Lamivudine (Epivir)

Lamivudine (3TC, Epivir) is an antiviral drug that reduces the amount of HIV in the body. Anti-HIV drugs such as lamivudine slow down or prevent damage to the immune system, and reduce the risk of developing AIDS-related illnesses. Lamivudine is also active against hepatitis B virus (HBV).

Lamivudine is one of the nucleoside reverse transcriptase inhibitors (NRTIs). These drugs disrupt an HIV protein or enzyme called reverse transcriptase, which is involved in making new viruses. For more information about how NRTIs work, see Nucleoside RT inhibitors.

In 1996, lamivudine was licensed in Europe as a treatment for HIV when used in combination with other anti-HIV drugs. It was discovered by BioChem Pharma and is manufactured by ViiV Healthcare under the trade name Epivir. Numerous generic versions of lamivudine are available. 

Lamivudine is available as part of several co-formulations.

Lamivudine is co-formulated with zidovudine in one pill, known by the trade name Combivir from ViiV Healthcare. Each Combivir pill contains 150mg lamivudine and 300mg zidovudine. Generic versions of this co-formulation are also available. This combination is rarely prescribed nowadays.

A pill that combines 300mg zidovudine, 150mg lamivudine, and 300mg abacavir, known as Trizivir, is also available from ViiV Healthcare. It was approved in the United States in November 2000 and in the European Union in March 2001. This combination is rarely prescribed nowadays and is no longer recommended for use.

ViiV Healthcare also produces a fixed-dose combination of 300mg lamivudine with 600mg abacavir that is suitable for once-daily dosing. It is marketed as Kivexa in Europe and as Epzicom in the United States. Generic versions are now available. See Kivexa for further details.

Lamivudine is also co-formulated with abacavir and dolutegravir in the fixed-dose combination Triumeq. See Triumeq for further details.

Lamivudine is also approved as a treatment for HBV. In the European Union it is known by the trade name Zeffix and in the United States as Epivir-HBV.

Effectiveness

Lamivudine (Epivir) is able to reduce HIV viral load and increase CD4 cell counts in the majority of people when taken in combination with at least two other antiretroviral drugs.[ref] It is effective against HIV-1 and HIV-2 and some evidence indicates that lamivudine can penetrate the central nervous system where it is active against HIV.

Lamivudine is given in combination, usually with a protease inhibitor or a non-nucleoside reverse transcriptase inhibitor (NNRTI) and at least one other nucleoside or nucleotide reverse transcriptase inhibitor (NRTI), particularly zidovudine (AZT, Retrovir) or abacavir (Ziagen). Lamivudine was first licensed before protease inhibitors and NNRTIs were developed. Its licence was granted after clinical studies showed that it reduced disease progression, AIDS, and death by 66% when added to zidovudine monotherapy in both zidovudine-experienced and zidovudine-naive patients.[ref] [ref] [ref] [ref]

Epivir-HBV oral solution and tablets contain a sub-therapeutic dose of lamivudine for treating HIV infection. Unless a child with HIV/HBV (hepatitis B virus) co-infection requires a lamivudine 100mg dose for treating HIV, these drugs are not interchangeable.

Taking it

Lamivudine (Epivir) can be taken once or twice daily. Once-daily dosing involves taking one 300mg tablet, and twice-daily dosing involves taking two 150mg tablets 12 hours apart. Lamivudine can be taken either with food or on an empty stomach. Once-daily dosing of lamivudine produces the same effects in the body as twice-daily dosing, and it is safe to switch between these regimens.

An oral solution of lamivudine is available at a concentration of 10mg/ml.

See Kivexa and Triumeq for details of how to take lamivudine when co-formulated with other drugs.

Side-effects

Lamivudine (Epivir) is generally a safe drug, with fewer side-effects than other nucleoside reverse transcriptase inhibitors (NRTIs). Its commonest side-effects are headache, fatigue, and nausea which generally subside over time. Other side-effects include decreased appetite, diarrhoea, skin rash, and abdominal pain. Nausea and diarrhoea can be controlled with other medicines, which can be prescribed before starting lamivudine. Lamivudine's side-effects are most likely to occur during the early weeks of treatment.

Discontinuation of lamivudine may result in a flare-up of hepatitis B infection in people with HIV/HBV co-infection. Careful monitoring of these individuals is advised.

Less common side-effects of lamivudine are pancreatitis (usually in advanced disease) peripheral neuropathy, anaemia, decreased neutrophil count, increased liver enzymes, fat redistribution. neutropenia (low white blood cell counts) and rash. There have also been reports of hair loss, severe anaemia and lactic acidosis (a serious increase in levels of lactic acid in the blood) among people receiving lamivudine, while pancreatitis has been reported in children.

Children

Lamivudine (Epivir) is approved for use by children aged over three months at a dose of 4mg/kg twice daily, to a maximum dose of 300mg per day. It is available as a solution or tablet. Scored tablets can be split according to weight.

In the US lamivudine can be used in infants under 30 days of age, dosed twice daily at 2mg/kg.

It was licensed for children following demonstration that adding lamivudine to zidovudine (Retrovir), didanosine (Videx) or a combination of zidovudine and didanosine resulted in CD4 cell count increases and reductions in viral load, and a lowered risk of disease progression and death.[ref] [ref] Once-daily lamivudine dosing may also be possible in children, although this is not an approved dosing regimen.[ref]

Lamivudine should be used with caution in children with a history or risk of pancreatitis. It should not be used in combination with emtricitabine. Any patient with creatinine clearance of less than 50ml/minute or impaired hepatic function should not use Combivir, Trizivir, or Kivexa. Other side-effects are similar to those found in adults.

The formulation of Epivir-HBV is not sufficient for children who have HIV and hepatitis B co-infection, unless the child requires a 100mg lamivudine dose.

Pregnancy

Lamivudine has been widely used in antiretroviral therapy in pregnant women and there is no evidence that it is linked to an increased risk of adverse foetal or pregnancy outcomes.[ref]

Resistance

As with all other anti-HIV drugs, strains of HIV that are resistant to lamivudine (Epivir) may emerge after a period of treatment. The emergence of drug-resistant strains coincides with a fall in the effectiveness of the drug.

HIV can rapidly develop resistance to lamivudine if viral load is not suppressed below the limit of detection. This is likely to occur due to poor adherence, or if a patient takes a treatment interruption, due to the slow rate of decline of lamivudine levels within cells.[ref] [ref] Resistance to lamivudine seems to develop at the same rate in people taking the drug once or twice a day.[ref]

The primary mutation associated with lamivudine resistance occurs at codon 184 of the reverse transcriptase enzyme, called M184V or M184I.[ref] Drug resistance generally increases the risk of treatment failure and disease progression, but the presence of the M184V mutation appears to decrease viral fitness by reducing its ability to replicate and increasing susceptibility to other nucleoside reverse transcriptase inhibitors (NRTIs).

This is demonstrated by the fact that viral load may increase by a small amount when people with this mutation stop taking lamivudine, indicating that the drug had an antiviral effect despite resistance.[ref] [ref] The presence of M184V also seems to prevent or delay emergence of thymidine-associated mutations.[ref] Other mutations that cause low-level resistance to lamivudine include K65R and amino acid insertions at codon 69.

There is considerable cross-resistance amongst the NRTIs, meaning that once an individual develops resistance to one NRTI, the effectiveness of the other NRTIs will be diminished. Virus with the M184V/I mutation is also cross-resistant to emtricitabine (Emtriva) and abacavir (Ziagen). However, resistance to some of the other NRTIs is unlikely to cause high-level resistance to lamivudine, and vice versa. A patient is likely to get some benefit from lamivudine even after exposure to zidovudine or stavudine (Zerit).

Drug interactions

Drugs that are eliminated in the same way as lamivudine may interact with lamivudine. These drugs include trimethoprim (Monotrim), an antibiotic which is included in cotrimoxazole (Septrin). Consequently, levels of lamivudine may be increased by 40% when it is taken together with cotrimoxazole tablets for Pneumocystis pneumonia (PCP) prophylaxis or toxoplasmosis treatment, although no dose adjustments are necessary.

Lamivudine should not be taken with intravenous foscarnet (Foscavir) or ganciclovir (Cymevene).

Hepatitis B treatment

Lamivudine (Epivir / Zeffix) is licensed as a treatment for hepatitis B in an increasing number of countries. It may be prescribed to people with chronic hepatitis B virus (HBV) infection with liver damage, liver inflammation or fibrosis. The standard dose for hepatitis B infection is 100mg once daily. Lamivudine can also improve liver function in people with HIV co-infection.[ref]

A number of trials have found that lamivudine normalises liver function in the majority of people with hepatitis B. Clinical trials have found improved liver function in more people taking lamivudine than placebo, and less progression to fibrosis and liver cancer.[ref] [ref] However, some experts have questioned the appropriateness of once-daily, single drug therapy due to the likelihood of people with hepatitis B developing drug resistance in the long term.

Resistance to lamivudine in HBV usually occurs in the YMDD domain.[ref] Resistance emerges more slowly in HBV than in HIV. Lamivudine resistance appears to emerge more quickly in individuals with a higher body mass index, suggesting that resistance to lamivudine may develop if the dose of lamivudine used is not large enough.

The inclusion of lamivudine in antiretroviral therapy regimens for people with co-infection has also been questioned, since this would lead to lamivudine monotherapy for hepatitis B and the possibility of resistance developing.[ref] [ref] Combination approaches to hepatitis B treatment are being explored, using adefovir (Hepsera), tenofovir (Viread), interferon alfa (Roferon-A / Viraferon) or famciclovir (Famvir) alongside lamivudine.

People with HBV may experience a flare-up of hepatitis B when they stop lamivudine treatment.[ref] Additionally, cases of hepatitis B flare-up in people with HIV co-infection receiving lamivudine have been reported in the absence of any evidence of lamivudine resistance. This is probably caused by the reconstitution of the immune system before the lamivudine has time to control the HBV.[ref] [ref] A possible way to avoid this is to combine lamivudine with tenofovir in people with co-infection, to delay the addition of other anti-HIV drugs until the HBV is controlled, or to assess the extent of liver damage before initiation of antiretroviral therapy.