Daily Pill Research Articles

Determinants of adherence to highly active antiretroviral therapy among HIV-1-infected patients in Côte d'Ivoire

To assess adherence to HAART and to determine factors associated with poor adherence among HIV-1-infected patients in Abidjan, Côte d'Ivoire. A prospective observational study of 614 consecutive patients attending an HIV/AIDS outpatient clinic. Adherence was measured twice at 3-month intervals by self-report of missing doses over 4 days. An adherence level of less than 95% was defined as poor adherence. We used generalized estimating equation models for binomial distribution with repeated measures for data analysis. Of the 591 subjects who completed the study, 74.3% reported adherence levels of 95% or greater. Six factors were independently related to poor adherence: age less than 35 years [relative risk (RR) 1.45; 95% confidence interval (CI) 1.17-1.79], absence of social support (RR 1.66; 95% CI 1.24-2.24), number of daily pills 10 or more (RR 1.47; 95% CI 1.14-1.91), time of adherence assessment (first versus second time assessment RR 1.36; 95% CI 1.12-1.66), CD4 cell count of 250 cells/mul or greater (RR 1.43; 95% CI 1.10-1.88), and not being less worried about HIV infection now that treatments have improved (RR 1.26; 95% CI 1.01-1.58). Drug supply interruptions in the pharmacies were reported by 10.0% of the non-adherent patients as the reason for missing pills. Psychosocial factors were found to impact adherence and should be analysed in more detail by further studies. Scaling up antiretroviral therapy in sub-Saharan Africa should be preceded by reliable drug supply and distribution systems.

The Value Meal: How to Save $1,700 Per Month or More on Lapatinib

The Value Meal: How to Save $1,700 Per Month or More on Lapatinib

Snapshots for July 2007

Snapshots for July 2007

A comparison of patient adherence and preference of packaging method for oral anticancer agents using conventional pill bottles versus daily pill boxes

Adherence to medications is an important issue in oncology due to the increasing number of anticancer agents, such as targeted therapies, formulated for oral dosing. A prospective, crossover design was utilized in which patients on capecitabine were randomly assigned to one of two packaging methods for one cycle, and then switched over to the alternate packaging method in the subsequent cycle. Twenty-five patients were accrued to this study. Adherence rates were similar when using the daily pill boxes (17/21 = 81%) and when using the conventional pill bottles (18/21 = 86%). However, more patients were satisfied with the daily pill boxes (61% versus 11%, P = 0.027), preferred the daily pill boxes (61% versus 17%, P = 0.061), and thought the daily pill boxes were more helpful in reminding them to take their medications (50% versus 11%, P = 0.070). In conclusion, this small pilot study did not demonstrate that the use of daily pill boxes improved patient adherence with capecitabine, but patient satisfaction and preference for this packaging method were greater than for the conventional pill bottles. Further exploration of this intervention in a larger study is warranted.

Contraception Today

Modern contraceptive methods represent more than a technical advance: they are the instrument of a true social revolution-the "first reproductive revolution" in the history of humanity, an achievement of the second part of the 20th century, when modern, effective methods became available. Today a great diversity of techniques have been made available and-thanks to them, fertility rates have decreased from 5.1 in 1950 to 3.7 in 1990. As a consequence, the growth of human population that had more than tripled, from 1.8 to more than 6 billion in just one century, is today being brought under control. At the turn of the millennium, all over the world, more than 600 million married women are using contraception, with nearly 500 million in developing countries. Among married women, contraceptive use rose in all but two developing countries surveyed more than once since 1990. Among unmarried, sexually active women, it grew in 21 of 25 countries recently surveyed. Hormonal contraception, the best known method, first made available as a daily pill, can today be administered through seven different routes: intramuscularly, intranasally, intrauterus, intravaginally, orally, subcutaneously, and transdermally. In the field of oral contraception, new strategies include further dose reduction, the synthesis of new active molecules, and new administration schedules. A new minipill (progestin-only preparation) containing desogestrel has been recently marketed in a number of countries and is capable of consistently inhibiting ovulation in most women. New contraceptive rings to be inserted in the vagina offer a novel approach by providing a sustained release of steroids and low failure rates. The transdermal route for delivering contraceptive steroids is now established via a contraceptive patch, a spray, or a gel. The intramuscular route has also seen new products with the marketing of improved monthly injectable preparations containing an estrogen and a progestin. After the first device capable of delivering progesterone directly into the uterus was withdrawn, a new system releasing locally 20 microg evonorgestrel is today marketed in a majority of countries with excellent contraceptive and therapeutic performance. Finally, several subcutaneously implanted systems have been developed: contraceptive "rods," where the polymeric matrix is mixed with the steroid and "capsules" made of a hollow polymer tube filled with free steroid crystals. New advances have also been made in nonhormonal intrauterine contraception with the development of "frameless" devices. The HIV/AIDS pandemic forced policy makers to look for ways to protect young people from sexually transmitted diseases as well as from untimely pregnancies. This led to the development of the so-called dual protection method, involving the use of a physical barrier (condom) as well as that of a second, highly effective contraceptive method. More complex is the situation with antifertility vaccines, still at a preliminary stage of development and unlikely to be in widespread use for years to come. Last, but not least, work is in progress to provide effective emergency contraception after an unprotected intercourse. Very promising in this area is the use of selective progesterone receptor modulators (antiprogestins).

The Combined Contraceptive Vaginal Ring (NuvaRing): Evaluation of the Clinical and Pharmacological Evidence

The NuvaRing((R)) is a vaginal ring contraceptive that releases a daily dose of 15 microg ethinylestradiol and 120 microg etonogestrel through the vaginal epithelium, thereby avoiding the daily fluctuations in serum levels typically observed with combined oral contraceptives. Each ring is designed for a single 3-week use followed by a 1-week ring-free period. The ring offers robust inhibition of ovulation, yielding a Pearl Index of 0.65 for European women in registration trials. The ring has the same contraindications as combined oral contraceptives. The vaginal ring is a highly effective, safe and well-tolerated method of hormonal contraception designed for reproductive-aged women who desire freedom from the daily pill.

Subcutaneous versus Intramuscular Depot Methoxyprogesterone Acetate: A Comparative Review

Depot medroxyprogesterone acetate (DMPA; Depo-Provera) is a highly effective and convenient contraceptive method that has been used worldwide for many decades. Recently, a new lower dose of DMPA, administered as a subcutaneous injection, has been approved for use in the USA as a contraceptive and a treatment for pain associated with endometriosis. The newer formulation has a similar efficacy to the older version and, more importantly, has fewer side effects, with improved user tolerability. Similar to the intramuscular DMPA injection (Depo-Provera intramuscular or contraceptive injection), the subcutaneous injection provides effective contraceptive and pain-management therapy for endometriosis, with a 3-monthly injectable protocol for women who seek long-term and reversible contraception without the need for a daily pill or a more frequent dosing regimen.

A safe strategy for addition of vitamins and minerals to foods

Addition of vitamins and minerals to foods must be done without health risk to any consumer group. International expert groups have aimed at establishing tolerable upper intake levels (ULs) for vitamins and minerals although lack of solid data on their safety is a major obstacle to this work. In this paper, we summarize the existing ULs and suggest the use of guidance levels (GLs) set by others and temporary guidance levels (TGLs) proposed here, whenever no consensus UL has been established for adults. We suggest the use of body surface area ratios to establish similar levels for younger age groups. The levels are applied in a model for calculation of safe fortification levels for all ages. We have estimated the upper 95(th) percentile intake of vitamins and minerals from food in various Danish age and gender groups and suggest that a daily multivitamin-mineral pill is included in the calculation of total dietary intake levels of all vitamins and minerals. By subtracting this dietary intake level from the UL, GL or TGL, we calculate the amount that can be safely used for fortification. Since safety must be assured for all age groups, the smallest difference relative to energy intake calculated for any age group is proposed as the maximal allowance (MA) for fortification with each nutrient. We suggest that the MA should be expressed in weight units per energy unit in order to distribute it equally between potentially fortifiable food groups according to their usual contribution to total energy intakes.

The 'polypill', friend or foe?

In June 2003 the British Medical Journal (BMJ) published a paper which claimed that taking a daily pill containing six active ingredients would prevent more than 80% of cardiovascular events.

Intentions to use hormonal male contraception: The role of message framing, attitudes and stress appraisals

Two studies are reported. Study one (N = 104) explored the extent to which male hormonal contraception is perceived as risky compared to other prevention behaviours. Study two examined the effects of message framing on intentions to use hormonal male contraception and investigated whether attitude moderates message framing effects. Three hundred and four participants read either a loss frame or gain frame message and then completed questionnaires assessing their intentions to use hormonal male contraception, stress appraisals and the theory of planned behaviour (TPB) variables. Exposure to a loss frame influenced intention to use the daily male pill in men with a more positive attitude. This suggests that attitude, but not other TPB variables or stress appraisals have the capacity to moderate framing effects. Stress appraisals, in addition to TPB variables, significantly predicted variance in behavioural intentions in men and women. These findings are discussed within the context of Prospect Theory, perceived risk and prevention/detection behaviours.

Comparison of gastrointestinal tolerability and patient preference for treatment with the 625 mg and 250 mg nelfinavir tablet formulations

To compare gastrointestinal (GI) tolerability and patient preference for the new 625 mg formulation of nelfinavir (NFV) and the marketed 250 mg tablets (Viracept) in HIV-1-infected patients. Virologically controlled patients (n=126) treated with a nelfinavir (NFV) 250 mg-containing regimen for > or =8 weeks completed a stool diary for 14 days to assess baseline bowel function. After switching to the NFV 625 mg formulation [1250 mg twice a day (bid)] for 28 days, patients continued their stool diaries and at study completion answered a questionnaire regarding formulation preferences. The incidence and mean weekly duration of GI upset over a 2-week period were lower with NFV 625 mg than with NFV 250 mg (79.8% vs. 84.9% of patients and 2.1 vs. 3.0 days, respectively). Fewer patients experienced moderate or severe diarrhoea with NFV 625 mg (6.5% vs. 11.1%), and the incidence of investigator-assessed diarrhoea also decreased with NFV 625 mg. Importantly, there was a significant improvement overall in the incidence of diarrhoea (any grade) when patients switched to NFV 625 mg [38 of 124 (31%) improving, 69 of 124 (56%) stable and 17 of 124 (14%) worsening on NFV 625 mg; P<0.01]. At study completion, most patients expressed a preference to continue treatment with NFV 625 mg [112 of 122 (91.8%); P<0.0001], with only one patient (0.8%) preferring to resume treatment with NFV 250 mg. The new formulation was well tolerated with no new safety concerns. The new NFV 625 mg formulation is better tolerated and preferred by patients switching from NFV 250 mg tablets. By reducing the daily pill count and improving GI tolerability, the NFV 625 mg formulation may enhance patient adherence to NFV-containing antiretroviral regimens and thus potentially improve virological outcomes.

Assessment of the bioequivalence of two nelfinavir tablet formulations under fed and fasted conditions in healthy subjects

This study was designed to assess the bioequivalence between the commercial 250 mg nelfinavir tablet and the new 625 mg nelfinavir tablet (Roche) which was developed to reduce the daily pill burden for patients from 10 to 4 tablets in a nelfinavir 1250 mg twice daily regimen. A total of 52 healthy male subjects were enrolled in this randomized four-period crossover study to receive single oral doses of 1250 mg nelfinavir administered as five commercial 250 mg tablets (reference formulation) and as two new 625 mg tablets (test formulation). Each of the two formulations were taken after an overnight fast and immediately after intake of a standard breakfast (820 kcal) on separate occasions. Blood samples were collected pre-dose and at appropriate intervals after drug administration. Plasma concentrations of nelfinavir and its main metabolite M8 were assayed by a validated LC-MS/ MS assay and the pharmacokinetics of nelfinavir and M8 were derived using standard non-compartmental analysis. The primary parameters for bioequivalence testing were the logarithmically transformed AUC(0-inf) and C(max) of nelfinavir taken from 50 subjects who completed all four treatments. Bioequivalence was accepted if the 90% confidence interval (CI) was contained entirely in the equivalence region (80%, 125%). In the fed state, this criterion was met for AUC (effect ratio = 95%; CI = 87%, 103%) and Cmax (effect ratio = 101%; CI = 94%, 109%) and bioequivalence of the two treatments could be concluded. In the fasted state, AUC clearly failed to meet the bioequivalence criteria (effect ratio = 73%; CI = 59%, 90%) and Cmax was borderline outside the lower acceptance region (effect ratio = 97%; CI = 79.6%, 118%). Therefore, bioequivalence could not be concluded under fasted condition. Food increased the systemic exposure to nelfinavir (as reflected by comparison of the logarithmically transformed AUC(0-inf) values under fed and fasted conditions) by six- and eight-fold after dosing with the 250 mg and the 625 mg tablet, respectively. Bioequivalence of the new 625 mg nelfinavir tablet relative to the commercial 250 mg tablet, at a dose of 1250 mg, was confirmed in the fed state but not under fasted conditions. As nelfinavir is recommended to be taken with food, the new tablet is well-suited to decrease the daily pill burden for patients on a nelfinavir twice daily regimen and to enhance patient's compliance and adherence.

Antiprogestins for Contraception?

Antiprogestins could be a very promising group of compounds for contraception because they counteract the effects of progesterone, a key hormone for normal reproductive functioning. Great efforts have therefore been devoted to testing various ways of using these compounds for family planning. Most of this work has involved mifepristone; other antiprogestins have not been available for trials. With a few exceptions, the outcome of the studies performed to date has not met expectations. The most promising approaches seem to be the use of antiprogestins for emergency contraception, perhaps also as a daily pill when the dose is high enough to block ovulation, and in sequential regimens followed by a progestin. Given that antiprogestins differ in their affinity for target organs, better results could possibly be achieved by using more specific compounds than mifepristone. It is hoped that a wider choice of antiprogestational compounds will soon become available for research.

Supplements and Tuning Up Metabolism

Americans’ intake of the 40 essential micronutrients (vitamins, minerals, and other biochemicals that humans require) is commonly thought to be adequate. Classic deficiency diseases, such as scurvy, beriberi, pernicious anemia, and rickets, are rare. The evidence suggests, however, that much chronic metabolic damage occurs at levels between the level that causes acute micronutrient deficiency disease and the recommended dietary allowances (RDAs). 5 In addition, the prevention of more subtle metabolic damage may not be addressed by current RDAs. When one input in the metabolic network is inadequate, repercussions are felt on a large number of systems and can lead to degenerative disease. This may, for example, result in an increase in DNA damage (and cancer), neuron decay (and cognitive dysfunction) or mitochondrial decay (and accelerated aging and degenerative diseases). The optimum amount of folic acid or zinc that truly is ‘‘required” is the amount that minimizes DNA damage and maximizes a healthy life span, which is higher than the amount needed to prevent acute deficiency disease. The requirements of the elderly for vitamins and metabolites are likely to differ from those of the young, but this issue has not been examined seriously. An optimal intake of micronutrients and metabolites also varies with genetic constitution. A tune-up of micronutrient metabolism should give a marked increase in health at little cost. It is a distortion of priorities for much of the world’s population to have an inadequate intake of a vitamin or mineral, at great cost to health, when a year’s supply of a daily multivitaminmineral pill as insurance against deficiencies costs less than a few packs of cigarettes. The poor, in general, eat the worst diets and have the most to gain from multivitamin-mineral supplementation and improvement in diet.

“Polypill” for Cardiovascular Disease Prevention

Objective. To assess the components of, and potential benefit and adverse effects of, a single daily pill (a theoretical “polypill”)to prevent cardiovascular disease (CVD) by simultaneously reducing four CVD risk factors (LDL cholesterol, blood pressure, platelet function, and serum homocysteine).Design. Meta-analyses of published randomized trials and cohort studies.End points. Proportional reduction in fatal and nonfatal ischemic heart disease (IHD) and stroke events, life years gained, and prevalence of adverse effects.Results. A polypill composed of a statin; three pressure-lowering drugs, each at half of its standard dose; aspirin, 75 mg; and folic acid, 0.8 mg, was estimated to potentially reduce IHD events by 88% (95% CI 84-91%) and stroke by 80% (71-87%). One-third of those taking this polypill from age 55 years or from diagnosis of diabetes or CVD would potentially benefit, gaining on average about 11 years of life free from IHD event or stroke. Such a polypill would cause adverse symptoms in 8-15% of those taking it, depending on the specific components in the formulation.Conclusion. The polypill strategy could prevent IHD and stroke if taken by everyone (without contraindications) aged 55 years and older and everyone with existing CVD or diabetes regardless of their age. This potentially new and different strategy merits further consideration and careful evaluation.

Amlodipine/atorvastatin: the first cross risk factor polypill for the prevention and treatment of cardiovascular disease

In 2002, the World Health Organization estimated that over 58% of cardiovascular disease in North America is due to ‘both blood pressure and cholesterol higher than optimal’. Unfortunately, less than a third of patients with both conditions are identified, and fewer than one in ten reach the treatment goals for both factors. Adherence to treatment is notably improved when therapy is initiated simultaneously. Combination therapy of amlodipine besylate (Norvasc®, Pfizer Ltd) with atorvastatin calcium (Lipitor®, Pfizer Ltd), marketed as Caduet® (Pfizer Ltd) is the first dual-therapy compound designed to treat hypertension and/or angina and dyslipidemia concurrently with a single daily pill in the full range of dosing combinations. Amlodipine/atorvastatin retains the safety and efficacy of its parent compounds whilst simplifying the management of these comorbid conditions, in what may be considered the first version of a polypill.

Maintenance therapy with cotrimoxazole for toxoplasmic encephalitis in the era of highly active antiretroviral therapy.

To reduce the number of daily pills for improving adherence to antiretrovirals, 17 protease inhibitor-treated patients receiving toxoplasmic encephalitis (TE) standard maintenance therapy were instead given cotrimoxazole 960 mg twice daily. After a median follow-up of 31 months, one relapsed after three months, TE relapse incidence = 2.1 cases per 100 patient-years (95% confidence interval, 0.05-11.3). This strategy could be useful for patients awaiting immune reconstitution which allows the interruption of TE maintenance therapy.

Actual medication pill burden and dosing frequency in HIV-infected patients with undetectable viral loads.

Studies have shown equivalent or improved outcomes with once-daily antiretroviral (ARV) regimens, but have failed to quantify the true daily dosing frequency and pill burden of HIV-infected patients, by not considering concomitant medications. This study was conducted to describe the total daily number (pill burden) and dosing frequency for all oral medicines, and not just ARV medications in HIV-infected patients with undetectable viral loads. A retrospective chart review of patients with undetectable viral loads in an HIV primary care clinic identified dosing frequency and pill burden for all prescribed medications. These patients were divided into those with concomitant medications (WITH) and those only on ARV medications (WITHOUT). One hundred and seventeen patients qualified for the evaluation. Ninety-three were in the WITH group and 24 were in the WITHOUT group. WITH patients were older (p < 0.05), and had advanced US Centers for Disease Control and Prevention (CDC)-defined HIV disease stage (p< 0.05), a longer duration of HIV infection (p= 0.03), and a longer duration of AIDS (p= 0.02). WITH patients had a significantly greater total pill burden (p<0.01) and dosing frequency (p<0.001) when considering all medications. Assessing only ARV medications, a significant difference existed only in pill burden (mean +/- SD) (WITH = 9.91 +/- 2.1 versus WITHOUT = 6.6 +/- 1; p < 0.01), and no difference existed in ARV dosing frequency of 2.09 +/- 1.9 and 1.83 +/- 1.7, respectively (p = 0.07). Higher dosing frequencies and pill burdens were present in patients with co-morbid conditions. All patients were on more than once-daily therapies. Dosing requirements for non-ARV medications should also be considered when optimizing or simplifying ARV regimens.

Effect on CD4 T-cell count of replacing protease inhibitors in patients with successful HIV suppression: a meta-analysis.

Protease inhibitor (PI) therapy may be associated with adverse events. Switching the PI component to a non-PI may reduce some side-effects, but the immune effects are unclear. In a meta-analysis using strict inclusion criteria, a randomized switch from PI was associated with impaired CD4 T-cell gains compared with maintaining PI (PI arm +32 cells, effect size 0.130, P = 0.05). Therefore, PI-based therapy results in superior CD4 T-cell gains compared with switching to a non-PI regimen.

A Pilot Intervention to Increase Calcium Intake in Female Collegiate Athletes

Calcium intake in adolescent and young adult female athletes often is inadequate to optimize peak bone mass, an important determinant of osteoporosis risk. The purpose of this study was to determine if calcium supplementation in eumenorrheic female collegiate athletes increases intake to recommended levels and promotes increases in bone mineral density (BMD). Forty-eight eumenorrheic female athletes from several college teams (15 soccer, 7 cross-country, 8 indoor track, and 18 basketball) were randomized at the beginning of a competitive season to receive either an oral calcium supplement (1000 mg calcium citrate/400 I.U. Vitamin D) or placebo daily throughout the training season (16 weeks). Self-reported daily pill intake was obtained every 2 weeks to assess adherence. Calcium intake was evaluated using the Rapid Assessment Method, and total body and leg BMD was measured at pre-, mid-, and postseason using dual energy x-ray absorptiometry (DEXA; Hologic QDR-2000). Pre-season calcium intake was lower than national recommendations for this age group (12), averaging 842 mg/d (SD = 719) and was lower in the placebo group compared to the supplemented group (649 +/- 268 vs. 1071 +/- 986 mg/d, respectively; p = .064). Adherence to supplementation was good, averaging 70% across the training season. Supplementation boosted total calcium intake to a mean of 1397 +/- 411 mg/d, which is consistent with recommended levels for this group (37). Supplementation did not influence BMD change during this 16-week intervention. Across teams, a small increase of 0.8% was observed in leg BMD. Change in total body BMD was modified by team, with a significant increase of 1.5% observed in basketball players. These results indicate that providing calcium supplements of 1000 mg/d is adequate to boost total intake to recommended levels during athletic training. Longer intervention trials are required to determine whether calcium supplementation has a positive effect on BMD.