Tenofovir

Additional information

Antiretrovirals for treatment of HIV are always given as a combination of at least three medicines. Cobicistat is used to boost the effect of other antiretroviral drugs. As studies on HIV patients always include patients receiving combination therapy it is difficult to know which of the studied medicines that cause changes in effect and/or adverse events.

Pharmacokinetics and dosing

In patients on triple highly active antiretroviral therapy regimen including 300 mg of tenofovir disoproxil (20 men, 7 women), women were found to have higher tenofovir triphosphate concentrations compared to men [1]. The manufacturer reports that there are no major differences in pharmacokinetics between men and women with the caveat that this is based on limited data [2, 3]. The manufacturer does not recommend different dosing in men and women [2, 3].

Effects

Both men and women have been included in most of the randomized studies of the effect and safety of tenofovir, but the number of women was low, overall (around 20%) [4].

In a randomized study on HIV-1-infected adults (1040 men, 328 women) treated with rilpivirine or efavirenz plus tenofovir/emtricitabine or tenofovir/emtricitabine, zidovudine/lamivudine or abacavir/lamivudine no difference between men and women was found in response rate [5]. In contrast, a cross-sectional observational study from Zimbabwe in non-pregnant or breast-feeding HIV patients (32 men, 86 women) on stavudine, tenofovir or zidovudine combined with lamivudine and nevirapine or efavirenz women had a lower odds ratio of treatment failure [6].

In an Ethiopian analysis of a treatment program with tenofovir disoproxil fumarate in patients with chronic Hepatitis B (162 men, 138 women), men had higher risk of fibrosis [7]. Similar findings were made in a Zambian cohort of HIV-positive patients with and without HBV infection treated with tenofovir disoproxil fumarate-containing antiretroviral treatment (214 men, 249 women) [8].  Significant fibrosis/cirrhosis was found to decreased in frequency from 14.0% to 6.7%. Higher age, male sex, and HBV coinfection predicted significant fibrosis/cirrhosis at 1 year [8]. Also a registry based cohort study in patients with chronic Hepatitis B treated with entecavir or tenofovir  (923 men, 402 women) found the risk of hepatocellular carcinoma to be higher in men [9]. Other associated risk factors were lower platelet, higher age and presence of cirrhosis [9].

Adverse effects

If the risk of tenofovir associated nephrotoxicity differs in men and women is unclear as different studies have shown conflicting results. An Italian cohort study in HIV patients on antiretroviral treatment (1082 men, 423 women) a higher risk of renal impairment was seen in women, older patients, those who had diabetes and/or hypertension, and in patients with higher baseline CD4. Current exposure to didanosine, tenofovir or protease inhibitors was the major determinants [10]. Similarly, a retrospective data base study in tenofovir disoproxil fumarate treated HIV patients (114 men, 49 women) found a negative impact of high through concentrations of tenofovir on renal filtration in both men and women. In women but not in men, a tenofovir disoproxil fumarate concentration >90 ng/mL was predictive of renal impairment which suggests an earlier or greater susceptibility of renal toxicity in women [11]. In contrast to this in a study where patients with HIV and a few co-infected with HBV or HCV (in all, 171 men, 104 women) were retrospectively followed-up for three years to evaluate risk factors involved in impaired renal function men were found to have a higher risk. Of these, 97% were on tenofovir/lamivudine based treatment. After 36 months of tenofovir use, patients showed impairment of renal function that worsened over time, men more than women [12]. Yet another retrospective case-note audit from the UK of children (31 boys, 39 girls) with perinatally-acquired HIV treated with tenofovir disoproxil fumarate found no association between children’s sex and nephrotoxicity [13].

Nausea and lipodystrophy have been found to be more common in women treated with antiretroviral treatments containing tenofovir [5, 14-16]. In a randomized study on HIV-1-infected adults (1040 men, 328 women) treated with rilpivirine or efavirenz plus tenofovir/emtricitabine or tenofovir/emtricitabine, zidovudine/lamivudine or abacavir/lamivudine nausea was more common in women than in men in both treatment groups while abnormal dreams/nightmares were more frequent in men. Diarrhoea was more frequent in men in the efavirenz group [5]. Similarly, a study of side effects in persons receiving post-exposure treatment with zidovudine, lamivudine, and tenofovir found women at higher risk for nausea [14].

A retrospective analysis of the presence of lipodystrophy in a randomized, placebo-controlled study of tenofovir disoproxil fumarate or stavudine (d4T) in antiretroviral-naive adults (444 men, 156 women) increasing age, female sex and higher baseline triglycerides were found to be independent risk factors [15]. A similar finding was made in a large European cohort study of safety and tolerability in HIV patients on antiretroviral treatment (958 men, 336 women). Women had a higher risk of treatment discontinuation than men (hazard ratio [HR], 1.54; 95%CI: 1.28, 1.85) but no increased risk of viral failure (HR, 1.06; 95%CI: 0.85, 1.33). Compared to men, women had less diarrhea and severe lipid disturbances but more lipodystrophy [16] .

In a small cohort study in HIV-1 infected adults on stable antiretroviral regimes comparing biochemical and bone mineral density parameters between patients receiving either tenofovir or another nucleoside reverse transcriptase inhibitor (43 men, 13 women) non-white men but not women, on tenofovir had higher PTH levels than non-white men not on tenofovir (mean difference 3.1 pmol/L, 95% CI 5.3 to 0.9; p = 0.007) [17].

In a study on glucose tolerance in HIV-infected adults on efavirenz, tenofovir, and emtricitabine (40 men, 30 women) half of the subjects were obese and these were matched with 30 obese HIV-negative controls. HIV-infected women on non-nucleoside reverse transcriptase inhibitor-based antiretroviral treatment had superior glucose tolerance and lower plasma metabolites associated with the development of diabetes compared with men with similar metabolic disease risk profiles. The relationship between patients’ sex and plasma metabolite levels did not significantly differ according to HIV-status among obese subjects, suggesting the observed sex-differences may not be specific to HIV infection [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%) found a significant time trend for developing lactic acidosis over time in women with cirrhosis [19].

Reproductive health issues

Regarding teratogenic aspects, please consult Janusmed Drugs and Birth Defects (in Swedish, Janusmed fosterpåverkan).

Other information

A descriptive retrospective Brazilian study on HIV patients on highly active antiretroviral therapy those who modified their treatment within the first year of treatment (52 men, 35 women) were mostly men. Efavirenz was the most often changed drug, followed by tenofovir, zidovudine and lopinavir/ritonavir [20].

An east African registry based studied lipid profiles in patients with HIV (55 men, 176 women) treated with zidovudine (76%), efavirenz (66%), zidovudine and efavirenz in combination with lamivudine (42%), zidovudine and lamivudine in nevirapine (34%), and the remaining tenofovir-based treatments (24%). They found increased LDL in 60% of the patients, no difference between men and women. However, men were twice as likely to have decreased HDL-C [21]

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 [22].