Lamivudine

Fri, 06 May 2022 | Drug Safety

Name: LAMIVUDINE
Class: Antiviral
Risk Factor: CM

Fetal Risk Summary

Lamivudine (2ў,3ў-dideoxy-3ў-thiacytidine, 3TC), an antiviral agent structurally similar to zalcitabine, inhibits viral reverse transcription via viral DNA chain termination (1). It is classified as a nucleoside analog reverse transcriptase inhibitor (NRTI), that is used for the treatment of human immunodeficiency virus (HIV) infection. Other drugs in this class are abacavir, didanosine, stavudine, zalcitabine, and zidovudine. Lamivudine is believed to be converted by intracellular enzymes to the active metabolite, lamivudine-5ў-triphosphate (3TC-TP).

No teratogenic effects were observed in rats and rabbits administered lamivudine up to approximately 130 and 60 times, respectively, the usual human adult dose (1). Early embryo lethality was observed in rabbits at doses close to those used in humans and above. This effect was not observed in rats given up to 130 times the usual human dose. Lamivudine crossed the placenta to the fetus in both animal types.

Adverse effects on neurobehavior development in mice offspring resulting from a combination of lamivudine and zidovudine were described in a 2001 study (2). Pregnant mice received both drugs from day 10 of gestation to delivery. The effects on somatic and sensorimotor development were minor but more marked in exposed offspring then when either drug was given alone (2). Both developmental endpoints were delayed with respect to control animals. Further, alterations of social behavior were observed in both sexes of exposed offspring (2).

The low molecular weight (about 229) of lamivudine is predictive of placental transfer. A study published in 1997 described the human placental transfer of lamivudine using an ex vivo single cotyledon perfusion system (3). Lamivudine crossed the placenta to the fetal side by simple diffusion. Transfer did not appear to be affected by the presence of zidovudine. Confirming this, a 1998 study found that combination therapy with zidovudine did not affect the pharmacokinetics of lamivudine (4). Lamivudine freely crossed the placenta when given near term with nearly equivalent drug levels in the mother, cord blood, and newborn.

The Antiretroviral Pregnancy Registry reported, for the period January 1989 through July 2000, prospective data (reported to the Registry before the outcomes were known) involving 526 live births that had been exposed during the 1st trimester to one or more antiretroviral agents (5). Nine of the newborns had congenital defects (1.7%, 95% confidence interval [CI] 0.8–3.3). There were 25 infants with birth defects among 1256 live births with exposure anytime during pregnancy (2.0%, 95% CI 1.3–3.0). The prevalence rates for the two periods did not differ significantly nor did they differ from the rates expected in a nonexposed population (5).

There were 786 outcomes exposed to lamivudine (367 in the 1st trimester and 419 in the 2nd and/or 3rd trimesters) either alone (6 in the 1st trimester and 3 in the 2nd trimester) or in combination with other antiretroviral agents (5). There were 13 birth defects (7 exposed in 1st trimester and 6 exposed in the 2nd and/or 3 trimesters), but the specific defects and treatments were not identified. In comparing the outcomes of prospectively registered cases to the birth defects among retrospective cases (pregnancies reported after the outcomes were known), the Registry concluded that there was no pattern of anomalies to suggest a common cause (5). (See the required statement below).

A study published in 1999 evaluated the safety, efficacy, and perinatal transmission rates of HIV in 30 pregnant women receiving various combinations of antiretroviral agents (6). Many of the women were substance abusers. Lamivudine was taken by 29 women in various combinations that included zidovudine, nelfinavir, indinavir, stavudine, nevirapine, and saquinavir. Antiretroviral therapy was initiated at a median of 14 weeks' gestation (range preconception to 32 weeks). In spite of previous histories of extensive antiretroviral experience and of vertical transmission of HIV, combination therapy was effective in treating maternal disease and in preventing transmission to the current newborns. The outcomes of the pregnancies included one stillbirth, one case of microcephaly, and five infants with birth weights less than 2500 g, two of which were premature (6).

In an unusual case, a woman was exposed to HIV through self-insemination with fresh semen obtained from a man with a high HIV ribonucleic acid viral load (>750,000 copies/mL plasma) (7). Ten days later, she was started on a prophylactic regimen of lamivudine (300 mg/day), zidovudine (600 mg/day), and indinavir (2400 mg/day). Pregnancy was confirmed 14 days after insemination. The indinavir dose was reduced to 1800 mg/day, 4 weeks after the start of therapy because of the development of renal calculi. All antiretroviral therapy was stopped after 9 weeks because of negative tests for HIV. She gave birth at 40 weeks' gestation to a healthy 3490-g male infant, without evidence of HIV disease, who was developing normally at 2 years of age (7).

Several reports have described the apparent safe use of lamivudine, usually in combination with other agents, during human pregnancy (8,9,10 and 11). Occasional mild adverse effects were observed in the newborns (e.g., anemia), but no birth defects attributable to drug therapy. In one report, lamivudine concentrations in the newborn were similar to those in the mother (10).

A 1999 report from France described the possible association of zidovudine and lamivudine (NRTIs) use in pregnancy with mitochondrial dysfunction in the offspring (12). Mitochondrial disease is relatively rare in France (estimated prevalence 1 in 5,000–20,000 children) (12). From an ongoing epidemiological survey of 1,754 mother-child pairs exposed to zidovudine and other agents during pregnancy, however, 8 children with possible mitochondrial dysfunction were identified. None of the eight infants were infected with HIV, but all received prophylaxis for up to 6 weeks after birth with the same antiretroviral regimen as given during pregnancy. Four of the cases were exposed to zidovudine alone and four to a combination of zidovudine and lamivudine. Two from the combination group died at about 1 year of age. All eight cases had abnormally low respiratory-chain enzyme activities. The authors concluded that their results supported the hypothesis of a causative association between mitochondrial respiratory-chain dysfunction and NRTIs. Moreover, the toxicity may have been potentiated by combination of these agents (12).

In a paper following the above study, investigators noted that NRTIs inhibit DNA polymerase g, the enzyme responsible for mitochondrial DNA replication (13). They then hypothesized that this inhibition would induce depletion of mitochondrial DNA and mitochondrial DNA-encoded mitochondrial enzymes, thus resulting in mitochondrial dysfunction (13). Moreover, they stated that support for their hypothesis was suggested by the closeness of the clinical manifestations of inherited mitochondrial diseases with the adverse effects attributed to NRTIs. These adverse effects included polyneuropathy, myopathy, cardiomyopathy, pancreatitis, bone marrow suppression, and lactic acidosis. They also postulated this mechanism was involved in the development of a lipodystrophy syndrome of peripheral fat wasting and central adiposity, a condition that has been thought to be related to protease inhibitors (13).

A commentary on the above two studies concluded that the evidence for NRTI-induced mitochondrial dysfunction was equivocal (14). First, the clinical presentations in the infants were varied and not suggestive of a single cause; indeed, three of the infants were symptom-free and one had Leigh's syndrome, a classic mitochondrial disease (14). Second, the clinical features, in some cases, were not suggestive of mitochondrial dysfunction. Although three had neurological symptoms, none had raised levels of lactate in the cerebrospinal fluid. Moreover, histological or histochemical features of mitochondrial disease were only found in two cases. Finally, low mitochondrial DNA, that would have been direct evidence of NRTI toxicity, was not found in the three cases in which it was measured (14).

A case of combined transient mitochondrial and peroxisomal b-oxidation dysfunction after exposure to NRTIs (lamivudine and zidovudine) combined with protease inhibitors (ritonavir and saquinavir) throughout gestation was reported in 2000 (15). A male infant was delivered at 38 weeks' gestation. He received postnatal prophylaxis with lamivudine and zidovudine for 4 weeks until the agents were discontinued because of anemia. Other adverse effects that were observed in the infant (age at onset) were hypocalcemia (shortly after birth), Group B streptococcal sepsis, ventricular extrasystoles, prolonged metabolic acidosis, and lactic acidemia (8 weeks), a mild elevation of long chain fatty acids (9 weeks), and neutropenia (3 months). The metabolic acidosis required treatment until 7 months of age, whereas the elevated plasma lactate resolved over 4 weeks. Cerebrospinal fluid lactate was not determined nor was a muscle biopsy conducted. Both the neutropenia and the cardiac dysfunction had resolved by 1 year of age. The elevated plasma fatty acid level was confirmed in cultured fibroblasts, but other peroxisomal functions (plasmalogen biosynthesis and catalase staining) were normal. Although mitochondrial dysfunction has been linked to NRTIs, the authors were unable to identify the cause of the combined abnormalities in the infant (15). The child was reported to be healthy and developing normally at 26 months of age.

A case of life-threatening anemia following in utero exposure to antiretroviral agents was described in 1998 (16). A 30-year-old woman with HIV infection was treated with zidovudine, didanosine, and trimethoprim/sulfamethoxazole (three times weekly) during the 1st trimester. Vitamin supplementation was also given. Because of an inadequate response, didanosine was discontinued and lamivudine and zalcitabine were started in the 3rd trimester. Two weeks before delivery the HIV viral load was undetectable. At term, a pale, male infant was delivered who developed respiratory distress shortly after birth. Examination revealed a hyperactive precordium and hepatomegaly without evidence of hydrops. The hematocrit was 11% with a reticulocyte count of zero. An extensive work-up of the mother and infant failed to determine the cause of the anemia. Bacterial and viral infections, including HIV, parvovirus B19, cytomegalovirus, and others, were excluded. The infant received a transfusion and was apparently doing well at 10 weeks of age. Because no other cause of the anemia could be found, the authors attributed the condition to bone morrow suppression, most likely to zidovudine (16). A contribution of the other agents to the condition, however, could not be excluded.

In summary, the animal and human data suggest that lamivudine presents a low risk to the developing fetus for structural malformations. Theoretically, exposure to agents in this class at the time of implantation could result in impaired fertility as a result of embryonic cytotoxicity (see, for example, Didanosine, Stavudine, Zidovudine, or Zalcitabine), but this has not been studied in humans. The risk of mitochondrial dysfunction with NRTIs needs confirmation. However, even if an association is proven, the risk of mortality and morbidity from HIV infection appears to far outweigh the risk of mitochondrial dysfunction (14).

Two reviews, one in 1996 and the other in 1997, concluded that all women currently receiving antiretroviral therapy should continue to receive therapy during pregnancy and that treatment of the mother with monotherapy should be considered inadequate therapy (17,18). In 1998, the Centers for Disease Control and Prevention (CDC) made a similar recommendation that antiretroviral therapy should be continued during pregnancy, but discontinuation of all therapy during the 1st trimester was a consideration (19). If indicated, therefore, lamivudine should not be withheld in pregnancy (with the possible exception of the 1st trimester) because the expected benefit to the HIV-positive mother probably outweighs the unknown risk to the fetus.

A review published in 2000 described seven clinical trials that have been effective in reducing perinatal transmission, five with zidovudine alone, one with zidovudine plus lamivudine, and one with nevirapine (20). Six of the trials were in less-developed countries. Prolonged use of zidovudine in the mother and infant was the most effective for preventing vertical transmission, but also the most expensive. The combination of lamivudine and zidovudine, consisting of antepartum, intrapartum, and postpartum maternal therapy with continued therapy in the infant for 1 week, may have been as effective as prolonged zidovudine (20). More data are needed, however, before the efficacy and safety of combined therapy in preventing vertical transmission of HIV to the newborn can be assessed. Currently, zidovudine remains the only antiretroviral agent recommended for this purpose in developed countries (17,18).

Required statement: “The Registry's approach is to evaluate specific classes of antiretroviral drugs (NRTIs [nucleoside analog reverse transcriptase inhibitor(s)], nnRTIs [nonnucleoside reverse transcriptase inhibitor(s)], and PIs [protease inhibitor(s)]). To date, however, accumulated cases of exposures to the antiretroviral agents followed in the Registry used alone or in combination are insufficient for reaching any reliable and definitive conclusions regarding the risk to pregnant women and their developing fetuses. Currently only the zidovudine monotherapy group is large enough to warrant a separate analysis.” (See also Zidovudine.)

Breast Feeding Summary

One report describing the use of lamivudine during human lactation has been located. In 10 women on lamivudine monotherapy (300 mg/day), the mean drug concentrations in maternal serum and breast milk were 0.55 and 1.22 µg/mL, respectively (4). The infants were not allowed to breast-feed. The agent is also excreted into the milk of lactating rats at concentrations slightly greater than those in the maternal plasma (1). Both of these findings are supported by the low molecular weight (about 229) of lamivudine.

Reports on the use of lamivudine during human breast feeding are unlikely because the antiviral agent is used in the treatment of human immunodeficiency virus (HIV) infections. HIV-1 is transmitted in milk, and in developed countries, breast feeding is not recommended (17,18,21,22 and 23). In developing countries, breast feeding is undertaken, despite the risk, because there are no affordable milk substitutes available. Until 1999, no studies had been published that examined the effect of any antiretroviral therapy on HIV-1 transmission in milk. In that year, a study involving zidovudine was published that measured a 38% reduction in vertical transmission of HIV-1 infection despite breast feeding when compared to controls (see Zidovudine).

References

  1. Product information. Epivir. Glaxo Wellcome, 2001.
  2. Venerosi A, Valanzano A, Alleva E, Calamandrei G. Prenatal exposure to anti-HIV drugs: neurobehavioral effects of zidovudine (AZT) + lamivudine (3TC) treatment in mice. Teratology 2001;63:26–37.
  3. Bloom SL, Dias KM, Bawdon RE, Gilstrap LC III. The maternal-fetal transfer of lamivudine in the ex vivo human placenta. Am J Obstet Gynecol 1997;176:291–3.
  4. Moodley J, Moodley D, Pillay K, Coovadia H, Saba J, van Leeuwen R, Goodwin C, Harrigan PR, Moore KHP, Stone C, Plumb R, Johnson MA. Pharmacokinetics and antiretroviral activity of lamivudine alone or when coadministered with zidovudine in human immunodeficiency virus type 1-infected pregnant women and their offspring. J Infect Dis 1998;178:1327–33.
  5. The Antiretroviral Pregnancy Registry for abacavir (Ziagen), amprenavir (Agenerase, APV), delavirdine mesylate (Rescriptor), didanosine (Videx, ddl), efavirenz (Sustiva, Stocrin), indinavir (Crixivan, IDV), lamivudine (Epivir, 3TC), lamivudine/zidovudine (Combivir), nelfinavir (Viracept), nevirapine (Viramune), ritonavir (Norvir), saquinavir (Fortovase, SQV-SGC), saquinavir mesylate (Invirase, SQV-HGC), stavudine (Zerit, d4T), zalcitabine (Hivid, ddC), zidovudine (Retrovir, ZDV). Interim Report. 1 January 1989 through 31 July 2000. 2000(December);11(No. 2):1–55.
  6. McGowan JP, Crane M, Wiznia AA, Blum S. Combination antiretroviral therapy in human immunodeficiency virus-infected pregnant women. Obstet Gynecol 1999;94:641–6.
  7. Bloch M, Carr A, Vasak E, Cunningham P, Smith D. The use of human immunodeficiency virus postexposure prophylaxis after successful artificial insemination. Am J Obstet Gynecol 1999;181:760–1.
  8. Scott GB, Tuomala R. Combination antiretroviral therapy during pregnancy. AIDS 1998;12:2495–7.
  9. Lorenzi P, Spicher VM, Laubereau B, Hirschel B, Kind C, Rudin C, Irion O, Kaiser L. Antiretroviral therapies in pregnancy: maternal, fetal and neonatal effects. Swiss HIV Cohort Study, the Swiss Collaborative HIV and Pregnancy Study, and the Swiss Neonatal HIV Study. AIDS 1998;12:F241–7.
  10. Grubert TA, Wintergerst U, Lutz-Friedrich R, Belohradsky BH, Rolinski B. Long-term antiretroviral combination therapy including lamivudine in HIV-1 infected women during pregnancy. AIDS 1999;13:1430–1.
  11. Ristola M, Salo E, Ammala P, Suni J. Combined stavudine and lamivudine during pregnancy. AIDS 1999;13:285.
  12. Blanche S, Tardieu M, Rustin P, Slama A, Barret B, Firtion G, Ciraru-Vigneron N, Lacroix C, Rouzioux C, Mandelbrot L, Desguerre I, Rotig A, Mayaux MJ, Delfraissy JF. Persistent mitochondrial dysfunction and perinatal exposure to antiretroviral nucleoside analogues. Lancet 1999;354:1084–9.
  13. Brinkman K, Smeitink JA, Romijn JA, Reiss P. Mitochondrial toxicity induced by nucleoside-analogue reverse-transcriptase inhibitors is a key factor in the pathogenesis of antiretroviral-therapy-related lipodystrophy. Lancet 1999;354:1112–15.
  14. Morris AAM, Carr A. HIV nucleoside analogues: new adverse effects on mitochondria? Lancet 1999;354:1046–7.
  15. Stojanov S, Wintergerst U, Belohradsky BH. Mitochondrial and peroxisomal dysfunction following perinatal exposure to antiretroviral drugs. AIDS 2000;14:1669.
  16. Watson WJ, Stevens TP, Weinberg GA. Profound anemia in a newborn infant of a mother receiving antiretroviral therapy. Pediatr Infect Dis J 1998;17:435–6.
  17. Carpenter CCJ, Fischi MA, Hammer SM, Hirsch MS, Jacobsen DM, Katzenstein DA, Montaner JSG, Richman DD, Saag MS, Schooley RT, Thompson MA, Vella S, Yeni PG, Volberding PA. Antiretroviral therapy for HIV infection in 1996. JAMA 1996;276;146–54.
  18. Minkoff H, Augenbraun M. Antiretroviral therapy for pregnant women. Am J Obstet Gynecol 1997;176:478–89.
  19. Centers for Disease Control and Prevention. Public Health Service Task Force recommendations for the use of antiretroviral drugs in pregnant women infected with HIV-1 for maternal health and for reducing perinatal HIV-1 transmission in the United States. MMWR 1998;47:N0. RR-2.
  20. Mofenson LM, McIntrye JA. Advances and research directions in the prevention of mother-to-child HIV-1 transmission. Lancet 2000;355:2237–44.
  21. Brown ZA, Watts DH. Antiviral therapy in pregnancy. Clin Obstet Gynecol 1990;33:276–89.
  22. de Martino M, Tovo P-A, Tozzi AE, Pezzotti P, Galli L, Livadiotti S, Caselli D, Massironi E, Ruga E, Fioredda F, Plebani A, Gabiano C, Zuccotti GV. HIV-1 transmission through breast-milk: appraisal of risk according to duration of feeding. AIDS 1992;6:991–7.
  23. Van de Perre P. Postnatal transmission of human immunodeficiency virus type 1: the breast feeding dilemma. Am J Obstet Gynecol 1995;173:483–7.

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