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BackgroundCabotegravir (CAB) is a novel strand-transfer integrase inhibitor being developed for HIV treatment and prevention. CAB is formulated both as an immediate-release oral tablet for daily administration and as a long-acting injectable suspension (long-acting CAB [CAB LA]) for intramuscular (IM) administration, which delivers prolonged plasma exposure to the drug after IM injection. HIV Prevention Trials Network study 077 (HPTN 077) evaluated the safety, tolerability, and pharmacokinetics of CAB LA in HIV-uninfected males and females at 8 sites in Brazil, Malawi, South Africa, and the United States.Methods and findingsHPTN 077 was a double-blind, placebo-controlled phase 2a trial. Healthy individuals age 18–65 years at low HIV risk were randomized (3:1) to receive CAB or placebo (PBO). In the initial oral phase, participants received 1 daily oral tablet (CAB or PBO) for 4 weeks. Those without safety concerns in the oral phase continued and received injections in the injection phase (Cohort 1: 3 injections of CAB LA 800 mg or 0.9% saline as PBO IM every 12 weeks for 3 injection cycles; Cohort 2: CAB LA 600 mg or PBO IM for 5 injection cycles; the first 2 injections in Cohort 2 were separated by 4 weeks, the rest by 8 weeks). The primary analysis included weeks 5 to 41 of study participation, encompassing the injection phase. The cohorts were enrolled sequentially. Primary outcomes were safety and tolerability. Secondary outcomes included pharmacokinetics and events occurring during the oral and injection phases. Between February 9, 2015, and May 27, 2016, the study screened 443 individuals and enrolled 110 participants in Cohort 1 and 89 eligible participants in Cohort 2. Participant population characteristics were as follows: 66% female at birth; median age 31 years; 27% non-Hispanic white, 41% non-Hispanic black, 24% Hispanic/Latino, 3% Asian, and 6% mixed/other; and 6 transgender men and 1 transgender woman. Twenty-two (11%) participants discontinued the oral study product; 6 of these were for clinical or laboratory adverse events (AEs). Of those who received at least 1 CAB LA injection, 80% of Cohort 1 and 92% of Cohort 2 participants completed all injections; injection course completion rates were not different from those in the PBO arm. Injection site reactions (ISRs) were common (92% of Cohort 1 and 88% of Cohort 2 participants who received CAB LA reported any ISR). ISRs were mostly Grade 1 (mild) to Grade 2 (moderate), and 1 ISR event (Cohort 1) led to product discontinuation. Grade 2 or higher ISRs were the only AEs reported more commonly among CAB LA recipients than PBO recipients. Two Grade 3 (severe) ISRs occurred in CAB recipients, 1 in each cohort, but did not lead to product discontinuation in either case. Seven incident sexually transmitted infections were diagnosed in 6 participants. One HIV infection occurred in a participant 48 weeks after last injection of CAB LA: CAB was not detectable in plasma both at the time of first reactive HIV test and at the study visit 12 weeks prior to the firs...

This study investigated whether a polymorphism in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene (C677T) modifies responses to methotrexate (MTX) in patients undergoing bone marrow transplantation. About 10% to 12% of the population carry the MTHFR TT genotype (enzyme activity, 30% of wild type [CC]). Patients (n ‫؍‬ 220) with chronic myelogenous leukemia underwent marrow allografts and were given a short course of MTX. MTX toxicity measures included the oral mucositis index (OMI), speed of engraftment (platelet and granulocyte counts), and bilirubin. Patients with lower MTHFR activity (TT genotype) had 36% higher mean OMI during days 1 to 18 (؉5.7, P ‫؍‬ .046) and 20% higher OMI between days 6 and 12 (؉3.8, P ‫؍‬ .27). Platelet counts recovered more slowly among patients with the TT genotype compared to wild type (24% slower recovery to 10 000 platelets/L, P ‫؍‬ .23; 34% slower to 20 000/ L, P ‫؍‬ .08 Folate is essential for nucleotide synthesis. The effectiveness of MTX is largely attributable to its role as an inhibitor of dihydrofolate reductase. Its metabolites also inhibit other folate enzymes, including 5,10-methylenetetrahydrofolate reductase (MTHFR), 1,3,4 which converts 5,10-methylenetetrahydrofolate to 5,10-methyltetrahydrofolate.A common MTHFR polymorphism (C677T) results in reduced activity. 5 The variant TT genotype, associated with about 30% of wild-type (CC) activity, is present in about 10% to 12% of white and Asian populations. Heterozygotes (CT) (about 60% activity) constitute approximately 40% of the population. Variations are seen in risk of acute lymphocytic leukemia, 6 colorectal neoplasia, 7-10 neural tube defects, 11,12 and possibly cardiovascular disease, 13 largely in the presence of low folate levels. Because MTX induces a low folate state, we hypothesized that toxicity would be aggravated among patients with the TT and, possibly, the CT genotype. Study design Study design and patient populationWe undertook a study of patients undergoing marrow transplantation at the Fred Hutchinson Cancer Research Center (FHCRC) from 1992 to 1999.The following criteria applied: (1) first chronic phase of chronic myelogenous leukemia 14 ; (2) first transplantation; (3) conditioning regimen: either busulfan/cyclophosphamide 15 or cyclophosphamide/total body irradiation, as described 15,16 ; (4) age at transplantation, at least 18 years; and (5) available DNA. All patients received 4 doses of MTX (intravenously, day 1, at 15 mg/m, 2 and days 3, 6, and 11, at 10 mg/m 2 ) and cyclosporine (as previously described 15 ) for prevention of GVHD. 2 All patients gave informed consent. The study was approved by the FHCRC Institutional Review Board. Data collectionData were abstracted by a single abstractor (blinded to genotypes) on previous interferon treatment, smoking, MTX administration, and, if applicable, MTX serum levels and leucovorin administration.Data from the patient database included: (1) conditioning regimen; (2) donor/matching status; (3) demographics; (4) weight, height, and calculated ...

Variation in human major histocompatibility genes may influence the risk of squamous cell cervical cancer (SCC) by altering the efficiency of the T-cell-mediated immune response to human papillomavirus (HPV) antigens. We used high-resolution methods to genotype human leukocyte antigen (HLA) class I (A, B, and Cw) and class II (DRB1 and DQB1) loci in 544 women with SCC and 542 controls. Recognizing that HLA molecules are codominantly expressed, we focused on co-occurring alleles. Among 137 allele combinations present at >5% in the case or control groups, 36 were significantly associated with SCC risk. All but one of the 30 combinations that increased risk included DQB1*0301, and 23 included subsets of A*0201-B*4402-Cw*0501-DRB1*0401-DQB1*0301. Another combination, B*4402-DRB1*1101-DQB1*0301, conferred a strong risk of SCC (odds ratio, 10.0; 95% confidence interval, 3.0-33.3). Among the six combinations that conferred a decreased risk of SCC, four included Cw*0701 or DQB1*02. Most multilocus results were similar for SCC that contained HPV16; a notable exception was A*0101-B*0801-Cw*0701-DRB1*0301-DQB1*0201 and its subsets, which were associated with HPV16-positive SCC (odds ratio, 0.5; 95% confidence interval, 0.3-0.9). The main multilocus associations were replicated in studies of cervical adenocarcinoma and vulvar cancer. These data confirm that T helper and cytotoxic T-cell responses are both important cofactors with HPV in cervical cancer etiology and indicate that cooccurring HLA alleles across loci seem to be more important than individual alleles. Thus, certain co-occurring alleles may be markers of disease risk that have clinical value as biomarkers for targeted screening or development of new therapies. [Cancer Res 2008;68(9):3532-9]

enzymes (2,3). Induction or inhibition of biotransformation enzymes,CYP1A2 metabolizes various environmental procarcinoenzymes that activate or detoxify numerous xenobiotics, is gens, such as heterocyclic amines (4), nitrosamines (5) and one mechanism by which vegetables may alter cancer risk.aflatoxin B 1 (6). In humans, CYP1A2 activity, as measured by Using a randomized crossover design, we examined the caffeine metabolite ratios, is increased by cigarette smoke effect of various vegetable diets on cytochrome P450 (CYP) (7,8), cruciferous vegetables (9,10) and well-cooked meat (11). 1A2, N-acetyltransferase 2 (NAT2) and xanthine oxidaseCertain drugs and a few dietary constituents (12-14) have activity in humans. Men and women, non-smokers, on no been associated with reduced CYP1A2 activity in vivo. Genetic medication and 20-40 years of age ate four 6-day controlled polymorphisms in glutathione S-transferase (GST) have been diets: basal (vegetable-free) and basal with three botanically shown to associate with CYP1A2 activity, perhaps by modulatdefined vegetable groups. Enzyme activities were detering circulating levels of phytochemicals that induce this P450 mined by measuring urinary caffeine metabolite ratios enzyme (15,16). after a 200 mg caffeine dose on the last day of each feeding N-acetyltransferase 2 (NAT2) catalyzes acetylation of a period. Mean CYP1A2 activity for 19 men and 17 women variety of aromatic amines and hydrazines, including known (least squares means adjusted for sex, GSTM1 genotype, carcinogens. The NAT2 gene is polymorphic; point mutations urine volume and feeding period) with basal, brassica, in both coding and non-coding regions can result in decreased allium and apiaceous vegetable diets differed significantly expression, low activity or enzyme instability (17,18). Rapid (P ഛ ഛ 0.0005) by diet, irrespective of the caffeine metabolite and slow NAT2 phenotypes and the associated genotypes have molar ratio used to describe CYP1A2 activity; brassica been identified and both rapid and slow acetylation have been vegetables increased (P Ͻ0.04) and apiaceous vegetables associated with the risk of several cancers (19). Although decreased (P ഛ ഛ 0.02) activity compared with the basal and NAT2 is believed to be predominantly under genetic control, allium diets. There was no effect of diet on NAT2 and wide ranges exist in enzyme activity and associations have xanthine oxidase activities and none of the subjects differed been identified between NAT2 activity and some exposures, by GSTM1 genotype. These results demonstrate that while such as use of gout medication and intake of heavily browned one vegetable subgroup induces human CYP1A2 activity, fish (17). To date, controlled dietary interventions have not another subgroup inhibits it. This points to a complex found any effects of vegetables (9) or well-cooked meat (11) association between consumption of a typical diet of various vegetables and biotransformation enzyme activities in on NAT2 activity. humans, an association that may be difficult to...

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The capacity to convert the soy isoflavone daidzein to equol in vivo is presumably determined by an individual's intestinal microfloral populations; however, diet may also influence this conversion. The objectives of the present study were to determine whether a 1-mo supplementation of dietary fiber as wheat bran increases urinary equol excretion in equol excreters and stimulates equol production in nonexcreters and whether longer-term soy isoflavone intake increases equol production or alters overall urinary isoflavone excretion. First, we screened 74 women, ages 20-40 y, and determined their equol-excreter status. In these women, health and lifestyle patterns and habitual dietary intake did not differ according to equol-excreter status. Next, 26 of the women (13 equol excreters and 13 nonexcreters) were assigned (blocked on equol-excreter status) to either longer-term (1 mo) or short-term (4 d) soy protein supplementation. Within each soy treatment group, women participated in two 1-mo intervention periods (the exact length was determined by each woman's menstrual cycle) during which they consumed their usual diets supplemented daily with either 0 or 16 g dietary fiber in a randomized crossover design. A 1-mo washout period separated the two diet periods. Among the 19 women who completed both periods, fiber supplementation did not increase equol production in equol excreters or nonexcreters. In addition, isoflavonoid excretion did not differ by fiber dose or length of soy intervention. These results suggest that a daily 16 g-fiber dose as wheat bran and the addition of soy protein do not alter significantly the capacity of colonic microflora to produce equol.