Lamivudine
Classification: CATC code: J05AF05, J05AR01, J05AR02, J05AR04, J05AR13, J05AR25
Summary
Lamivudine is effective in both men and women. Some studies have shown a slightly better effect in reducing the risk of hepatitis or hepatocellular carcinoma in women but there are also studies showing no difference in outcome between men and women. While some observational studies found no differences in safety outcomes between men and women, nausea has been reported to be more common in women in other studies. There are also several studies of the risk of lactic acidosis in patients treated with nucleoside analogs such as lamivudine, describing a higher risk in women, particularly if overweight.
Additional information
Pharmacokinetics and dosing
The manufacturer does not recommend any difference in dosing between men and women [1]. In a large study of sex differences in lamivudine pharmacokinetics (684 male samples, 104 female samples) no differences were found if correction for weight was done, otherwise higher clearance was found in men [2]. In contrast, a small pharmacokinetic study of patients (10 samples each from 29 men, 4 women) treated with indinavir, zidovudine and lamivudine found 1.6-fold higher lamivudine triphosphate (but not lamivudine) concentrations in women. Also tenofovir triphosphate concentration has been shown to be higher in women [3, 4]. Similar conclusions were made in a review of pharmacokinetic properties regarding Non-Nucleoside Reverse Transcriptase Inhibitors [5].
Effects
Both men and women have been included in the pivotal studies and sub group analyses did not find any differences between men and women, according to the SPC [1]. Similarly, a randomized study on HIV-1-infected adults treated with rilpivirine or efavirenz/ tenofovir/emtricitabine, zidovudine/lamivudine or abacavir/lamivudine (1040 men, 328 women) found no difference between men and women in response rates [6]. Furthermore, there was no difference between men and women in effect on T-lymphocyte count after post-exposure prophylaxis including zidovudine, zidovudine plus lamivudine, or zidovudine, lamivudine, and indinavir [7].
However, in an observational study in East African children (51 boys, 58 girls) treated with efavirenz, lamivudine, and one of abacavir, stavudine, or zidovudine, virological non suppression was more common in children older than 8 years and in children younger than 8 years, boys had a 5.3 times higher risk than girls [8]. Also, in a cross-sectional observational study from Zimbabwe in non-pregnant, non-breast-feeding HIV patients (32 men, 86 women) on stavudine, tenofovir or zidovudine combined with lamivudine and nevirapine or efavirenz women had a lower risk of treatment failure [9]
In a small pharmacodynamic sub study of a prospective, randomized, open-label trial (29 men, 4 women) women reached an HIV-RNA level below 50 copies/ml twice as fast as men [4].
Most, but not all, studies on the effect of antiviral treatments including lamivudine in patients with chronic hepatitis B have reported better outcome in women.An analysis of risk and predictors of hepatocellular carcinoma in HBeAg-negative chronic hepatitis B patients (528 men, 290 women) from a retrospective-prospective cohort treated with nucleos(t)ide analogue(s) starting with lamivudine monotherapy for ≥12 months found the risk to be higher in men, in patients with older age at onset and in individuals with cirrhosis [10]. Similarly, a retrospective chart review of Korean patients treated with lamivudine for chronic hepatitis B (224 men, 93 women) found female sex and low platelet count in HBeAg(/) patients to be factors predicting a positive response (normalized ALT levels) to lamivudine [11].A prospective cohort study of predictors of developing HBeAg-negative hepatitis in chronic HBV-infected individuals (216 boys, 143 girls) followed from childhood to adulthood found the overall annual incidence of HBeAg-negative hepatitis increased to 2.64% in lamivudine-treated subjects but did not increase in those treated with interferon-alpha (0.58%). Predictors of HBeAg-negative hepatitis in HBeAg seroconverters were male sex, HBV genotype C, HBeAg seroconversion after 18 years of age, and lamivudine therapy prior to HBeAg seroconversion [12].
A Polish study of correlation between efficacy of antiviral therapy and prevalence of HBV pretreatment drug-resistant variants in patients treated with lamivudine only (55%) or in combination with adefovir (2%), entecavir (30%), or tenofovir (13%) (29 men, 25 women) found good response to antiviral therapy to be more common in women. Other positive predictors were younger age, immunocompetence, a low viral load, and higher ALT activity [13].
In contrast to this, a study from Taiwan, patients with chronic hepatitis B were treated with lamivudine, telbivudine, or entecavir (65 men, 15 women) (14 on lamivudine, 19 on telbivudine, and 47 on entecavir) no differences between men and women were found in relapse rate, cirrhosis or ALT levels [14]. A prospective cohort study of patients with chronic Hepatitis B treated with lamivudine (67 men, 18 women) found the rate of lamivudine resistance to increase over time from 6% at 12 months to 51% at 48 months. Female sex predicted early resistance (rate ratio 5.27 [95%CI: 1.23-22.5, P < 0.05]) although numbers were small [15].
Adverse effects
Some studies have shown similar frequency of adverse reactions in men and women while other show varying patterns. A large observational study from Nigeria in HIV-patients treated with zidovudine/lamivudine, stavudine/lamivudine, or tenofovir/lamivudine in combination with either nevirapine or efavirenz (944 men, 1706 women) men and women reported ADRs in the same frequency (64%) [16]. Most ADRs were mild [16]. In contrast, a randomized study of HIV-1-infected adults treated with rilpivirine or efavirenz/tenofovir/emtricitabine, or tenofovir/emtricitabine, zidovudine/lamivudine or abacavir/lamivudine (1040 men, 328 women) nausea was more common in women than in men in both treatment groups while abnormal dreams/nightmares were more frequent in men [6]. Similarly, a study of side effects in persons receiving post-exposure treatment with zidovudine, lamivudine, and tenofovir found women at higher risk for nausea [17].
There are also several studies of the risk of lactic acidosis in patients treated with nucleoside analogs describing a higher risk in overweight women [18-20]. In a systematic review of case reports of lactic acidosis 90 patients were taking nucleoside reverse transcriptase inhibitors at the time of the episode [18]. Among the 83 patients with details of their antiretroviral therapy regimen 51 patients were taking stavudine, 29, zidovudine, 27 didanosine, and 25 lamivudine. Estimated, based on the infection sex distribution, lactic acidosis is concluded to be more common in women [18]. In a prospective study of patients with chronic Hepatitis B (69 men, 38 women) treated with lamivudine (7,5%), tenofovir (35.5%), entecavir (31.8%) or combined treatment (25.2%), a significant time trend for developing lactic acidosis over time was found in women with cirrhosis [19]. In an analysis of the risk of lactic acidosis in a randomized open-label study of stavudine/lamivudine-based versus didanosine/zidovudine-based therapy and lopinavir/ritonavir-based versus efavirenz-based therapy in HIV-infected individuals (1204 men, 567 women) 13 cases of lactic acidosis were found (3 men, 10 women). The risk of lactic acidosis was significantly higher in women regardless of therapy choice. Higher body mass index was also a risk factor [20].
In a prospective observational study from Uganda of liver enzyme elevation in HIV-infected patients on antiretroviral therapy with lamivudine in combination with nevirapine and stavudine (74%) or efavirenz and zidovudine (26%) (in all 169 men, 377 women) male sex was associated with AST elevation [21].
An observational cohort study of treatment regimen modification in Thailand treated with a combination of stavudine, lamivudine and nevirapine (461 men, 453 women) found female sex to be a predictor of regimen modification due to lipodystrophy. Female sex, older age, and having HLA-B*40:01 had protective effects on treatment failure-related regimen modification [22].
A study in patients treated with zidovudine/ lamivudine combined with different protease or non-nucleoside reverse transcriptase inhibitors found increased age and male sex to be independently associated with lower limb fat and less abdominal subcutaneous tissue, but more visceral adipose tissue [23].
In a randomized open-label study of HIV-positive patients treated with atazanavir/ritonavir or efavirenz combined with abacavir/lamivudine or tenofovir/emtricitabine from USA (1535 men, 322 women) [24], women on abacavir/lamivudine were found to have a higher (32%) safety risk (more gastrointestinal adverse events) compared to men.
In a study in HIV-patients treated with blinded lamivudine or emtricitabine, stavudine, and nevirapine (156 men, 229 women) or efavirenz, early hepatotoxicity occurred in 17% of the patients in the nevirapine group and none in the efavirenz group and was balanced between the lamivudine and emtricitabine arms. Multivariate analysis found women to be at higher risk of hapatotoxicity, as were patients with body-mass index (BMI) <18.5, serum albumin level <35 g/L, mean corpuscular volume 185 fL, plasma HIV-1 RNA load <20,000 copies/mL, aspartate aminotransferase level <75 IU/L, and lactate dehydrogenase level <164 IU/L [25].
In an analysis of the effect on cholesterol levels in an open-label study of treatment with efavirenz / zidovudine / lamivudine, efavirenz / indinavir, and indinavir / zidovudine / lamivudine (in all 509 men, 126 women) increased cholesterol was more common in the efavirenzefivarenz/indinavir group. Women had higher HDL baseline levels and HDL increased significantly in women in all groups but only in the efavirenz-containing arms in men [26]. An East African registry based study of lipid profiles in patients with HIV (55 men, 176 women) treated with zidovudine (76%), efavirenz (66%), zidovudine/efavirenz/lamivudine (42%), zidovudine/lamivudine/neverapine (34%), or tenofovir-based treatments (24%) found increased LDL in 60% of the patients with no difference between men and women. However, men were twice as likely to have decreased HDL [27].
A multicenter randomized study on sex differences in antiretroviral treatment with efavirenz/lamivudine/zidovudine, atazanavir/didanosine/emtricitabine or efavirenz/emtricitabine/tenofovir (832 men, 739 women) has been performed [28]. It found women to have higher pretreatment CD4/ and lower HIV-1 RNA compared to men. Women assigned to efavirenz plus lamivudine-zidovudine were more likely to have a primary safety event compared to men, a difference driven by an increased rate of neutropenia among women. As this adverse effect is commonly associated with zidovudine, it seems likely that the safety difference may be due to the zidovudine component of this regimen [28].
In a prospective follow-up study (57 men, 55 women) of HIV-infected patients treated with zidovudine, zalcitabine, lamivudine, didanosine, stavudine, or a combination of didanosine/stavudine 29% developed polyneuropathy, more commonly in the didanosine/stavudine combination-treatment group and more often in women [29].
Reproductive health issues
Regarding teratogenic aspects, please consult the Drugs and Birth Defects Database (in Swedish, Janusmed fosterpåverkan).
Other information
A retrospective study of high sensitivity CRP (hsCRP) levels in HIV patients treated with zidovudine/lamivudine and abacavir and/or efavirenz (145 men, 51 women).There was no difference in hsCRP between men and women at baseline but at week 96 higher levels were seen in women compared to men [30].
A review has described drug exposure in the genital tract of men and women which is of interest in viral transferal and in effect of pre-exposure prophylactic treatment. In men, concentrations in seminal fluid were described to be highest for nucleoside analogues and lowest for protease inhibitors and efavirenz. Seminal accumulation of raltegravir and maraviroc was defined as moderate.The rank order of accumulation presented in the review is nucleoside/nucleotide reverse transcriptase inhibitors [lamivudine/zidovudine/tenofovir/didanosine > stavudine/abacavir] > raltegravir > indinavir/maraviroc/nevirapine >> efavirenz/protease inhibitors [amprenavir/atazanavir/darunavir > lopinavir/ritonavir > saquinavir] > enfuvirtide. In the female genital tract, the nucleoside analogues also were described as having high accumulation ratios, whereas protease inhibitors have limited penetration; however, substantial variability exists. Second generation non-nucleoside reverse transcriptase inhibitor etravirine, and maraviroc and raltegravir, have been found to demonstrate effective accumulation in cervicovaginal secretions. The rank of accumulation presented in the review is nucleoside/nucleotide reverse transcriptase inhibitor [zidovudine/lamivudine/didanosine > emtricitabine/tenofovir] > indinavir > maraviroc/raltegravir/darunavir/etravirine > nevirapine/abacavir > protease inhibitors [amprenavir/atazanavir/ritonavir] > lopinavir/stavudine/efavirenz > saquinavir [31].
Updated: 2019-04-08
Date of litterature search: 2018-07-23
References
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Reviewed by: Karin Schenck-Gustafsson, Jaran Eriksen
Approved by: Karin Schenck-Gustafsson