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BackgroundThe magnitude of infant antiretroviral (ARV) exposure from breast milk is unknown MethodsWe measured concentrations of nevirapine, lamivudine, and zidovudine in serum and whole breast milk from human immunodeficiency virus type 1 (HIV-1)–infected women in Botswana receiving ARV treatment and serum from their uninfected, breast-feeding infants ResultsTwenty mother-infant pairs were enrolled. Maternal serum concentrations of nevirapine were high (median, 9534 ng/mL at a median of 4 h after nevirapine ingestion). Median breast-milk concentrations of nevirapine, lamivudine, and zidovudine were 0.67, 3.34, and 3.21 times, respectively, those in maternal serum. The median infant serum concentration of nevirapine was 971 ng/mL, at least 40 times the 50% inhibitory concentration and similar to peak concentrations after a single 2-mg/kg dose of nevirapine. The median infant serum concentration of lamivudine was 28 ng/mL, and the median infant serum concentration of zidovudine was 123 ng/mL, but infants were also receiving zidovudine prophylaxis ConclusionsHIV-1 inhibitory concentrations of nevirapine are achieved in breast-feeding infants of mothers receiving these ARVs, exposing infants to the potential for beneficial and adverse effects of nevirapine ingestion. Further study is needed to understand the impact of maternal ARV treatment on breast-feeding HIV-1 transmission, infant toxicity, and HIV-1 resistance mutations among infected infants

Lipoatrophy is known to be associated with stavudine as part of the treatment for HIV infection, but it is less clear if this serious side effect is also related to other nucleoside reverse transcriptase inhibitors like zidovudine. We aimed to determine whether zidovudine-sparing first-line antiretroviral therapy would lead to less lipoatrophy and other metabolic changes than zidovudine-containing therapy. Fifty antiretroviral therapy-naïve HIV-1 infected men with an indication to start antiretroviral therapy were included in a randomized single blinded clinical trial. Randomisation was between zidovudine-containing therapy (zidovudine/lamivudine+lopinavir/ritonavir) and zidovudine-sparing therapy (nevirapine+lopinavir/ritonavir). Main outcome measures were body composition assessed by computed tomography and dual-energy X-ray absorptiometry scan and lipid profile before and after 3, 12, 24 months of antiretroviral therapy. In the zidovudine/lamivudine+lopinavir/ritonavir group, from 3 months onward limb fat decreased progressively by 684+/-293 grams (estimated mean+/-standard error of the mean)(p = 0.02) up to 24 months whereas abdominal fat increased, but exclusively in the visceral compartment (+21.9+/-8.1 cm(2), p = 0.008)). In contrast, in the nevirapine+lopinavir/ritonavir group, a generalized increase in fat mass was observed. After 24 months no significant differences in high density lipoprotein and total/high density lipoprotein cholesterol ratio were found between both treatment groups, but total and low density lipoprotein cholesterol levels were higher in the nevirapine+lopinavir/ritonavir group (6.1+/-0.2 versus 5.3+/-0.2 and 3.6+/-0.1 versus 2.8+/-0.1 mmol/l respectively, p<0.05). Virologic response and safety were comparable in both groups. Zidovudine/lamivudine+lopinavir/ritonavir, but not nevirapine+lopinavir/ritonavir in antiretroviral therapy-naïve patients, is associated with lipoatrophy and greater relative intraabdominal lipohypertrophy, suggesting that zidovudine/lamivudine contributes to both these features of lipodystrophy. These findings support to no longer consider zidovudine/lamivudine as one of the preferred possible components of first-line antiretroviral therapy where alternative treatments are available. ClinicalTrials.gov NCT 00122226.

Treatment and prevention of HIV-1-related central-nervous-system disease may be dependent on penetration of antiretroviral drugs into the central nervous system. Few data are available about cerebrospinal-fluid penetration and concomitant changes of HIV-1-RNA concentrations during treatment with antiretroviral agents. We investigated these effects in HIV-1-infected people. 28 antiretroviral-naive individuals with CD4 cell counts of 200μL or more and plasma HIV-1-RNA concentrations of 10 000 or more copies/mL who were free of neurological symptoms were randomly assigned lamivudine plus either stavudine (n=17) or zidovudine (n=11). We did lumbar punctures on 28 individuals before and 22 individuals after 12 weeks of treatment to assess HIV-1-RNA and drug concentrations in cerebrospinal fluid. All 28 individuals had detectable HIV-1-RNA concentrations in the cerebrospinal fluid (median 4·64 log 10 copies/mL and 4·20 log 10 copies/mL in the lamivudine plus zidovudine and lamivudine plus stavudine groups, respectively). There was no correlation between plasma and cerebrospinal-fluid HIV-1-RNA concentrations (r=0·18, p=0·35). After 12 weeks of treatment none of the individuals had detectable HIV-1-RNA concentrations in the cerebrospinal fluid. The highest drug concentration in the cerebrospinal fluid was for lamivudine followed by stavudine and zidovudine. Concentrations were consistent over time, unlike plasma concentrations. Therefore, we found time-dependent cerebrospinal-fluid to plasma drug-penetration ratios, which were highest for zidovudine followed by stavudine and lamivudine. The two drug combinations were equally effective in the decrease of cerebrospinal fluid HIV-1-RNA concentrations. All drugs penetrated the cerebrospinal fluid. Antiretroviral drugs other than zidovudine might be useful in the prevention of AIDS dementia complex.

The AIDS Clinical Trials Group Study 850 (ACTG 850) evaluated the penetration of zidovudine (ZDV), lamivudine (3TC), and amprenavir (APV), given alone and in combination with the 2 nucleoside analogues, into the male genital tract, because these factors may affect human immunodeficiency virus (HIV) type 1 suppression and transmission. Nineteen men receiving APV monotherapy and 12 men receiving triple therapy donated blood plasma (BP) and seminal plasma (SP) during therapy. Paired SP and BP were used to calculate compartmental concentration ratios. APV SP concentrations were consistently lower than BP concentrations, ZDV SP concentrations approximated BP concentrations early but became greater later in the dosing interval, and 3TC SP concentrations were substantially greater than BP concentrations throughout. Observed SP concentrations plotted with population BP concentration-time curves confirmed these findings, suggesting that passive diffusion (APV), slowed elimination (ZDV), and either active accumulation and/or inhibition of elimination (3TC) are responsible for SP concentrations of these agents. The antiretroviral effect of APV monotherapy was related to APV concentrations

HIV infection is often associated with liver failure, which alters the pharmacokinetics of many drugs. In this study we investigated whether acute liver failure （ALF） altered the pharmacokinetics of the first-line anti-HIV agent zidovudine （AZT）, a P-gp/BCRP substrate, in rats. ALF was induced in rats by injecting thioacetamide （TAA, 300 mg·kg1·d-1, ip） for 2 days. On the second day after the last injection of TAA, the pharmacokinetics of AZT was investigated following both oral （20 mg/kg） and intravenous （10 mg/kg） administration. ALF significantly increased the plasma concentrations of AZT after both oral and intravenous doses of AZT, but without affecting the urinary excretion of AZT. AZT metabolism was studied in rat hepatic microsomes in vitro, which revealed that hepatic UGT2B7 was the main enzyme responsible for the formation of AZT O-glucuronide （GAZT）; ALF markedly impaired AZT metabolism in hepatic microsomes, which was associated with the significantly decreased hepatic UGT2B7 expression. Intestinal absorption of AZT was further studied in rats via in situ single-pass intestinal perfusion. Intestinal P-gp function and intestinal integrity were assessed with rhodamine 123 and FD-70, respectively. We found that ALF significantly downregulated intestinal P-gp expression, and had a smaller effect on intestinal BCRP. Further studies showed that ALF significantly increased the intestinal absorption of both rhodamine 123 and AZT without altering intestinal integrity, thus confirming an impairment of intestinal P-gp function. In conclusion, ALF significantly increases the oral plasma exposure of AZT in rats, a result partly attributed to the impaired function and expression of hepatic UGT2B7 and intestinal P-gp.

Pharmacokinetics of lamivudine (3TC)/zidovudine (ZDV) and lopinavir/ritonavir (LPV/r) are described in a gravid 27-year-old HIV-infected woman with gastric bypass. Blood levels were obtained for these medications at time points 0 (predose) and 1, 2, 4, 6, 8, and 12 hours postdose. For these times, the levels (µg/mL) of 3TC were 0.0801, 0.69, 0.339, 0.237, 0.202, 0.108, and 0.0461; the levels of ZDV were 0.0153, 0.433, 0.0717, 0.0481, 0.0107, 0.0214, and 0.00864; the levels of lopinavir (LPV) were 2.45, 2.64, 1.95, 2.78, 3.83, 3.20, and 1.92; and the levels of ritonavir (RTV) were 0.09, 0.10, 0.07, 0.11, 0.15, 0.15, and 0.06. These data suggest that gastric bypass affected these antiretroviral drug levels. A functional, intact small bowel is responsible for absorption of these medications.

Combination therapy with interferon-α and zidovudine (IFN/AZT) has been regarded as standard care for acute and indolent (i.e., chronic and smouldering) ATL based on reports involving a limited number of patients. This treatment approach has not been evaluated in Japan, a major endemic area of this disease in the world. This is the first Japanese report of IFN/AZT for ATL. It is impossible to draw any definitive conclusion from this small study; however, IFN/AZT showed clear anti-ATL effects for refractory/relapsed ATL patients. This report would contribute for developing future ATL treatment in Japan.

A high-performance liquid chromatography (HPLC) method utilizing triple quadrupole mass spectrometry (MS) detection was developed and validated for the simultaneous measurement of the intracellular nucleoside 5′-triphosphate anabolites of zidovudine (ZDV-TP), lamivudine (3TC-TP), and stavudine (d4T-TP). These compounds were extracted from patient peripheral blood mononuclear cells (PBMCs) which are the sites of HIV replication and drug action. Ion-exchange solid phase extraction (SPE) followed by enzymatic digestion with alkaline phosphatase was utilized to yield the measurable nucleoside forms of the nucleotides. Reversed phase C-18 SPE with addition of a nucleoside internal standard, 3′-azido-2′,3′-dideoxyuridine (AzdU) allowed for the indirect measurement of the original 5′-triphosphate concentration by HPLC/MS/MS. Quantitation was performed from calibration curves generated from authentic 5′-triphosphate standards spiked in PBMCs from healthy volunteers. Analytical range for the three 5′-triphosphates was equivalent to 50–45,000 pg. Mean interassay accuracies for 3TC-TP, d4T-TP, and ZDV-TP ( n > 90) were 99.4%, 100.1%, and 108.0%, respectively. Mean interassay precisions (%C.V.) for 3TC-TP, d4T-TP, and ZDV-TP ( n > 90) were 8.8%, 10.4%, and 8.2%, respectively. Recovery of the extraction method was 79.2%, 83.1%, and 98.3% for 3TC-TP, d4T-TP, and ZDV-TP, respectively. This method can be utilized to measure the intracellular 5′-triphosphate levels in HIV infected patients receiving antiretroviral therapy containing the nucleoside reverse transcriptase inhibitors 3TC, d4T, or ZDV.

Systemic and intracellular pharmacokinetics of zidovudine were determined for 28 human immunodeficiency virus type 1—infected pregnant women and their newborn infants. Plasma zidovudine and intracellular zidovudine monophosphate and triphosphate concentrations were determined in serial maternal samples and cord blood at delivery. Higher levels of cord blood zidovudine were associated with lower maternal zidovudine clearance and longer infusion times. Median levels of zidovudine monophosphate and triphosphate in maternal (1556 and 67 fmol/106 cells) and cord (1464 and 70 fmol/106 cells) blood were similar but highly variable. Intersubject pharmacokinetic variability for zidovudine is substantial, but intravenous therapy provides plasma concentrations and intracellular zidovudine triphosphate levels consistent with high antiviral activity. The substantial amount of intracellular zidovudine triphosphate in cord blood provides an explanation for the clinical success of zidovudine in reducing vertical transmission. Studies of simpler oral regimens of zidovudine can now be evaluated regarding the ability to achieve these pharmacologic end points associated with highly effective parenteral therapy.

A solid-phase extraction methodology, followed by high-performance liquid chromatography (HPLC) quantification with UV absorbance detection (λ=267 nm), was developed in order to study the stability of 3'-azido-3'-deoxy-5'-O-isonicotinoylthymidine (AZT-Iso), a novel derivative of the antiretroviral AZT, in different matrixes. The half-lives (t ₁/₂) for AZT-Iso were 1.19, 1.13 and 0.30 h for human, rat and rabbit plasma, respectively, and 14.91 and 25.49 h for potassium phosphate buffer (pH 7.4) and human serum albumin solution, respectively. The HPLC method proved to be selective, sensitive and accurate. Good recovery, linearity and precision were achieved using p-fluorophenol as an internal standard. The validity of this method was tested using synthetic mixtures of the intact drug with its decomposition products. In conclusion, the method presented is applicable to in vivo pharmacokinetics studies of AZT-Iso in rats.