Ziagen

Nucleoside and Nucleotide Reverse Transcriptase Inhibitors (NRTI)s

Hazardous Drugs Classification
NIOSH 2016 List: Group 2
NIOSH (Draft) 2020 List: Table 2
Observe and exercise appropriate precautions for handling, preparation, administration, and disposal of hazardous drugs.
Use gloves to handle. Cutting, crushing, or otherwise manipulating tablets/capsules will increase exposure and require additional protective equipment. Oral liquid drugs require double chemotherapy gloves and protective gown; may require eye/face protection.

May be administered without regard to meals.

The oral solution may turn brown over time.

diarrhea / Early / 2.0-2.0
pancreatitis / Delayed / Incidence not known
lactic acidosis / Delayed / Incidence not known
hepatotoxicity / Delayed / Incidence not known
toxic epidermal necrolysis / Delayed / Incidence not known
erythema multiforme / Delayed / Incidence not known
Stevens-Johnson syndrome / Delayed / Incidence not known
myocardial infarction / Delayed / Incidence not known
hepatic failure / Delayed / Incidence not known
renal failure (unspecified) / Delayed / Incidence not known
azotemia / Delayed / Incidence not known
rhabdomyolysis / Delayed / Incidence not known
serious hypersensitivity reactions or anaphylaxis / Rapid / Incidence not known
respiratory arrest / Rapid / Incidence not known
acute respiratory distress syndrome (ARDS) / Early / Incidence not known

migraine / Early / 1.0-13.0
gastritis / Delayed / 6.0-6.0
hypertriglyceridemia / Delayed / 2.0-6.0
elevated hepatic enzymes / Delayed / 6.0-6.0
depression / Delayed / 6.0-6.0
neutropenia / Delayed / 2.0-5.0
hyperamylasemia / Delayed / 2.0-4.0
anemia / Delayed / 0-1.0
hyperglycemia / Delayed / 0-1.0
thrombocytopenia / Delayed / 1.0-1.0
leukopenia / Delayed / 0-1.0
hepatomegaly / Delayed / Incidence not known
steatosis / Delayed / Incidence not known
lipodystrophy / Delayed / Incidence not known
hypotension / Rapid / Incidence not known
conjunctivitis / Delayed / Incidence not known
edema / Delayed / Incidence not known
oral ulceration / Delayed / Incidence not known
lymphadenopathy / Delayed / Incidence not known
dyspnea / Early / Incidence not known
lymphopenia / Delayed / Incidence not known

nausea / Early / 7.0-19.0
headache / Early / 1.0-13.0
fatigue / Early / 7.0-12.0
malaise / Early / 7.0-12.0
vomiting / Early / 2.0-10.0
insomnia / Early / 10.0-10.0
nightmares / Early / 10.0-10.0
fever / Early / 6.0-9.0
chills / Rapid / 6.0-9.0
rash / Early / 5.0-7.0
abdominal pain / Early / 6.0-6.0
dizziness / Early / 6.0-6.0
musculoskeletal pain / Early / 5.0-6.0
anxiety / Delayed / 5.0-5.0
infection / Delayed / 4.0-5.0
paresthesias / Delayed / Incidence not known
maculopapular rash / Early / Incidence not known
urticaria / Rapid / Incidence not known
lethargy / Early / Incidence not known
pharyngitis / Delayed / Incidence not known
arthralgia / Delayed / Incidence not known
myalgia / Early / Incidence not known
cough / Delayed / Incidence not known

Ziagen, Ziagen Solution

Rx

Synthetic guanosine nucleoside reverse transcriptase inhibitor (NRTI)
Indicated for the treatment of human immunodeficiency virus (HIV) infection
Associated with fatal hypersensitivity reactions during initial treatment and with reintroduction of therapy

300 mg PO twice daily or 600 mg PO once daily.

300 mg PO twice daily or 600 mg PO once daily. Data regarding the efficacy of once-daily dosing are limited to patients who transitioned from twice-daily dosing to once-daily dosing after 36 weeks of treatment. Guidelines state that therapy can be initiated with once-daily dosing in those able to take pill formulations. However, if therapy was initiated with twice-daily abacavir solution, twice-daily dosing should be used with consideration to switching to once-daily dosing in clinically stable patients with undetectable viral loads and stable CD4 counts.

150 mg PO once daily in the morning and 300 mg PO once daily in the evening or 450 mg PO once daily. Data regarding the efficacy of once-daily dosing are limited to patients who transitioned from twice-daily dosing to once-daily dosing after 36 weeks of treatment. Guidelines state that therapy can be initiated with once-daily dosing in those able to take pill formulations. However, if therapy was initiated with twice-daily abacavir solution, twice-daily dosing should be used with consideration to switching to once-daily dosing in clinically stable patients with undetectable viral loads and stable CD4 counts.

150 mg PO twice daily or 300 mg PO once daily. Data regarding the efficacy of once-daily dosing are limited to patients who transitioned from twice-daily dosing to once-daily dosing after 36 weeks of treatment. Guidelines state that therapy can be initiated with once-daily dosing in those able to take pill formulations. However, if therapy was initiated with twice-daily abacavir solution, twice-daily dosing should be used with consideration to switching to once-daily dosing in clinically stable patients with undetectable viral loads and stable CD4 counts.

300 mg PO twice daily or 600 mg PO once daily.

300 mg PO twice daily or 600 mg PO once daily.

8 mg/kg/dose PO twice daily or 16 mg/kg/dose PO once daily (Max: 600 mg/day). Data regarding the efficacy of once-daily dosing are limited to patients who transitioned from twice-daily dosing to once-daily dosing after 36 weeks of treatment.

8 mg/kg/dose PO twice daily or 16 mg/kg/dose PO once daily. Data regarding the efficacy of once-daily dosing are limited to patients who transitioned from twice-daily dosing to once-daily dosing after 36 weeks of treatment. Guidelines recommend that infants and young children should be initiated with twice-daily dosing of the oral solution. A switch to once-daily dosing may be considered for clinically stable patients with undetectable viral loads and stable CD4 counts.

4 mg/kg/dose PO twice daily. Dosing recommendations are based on pharmacokinetic modeling and observational data supporting the safety of abacavir in infants younger than 3 months.

2 mg/kg/dose PO twice daily. Dosing recommendations are based on pharmacokinetic modeling and observational data supporting the safety of abacavir in neonates.

The US Public Health Service guidelines suggest abacavir 300 mg PO twice daily or 600 mg PO daily in combination with one of the following backbones (in order of preference) as acceptable alternative regimens for HIV post-exposure prophylaxis (PEP): tenofovir plus emtricitabine; tenofovir plus lamivudine; zidovudine plus lamivudine; zidovudine plus emtricitabine. Prior to administering an abacavir containing regimen, the US Public Health Service and the New York State Department of Health AIDS Institute (NYSDOH AI) recommend consultation with a clinician experienced in the management of PEP. This recommendation is due the potential for serious hypersensitivity reactions. According to PEP guidelines, individuals potentially exposed to HIV should receive a 3-drug regimen for a total of 28 days; however if tolerability is a concern, use of a 2-drug regimen may be considered and is preferred to prophylaxis discontinuation. Begin prophylaxis as soon as possible, ideally within 2 hours of exposure. If initiation of prophylaxis is delayed (beyond 36 hours or 72 hours after exposure), efficacy of the antiretroviral regimen may be diminished and treatment should be determined on a case-by-case basis. Exposures for which PEP is indicated include: skin puncture by a sharp object that has been contaminated with blood, body fluid, or other infectious material; bite from a patient with visible bleeding in the mouth which causes bleeding by the exposed worker; splash of blood, body fluid, or other infectious material onto the workers mouth, nose, or eyes; exposure of blood, body fluid, or other infectious material on a workers non-intact skin (i.e., open wound, chapped skin, abrasion, dermatitis).

4 mg/kg/dose PO twice daily may be considered as an alternative to zidovudine in situations where zidovudine is not available or the patient has zidovudine-associated toxicity. Due to abacavir-associated hypersensitivity, negative testing for HLA-B*5701 allele must be confirmed prior to administration. NOTE: Abacavir is not recommended as part of a presumptive HIV treatment regimen.

2 mg/kg/dose PO twice daily may be considered as an alternative to zidovudine in situations where zidovudine is not available or the patient has zidovudine-associated toxicity. Initiate treatment as close to birth as possible, preferably within 6 hours; however, due to abacavir-associated hypersensitivity, negative testing for HLA-B*5701 allele must be confirmed prior to administration. NOTE: Abacavir is not recommended as part of a presumptive HIV treatment regimen.

†Indicates off-label use

No dosage adjustment guidelines available for pediatric patients with hepatic impairment.
In patients with mild hepatic impairment (Child-Pugh A, score 5 to 6): Decrease the dose to 200 mg PO twice daily; abacavir oral solution (10 mL PO twice daily) can be used to enable this dose reduction.
Abacavir is contraindicated in patients with moderate to severe hepatic impairment (Child-Pugh B or C, score greater than 6) as safety, efficacy, and pharmacokinetic parameters have not yet been established.

Dosing in patients with renal impairment has not been studied. Renal excretion of unchanged abacavir is a minor route of elimination in humans.
 
Intermittent hemodialysis
It is not known if abacavir is removed by hemodialysis.
 
Peritoneal dialysis
It is not known if abacavir is removed by peritoneal dialysis.

Adefovir: (Major) Patients who are concurrently taking adefovir with antiretrovirals (i.e., anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs)) are at risk of developing lactic acidosis and severe hepatomegaly with steatosis. Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs alone or in combination with antiretrovirals. A majority of these cases have been in women; obesity and prolonged nucleoside exposure may also be risk factors. Particular caution should be exercised when administering nucleoside analogs to any patient with known risk factors for hepatic disease; however, cases have also been reported in patients with no known risk factors. Suspend adefovir in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).
Cabozantinib: (Minor) Monitor for an increase in cabozantinib-related adverse reactions if coadministration with abacavir is necessary. Cabozantinib is a Multidrug Resistance Protein 2 (MRP2) substrate and abacavir is an MRP2 inhibitor. MRP2 inhibitors have the potential to increase plasma concentrations of cabozantinib; however, the clinical relevance of this interaction is unknown.
Echinacea: (Moderate) Use Echinacea sp. with caution in patients taking medications for human immunodeficiency virus (HIV) infection. Some experts have suggested that Echinacea's effects on the immune system might cause problems for patients with HIV infection, particularly with long-term use. There may be less risk with short-term use (less than 2 weeks). A few pharmacokinetic studies have shown reductions in blood levels of some antiretroviral medications when Echinacea was given, presumably due to CYP induction. However, more study is needed for various HIV treatment regimens. Of the agents studied, the interactions do not appear to be significant or to require dose adjustments at the time of use. Although no dose adjustments are required, monitoring drug concentrations may give reassurance during co-administration. Monitor viral load and other parameters carefully during therapy.
Ethanol: (Major) Advise patients to avoid alcohol consumption while taking abacavir. Abacavir is metabolized via alcohol dehydrogenase. Alcohol decreases the elimination of abacavir causing an increase in overall exposure to abacavir. In a study involving HIV-infected men, coadministration of alcohol and abacavir resulted in a 41% increase in abacavir AUC and a 26% increase in abacavir half-life. In males, abacavir had no effect on the pharmacokinetic properties of alcohol; this interaction has not been studied in females. Abacavir has no effect on the pharmacokinetic properties of alcohol. (Major) Because abacavir is metabolized via alcohol dehydrogenase, alcohol decreases the elimination of abacavir causing an increase in overall exposure to abacavir. In a study involving HIV-infected men, coadministration of alcohol and abacavir resulted in a 41% increase in abacavir AUC and a 26% increase in abacavir half-life. In males, abacavir had no effect on the pharmacokinetic properties of alcohol; this interaction has not been studied in females. Abacavir has no effect on the pharmacokinetic properties of alcohol.
Interferon Alfa-2b: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving NRTIs and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
Interferon Alfa-n3: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving NRTIs and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
Interferon Beta-1a: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving NRTIs and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
Interferon Beta-1b: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving NRTIs and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
Interferon Gamma-1b: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving NRTIs and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
Interferons: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving NRTIs and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
Lopinavir; Ritonavir: (Moderate) Caution is advised when administering abacavir and ritonavir concurrently. Ritonavir appears to induce glucuronosyl transferase, and therefore, has the potential to reduce plasma concentrations of drugs that undergo glucuronidation, such as abacavir. The clinical significance of the potential for this interaction is unknown.
Methadone: (Moderate) In a study of 11 adult HIV-infected subjects receiving methadone maintenance therapy (40 to 90 mg/day) and abacavir 600 mg twice daily (twice the current recommended dose), methadone clearance increased by 22% (6% to 42%). While this interaction will not require dosage adjustment in the majority of patients, a small number of patients may require increased doses of methadone. In addition, a significant decrease in abacavir Cmax (34%) and increase in Tmax (67%) were noted, but no changes in overall abacavir clearance or half-life were reported. The clinical significance regarding abacavir therapy is not known.
Nirmatrelvir; Ritonavir: (Moderate) Caution is advised when administering abacavir and ritonavir concurrently. Ritonavir appears to induce glucuronosyl transferase, and therefore, has the potential to reduce plasma concentrations of drugs that undergo glucuronidation, such as abacavir. The clinical significance of the potential for this interaction is unknown.
Orlistat: (Moderate) According to the manufacturer of orlistat, HIV RNA levels should be frequently monitored in patients receiving orlistat while being treated for HIV infection with anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs). Loss of virological control has been reported in HIV-infected patients taking orlistat with atazanavir, ritonavir, tenofovir disoproxil fumarate, emtricitabine, lopinavir; ritonavir, and emtricitabine; efavirenz; tenofovir disoproxil fumarate. The exact mechanism for this interaction is not known, but may involve inhibition of systemic absorption of the anti-retroviral agent. If an increased HIV viral load is confirmed, orlistat should be discontinued.
Peginterferon Alfa-2a: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving NRTIs and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
Peginterferon Alfa-2b: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving NRTIs and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
Peginterferon beta-1a: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving NRTIs and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
Ribavirin: (Moderate) Use abacavir with ribavirin and interferon with caution and closely monitor for hepatic decompensation and anemia. Dose reduction or discontinuation of interferon, ribavirin, or both should be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh greater than 6). Hepatic decompensation (some fatal) has occurred in HCV/HIV coinfected patients who received both ribavirin/interferon and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) therapies.
Riociguat: (Moderate) Monitor for an increase in riociguat-related adverse effects like hypotension if concomitant use with abacavir is necessary. Consider a riociguat dose reduction in patients who may not tolerate the hypotensive effect of riociguat. Concomitant use of riociguat and abacavir may increase riociguat exposure although the magnitude of increase is unknown. Riociguat is a CYP1A1 substrate; abacavir may inhibit CYP1A1.
Ritonavir: (Moderate) Caution is advised when administering abacavir and ritonavir concurrently. Ritonavir appears to induce glucuronosyl transferase, and therefore, has the potential to reduce plasma concentrations of drugs that undergo glucuronidation, such as abacavir. The clinical significance of the potential for this interaction is unknown.
Ropeginterferon alfa-2b: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving NRTIs and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
Tipranavir: (Moderate) Concurrent administration of tipranavir and ritonavir with abacavir results in decreased abacavir concentrations. The clinical significance of this interaction has not been established, and no recommendations for abacavir dosage adjustments are available.

Abacavir/Abacavir Sulfate/Ziagen Oral Tab: 300mg
Abacavir/Abacavir Sulfate/Ziagen/Ziagen Solution Oral Sol: 1mL, 20mg

600 mg/day PO.

600 mg/day PO.

16 mg/kg/day PO (Max: 600 mg/day).

16 mg/kg/day PO (Max: 600 mg/day).

3 to 11 months: 16 mg/kg/day PO.
1 to 2 months: Safety and efficacy have not been established; however, doses up to 8 mg/kg/day PO have been used off-label.

Safety and efficacy have not been established; however, doses up to 4 mg/kg/day PO have been used off-label.

Abacavir inhibits viral reverse transcriptase. Intracellularly, abacavir is converted by cellular enzymes to the active metabolite carbovir triphosphate. Carbovir triphosphate is an analog of deoxyguanosine-5'-triphosphate (dGTP). Carbovir triphosphate inhibits the activity of HIV-1 reverse transcriptase (RT) both by competing with the natural substrate dGTP and by its incorporation into viral DNA. The lack of a 3'-hydroxyl group in the incorporated nucleoside analog prevents the formation of the 5' to 3' phosphodiester linkage essential for DNA chain elongation, and therefore, the viral DNA growth is inhibited.
 
In vitro and in vivo HIV-1 isolates with reduced sensitivity to abacavir have been reported. Genetic analysis of isolates from abacavir-treated patients showed point mutations in the reverse transcriptase gene that resulted in amino acid substitutions at key positions in the virus. Phenotypic analysis of HIV-1 isolates that harbor abacavir-associated mutations from 17 patients after 12 weeks of abacavir monotherapy exhibited a 3-fold decrease in susceptibility to abacavir in vitro. The clinical relevance of genotypic and phenotypic changes associated with abacavir therapy has not been established.
 
Cross-resistance between abacavir and other nucleoside reverse transcriptase inhibitors (i.e., tenofovir, emtricitabine, lamivudine, didanosine, and stavudine) has been observed in strains of HIV-1 containing multiple reverse transcriptase mutations.[29710] Cross-resistance between abacavir and HIV protease inhibitors is unlikely because of the different enzyme targets involved. Because of different binding sites on reverse transcriptase, cross-resistance between abacavir and non-nucleoside reverse transcriptase inhibitors is not expected.
 
Abacavir hypersensitivity may be related to an induced autoimmunity process related to HLA-B*5701. Human Leukocyte Antigens (HLA) help the body to distinguish "self" versus "foreign" proteins (peptides). A study determined that abacavir alters the quantity and quality of self-peptide loading into HLA-B*5701. These self-peptides are then presented for the first time, and because the body has not previously recognized them, it mistakenly treats them as foreign, resulting in a polyclonal T-cell autoimmune response and multi-organ systemic toxicity. Once the drug is discontinued, reactive T-cells would be reduced and then differentiate into T memory cells. Re-exposure would again generate these peptides leading to a rapid expansion of T memory cells which could cause severe and potentially life-threatening reactions.[50430]

Abacavir is administered orally. Once in the systemic circulation, abacavir distributes into extravascular space. Protein binding is approximately 50% and is independent of concentration. Based on radiolabeled studies, the drug readily distributes into erythrocytes. In humans, abacavir is not significantly metabolized by cytochrome P450 enzymes. The primary routes of elimination of abacavir are metabolism by alcohol dehydrogenase (to form the 5'-carboxylic acid) and glucuronyl transferase (to form the 5'glucuronide). The metabolites have no antiviral activity. In vitro experiments reveal that abacavir does not inhibit human CYP3A4, CYP2D6, or CYP2C9 activity at clinically relevant concentrations. Elimination of abacavir was quantified in a mass balance study following administration of a 600-mg dose of (14)C-abacavir: 83% of the radioactivity was recovered in urine, 1.2% as unchanged drug, 30% as the 5'-carboxylic acid metabolite, 36% as the 5'-glucuronide metabolite, and 15% as unidentified minor metabolites. Fecal elimination accounted for 16% of the dose. In single-dose studies, the observed elimination half-life was 1.54 +/- 0.63 hours.
 
Affected cytochrome P450 isoenzymes and drug transporters: CYP1A1, CYP3A4
Data from in vitro studies show abacavir has the potential to inhibit CYP1A1 and the limited potential to inhibit CYP3A4. Other CYP isoenzymes (e.g., CYP2C9 and CYP2D6) are not inhibited or induced by abacavir. Similarly, abacavir at therapeutic drug exposures is not expected to affect the pharmacokinetics of substrates of the following drug transporters: organic anion transporter polypeptide (OATP)1B1/3, breast cancer resistance protein (BCRP), P-glycoprotein (P-gp), organic cation transporter (OCT)1, OCT2, or multidrug and toxic extrusion protein (MATE)1 and MATE2-K.

After oral administration, abacavir is rapidly and extensively absorbed. Bioavailability is about 83% for the tablets. Systemic exposure to abacavir was comparable after administration of the solution, therefore, the solution and the tablets may be used interchangeably. There is no significant difference in systemic exposure during fed or fasted states.

Antiretroviral therapy should be provided to all patients during pregnancy, regardless of HIV RNA concentrations or CD4 cell count. Using highly active antiretroviral combination therapy (HAART) to maximally suppress viral replication is the most effective strategy to prevent the development of resistance and to minimize the risk of perinatal transmission. Begin HAART as soon as pregnancy is recognized, or HIV is diagnosed. HIV guidelines recommend the use of abacavir as part of a preferred 2-NRTI backbone in HLA-B*5701 negative patients who are pregnant or trying to conceive. Available data from the Antiretroviral Pregnancy Registry, which includes more than 1,410 first trimester exposures, have shown no difference in the risk of overall major birth defects with abacavir compared to the 2.7% background rate among pregnant women in the US. When exposure to abacavir occurred in the first trimester, prevalence of defects was 3.1% (95% CI: 2.3 to 4.2). As a class, nucleoside reverse transcriptase inhibitors (NRTIs) are known to induce mitochondrial dysfunction. An association of mitochondrial dysfunction in infants and in utero antiretroviral exposure has been suggested, but not established. While the development of severe or fatal mitochondrial disease in exposed infants appears to be extremely rare, more intensive monitoring of hematologic and electrolyte parameters during the first few weeks of life is advised. Nucleoside analogs have been associated with the development of lactic acidosis, especially during pregnancy. It is unclear if pregnancy augments the incidence of lactic acidosis/hepatic steatosis in patients receiving nucleoside analogs. However, because pregnancy itself can mimic some early symptoms of the lactic acid/hepatic steatosis syndrome or be associated with other significant disorders of liver metabolism, clinicians need to be alert for early diagnosis of this syndrome. Pregnant patients receiving nucleoside analogs should have LFTs and serum electrolytes assessed more frequently during the last trimester of pregnancy and any new symptoms should be evaluated thoroughly. Regular laboratory monitoring is recommended to determine antiretroviral efficacy. Monitor CD4 counts at the initial visit. Patients who have been on HAART for at least 2 years and have consistent viral suppression and CD4 counts consistently greater than 300 cells/mm3 do not need CD4 counts monitored after the initial visit during the pregnancy. However, CD4 counts should be monitored every 3 months during pregnancy for patients on HAART less than 2 years, patients with CD4 count less than 300 cells/mm3, or patients with inconsistent adherence or detectable viral loads. Monitor plasma HIV RNA at the initial visit (with review of prior levels), 2 to 4 weeks after initiating or changing therapy, monthly until undetectable, and then at least every 3 months during pregnancy. Viral load should also be assessed at approximately 36 weeks gestation, or within 4 weeks of delivery, to inform decisions regarding mode of delivery and optimal treatment for newborns. Patients whose HIV RNA levels are above the threshold for resistance testing (usually greater than 500 copies/mL but may be possible for levels greater than 200 copies/mL in some laboratories) should undergo antiretroviral resistance testing (genotypic testing, and if indicated, phenotypic testing). Resistance testing should be conducted before starting therapy in treatment-naive patients who have not been previously tested, starting therapy in treatment-experienced patients (including those who have received pre-exposure prophylaxis), modifying therapy in patients who become pregnant while receiving treatment, or modifying therapy in patients who have suboptimal virologic response to treatment that was started during pregnancy. DO NOT delay initiation of antiretroviral therapy while waiting on the results of resistance testing; treatment regimens can be modified, if necessary, once the testing results are known. First trimester ultrasound is recommended to confirm gestational age and provide accurate estimation of gestational age at delivery. A second trimester ultrasound can be used for both anatomical survey and determination of gestational age in those patients not seen until later in gestation. Perform standard glucose screening in patients receiving antiretroviral therapy at 24 to 28 weeks gestation, although it should be noted that some experts would perform earlier screening with ongoing chronic protease inhibitor-based therapy initiated prior to pregnancy, similar to recommendations for patients with high-risk factors for glucose intolerance. Liver function testing is recommended within 2 to 4 weeks after initiating or changing antiretroviral therapy, and approximately every 3 months thereafter during pregnancy (or as needed). All pregnant patients should be counseled about the importance of adherence to their antiretroviral regimen to reduce the potential for development of resistance and perinatal transmission. It is strongly recommended that antiretroviral therapy, once initiated, not be discontinued. If a patient decides to discontinue therapy, a consultation with an HIV specialist is recommended. There is a pregnancy exposure registry that monitors outcomes in pregnant patients exposed to abacavir; information about the registry can be obtained at www.apregistry.com or by calling 1-800-258-4263.[23512]

HIV treatment guidelines recommend clinicians provide mothers with evidence-based, patient-centered counseling to support shared decision-making regarding infant feeding. Inform patients that use of replacement feeding (i.e., formula or banked pasteurized donor human milk) eliminates the risk of HIV transmission; thus, replacement feeding is recommended for use when mothers with HIV are not on antiretroviral therapy (ART) or do not have suppressed viral load during pregnancy, as well as at delivery. For patients on ART who have achieved and maintained viral suppression during pregnancy (at minimum throughout the third trimester) and postpartum, the transmission risk from breast-feeding is less than 1%, but not zero. Virologically suppressed mothers who choose to breast-feed should be supported in this decision. If breast-feeding is chosen, counsel the patient about the importance of adherence to therapy and recommend that the infant be exclusively breast-fed for up to 6 months of age, as exclusive breast-feeding has been associated with a lower rate of HIV transmission as compared to mixed feeding (i.e., breast milk and formula). Promptly identify and treat mastitis, thrush, and cracked or bleeding nipples, as these conditions may increase the risk of HIV transmission through breast-feeding. Breast-fed infants should undergo immediate diagnostic and virologic HIV testing. Testing should continue throughout breast-feeding and up to 6 months after cessation of breast-feeding. For expert consultation, healthcare workers may contact the Perinatal HIV Hotline (888-448-8765). In countries where replacement feeding is unavailable, abacavir has been administered to nursing mothers as part of a regimen to decrease postnatal HIV transmission; the optimal regimen and duration of prophylaxis is undetermined. In 1 study conducted in Botswana, abacavir was found to be excreted in human breast milk; the mean breast milk-to-plasma drug ratio in the 15 women tested was 0.85. Further, an analysis of 9 breast-feeding infants found detectable plasma drug concentrations in 1 infant. Other antiretroviral medications whose passage into human breast milk have been evaluated include nevirapine, zidovudine, lamivudine, and nelfinavir.