Zalcitabine (Systemic)


VA CLASSIFICATION
Primary: AM890

Commonly used brand name(s): HIVID.

Another commonly used name is
ddC .
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Antiviral (systemic)—

Indications

Accepted

Human immunodeficiency virus (HIV) infection (treatment)—Zalcitabine is indicated, in combination with zidovudine, for the treatment of HIV infection in patients with limited prior exposure (< 3 months) to zidovudine {14} {19}. Zalcitabine is also indicated, in combination with antiretroviral protease inhibitors, for the treatment of HIV infection {14}.

Human immunodeficiency virus (HIV) infection, advanced (treatment) —Zalcitabine is indicated as a monotherapy for the treatment of advanced HIV infection in patients who are intolerant of, or who have disease progression while receiving, alternative antiretroviral therapy {14} {19}.

—The duration of clinical benefit from antiretroviral therapy may be limited. Alterations in antiretroviral therapy should be considered if disease progression occurs during treatment with zalcitabine. {14}


Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    211.22 {14}

Mechanism of action/Effect:

Zalcitabine is phosphorylated by cellular enzymes to its active moiety, 2,3-dideoxycytidine-5-triphosphate (ddCTP) {14}. It then competes with the natural substrates for formation of viral DNA by reverse transcriptase, thereby inhibiting viral replication. It also acts as a terminator of chain elongation {12}. In vitro , zalcitabine is approximately 10 times more potent than zidovudine against HIV {03}.

Absorption:

Bioavailability in adults is greater than 80% {01} {08} {14}; one small study done in children found a mean bioavailability of approximately 54% {13} {14}.

Administration with food resulted in a decrease in peak plasma concentration (C max) of 39%, a decrease in the mean area under the plasma concentration–time curve (AUC) of 14%, and a twofold increase in time to peak plasma concentration (T max). {14}

Distribution:

Crosses the blood-brain barrier and distributes into the cerebrospinal fluid (CSF); the mean CSF plasma concentration ratio is 20 (range, 7 to 37). {01} {03} {08} {14}


Vol D:

Adults: Approximately 0.54 L per kg (L/kg) {01} {14}.

Children: Approximately 9.3 L per square meter of body surface (L/m 2) {13} {14}.


Plasma protein binding

Low (< 4%) {14}

Biotransformation:

Phosphorylated intracellularly to ddCTP, the active substrate for HIV reverse transcriptase. Zalcitabine does not appear to undergo significant metabolism by the liver. The primary metabolite that has been identified is dideoxyuridine (ddU). {14}

Half-life:


Normal renal function:

Adults: 1 to 3 hours {01} {02} {03} {14}.

Children (ages 6 months to 13 years): Approximately 0.8 hour {13}.



Renal function impairment in adults (creatinine clearance < 55 mL/min [0.92 mL/sec]):

Up to 8.5 hours {14}.


Intracellular half-life of ddCTP is 2.6 to 10 hours {12} {14}.


Time to peak concentration:

1 to 2 hours {01} {02} {08}.

Peak serum concentration:

7.6 nanograms/mL after a single oral dose of 0.5 mg {02}.

25.2 nanograms/mL after a single oral dose of 1.5 mg {14}.

Elimination:
    Renal; approximately 70% of zalcitabine is excreted in the urine as the parent drug {01} {14}. Less than 10% (as ddCTP and ddU) is found in the feces {14}.
    In dialysis—It is not known whether zalcitabine is removed by hemodialysis or peritoneal dialysis {14}.


Precautions to Consider

Carcinogenicity

Carcinogenicity studies in animals have not yet been completed {14}.

Tumorigenicity

High doses of zalcitabine administered for 3 months to B 6C 3F 1 mice (resulting in plasma concentrations of over 1000 times those seen in patients taking the recommended doses of zalcitabine) induced an increased incidence of thymic lymphoma. {14}

Mutagenicity

No evidence of mutagenicity was found in the Ames test, in the mouse lymphoma cell test, or in the Chinese hamster lung cell test. An unscheduled DNA synthesis assay showed no increases in DNA repair when the assay was performed in rat hepatocytes. However, an in vitro mammalian cell transformation assay was positive at doses of 500 mg per mL and higher. Dose-related increases in chromosomal aberration were seen when human peripheral blood lymphocytes were exposed to zalcitabine, with and without metabolic activation, at concentrations of 1.5 mcg per mL and higher. Oral doses of zalcitabine at 2500 and 4500 mg per kg of body weight (mg/kg) were clastogenic in the mouse micronucleus assay. {14}

Pregnancy/Reproduction
Fertility—
No adverse effects on the rate of conception or general reproductive performance were observed in rats at concentrations of zalcitabine up to 2142 times those achieved with the maximum recommended human dose (MRHD). The fertility of F1 males was significantly reduced at a calculated dose of 2142 (but not 485) times the MRHD (based on area under the plasma concentration–time curve [AUC] measurements) in a teratology study in which rat mothers were dosed on gestation days 7 to 15. No adverse effects were observed on the fertility of parents or F1 generation in the study of fertility and general reproductive performance or in the perinatal and postnatal reproduction study. {14}

Pregnancy—
It is not known whether zalcitabine crosses the placenta. Adequate and well-controlled studies have not been done in pregnant women. Unlike zidovudine, it is not known whether zalcitabine reduces perinatal transmission of HIV infection {18}. Zalcitabine should be used in pregnancy only if the potential benefit to the mother outweighs the potential risk to the fetus {14}. Fertile women should not receive zalcitabine unless they are using effective contraception during therapy {14}.

Zalcitabine was teratogenic in mice at calculated exposure levels 1365 and 2730 times the MRHD. It was teratogenic in rats at a calculated exposure level 2142 times the MRHD, but not at 485 times the MRHD. Increased embryolethality was seen in pregnant mice at doses 2730 times the MRHD and in rats at doses above 485 times the MRHD. Average fetal body weight was significantly decreased in mice at doses 1365 times the MRHD and in rats at 2142 times the MRHD. {14}

FDA Pregnancy Category C {14}.

Breast-feeding

It is not known whether zalcitabine is distributed into breast milk. {14}

There have been case reports of HIV being transmitted from an infected mother to her nursing infant through breast milk. Therefore, breast-feeding is not recommended in HIV-infected mothers, to avoid potential postnatal transmission of HIV to the nursing infant. {05} {14} {21} {22} {23} {24}

Pediatrics

Safety and efficacy of zalcitabine in combination with zidovudine or as monotherapy have not been fully established in HIV-infected children up to 12 years of age. {14} However, zalcitabine has been both given as a monotherapy and alternated with zidovudine in children 6 months to 12 years of age. Preliminary data show that zalcitabine appears to be well tolerated, and there was clinical improvement and improvement in immunologic and virologic indicators of disease activity. The side effects profile appears to be similar in children and adults. {10} {11} {13}


Geriatrics


No information is available on the relationship of age to the effects of zalcitabine in geriatric patients. However, elderly patients are more likely to have an age-related decrease in renal function, which may require a reduction in dose.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

» Alcohol or
» Asparaginase or
» Azathioprine or
» Estrogens or
» Furosemide or
» Methyldopa or
» Pentamidine, intravenous or
» Sulfonamides or
» Sulindac or
» Tetracyclines or
» Thiazide diuretics or
» Valproic acid or
Other drugs associated with pancreatitis    (medications associated with the development of pancreatitis should be avoided during zalcitabine therapy or, if concurrent use is necessary, used with caution since zalcitabine may cause pancreatitis, which, on rare occasion, has been fatal {14})

    (treatment with zalcitabine should be interrupted if intravenous pentamidine is required {14})


» Aminoglycosides, parenteral or
» Amphotericin B or
» Foscarnet    (these medications may increase the toxicity of zalcitabine by interfering with its renal clearance {14})


» Antacids, aluminum- and/or magnesium-containing    (concurrent administration of antacids and zalcitabine resulted in a 25% reduction in zalcitabine absorption; it is recommended that antacids and zalcitabine not be administered together {14})


» Chloramphenicol or
» Cisplatin or
» Dapsone or
» Didanosine or
» Disulfiram or
» Ethambutol or
» Ethionamide or
» Gold or
» Hydralazine or
» Isoniazid or
» Lithium or
» Metronidazole or
» Nitrous oxide or
» Phenytoin or
» Ribavirin or
» Stavudine or
» Vincristine or
Other drugs associated with peripheral neuropathy    (since zalcitabine has been shown to cause peripheral neuropathy, other medications associated with the development of neuropathy should be avoided during zalcitabine therapy or, if concurrent use is necessary, used with caution {03} {14})


» Cimetidine or
» Probenecid    (use of these medications with zalcitabine has been shown to decrease the clearance of zalcitabine; this is thought to be due to decreased renal clearance; patients should be monitored for signs of toxicity and the dose of zalcitabine may need to be reduced {14})


» Nitrofurantoin    (concurrent use of nitrofurantoin with zalcitabine may increase the risk of pancreatitis and peripheral neuropathy; if concurrent use is necessary, patients should be monitored for signs of toxicity and the dose of zalcitabine may need to be reduced {03} {14})



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With physiology/laboratory test values
Alanine aminotransferase (ALT [SGPT]) and
Alkaline phosphatase and
Aspartate aminotransferase (AST [SGOT])    (serum values may be increased; values greater than five times the upper normal limit occurred more frequently in patients with abnormal baseline values {14})


» Amylase and
Lipase and
Triglycerides    (serum values may be increased {14})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Risk-benefit should be considered when the following medical problems exist
» Alcoholism, active or
» Hypertriglyceridemia, or history of or
» Pancreatitis, or history of    (zalcitabine has caused pancreatitis, which, on rare occasion, has been fatal; patients who have pancreatitis or a history of pancreatitis, or are at risk for pancreatitis, either should not take zalcitabine or should take it with extreme caution {14})


» Alcoholism, history of or
» Hepatic function impairment    (rare occurrences of lactic acidosis, in the absence of hypoxemia, and severe hepatomegaly with steatosis have been reported with the use of nucleoside analogues, including zalcitabine, and are potentially fatal; in addition, rare cases of hepatic failure and death considered possibly related to underlying hepatitis B and zalcitabine monotherapy have been reported {14})


» Peripheral neuropathy    (zalcitabine may cause peripheral neuropathy; patients with mild peripheral neuropathy should consider alternative agents; patients with moderate to severe peripheral neuropathy should not take zalcitabine {14})


Renal function impairment    (patients with renal function impairment may be at increased risk of toxicity due to decreased clearance of zalcitabine through the kidneys; patients with a creatinine clearance of < 55 mL/min [0.92 mL/sec] may require a reduction in dose {14})



Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

» Alanine aminotransferase (ALT [SGPT]) and
» Alkaline phosphatase and
» Aspartate aminotransferase (AST [SGOT])    (serum values may be increased to greater than five times the upper normal limit; the incidence of laboratory abnormalities is higher in patients with preexisting abnormal baseline values or a history of alcohol abuse {14})


» Amylase, serum and
» Lipase, serum and
Triglycerides, serum    (zalcitabine administration has been associated with pancreatitis; patients should be monitored for laboratory changes consistent with pancreatitis, such as elevated amylase, lipase, and triglyceride concentrations; zalcitabine should be discontinued if amylase concentration is elevated by 1.5 to 2 times normal limits and/or the patient has symptoms consistent with pancreatitis {14})


» Blood urea nitrogen (BUN) and
» Creatinine, serum    (blood urea nitrogen and serum creatinine concentrations should be monitored in patients with renal function impairment; an adjustment in dosage or dosage interval may be required {14})




Side/Adverse Effects

Note: In general, patients with decreased CD4 cell counts appear to have an increased incidence of adverse events related to zalcitabine {14}.
Some side effects of zalcitabine (ddC), such as peripheral neuropathy, may also be seen with severe HIV disease; therefore, differentiation between the side effects of ddC and the complications of HIV disease may be difficult {03}. Also, toxicities associated with zidovudine monotherapy are likely to occur when zidovudine is administered concurrently with zalcitabine; these side effects should also be monitored {14}.
Dose-related peripheral neuropathy occurred in 17 to 31% of adult patients treated with zalcitabine monotherapy. Sensorimotor neuropathy starts with numbness and a burning sensation in the distal extremities, followed by sharp shooting pain or severe continuous burning pain if the drug is not discontinued. Peripheral neuropathy is usually dose-related and slowly reversible; however, it is potentially irreversible if zalcitabine is not stopped promptly, and may initially progress despite discontinuation of the drug. Patients with a very low CD4 count (< 50 cells/mm 3) are at the greatest risk of developing peripheral neuropathy. Zalcitabine should be discontinued as soon as there is mild progressive discomfort from numbness, tingling, burning, or pain of the extremities. {04} {09} {14} {15}
Fatal pancreatitis has been observed when zalcitabine was given alone and in combination with zidovudine. Pancreatitis is relatively uncommon with zalcitabine monotherapy, occurring in < 1% of patients; asymptomatic elevations in serum amylase also occurred in < 1% of patients. Of the patients treated in the expanded access trial (n=633) who had a prior history of pancreatitis or an elevated serum amylase, 1.6% developed pancreatitis and 1.6% developed an asymptomatic increase in serum amylase. {14}
Severe hepatotoxicity has occurred rarely. Lactic acidosis, in the absence of hypoxemia, and severe hepatomegaly with steatosis have been reported with the use of nucleoside analogues, including zidovudine and zalcitabine, and are potentially fatal. In addition, rare cases of hepatic failure and death considered possibly related to underlying hepatitis B and zalcitabine monotherapy have been reported. {14}

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent
    
Peripheral neuropathy {03}{04}{09}{14}{17}(tingling, burning, numbness, or pain in the hands, arms, feet, or legs)

Incidence less frequent
    
Arthralgia {04}{06}{14}(joint pain)
    
hypersensitivity {03}{04}{06}{13}{14}(fever; skin rash)
    
myalgia {14}(muscle pain)
    
ulceration of the mouth and throat {03}{04}{07}{12}{14}{17}

Incidence rare
    
Hepatotoxicity {14}(yellow eyes or skin)
    
leukopenia or neutropenia {03}{14}(fever and sore throat)
    
pancreatitis {14}{20}(abdominal pain, severe; nausea; vomiting)



Those indicating need for medical attention only if they continue or are bothersome
Incidence less frequent
    
Gastrointestinal disturbances {14}(abdominal pain, mild; diarrhea; nausea)
    
headache {14}





Overdose
For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).

Clinical effects of overdose
Doses of up to 1.5 mg per kg of body weight have inadvertently been given to pediatric patients. The children received prompt gastric lavage and treatment with activated charcoal and had no sequelae. Mixed overdoses of zalcitabine with other medications have caused drowsiness and vomiting, increased gamma-glutamyltransferase values, or increased creatine kinase (CK) serum values. There is no known antidote for zalcitabine overdosage. {14}
Chronic
    
Peripheral neuropathy {14}(tingling, burning, numbness, or pain in the hands, arms, feet, or legs)


Treatment of overdose
Supportive care—Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation.


Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Zalcitabine (Systemic) .

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:

Pregnancy—Zalcitabine should be used during pregnancy only if the benefit to the mother outweighs the potential risk to the fetus; fertile women should not receive zalcitabine unless they are using effective contraception during therapy





Breast-feeding—Not recommended, because of the potential for postnatal transmission of HIV to the nursing infant





Use in children—Preliminary data suggest zalcitabine is well tolerated and produces clinical improvement in some children; the side effect profile is similar to that for adults

Other medications, especially parenteral aminoglycosides, amphotericin B, antacids, cimetidine, foscarnet, nitrofurantoin, other drugs associated with pancreatitis, other drugs associated with peripheral neuropathy, and probenecid
Other medical problems, especially active alcoholism or a history of alcoholism, hepatic function impairment, hypertriglyceridemia or a history of hypertriglyceridemia, pancreatitis or a history of pancreatitis, or peripheral neuropathy

Proper use of this medication
» Importance of not taking more medication than prescribed; importance of not discontinuing medication without checking with physician

» Compliance with full course of therapy

» Importance of not missing doses and of taking at evenly spaced times

Not sharing medication with others

» Proper dosing
Missed dose: Taking as soon as possible; not taking if almost time for next dose; not doubling doses

» Proper storage

Precautions while using this medication
» Regular visits to physician for blood tests

» Importance of not taking other medications concurrently without checking with physician

» Taking steps to avoid spreading HIV infection


Side/adverse effects
Signs of potential side effects, especially peripheral neuropathy, arthralgia, hypersensitivity, myalgia, ulceration of the mouth and throat, hepatotoxicity, leukopenia or neutropenia, and pancreatitis


General Dosing Information
No adjustment in dose needs to be made for patients who weigh 30 kg or more; this is based on pharmacokinetic weight-ranging data. {14}

If patients receiving zalcitabine and zidovudine combination therapy develop what are thought to be medication-related side effects, the dose of the medication associated with that particular toxicity profile should be modified. When the toxicity is more likely to be caused by zalcitabine, the dose of that drug should be reduced or the drug should be discontinued; the same is true for zidovudine. For severe toxicity in which the causative drug cannot be identified, or side effects continue despite dose reduction or discontinuation of one medication, the dose of the other medication should also be reduced or the medication discontinued. {14}

Patients with mild, new onset, or progressive symptoms of peripheral neuropathy should discontinue taking zalcitabine, especially if the symptoms last for more than 3 days and are bilateral. Zalcitabine may be reintroduced at 50% of the regular dose (0.375 mg every 8 hours) only if the peripheral neuropathy improves to very mild symptoms. {14}


Oral Dosage Forms

ZALCITABINE TABLETS USP

Usual adult and adolescent dose
Human immunodeficiency virus (HIV) infection
Oral, 0.75 mg in combination with 200 mg zidovudine, every eight hours {14} {19}.

Human immunodeficiency virus (HIV) infection, advanced
Oral, 0.75 mg every eight hours {14} {19}.


Note: Adults with acute or chronic renal impairment may require a reduction in dose of zalcitabine as follows {14}:

Creatinine clearance (mL/min)/(mL/sec)  Dose (mg)  Dosing interval (hr) 
> 40/0.67  0.75 
10–40/0.17–0.67  0.75  12 
0–10/0–0.17  0.75  24 



Usual pediatric dose
Safety and effectiveness of zalcitabine given alone or in combination with zidovudine have not been established in children up to 13 years of age {14}. The doses being studied in ongoing clinical trials are 0.005 and 0.01 mg per kg of body weight every eight hours {13} {16}.

Strength(s) usually available
U.S.—


0.375 mg (Rx) [HIVID (lactose)]{14}


0.75 mg (Rx) [HIVID (lactose)]{14}

Canada—


0.375 mg (Rx) [HIVID (lactose)]{19}


0.75 mg (Rx) [HIVID (lactose)]{19}

Packaging and storage:
Store between 15 and 30 °C (59 and 86 °F), in a tight, light-resistant container.

Auxiliary labeling:
   • Continue medicine for full time of treatment.



Revised: 04/17/1998



References
  1. Klecker RW, Collins JM, Yarchoan RC, et al. Pharmacokinetics of 2,3-dideoxycytidine in patients with AIDS and related disorders. J Clin Pharmacol 1988; 28: 837-42.
  1. Gustavson LE, Fukuda EK, Rubio FA, et al. A pilot study of the bioavailability and pharmacokinetics of 2,3-dideoxycytidine in patients with AIDS or AIDS-related complex. J Acquir Immune Defic Syndr 1990; 3(1): 28-31.
  1. Yarchoan R, Thomas RV, Allain J-P, et al. Phase I studies of 2,3-dideoxycytidine in severe human immunodeficiency virus infection as a single agent and alternating with zidovudine. Lancet 1988; 1: 76-81.
  1. Merigan TC, Skowron G, Bozzette SA, et al. Circulating p24 antigen levels and responses to dideoxycytidine in human immunodeficiency virus (HIV) infections. Ann Intern Med 1989; 110(3): 189-94.
  1. Pizzo PA, Butler KM. In the vertical transmission of HIV, timing may be everything. N Engl J Med 1991; 325(9): 652-4.
  1. McNeely MC, Yarchoan R, Broder S, et al. Dermatologic complications associated with administration of 2,3-dideoxycytidine in patients with human immunodeficiency virus infection. J Am Acad Dermatol 1989; 21(6): 1213-7.
  1. Indorf AS, Pegram PS. Esophageal ulceration related to zalcitabine (ddC). Ann Intern Med 1992; 117(2): 133-4.
  1. Broder S. Pharmacodynamics of 2,3-dideoxycytidine: an inhibitor of human immunodeficiency virus. Am J Med 1990; 88 Suppl 5B: 2S-7S.
  1. Merigan TC, Skowron G. Safety and tolerance of dideoxycytidine as a single agent. Study Group of the AIDS Clinical Trials Group of the National Institute of Allergy and Infectious Diseases. Am J Med 1990; 88 Suppl 5B: 11S-15S.
  1. Pizzo PA. Treatment of human immunodeficiency virus–infected infants and young children with dideoxynucleosides. Am J Med 1990; 88 Suppl 5B: 16S-19S.
  1. Spector SA, Blanchard S, Connor EM, et al. Results of a clinical trial comparing two doses of 2,3-dideoxycytidine (ddC) in the treatment of children with symptomatic human immunodeficiency virus (HIV) infection who were intolerant or had failed zidovudine (ZDV) therapy (ACTG 138) [abstract 1165]. Pediatr Res 1994; 35(4 Pt 2): 197A.
  1. Yarchoan R, Mitsuya H, Myers CE, et al. Clinical pharmacology of 3-azido-2,3-dideoxythymidine (zidovudine) and related dideoxynucleosides. N Engl J Med 1989; 321(11): 726-38.
  1. Pizzo PA, Butler K, Balis F, et al. Dideoxycytidine alone and in an alternating schedule with zidovudine in children with symptomatic human immunodeficiency virus infection. J Pediatr 1990; 117(5): 799-808.
  1. HIVID package insert (Roche—US), New 6/92, Rec 6/92; Rev 6/92, Rec 7/93; Rev 6/94, Rec 7/94; Rev 7/96, Rec 3/98.
  1. Meng T-C, Fischl MA, Boota AM, et al. Combination therapy with zidovudine and dideoxycytidine in patients with advanced human immunodeficiency virus infection. Ann Intern Med 1992; 116(1): 13-20.
  1. Panel comments, 12/92.
  1. Abrams DI, Goldman AI, Launer C, et al. A comparative trial of didanosine or zalcitabine after treatment with zidovudine in patients with human immunodeficiency virus infection. N Engl J Med 1994; 330(10): 657-62.
  1. Connor EM, Sperling RS, Gelber R, et al. Reduction of maternal-infant transmission of human immunodeficiency virus type 1 with zidovudine treatment. N Engl J Med 1994; 331(18): 1173-80.
  1. HIVID (Roche—Canada). In: Gillis MC, editor. CPS Compendium of pharmaceuticals and specialties. 32nd ed. Ottawa, Canada: Canadian Pharmaceutical Association; 1997. p. 667-71.
  1. Aponet-Cipriani SL, Teplitz C, Yancovitz S. Pancreatitis possibly related to 2,3-dideoxycytidine. Ann Intern Med 1993; 119(6): 539-40.
  1. Logan S, Newell M-L, Ades T, et al. Breast-feeding and HIV infection. Lancet 1988; 1: 1356.
  1. Bradbeer CS. Mothers with HIV. Br Med J 1989; 299: 806-7.
  1. Hira SK, Mangrola UG, Mwale C, et al. Apparent vertical transmission of human immunodeficiency virus type 1 by breast-feeding in Zambia. J Pediatr 1990; 117(3): 421-4.
  1. Van de Perre P, Simonon A, Msellati P, et al. Postnatal transmission of human immunodeficiency virus type 1 from mother to infant. N Engl J Med 1991; 325(9): 593-8.
Hide
(web4)