (Invirase [h-SQV], Fortovase [s-SQV]) — HIV protease inhibitor used as a part of a double of triple therapy with nucleosides and other protease inhibitors.
Adult Dose Hard gel capsules (Invirase): 600 mg PO tid
Soft gel capsules (Fortovase): 1200 mg PO tid
Pediatric Dose Infants and children: Fortovase 50 mg/kg PO (investigational)
Contraindications Documented hypersensitivity
Interactions May affect or be affected by medications metabolized by the CYP3A4 pathway; coadministration with propoxyphene, quinidine, amiodarone, bupropion, cisapride, clozapine, encainide, astemizole, bepridil, flecainide, meperidine, rifabutin, piroxicam, propafenone, and terfenadine may cause arrhythmias; rifampin, rifabutin and nevirapine, carbamazepine, dexamethasone, phenobarbital and phenytoin decrease levels; delavirdine, indinavir, ritonavir, nelfinavir, ketoconazole, and grapefruit juice increase levels
Pregnancy B – Usually safe but benefits must outweigh the risks.
Precautions Poor bioavailability (even with newer Fortovase formulation); diarrhea, abdominal discomfort, headache, nausea, paresthesias, and rash common; sun exposure can cause photosensitivity reactions; worsening of chronic liver disease, spontaneous bleeding in hemophiliacs, hyperglycemia, ketoacidosis, and diabetes uncommon; administer within 2 h of full meal
Drug Name Amprenavir (APV, Agenerase) — Indicated for the treatment of HIV-1 infection to be used in combination with other antiretroviral agents
Adult Dose 1.2 g PO bid
Pediatric Dose ❤ years: Do not administer (propylene glycol in liquid formulation)
>3 years and <50 kg:
Oral solution: 22.5 mg/kg PO bid or 17 mg/kg PO tid; not to exceed 2.4 g/d
Capsules: 20 mg/kg PO bid or 15 mg/kg PO tid; not to exceed 2.4 g/d
>50 kg: Administer as in adults
Contraindications Documented hypersensitivity; children❤ y; do not administer with astemizole, bepridil, cisapride, dihydroergotamine, ergotamine, midazolam, rifampin, or triazolam
Interactions Inhibits CYP450 isoenzyme 3A4; efavirenz decreases levels; increases rifabutin level; reduces hormonal contraceptive efficacy; potential interactions with amiodarone, lidocaine, tricyclic antidepressants, quinidine, and warfarin; monitor drug levels
Pregnancy D – Unsafe in pregnancy
Precautions Vomiting, diarrhea, perioral paresthesias, and rash frequent; Stevens-Johnson syndrome in 1% of patients; hypercholesterolemia, hyperglycemia, new or worsening diabetes mellitus, hemolytic anemia, and spontaneous bleeding in hemophiliacs rare; formulations include vitamin E 46 IU/mL and 109 IU/capsule; supplemental vitamin E should not be taken; vitamin E can potentiate the effects of oral anticoagulants; do not give with high-fat meal or within 1 h of antacid
Drug Name Lopinavir and ritonavir (Kaletra, LVP/r) — Lopinavir inhibits HIV protease and renders the enzyme incapable of processing polyprotein precursors, leading to the production of noninfectious immature HIV particles. Ritonavir inhibits CYP3A metabolism of lopinavir, which increases plasma levels of lopinavir.
Adult Dose 400 mg lopinavir/100 mg ritonavir (ie, 3 caps) PO bid
Pediatric Dose <6 months: Not established
6 months to 12 years:
7-15 kg: 12 mg/kg PO bid (based on lopinavir component)
15-40 kg: 10 mg/kg PO bid (based on lopinavir component)
>40 kg or >12 years: Administer as in adults
Contraindications Documented hypersensitivity; do not administer with benzodiazepines, narcotics, anesthetics, antiarrhythmics and amiodarone
Interactions Coadministration with quinidine, amiodarone, encainide, bepridil, flecainide, rifabutin, and propafenone may cause arrhythmias; alprazolam, propoxyphene, bupropion, clorazepate, diazepam, estazolam, meperidine, flurazepam, midazolam, triazolam, and zolpidem toxicity may significantly increase with concomitant lopinavir; carbamazepine, phenobarbital, dexamethasone, phenytoin, rifampin, efavirenz, and nevirapine may decrease lopinavir levels
Pregnancy C – Safety for use during pregnancy has not been established.
Precautions Pancreatitis (suspend therapy with symptoms); may exacerbate diabetes mellitus; caution in hepatic impairment; large increases of total cholesterol and triglyceride levels reported; hemophilia type A and type B reported with protease inhibitors

 

 

source : emedicine

 

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Editor in Chief :

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Copyright © 2009,  FIGHT AGAINST  AIDS, SAVE  INDONESIAN CHILDREN  Information Education Network. All rights reserved. 


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